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Prenatal administration of progesterone for preventing

preterm birth in women considered to be at risk of preterm

birth (Review)

Dodd JM, Jones L, Flenady V, Cincotta R, Crowther CA

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2013, Issue 7

http://www.thecochranelibrary.com

Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

20DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

92DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 1 Perinatal mortality. . . . . . . . . . . . . . . . . . . . . . . . 105

Analysis 1.2. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 2 Preterm birth less than 34 weeks. . . . . . . . . . . . . . . . . . . 106

Analysis 1.3. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 3 Preterm birth less than 37 weeks. . . . . . . . . . . . . . . . . . . 107

Analysis 1.4. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 4 Threatened preterm labour. . . . . . . . . . . . . . . . . . . . . 108

Analysis 1.5. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 5 Spontaneous vaginal delivery. . . . . . . . . . . . . . . . . . . . . 109

Analysis 1.6. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 6 Caesarean section. . . . . . . . . . . . . . . . . . . . . . . . 110

Analysis 1.7. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 7 Antenatal corticosteroids. . . . . . . . . . . . . . . . . . . . . . 111

Analysis 1.8. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 8 Antenatal tocolysis. . . . . . . . . . . . . . . . . . . . . . . . 112

Analysis 1.9. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 9 Infant birthweight less than 2500 g. . . . . . . . . . . . . . . . . . 113

Analysis 1.10. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 10 Respiratory distress syndrome. . . . . . . . . . . . . . . . . . . . 114

Analysis 1.11. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 11 Use of assisted ventilation. . . . . . . . . . . . . . . . . . . . . 115

Analysis 1.12. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 12 Intraventricular haemorrhage - all grades. . . . . . . . . . . . . . . . 116

Analysis 1.13. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 13 Intraventricular haemorrhage - grade III or IV. . . . . . . . . . . . . . 117

Analysis 1.14. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 14 Periventricular leucomalacia. . . . . . . . . . . . . . . . . . . . 118

Analysis 1.15. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 15 Retinopathy of prematurity. . . . . . . . . . . . . . . . . . . . . 118

Analysis 1.16. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 16 Necrotising enterocolitis. . . . . . . . . . . . . . . . . . . . . . 119

Analysis 1.17. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 17 Neonatal sepsis. . . . . . . . . . . . . . . . . . . . . . . . . 120

iPrenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.18. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 18 Patent ductus arteriosus. . . . . . . . . . . . . . . . . . . . . . 121

Analysis 1.19. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 19 Intrauterine fetal death. . . . . . . . . . . . . . . . . . . . . . 122

Analysis 1.20. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 20 Neonatal death. . . . . . . . . . . . . . . . . . . . . . . . . 123

Analysis 1.21. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 21 Developmental delay. . . . . . . . . . . . . . . . . . . . . . . 124

Analysis 1.22. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 22 Intellectual impairment. . . . . . . . . . . . . . . . . . . . . . 124

Analysis 1.23. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 23 Motor Impairment. . . . . . . . . . . . . . . . . . . . . . . 125

Analysis 1.24. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 24 Visual Impairment. . . . . . . . . . . . . . . . . . . . . . . . 126

Analysis 1.25. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 25 Hearing Impairment. . . . . . . . . . . . . . . . . . . . . . . 126

Analysis 1.26. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 26 Cerebral palsy. . . . . . . . . . . . . . . . . . . . . . . . . 127

Analysis 1.27. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 27 Learning difficulties. . . . . . . . . . . . . . . . . . . . . . . 128

Analysis 1.28. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 28 Height less than 5th centile. . . . . . . . . . . . . . . . . . . . . 128

Analysis 1.29. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 29 Weight less than 5th centile. . . . . . . . . . . . . . . . . . . . . 129

Analysis 1.30. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 30 Adverse drug reaction. . . . . . . . . . . . . . . . . . . . . . . 130

Analysis 1.31. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 31 Pregnancy prolongation (weeks). . . . . . . . . . . . . . . . . . . 130

Analysis 1.32. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 32 Apgar score < 7. . . . . . . . . . . . . . . . . . . . . . . . . 131

Analysis 1.33. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 33 Admission to neonatal intensive care unit. . . . . . . . . . . . . . . . 132

Analysis 1.34. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 34 Neonatal length of hospital stay (days). . . . . . . . . . . . . . . . . 133

Analysis 1.35. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 35 Infant weight at 6 months follow-up (g). . . . . . . . . . . . . . . . 133

Analysis 1.36. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 36 Infant weight at 12 months follow-up (g). . . . . . . . . . . . . . . . 134

Analysis 1.37. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 37 Infant weight at 24 months follow-up (g). . . . . . . . . . . . . . . . 135

Analysis 1.38. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 38 Infant length at 6 months follow-up (cm). . . . . . . . . . . . . . . . 135

Analysis 1.39. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 39 Infant length at 12 months follow-up (cm). . . . . . . . . . . . . . . 136

Analysis 1.40. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 40 Infant length at 24 months follow-up (cm). . . . . . . . . . . . . . . 137

Analysis 1.41. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 41 Infant head circumference at 6 months follow-up (cm). . . . . . . . . . . 137

Analysis 1.42. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 42 Infant head circumference at 12 months follow-up (cm). . . . . . . . . . . 138

Analysis 1.43. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth

(singletons), Outcome 43 Infant head circumference at 24 months follow-up (cm). . . . . . . . . . . 139

iiPrenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 2.1. Comparison 2 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth, by

timing of commencement (< 20 wk v > 20 wk, singletons), Outcome 1 Preterm birth less than 37 weeks. . . 140

Analysis 3.1. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by

cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 1 Perinatal death. . . . . . . . . 141

Analysis 3.2. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by

cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 2 Preterm birth less than 37 weeks. . 142

Analysis 3.3. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by

cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 3 Threatened preterm labour. . . . 143

Analysis 3.4. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by

cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 4 Caesarean section. . . . . . . . 144

Analysis 3.5. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by

cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 5 Antenatal corticosteroids. . . . . 145

Analysis 3.6. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by

cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 6 Need for tocolysis. . . . . . . . 146

Analysis 3.7. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by

cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 7 Respiratory distress syndrome. . . 147

Analysis 3.8. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by

cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 8 Intraventricular haemorrhage - all grades. 148

Analysis 3.9. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by

cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 9 Intraventricular haemorrhage - grade III or

IV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

Analysis 3.10. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by

cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 10 Necrotising enterocolitis. . . . . 150

Analysis 3.11. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by

cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 11 Intrauterine fetal death. . . . . 151

Analysis 3.12. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by

cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 12 Neonatal death. . . . . . . . 152

Analysis 4.1. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 1 Perinatal

death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

Analysis 4.2. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 2 Preterm

birth less than 34 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

Analysis 4.3. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 3 Preterm

labour. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

Analysis 4.4. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 4

Prelabour spontaneous rupture of membranes. . . . . . . . . . . . . . . . . . . . . . . 156

Analysis 4.5. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 5 Side

effects (any). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

Analysis 4.6. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 6 Side

effects (injection site). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

Analysis 4.7. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 7 Side

effects (urticaria). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

Analysis 4.8. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 8 Side

effects (nausea). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

Analysis 4.9. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 9

Pregnancy prolongation (days). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

Analysis 4.10. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 10

Caesarean section. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

Analysis 4.11. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 11

Antenatal tocolysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

Analysis 4.12. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 12

Preterm birth less than 37 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . 162

Analysis 4.13. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 13

Preterm birth less than 28 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

iiiPrenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.14. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 14

Infant birthweight less than 2500 g. . . . . . . . . . . . . . . . . . . . . . . . . . . 164

Analysis 4.15. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 15

Respiratory distress syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

Analysis 4.16. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 16 Apgar

score < 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

Analysis 4.17. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 17 Need

for assisted ventilation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

Analysis 4.18. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 18

Intraventricular haemorrhage - all grades. . . . . . . . . . . . . . . . . . . . . . . . . 167

Analysis 4.19. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 19

Intraventricular haemorrhage - grades III or IV. . . . . . . . . . . . . . . . . . . . . . . 168

Analysis 4.20. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 20

Periventricular leucomalacia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

Analysis 4.21. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 21

Retinopathy of prematurity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

Analysis 4.22. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 22

Necrotising enterocolitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

Analysis 4.23. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 23

Neonatal sepsis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

Analysis 4.24. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 24

Intrauterine fetal death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

Analysis 4.25. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 25

Neonatal death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

Analysis 4.26. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons, Outcome 26

Admission to neonatal intensive care unit. . . . . . . . . . . . . . . . . . . . . . . . . 175

Analysis 5.1. Comparison 5 Progesterone versus placebo: ultrasound identified short cervix, singletons by cumulative weekly

dose (<500 mg v >=500 mg), Outcome 1 Periventricular leucomalacia. . . . . . . . . . . . . . . 176

Analysis 5.2. Comparison 5 Progesterone versus placebo: ultrasound identified short cervix, singletons by cumulative weekly

dose (<500 mg v >=500 mg), Outcome 2 Admission to neonatal intensive care unit. . . . . . . . . . 177

Analysis 6.1. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 1 Perinatal death. . . . . 178

Analysis 6.2. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 2 Preterm birth less than 34

weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

Analysis 6.3. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 3 Preterm PROM. . . . . 180

Analysis 6.4. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 4 Adverse drug reaction. . . 181

Analysis 6.5. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 5 Caesarean section. . . . 182

Analysis 6.6. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 6 Spontaneous birth. . . . 183

Analysis 6.7. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 7 Assisted birth. . . . . . 184

Analysis 6.8. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 8 Satisfaction with therapy. . 185

Analysis 6.9. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 9 Antenatal tocolysis. . . . 186

Analysis 6.10. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 10 Antenatal corticosteroids. 187

Analysis 6.11. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 11 Preterm birth less than 37

weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

Analysis 6.12. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 12 Preterm birth less than 28

weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

Analysis 6.13. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 13 Infant birthweight less than

2500 g. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

Analysis 6.14. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 14 Apgar score < 7 at 5

minutes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

Analysis 6.15. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 15 Respiratory distress

syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

Analysis 6.16. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 16 Use of assisted ventilation. 193

ivPrenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.17. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 17 Intraventricular haemorrhage -

grades III or IV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

Analysis 6.18. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 18 Intraventricular haemorrhage -

all grades. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

Analysis 6.19. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 19 Periventricular leucomalacia. 196

Analysis 6.20. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 20 Retinopathy of prematurity. 197

Analysis 6.21. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 21 Chronic lung disease. . 198

Analysis 6.22. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 22 Necrotising enterocolitis. 199

Analysis 6.23. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 23 Neonatal sepsis. . . . 200

Analysis 6.24. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 24 Fetal death. . . . . . 201

Analysis 6.25. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 25 Neonatal death. . . . 202

Analysis 6.26. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 26 Admission to NICU. . 203

Analysis 6.27. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 27 Perinatal death. . . . 204

Analysis 6.28. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 28 Preterm birth less than 34

weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

Analysis 6.29. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 29 Preterm PROM. . . . 206

Analysis 6.30. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 30 Caesarean section. . . 207

Analysis 6.31. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 31 Antenatal tocolysis. . . 208

Analysis 6.32. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 32 Antenatal corticosteroids. 209

Analysis 6.33. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 33 Preterm birth less than 37

weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

Analysis 6.34. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 34 Preterm birth less than 28

weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211

Analysis 6.35. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 35 Infant birthweight less than

2500 g. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212

Analysis 6.36. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 36 Apgar score < 7 at 5

minutes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

Analysis 6.37. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 37 Use of assisted ventilation. 214

Analysis 6.38. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 38 Fetal death. . . . . . 215

Analysis 6.39. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 39 Neonatal death. . . . 216

Analysis 6.40. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 40 Admission to NICU. . 217

Analysis 6.41. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 41 Sensitivity analysis for perinatal

death (assuming total non-independence). . . . . . . . . . . . . . . . . . . . . . . . . 218

Analysis 6.42. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 42 Sensitivity analysis for perinatal

death (assuming 1% non-independence). . . . . . . . . . . . . . . . . . . . . . . . . 219

Analysis 7.1. Comparison 7 Progesterone versus placebo: multiple pregnancy, by timing of commencement (< 20 wk v > 20

wk), Outcome 1 Preterm birth < 37 weeks. . . . . . . . . . . . . . . . . . . . . . . . . 220

Analysis 7.2. Comparison 7 Progesterone versus placebo: multiple pregnancy, by timing of commencement (< 20 wk v > 20

wk), Outcome 2 Neonatal death. . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

Analysis 7.3. Comparison 7 Progesterone versus placebo: multiple pregnancy, by timing of commencement (< 20 wk v > 20

wk), Outcome 3 Admission to NICU. . . . . . . . . . . . . . . . . . . . . . . . . . 222

Analysis 8.1. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >=

500 mg), Outcome 1 Perinatal death. . . . . . . . . . . . . . . . . . . . . . . . . . 223

Analysis 8.2. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >=

500 mg), Outcome 2 Preterm birth less than 34 weeks. . . . . . . . . . . . . . . . . . . . 224

Analysis 8.3. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >=

500 mg), Outcome 3 Antenatal tocolysis. . . . . . . . . . . . . . . . . . . . . . . . . 225

Analysis 8.4. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >=

500 mg), Outcome 4 Preterm birth less than 37 weeks. . . . . . . . . . . . . . . . . . . . 226

Analysis 8.5. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >=

500 mg), Outcome 5 Infant birthweight less than 2500 g. . . . . . . . . . . . . . . . . . . 227

Analysis 8.6. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >=

500 mg), Outcome 6 Respiratory distress syndrome. . . . . . . . . . . . . . . . . . . . . 228

vPrenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 8.7. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >=

500 mg), Outcome 7 Fetal death. . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

Analysis 8.8. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >=

500 mg), Outcome 8 Admission to NICU. . . . . . . . . . . . . . . . . . . . . . . . . 230

Analysis 9.1. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 1 Perinatal death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

Analysis 9.2. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 2 Preterm birth less than 34 weeks’ gestation. . . . . . . . . . . . . . . . . . . . 232

Analysis 9.3. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 3 Pregnancy prolongation (days). . . . . . . . . . . . . . . . . . . . . . . . 233

Analysis 9.4. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 4 Pregnancy prolongation - less than 1 week. . . . . . . . . . . . . . . . . . . . 234

Analysis 9.5. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 5 Pregnancy prolongation - 1.0 to 1.9 weeks. . . . . . . . . . . . . . . . . . . . 234

Analysis 9.6. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 6 Pregnancy prolongation - 2 weeks or more. . . . . . . . . . . . . . . . . . . . 235

Analysis 9.7. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 7 Spontaneous birth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

Analysis 9.8. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 8 Caesarean section. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

Analysis 9.9. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 9 Use of tocolysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

Analysis 9.10. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 10 Preterm birth less than 37 weeks’ gestation. . . . . . . . . . . . . . . . . . . . 238

Analysis 9.11. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 11 Infant birthweight less than 2500 g. . . . . . . . . . . . . . . . . . . . . . 239

Analysis 9.12. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 12 Respiratory distress syndrome. . . . . . . . . . . . . . . . . . . . . . . . 240

Analysis 9.13. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 13 Intraventricular haemorrhage grade III or IV. . . . . . . . . . . . . . . . . . . 241

Analysis 9.14. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 14 Periventricular leucomalacia. . . . . . . . . . . . . . . . . . . . . . . . . 241

Analysis 9.15. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 15 Use of assisted ventilation. . . . . . . . . . . . . . . . . . . . . . . . . . 242

Analysis 9.16. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 16 Necrotizing enterocolitis. . . . . . . . . . . . . . . . . . . . . . . . . . 243

Analysis 9.17. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 17 Neonatal sepsis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244

Analysis 9.18. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 18 Fetal death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

Analysis 9.19. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 19 Neonatal death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246

Analysis 9.20. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 20 Neonatal length of hospital stay (days). . . . . . . . . . . . . . . . . . . . . 247

Analysis 9.21. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 21 Apgar score less than seven at five minutes. . . . . . . . . . . . . . . . . . . . 247

Analysis 9.22. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 22 Prelabour spontaneous rupture of membranes. . . . . . . . . . . . . . . . . . . 248

Analysis 9.23. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 23 Preterm birth less than 28 weeks’ gestation. . . . . . . . . . . . . . . . . . . . 249

Analysis 9.24. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 24 Apgar score less than seven at five minutes. . . . . . . . . . . . . . . . . . . . 249

viPrenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.25. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons,

Outcome 25 Admission to neonatal intensive care unit. . . . . . . . . . . . . . . . . . . . 250

Analysis 10.1. Comparison 10 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons, by

cumulative weekly dose (< 500 mg v >= 500 mg), Outcome 1 Pregnancy prolongation (days). . . . . . . 251

Analysis 10.2. Comparison 10 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons, by

cumulative weekly dose (< 500 mg v >= 500 mg), Outcome 2 Preterm birth less than 37 weeks’ gestation. . . 252

Analysis 10.3. Comparison 10 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons, by

cumulative weekly dose (< 500 mg v >= 500 mg), Outcome 3 Respiratory distress syndrome. . . . . . . 253

Analysis 10.4. Comparison 10 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons, by

cumulative weekly dose (< 500 mg v >= 500 mg), Outcome 4 Neonatal sepsis. . . . . . . . . . . . 254

Analysis 10.5. Comparison 10 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons, by

cumulative weekly dose (< 500 mg v >= 500 mg), Outcome 5 Neonatal death. . . . . . . . . . . . 255

Analysis 11.1. Comparison 11 Progesterone versus placebo: other reason at risk of preterm birth, singletons, Outcome 1

Perinatal death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256

Analysis 11.2. Comparison 11 Progesterone versus placebo: other reason at risk of preterm birth, singletons, Outcome 2

Preterm birth less than 34 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . 257

Analysis 11.3. Comparison 11 Progesterone versus placebo: other reason at risk of preterm birth, singletons, Outcome 3

Preterm birth less than 37 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . 258

Analysis 11.4. Comparison 11 Progesterone versus placebo: other reason at risk of preterm birth, singletons, Outcome 4

Infant birthweight less than 2500 g. . . . . . . . . . . . . . . . . . . . . . . . . . . 259

Analysis 11.5. Comparison 11 Progesterone versus placebo: other reason at risk of preterm birth, singletons, Outcome 5

Intrauterine fetal death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

Analysis 11.6. Comparison 11 Progesterone versus placebo: other reason at risk of preterm birth, singletons, Outcome 6

Neonatal death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

Analysis 11.7. Comparison 11 Progesterone versus placebo: other reason at risk of preterm birth, singletons, Outcome 7

Admission to neonatal intensive care unit. . . . . . . . . . . . . . . . . . . . . . . . . 261

Analysis 12.1. Comparison 12 Progesterone versus placebo: other reason at risk of preterm birth, by timing of

commencement (< 20 wk v > 20 wk, singletons), Outcome 1 Perinatal death. . . . . . . . . . . . . 262

Analysis 12.2. Comparison 12 Progesterone versus placebo: other reason at risk of preterm birth, by timing of

commencement (< 20 wk v > 20 wk, singletons), Outcome 2 Preterm birth less than 37 weeks. . . . . . . 263

Analysis 12.3. Comparison 12 Progesterone versus placebo: other reason at risk of preterm birth, by timing of

commencement (< 20 wk v > 20 wk, singletons), Outcome 3 Infant birthweight less than 2500 g. . . . . . 264

264APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

267WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

267HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

269CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

269DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

269SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

269DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

270NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

270INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

viiPrenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

[Intervention Review]

Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Jodie M Dodd1 , Leanne Jones2 , Vicki Flenady3 , Robert Cincotta4 , Caroline A Crowther5,6

1School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Women’s

and Children’s Hospital, Adelaide, Australia. 2Cochrane Pregnancy and Childbirth Group, Department of Women’s and Children’s

Health, The University of Liverpool, Liverpool, UK. 3Translating Research Into Practice (TRIP) Centre, Mater Research Institute - The

University of Queensland (MRI-UQ), Brisbane, Australia. 4Department of Maternal Fetal Medicine, Mater Mothers’ Hospital, South

Brisbane, Australia. 5Liggins Institute, The University of Auckland, Auckland, New Zealand. 6ARCH: Australian Research Centre for

Health of Women and Babies, Robinson Research Institute, Discipline of Obstetrics and Gynaecology, The University of Adelaide,

Adelaide, Australia

Contact address: Jodie M Dodd, School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, The

University of Adelaide, Women’s and Children’s Hospital, 72 King William Road, Adelaide, South Australia, 5006, Australia.

[email protected].

Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: Edited (no change to conclusions), published in Issue 7, 2015.

Review content assessed as up-to-date: 14 January 2013.

Citation: Dodd JM, Jones L, Flenady V, Cincotta R, Crowther CA. Prenatal administration of progesterone for preventing preterm

birth in women considered to be at risk of preterm birth. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD004947. DOI: 10.1002/14651858.CD004947.pub3.

A B S T R A C T

Background

Preterm birth is a major complication of pregnancy associated with perinatal mortality and morbidity. Progesterone for the prevention

of preterm labour has been advocated.

Objectives

To assess the benefits and harms of progesterone for the prevention of preterm birth for women considered to be at increased risk of

preterm birth and their infants.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (14 January 2013) and reviewed the reference list of all

articles.

Selection criteria

Randomised controlled trials, in which progesterone was given for preventing preterm birth.

Data collection and analysis

Two review authors independently evaluated trials for methodological quality and extracted data.

1Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

mailto:[email protected]

Main results

Thirty-six randomised controlled trials (8523 women and 12,515 infants) were included.

Progesterone versus placebo for women with a past history of spontaneous preterm birth

Progesterone was associated with a statistically significant reduction in the risk of perinatal mortality (six studies; 1453 women; risk

ratio (RR) 0.50, 95% confidence interval (CI) 0.33 to 0.75), preterm birth less than 34 weeks (five studies; 602 women; average RR

0.31, 95% CI 0.14 to 0.69), infant birthweight less than 2500 g (four studies; 692 infants; RR 0.58, 95% CI 0.42 to 0.79), use of

assisted ventilation (three studies; 633 women; RR 0.40, 95% CI 0.18 to 0.90), necrotising enterocolitis (three studies; 1170 women;

RR 0.30, 95% CI 0.10 to 0.89), neonatal death (six studies; 1453 women; RR 0.45, 95% CI 0.27 to 0.76), admission to neonatal

intensive care unit (three studies; 389 women; RR 0.24, 95% CI 0.14 to 0.40), preterm birth less than 37 weeks (10 studies; 1750

women; average RR 0.55, 95% CI 0.42 to 0.74) and a statistically significant increase in pregnancy prolongation in weeks (one study;

148 women; mean difference (MD) 4.47, 95% CI 2.15 to 6.79). No differential effects in terms of route of administration, time of

commencing therapy and dose of progesterone were observed for the majority of outcomes examined.

Progesterone versus placebo for women with a short cervix identified on ultrasound

Progesterone was associated with a statistically significant reduction in the risk of preterm birth less than 34 weeks (two studies; 438

women; RR 0.64, 95% CI 0.45 to 0.90), preterm birth at less than 28 weeks’ gestation (two studies; 1115 women; RR 0.59, 95% CI

0.37 to 0.93) and increased risk of urticaria in women when compared with placebo (one study; 654 women; RR 5.03, 95% CI 1.11

to 22.78). It was not possible to assess the effect of route of progesterone administration, gestational age at commencing therapy, or

total cumulative dose of medication.

Progesterone versus placebo for women with a multiple pregnancy

Progesterone was associated with no statistically significant differences for the reported outcomes.

Progesterone versus no treatment/placebo for women following presentation with threatened preterm labour

Progesterone, was associated with a statistically significant reduction in the risk of infant birthweight less than 2500 g (one study; 70

infants; RR 0.52, 95% CI 0.28 to 0.98).

Progesterone versus placebo for women with ’other’ risk factors for preterm birth

Progesterone, was associated with a statistically significant reduction in the risk of infant birthweight less than 2500 g (three studies;

482 infants; RR 0.48, 95% CI 0.25 to 0.91).

Authors’ conclusions

The use of progesterone is associated with benefits in infant health following administration in women considered to be at increased risk

of preterm birth due either to a prior preterm birth or where a short cervix has been identified on ultrasound examination. However,

there is limited information available relating to longer-term infant and childhood outcomes, the assessment of which remains a priority.

Further trials are required to assess the optimal timing, mode of administration and dose of administration of progesterone therapy

when given to women considered to be at increased risk of early birth.

P L A I N L A N G U A G E S U M M A R Y

Prenatal administration of progesterone to prevent preterm birth in women considered to be at risk of having their baby early

Babies who are born before 37 weeks, and particularly those born before 34 weeks, are at greater risk of having problems at birth

and complications in infancy. Infants who are born preterm are at greater risk of dying in their first year of life, and of those infants

who survive, there is an increased risk of repeated admission to hospital and adverse outcomes including cerebral palsy and long-term

disability. Progesterone is a hormone that reduces contractions of the uterus and has an important role in maintaining pregnancy and

is suggested for the prevention of preterm labour. Maternal side-effects from progesterone therapy include headache, breast tenderness,

nausea, cough and local irritation if administered intramuscularly. At present, there is little information available regarding the optimal

dose of progesterone, mode of administration, gestation to commence therapy, or duration of therapy.

2Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

The review of 36 randomised controlled trials, involving a total of 8523 women considered to be at increased risk of preterm birth, and

12,515 infants, found that where progesterone was given (by injection into the muscle in some studies and as a pessary into the vagina

in others), it had beneficial effects, including reducing the risk of the baby dying after birth, suffering complications such as requiring

assisted ventilation, necrotising enterocolitis or requiring admission to neonatal intensive care, prolonging the pregnancy, and reducing

the chance of neonatal intensive care admission.

Information related to longer-term infant and childhood outcomes was limited. Overall, the trials included in this review were considered

to be of good to fair quality. Further trials are required to assess the optimal timing, mode of administration and dose of administration

of progesterone therapy.

B A C K G R O U N D

Description of the condition

Preterm birth before 37 weeks’ gestation is a common problem in

obstetric care, with estimates ranging from 5% in several European

countries to 18% in some African countries (Blencowe 2012). In

Australia, approximately 8% of all infants were born preterm in

2000, with 2.7% of these births occurring prior to 34 weeks’ ges-

tation (AIHW 2003). Figures are similar for the United States,

with a preterm birth rate of 12.0% (Blencowe 2012). While less

than 2% of these infants were born prior to 32 weeks’ gestation

(Martin 2003), they are at increased risk of complications in in-

fancy, and contribute in excess of 50% of the overall perinatal mor-

tality (AIHW 2003). Infants who are born preterm are at greater

risk of dying in their first year of life (Martin 2003), and of those

infants who survive, there is an increased risk of repeated admission

to hospital (Elder 1999) and adverse outcomes including cerebral

palsy and long-term disability (Hack 1999; Stanley 1992), creat-

ing a significant burden upon the community (Kramer 2000).

The ’cause’ of preterm labour is multifactorial in origin, and it is

important to consider the role of any identifiable risk factors in a

woman’s pregnancy.

The most significant and consistently identified risk factor for

preterm birth, is a woman’s history of previous preterm birth

(Adams 2000; Bakketeig 1979; Berkowitz 1993; Bloom 2001;

Goldenberg 1998; Kaminski 1973; Kistka 2007; Papiernik 1974;

Petrini 2005; Robinson 2001). Estimates suggest the rate of recur-

rent preterm birth in this group of women to be 22.5% (Petrini

2005), a 2.5 times increased risk ratio when compared with women

with no previous spontaneous preterm birth (Mercer 1999). For

women with a history of a single preterm birth, the recurrence

risk in a subsequent pregnancy is approximately 15%, increas-

ing to 32% where there have been two previous preterm births

(Carr-Hill 1985). Information derived from population-based co-

hort data suggests that for women who give birth between 20 and

31 weeks’ gestation in one pregnancy, 29.3% will give birth prior

to 37 weeks in a subsequent pregnancy (Adams 2000). For ap-

proximately 10% of these women, the preterm birth will occur at a

similar gestational age (Adams 2000; Kistka 2007). In up to 50%

of cases of preterm birth, the cause is spontaneous onset of labour

or preterm premature rupture of membranes (PPROM) (Hewitt

1988; Mattison 2001; McLaughlin 2002).

Other characteristics in a woman’s current pregnancy may place

her at increased risk of preterm birth, including women with a

short cervix identified by ultrasound assessment, the presence of

fetal fibronectin in the vaginal secretions, and presentation with

symptoms or signs of threatened preterm labour.

The identification of a short cervix (considered to be less than

2.5cm) on ultrasound examination has been associated with an

increased likelihood of preterm birth before 34 weeks’ gestation

(Smith 2007). Identification of fetal fibronectin present in cer-

vico-vaginal secretions has also been proposed as a means of iden-

tifying women at risk of preterm birth. Overall, the value of fetal

fibronectin in women presenting with symptoms of threatened

preterm labour, is a negative test, where women are unlikely to pro-

ceed to preterm birth before 34 weeks’ gestation or within seven

days of testing (Smith 2007).

Multiple pregnancy is a strong risk factor for preterm birth though

the mechanisms may be different to those operating in women

with a singleton pregnancy. Up to 50% of women with a twin

pregnancy will give birth prior to 37 weeks’ gestation (AIHW

2003). The preterm birth risk of early birth before 37 weeks for

women with a singleton pregnancy is 6.3% compared with 97%

for women with a triplet pregnancy (AIHW 2003).

Description of the intervention

Progesterone may be administered in various forms and by various

routes. These different formulations and modes of administration

will have different absorption patterns and potentially have differ-

ing bio effects. Whilst no teratogenic effects have been described

3Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

with most progesterones, there is little in the way of long-term sa-

fety data. Maternal side-effects from progesterone therapy include

headache, breast tenderness, nausea, cough and local irritation if

administered intramuscularly. At present, there is little informa-

tion available regarding the optimal dose of progesterone, mode

of administration, gestation to commence therapy, or duration of

therapy (Greene 2003; Iams 2003).

How the intervention might work

Progesterone has a role in maintaining pregnancy (Haluska 1997;

Pepe 1995; Pieber 2001) and is thought to act by suppressing

smooth muscle activity in the uterus (Astle 2003; Grazzini 1998).

In many animal species, there is a reduction in the amount of

circulating progesterone before the onset of labour. While these

changes have not been shown to occur in women (Astle 2003;

Block 1984; Lopez-Bernal 2003; Pieber 2001; Smit 1984), it has

been suggested that there is a ’functional’ withdrawal of proges-

terone related to changes in the expression of progesterone re-

ceptors in the uterus (Astle 2003; Condon 2003; Haluska 2002;

Pieber 2001). There have been recent reports in the literature ad-

vocating the use of progesterone to reduce the risk of preterm birth

(da Fonseca 2003; Meis 2003), rekindling interest that dates back

to the 1960s (Le Vine 1964).

This review was modified in 2006, from the original protocol pub-

lished in The Cochrane Library in Issue 4, 2004, in order to clar- ify the scope of the review. The title and objectives changed, and

the description of participants expanded to include the reason the

women were considered to be at increased risk of preterm birth.

The primary outcome measure of preterm birth less than 32 weeks’

gestation has been changed to preterm birth less than 34 weeks’

gestation to be consistent with World Health Organization defi-

nitions of preterm birth. Secondary outcome measures reflecting

childhood developmental assessment have been added, reflecting

the need for ongoing evaluation of children participating in ran-

domised trials.

Why it is important to do this review

Preterm birth and its consequences for women and their babies is

a significant health problem in pregnancy and childbirth. While

the suppression or prevention of preterm labour should lead to im-

proved survival through a lower incidence of premature delivery,

there are theoretical reasons why a fetus may not survive without

disability. It is possible that an intrauterine mechanism that would

trigger preterm labour could also cause neurological injury to the

fetus and that progesterone may prevent labour but not fetal in-

jury. The purpose of this review is to assess the benefits and harms

of progesterone administration for the prevention of preterm birth

for both women and their infants, when considering the risk fac-

tors present for preterm birth.

O B J E C T I V E S

To assess the benefits and harms of progesterone administration

for the prevention of preterm birth in women and their infants.

M E T H O D S

Criteria for considering studies for this review

Types of studies

All published and unpublished randomised controlled trials,

in which progesterone was administered for the prevention of

preterm birth, subdivided by the reason women were considered

to be at risk for preterm birth.

Trials were excluded if:

• they utilised quasi-randomised methodology; cross-over

design;

• progesterone was administered for the acute treatment of

actual or threatened preterm labour (that is, where progesterone

was administered as an acute tocolytic medication); or

• progesterone was administered in the first trimester only for

preventing miscarriage.

Types of participants

Pregnant women considered to be at increased risk of preterm

birth. These reasons include:

• past history of spontaneous preterm birth (including

preterm prelabour rupture of membranes);

• multiple pregnancy;

• ultrasound identified short cervical length;

• fetal fibronectin testing;

• following acute presentation with symptoms or signs of

threatened preterm labour (where a tocolytic medication may

have been administered);

• other reason considered to be at increased risk of preterm

birth.

Types of interventions

Administration of progesterone by any route for the prevention of

preterm birth.

Types of outcome measures

Primary outcomes

1. Perinatal mortality

4Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

2. Preterm birth (less than 34 weeks’ gestation)

3. Major neurodevelopmental handicap at childhood follow-

Secondary outcomes

Maternal

1. Threatened preterm labour (as defined by trial authors)

2. Prelabour spontaneous rupture of membranes

3. Adverse drug reaction

4. Pregnancy prolongation (interval between randomisation

and birth)

5. Mode of birth

6. Number of antenatal hospital admissions

7. Satisfaction with the therapy

8. Use of tocolysis

9. Antenatal corticosteroids (not a prespecified outcome)

10. Maternal quality of life (not a prespecified outcome)

Infant

1. Birth before 37 completed weeks

2. Birth before 28 completed weeks

3. Birthweight less than the third centile for gestational age

4. Birthweight less than 2500 g

5. Apgar score of less than seven at five minutes

6. Respiratory distress syndrome

7. Use of mechanical ventilation

8. Duration of mechanical ventilation

9. Intraventricular haemorrhage - grades III or IV

10. Periventricular leucomalacia

11. Retinopathy of prematurity

12. Retinopathy of prematurity - grades III or IV

13. Chronic lung disease

14. Necrotising enterocolitis

15. Neonatal sepsis

16. Fetal death

17. Neonatal death

18. Admission to neonatal intensive care unit

19. Neonatal length of hospital stay

20. Teratogenic effects (including virilisation in female infants)

21. Patent ductus arteriosis (not a prespecified outcome)

Child

1. Major sensorineural disability (defined as any of legal

blindness, sensorineural deafness requiring hearing aids,

moderate or severe cerebral palsy, or developmental delay or

intellectual impairment (defined as developmental quotient or

intelligence quotient less than -2 standard deviations below

mean))

2. Developmental delay (however defined by the authors)

3. Intellectual impairment

4. Motor impairment

5. Visual impairment

6. Blindness

7. Deafness

8. Hearing impairment

9. Cerebral palsy

10. Child behaviour

11. Child temperament

12. Learning difficulties

13. Growth assessments at childhood follow-up (weight, head

circumference, length, skin fold thickness)

Search methods for identification of studies

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group’s Tri-

als Register by contacting the Trials Search Co-ordinator (14 Jan-

uary 2013).

The Cochrane Pregnancy and Childbirth Group’s Trials Register

is maintained by the Trials Search Co-ordinator and contains trials

identified from:

1. monthly searches of the Cochrane Central Register of

Controlled Trials (CENTRAL);

2. weekly searches of MEDLINE;

3. weekly searches of Embase;

4. handsearches of 30 journals and the proceedings of major

conferences;

5. weekly current awareness alerts for a further 44 journals

plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and

Embase, the list of handsearched journals and conference pro-

ceedings, and the list of journals reviewed via the current aware-

ness service can be found in the ‘Specialized Register’ section

within the editorial information about the Cochrane Pregnancy

and Childbirth Group.

Trials identified through the searching activities described above

are each assigned to a review topic (or topics). The Trials Search

Co-ordinator searches the register for each review using the topic

list rather than keywords.

For details of searching carried out for the initial version of the

review, please see Appendix 1.

Searching other resources

We also manually cross-referenced key publications.

We did not apply any language restrictions.

5Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/preg/frame.html

Data collection and analysis

For the methods used when assessing the trials identified in the

previous version of this review, see Appendix 2.

For this update we used the following methods when assessing the

reports identified by the updated search.

Selection of studies

Two review authors independently assessed for inclusion all the

potential studies identified as a result of the search strategy. We

resolved any disagreement through discussion or, if required, we

consulted a third author.

Data extraction and management

We designed a form to extract data. For eligible studies, two review

authors extracted the data using the agreed form. We resolved

discrepancies through discussion or, if required, we consulted third

author. We entered data into Review Manager software (RevMan

2012) and checked for accuracy. When information regarding any

of the above was unclear, we contacted authors of the original

reports to provide further details.

Assessment of risk of bias in included studies

Two review authors independently assessed the risk of bias for each

study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Disagreement was resolved by discussion or by involving the third author.

(1) Sequence generation (checking for possible selection

bias)

We described for each included study the method used to generate

the allocation sequence in sufficient detail to allow an assessment

of whether it should produce comparable groups.

We assessed the method as:

• low risk of bias (any truly random process, e.g. random

number table; computer random number generator);

• high risk of bias (any non-random process, e.g. odd or even

date of birth; hospital or clinic record number);

• unclear risk of bias.

(2) Allocation concealment (checking for possible selection

bias)

We described for each included study the method used to con-

ceal allocation to interventions prior to assignment and assessed

whether intervention allocation could have been foreseen in ad-

vance of, or during recruitment, or changed after assignment.

We assessed the methods as:

• low risk of bias (e.g. telephone or central randomisation;

consecutively numbered sealed opaque envelopes);

• high risk of bias (open random allocation; unsealed or non-

opaque envelopes, alternation; date of birth);

• unclear risk of bias.

(3.1) Blinding of participants and personnel (checking for

possible performance bias)

We described for each included study the methods used, if any, to

blind study participants and personnel from knowledge of which

intervention a participant received. We considered that studies

were at low risk of bias if they were blinded, or if we judged that the

lack of blinding would be unlikely to affect results. We planned

to assess blinding separately for different outcomes or classes of

outcomes.

We assessed the methods as:

• low, high or unclear risk of bias for participants;

• low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible

detection bias)

We described for each included study the methods used, if any, to

blind outcome assessors from knowledge of which intervention a

participant received. We planned to assess blinding separately for

different outcomes or classes of outcomes.

We assessed methods used to blind outcome assessment as:

• low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition

bias due to the amount, nature and handling of incomplete

outcome data)

We described for each included study, and for each outcome or

class of outcomes, the completeness of data including attrition and

exclusions from the analysis. We stated whether attrition and ex-

clusions were reported and the numbers included in the analysis at

each stage (compared with the total randomised participants), rea-

sons for attrition or exclusion where reported, and whether miss-

ing data were balanced across groups or were related to outcomes.

Where sufficient information was reported, or could be supplied

by the trial authors, we planned to re-include missing data in the

analyses which we undertook.

We assessed methods as:

• low risk of bias (e.g. no missing outcome data; missing

outcome data balanced across groups; or less than 20% losses to

follow-up);

• high risk of bias (e.g. numbers or reasons for missing data

imbalanced across groups; ‘as treated’ analysis done with

substantial departure of intervention received from that assigned

at randomisation);

• unclear risk of bias.

6Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

(5) Selective reporting bias

We described for each included study how we investigated the

possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

• low risk of bias (where it is clear that all of the study’s pre-

specified outcomes and all expected outcomes of interest to the

review have been reported);

• high risk of bias (where not all the study’s pre-specified

outcomes have been reported; one or more reported primary

outcomes were not prespecified; outcomes of interest are

reported incompletely and so cannot be used; study fails to

include results of a key outcome that would have been expected

to have been reported);

• unclear risk of bias.

(6) Other sources of bias (checking for bias due to problems

not covered by (1) to (5) above)

We described for each included study any important concerns we

had about other possible sources of bias.

We assessed whether studies that included multiple pregnancies

accounted appropriately for non-independence of babies from the

same pregnancy in the analysis. There are several ways this can

be done, and these studies should present something like an odds

ratio adjusted for non-independence. If adjustment was not done,

we assessed the potential for bias i.e. if multiples only made up

a small proportion of the total then there is probably not much

potential for bias.

We assessed whether each study was free of other problems that

could put it at risk of bias:

• low risk of other bias;

• high risk of other bias;

• unclear whether there is risk of other bias.

(7) Overall risk of bias

We made explicit judgements about whether studies were at high

risk of bias, according to the criteria given in the Cochrane Hand- book (Higgins 2011). With reference to (1) to (6) above, we as- sessed the likely magnitude and direction of the bias and whether

we considered it likely to impact on the findings. We planned to

explore the impact of the level of bias through undertaking sensi-

tivity analyses - see Sensitivity analysis.

Measures of treatment effect

Dichotomous data

For dichotomous data, we presented results as summary risk ratio

with 95% confidence intervals.

Continuous data

For continuous data, we used the mean difference if outcomes

were measured in the same way between trials. We planned to use

the standardised mean difference to combine trials that measured

the same outcome, but used different methods, if required.

Unit of analysis issues

Cluster-randomised trials

We did not identify any cluster-randomised trials for inclusion in

this review, but we may include trials of this type in future up-

dates. If we do, we plan to include cluster-randomised trials in the

analyses along with individually-randomised trials. Their sample

sizes will be adjusted using the methods described in the Cochrane Handbook (Higgins 2011) using an estimate of the intracluster correlation co-efficient (ICC) derived from the trial (if possible), or

from another source. If ICCs from other sources are used, we will

report this and conduct sensitivity analyses to investigate the effect

of variation in the ICC. If we identify both cluster-randomised

trials and individually-randomised trials, we planned to synthesise

the relevant information. We consider it reasonable to combine the

results from both if there is little heterogeneity between the study

designs and the interaction between the effect of intervention and

the choice of randomisation unit is considered to be unlikely. We

also planned to acknowledge heterogeneity in the randomisation

unit and perform a sensitivity analysis to investigate the effects of

the randomisation unit.

Cross-over trials

Cross-over trials were not included.

Other unit of analysis issues

The analysis in this review involves multiple pregnancies, there-

fore, wherever possible, analyses should be adjusted for cluster-

ing to take into account the non-independence of babies from

the same pregnancy (Gates 2004). Treating babies from multiple

pregnancies as if they are independent, when they are more likely

to have similar outcomes than babies from different pregnancies,

will overestimate the sample size and give confidence intervals that

are too narrow. Each woman can be considered a cluster in multi-

ple pregnancy, with the number of individuals in the cluster being

equal to the number of fetuses in her pregnancy. Analysis using

cluster trial methods allows calculation of relative risk and adjust-

ment of confidence intervals. Usually this will mean that the confi-

dence intervals get wider. Although this may make little difference

to the conclusion of a trial, it avoids misleading results in those

trials where the difference may be substantial.

We planned to adjust for clustering in the analyses, wherever pos-

sible, and to use the inverse variance method for adjusted analyses,

7Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). However, due to insufficient infor- mation in the included trials, we were not able to adjust our anal-

yses. In future updates, if possible, we will adjust for clustering in

the analyses.

Dealing with missing data

For included studies, we noted levels of attrition. We explored the

impact of including studies with high levels of missing data in the

overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we carried out analyses, as far as possible, on

an intention-to-treat basis, i.e. we attempted to include all partic-

ipants randomised to each group in the analyses, and all partici-

pants were analysed in the group to which they were allocated, re-

gardless of whether or not they received the allocated intervention.

The denominator for each outcome in each trial was the number

randomised minus any participants whose outcomes were known

to be missing.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta-analysis using

the T², I² and Chi² statistics. We regarded heterogeneity as sub-

stantial if an I² was greater than 30% and either the T² was greater

than zero, or there was a low P value (less than 0.10) in the Chi²

test for heterogeneity.

Assessment of reporting biases

If 10 or more studies contributed data to meta-analysis for any

particular outcome, we investigated reporting biases (such as pub-

lication bias) using funnel plots. We assessed possible asymmetry

visually. If asymmetry was suggested by a visual assessment, we

planned to perform exploratory analyses to investigate it. In this

version of the review insufficient data were available to allow us to

carry out this planned analysis.

Data synthesis

We carried out statistical analysis using the RevMan software

(RevMan 2012). We used fixed-effect meta-analysis for combining

data where it was reasonable to assume that studies were estimating

the same underlying treatment effect: i.e. where trials examined

the same intervention, and where we judged the trials’ populations

and methods to be sufficiently similar. If we suspected clinical

heterogeneity sufficient to expect the underlying treatment effects

to differ between trials, or if substantial statistical heterogeneity

was detected, we used random-effects meta-analysis to produce

an overall summary provided that we considered an average treat-

ment effect across trials was clinically meaningful. The random-

effects summary was treated as the average of the range of possible

treatment effects and the clinical implications of treatment effects

differing between trials is discussed. If the average treatment effect

was not clinically meaningful we did not combine trials.

Where we used random-effects analyses, the results were presented

as the average treatment effect with 95% confidence intervals, and

the estimates of T² and I².

Results were analysed according to the reason women were con-

sidered to be at risk of preterm birth, including:

• past history of spontaneous preterm birth (including

preterm prelabour rupture of membranes);

• multiple pregnancy;

• ultrasound identified short cervical length;

• fetal fibronectin testing;

• presentation with symptoms or signs of threatened preterm

labour;

• other reason for risk of preterm birth.

For analyses where there are high levels of heterogeneity we have

provided an estimate of the 95% range of underlying intervention

effects (prediction interval).

Subgroup analysis and investigation of heterogeneity

If we identified substantial heterogeneity, we investigated it using

subgroup analyses and sensitivity analyses. We considered whether

an overall summary was meaningful, and if it was, we used random-

effects analysis to produce it.

We planned, where possible, to carry out the following subgroup

analyses:

1. time of treatment commencing (before 20 weeks’ gestation

versus after 20 weeks’ gestation);

2. route of administration (intramuscular, intravaginal, oral,

intravenous);

3. different dosage regimens (divided arbitrarily into a

cumulative dose of less than 500 mg per week and a dose of

greater than or equal to 500 mg per week).

All outcomes were considered in subgroup analyses.

We assessed subgroup differences by interaction tests available

within RevMan (RevMan 2012).

Sensitivity analysis

We planned to carry out sensitivity analyses to explore the effect of

trial quality assessed by concealment of allocation, high attrition

rates (greater than 20%), or both, with poor-quality studies being

excluded from the analyses in order to assess whether this made

any difference to the overall result.

R E S U L T S

8Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Description of studies

Results of the search

In the 2006 update, our search strategy identified 22 stud-

ies for consideration. Eleven studies met the inclusion criteria

stated (Borna 2008; da Fonseca 2003; Facchinetti 2007; Fonseca

2007; Hartikainen 1980; Hauth 1983; Johnson 1975; Meis 2003;

O’Brien 2007; Papiernik 1970; Rouse 2007) involving a total of

2714 women and 3452 infants. The study by Northern (Northen

2007) reports the follow-up of children involved in the Meis study

(Meis 2003).

Sixty-four reports from an updated search in January 2013 have

been assessed for this update. Of these 64 reports, an addi-

tional 25 studies (33 reports) to the original 11 studies, were

included (Aboulghar 2012; Akbari 2009; Briery 2011; Caritis

2009; Cetingoz 2011; Combs 2010; Combs 2011; Combs 2011a;

Elsheikhah 2010; Glover 2011; Grobman 2012; Hassan 2011;

Ibrahim 2010; Lim 2011; Majhi 2009; Moghtadaei 2008; Ndoni

2010; Norman 2009; Rai 2009; Rode 2011; Rozenberg 2012;

Saghafi 2011a; Senat 2012; Serra 2013; Sharami 2010); seven

studies (seven reports) were excluded (Abbott 2012; Arikan

2011; Berghella 2010; Chandiramani 2012; Ionescu 2012; Keeler

2009; Rust 2006); two studies (two reports) are ongoing studies

(Coomarasamy 2012; van Os 2011); one is an additional report

of an ongoing study (Crowther 2007); one additional report was

added to each of the following included studies (Combs 2010;

Combs 2011; Facchinetti 2007; Lim 2011; Nassar 2007). Two

additional reports were identified for the Norman 2009; O’Brien

2007; Rode 2011 and Rouse 2007 included studies. Three addi-

tional reports were identified for the Meis 2003 included study.

A total of 36 studies are included in this update.

Included studies

Refer to table Characteristics of included studies for further details.

Use of progesterone in women with a history of prior

spontaneous preterm birth

Description of studies

Eleven studies were included involving a total of 1936 women

with a past history of spontaneous preterm birth (Akbari 2009;

Cetingoz 2011; da Fonseca 2003; Glover 2011; Johnson 1975;

Ibrahim 2010; Majhi 2009; Meis 2003; O’Brien 2007; Rai 2009;

Saghafi 2011a). Four studies compared weekly intramuscular in-

jection with placebo (Ibrahim 2010; Johnson 1975; Meis 2003)

or routine care (Saghafi 2011a); five studies compared daily vagi-

nal progesterone, three with placebo (Cetingoz 2011; da Fonseca

2003; O’Brien 2007) and two with routine care (Akbari 2009;

Majhi 2009); and two studies compared daily oral progesterone

with placebo (Glover 2011; Rai 2009). Dose of progesterone

administered varied from 90 mg daily (O’Brien 2007), to 100

mg daily (Akbari 2009; Cetingoz 2011; da Fonseca 2003; Majhi

2009), to 200 mg daily (Rai 2009), to 400 mg daily (Glover 2011),

to 200 mg weekly (Rai 2009), to 250 mg weekly (Johnson 1975;

Meis 2003; Saghafi 2011a). Supplementation commenced prior

to 20 weeks’ gestation in four trials (Glover 2011; Johnson 1975;

Meis 2003; O’Brien 2007), and continued up to a gestational age

varying from 24 weeks (Johnson 1975; Majhi 2009; Rai 2009), to

28 weeks (da Fonseca 2003), to 34 weeks (Akbari 2009; Cetingoz

2011), to 36 weeks (Ibrahim 2010; Meis 2003), and to 37 weeks

(O’Brien 2007; Saghafi 2011a) gestation.

The primary outcomes reported by the trials related to the oc-

currence of preterm birth prior to 28 weeks’ gestation (Rai

2009), 32 weeks’ gestation (O’Brien 2007), 34 weeks’ gestation

(Akbari 2009; Majhi 2009), and 37 weeks’ gestation (Akbari 2009;

Cetingoz 2011; da Fonseca 2003; Ibrahim 2010; Johnson 1975;

Majhi 2009; Meis 2003; Saghafi 2011a). Eight trials involved sin-

gle centres (Akbari 2009; da Fonseca 2003; Glover 2011; Ibrahim

2010; Johnson 1975; Majhi 2009; Rai 2009; Saghafi 2011a), and

two were multicentre trials (Meis 2003; O’Brien 2007), conducted

principally from the United States of America (Glover 2011;

Johnson 1975; Meis 2003; O’Brien 2007), India (Majhi 2009;

Rai 2009), Iran (Akbari 2009; Saghafi 2011a), Egypt (Ibrahim

2010), Istanbul (Cetingoz 2011), and Brazil (da Fonseca 2003).

The report by Northen 2007 reports childhood follow-up of 348

participants in the Meis randomised trial (Meis 2003).

One study (Cetingoz 2011) included a mix of women with a

history of prior preterm birth (n = 71) and women with a multiple

pregnancy (n = 67) and the results for this study have been analysed

separately for the two risk groups.

Use of progesterone in women with a short cervix identified

on transvaginal ultrasound examination

Description of studies

Four studies were included involving 1560 women who were iden-

tified with a short cervix (various definitions: less than 15 mm

(Fonseca 2007); less than 30 mm (Grobman 2012); between 10

and 20mm (Hassan 2011); and less than 25 mm (Rozenberg

2012)) at the time of transvaginal ultrasound examination. One

study compared weekly intramuscular injection with placebo

(Grobman 2012); one study compared twice weekly intramuscu-

lar injection with no treatment (Rozenberg 2012) and two studies

compared daily intravaginal progesterone with placebo (Fonseca

2007; Hassan 2011). Dose of progesterone administered varied

from 90 mg daily in the morning (Hassan 2011), to 200 mg

nightly (Fonseca 2007), to 250 mg weekly (Grobman 2012), to

500 mg twice weekly (Rozenberg 2012). Supplementation com-

menced from 16 to 22 weeks’ gestation in one study (Grobman

9Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

2012), from 19 to 23 weeks in another study (Hassan 2011), from

24 to 31 weeks in another study (Rozenberg 2012), and from 24 to

33 completed weeks of gestation in another study (Fonseca 2007).

The primary outcomes reported by the trials related to the occur-

rence of preterm birth prior to 33 weeks’ gestation (Hassan 2011),

34 weeks’ gestation (Fonseca 2007), 35 weeks’ gestation (Grobman

2012), or 37 weeks’ gestation (Grobman 2012) and time from

randomisation to delivery in one study (Rozenberg 2012). All tri-

als were multicentre conducted in centres worldwide, including

the United Kingdom, USA, France, Greece, Chile and Brazil.

One study (Fonseca 2007) included a mix of singleton and twin

pregnancies (226 singleton and 24 twin pregnancies), but due to

the small proportion of twin pregnancies in this study, we have

analysed all of this data within the short cervix subgroup.

Use of progesterone in women with a multiple pregnancy

Description of studies

Fourteen studies were included involving 3792 women; 11 tri-

als with a twin pregnancy (Aboulghar 2012; Cetingoz 2011;

Combs 2011; Elsheikhah 2010; Fonseca 2007; Hartikainen 1980;

Norman 2009; Rode 2011; Rouse 2007; Senat 2012; Serra 2013),

two trials with a triplet pregnancy (Caritis 2009; Combs 2010)

or one trial with any multiple pregnancy, e.g. twins, triplets or

quadruplets (Lim 2011). Six studies compared 250 mg weekly in-

tramuscular progesterone injections with placebo (Caritis 2009;

Combs 2010; Combs 2011; Hartikainen 1980; Lim 2011; Rouse

2007); one study compared 1000 mg weekly intramuscular pro-

gesterone injections with no treatment (Senat 2012); three stud-

ies compared intravaginal progesterone with placebo (Aboulghar

2012; Cetingoz 2011; Elsheikhah 2010), one at a daily dose of 100

mg (Cetingoz 2011), one at a daily dose of 200 mg (Elsheikhah

2010) and one at a daily dose of 400 mg Aboulghar 2012);

one study compared 90 mg daily intravaginal gel with placebo

(Norman 2009); and one study compared 100 mg daily oral pro-

gesterone with placebo (Rode 2011). One trial (Serra 2013) con-

sisted of three groups and compared 200 mg daily intravaginal

progesterone with 400 mg daily intravaginal progesterone with

placebo. Supplementation commenced from 16 to 20 weeks’ ges-

tation in three studies (Caritis 2009; Lim 2011; Rouse 2007),

from 16 to 22 weeks in one study (Combs 2010), from 16 to 24

weeks in one study (Combs 2011), from 18 to 24 weeks in one

study (Aboulghar 2012; Rode 2011), from 24 to 34 weeks in two

studies (Cetingoz 2011; Elsheikhah 2010), from 24 weeks’ gesta-

tion in one study (Norman 2009), and from 28 completed weeks’

of gestation in one study (Hartikainen 1980).

The primary outcomes reported by the trials related to the oc-

currence of preterm birth prior to 34 weeks’ gestation (Aboulghar

2012; Cetingoz 2011; Rode 2011; Senat 2012) or 37 weeks’ ges-

tation (Aboulghar 2012; Cetingoz 2011; Serra 2013), delivery or

fetal loss before 34 weeks’ gestation (Norman 2009), delivery or

fetal loss before 35 weeks’ gestation (Caritis 2009), mean cervical

length and mean gestational age at delivery (Elsheikhah 2010),

perinatal death (Hartikainen 1980) or composite neonatal mor-

bidity (Combs 2010; Combs 2011; Lim 2011; Senat 2012). Five

trials were multicentre conducted in centres worldwide, including

the United Kingdom, USA, the Netherlands, Denmark, Austria

and France (Caritis 2009; Combs 2010; Combs 2011; Lim 2011;

Norman 2009; Rode 2011; Rouse 2007) and four were single-

centre trials conducted in Istanbul, Egypt and Finland (Aboulghar

2012; Cetingoz 2011; Elsheikhah 2010; Hartikainen 1980).

Two studies included a mix of women with multiple and single-

ton pregnancies (Aboulghar 2012; Cetingoz 2011). One study

(Aboulghar 2012) included a mix of women with singleton preg-

nancies (n = 215) and women with a multiple pregnancy (n = 91)

all conceived by IVF/ICSI (in vitro fertilisation/intracytoplasmic

sperm injection) and the results for this study have been analysed

separately for the two risk groups: women at risk of preterm birth

for ’other’ reasons; and women with a multiple pregnancy. One

study (Cetingoz 2011) included a mix of women with a history

of prior preterm birth (n = 71) and women with a multiple preg-

nancy (n = 67) and the results for this study have been analysed

separately for the two risk groups.

Use of progesterone in women following symptoms or signs

of threatened preterm labour

Description of studies

Six small studies were included involving a total of 505 women

presenting with symptoms or signs of threatened preterm labour

(Borna 2008; Briery 2011; Combs 2011a; Facchinetti 2007;

Ndoni 2010; Sharami 2010). Two studies compared 250 mg

weekly progesterone injections with placebo (Briery 2011; Combs

2011a), one study compared vaginal progesterone pessaries on a

daily basis (400 mg) with no treatment (Borna 2008), one study

compared 341 mg intramuscular progesterone injection every four

days with no treatment (Facchinetti 2007), one study had three

arms and compared intramuscular progesterone with oral pro-

gesterone with placebo (Ndoni 2010) and one study compared

vaginal pessaries on a daily basis (200 mg) with placebo pessaries

(Sharami 2010). Women presented with symptoms and signs be-

tween 24 and 34 weeks’ gestation (Borna 2008), between 25

and 33 weeks’ gestation (Facchinetti 2007), between 20 and 30

weeks’ gestation (Briery 2011), between 23 and 31.9 weeks’ gesta-

tion (Combs 2011a), between 15 and 22 weeks’ gestation (Ndoni

2010) and between 28 and 36 weeks’ gestation (Sharami 2010).

The primary outcomes reported included the interval from ran-

domisation to birth in one study (Borna 2008), transvaginal ul-

trasound assessment of cervical length in one study (Facchinetti

2007), gestational age at birth in one study (Briery 2011), pro-

longation of pregnancy and composite neonatal morbidity in one

10Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

study (Combs 2011a) and time until delivery and birth before 34

or 37 completed weeks in one study (Sharami 2010). In one study,

reported only in abstract form, data relating to outcomes was not

reported (Ndoni 2010). One study was a multicentre study con-

ducted in the USA (Combs 2011a) and the remaining five stud-

ies were single-centre studies conducted in Iran, the USA, Italy,

and Albania (Borna 2008; Briery 2011; Facchinetti 2007; Ndoni

2010; Sharami 2010).

Use of progesterone in women at risk of preterm birth for

’other’ reasons

Description of studies

Papiernik 1970 recruited 99 women from Paris, France, in a single

centred trial, with a ’high preterm risk score’. Women were allo-

cated to receive intramuscular progesterone three times per week

or placebo, from 28 to 32 weeks’ gestation.

Hauth 1983 involved 168 women from the United States of Amer-

ica who were considered to be at risk of preterm birth due to ac-

tive military service. Women received 1000 mg of progesterone

weekly or placebo, from 16 to 20 weeks’ gestation, up until 36

weeks’ gestation. The primary outcome for the study related to

the incidence of preterm birth at less than 37 weeks’ gestation.

Moghtadaei 2008 involved 260 women from Iran, in a single

centre trial, who were considered to be at risk of preterm birth

due to advanced maternal age (greater than 35 years). Women

received weekly injections of 17P (250 mg) starting at 16 to 20

weeks’ gestation until 34 weeks or matching placebo. The main

outcomes for the study included delivery before 37, 35 or 32 weeks’

gestation, hypertension, diabetes, intrauterine growth restriction

or side effects at the injection site. Data from this study could

not be included in a meta-analysis because the number of women

randomised to each group was not reported in the brief abstract

report of the study.

Aboulghar 2012 recruited 313 women from Egypt who were con-

sidered to be at high risk of preterm birth because all the preg-

nancies were conceived by IVF or ICSI. Women received vaginal

progesterone 200 mg twice daily from randomisation until deliv-

ery or 37 weeks’ gestation or matching placebo. The primary out-

comes included preterm birth of singleton and twin pregnancies

before 37 completed weeks and before 34 completed weeks. This

study contains a mix of singleton pregnancies (n = 215) and twin

pregnancies (n = 91) and presented some outcome data separately,

as well as for the whole group. The results for this study have been

analysed separately for the two risk groups: multiple pregnancies

and women at risk for ’other’ reasons.

Excluded studies

In total, 16 studies were excluded (Abbott 2012; Arikan 2011;

Berghella 2010; Breart 1979; Brenner 1962; Chandiramani 2012;

Corrado 2002; Hobel 1986; Ionescu 2012; Keeler 2009; Le

Vine 1964; Rust 2006; Suvonnakote 1986; Turner 1966; Walch

2005; Yemini 1985). Three studies were excluded as they used a

quasi-randomised method of treatment allocation (Le Vine 1964;

Suvonnakote 1986; Yemini 1985). One study (Hobel 1986) com-

pared an oral progestogen with placebo, but presented outcomes

only as percentages. Five studies were excluded as progesterone was

administered in the first trimester to prevent miscarriage (Breart

1979; Brenner 1962; Corrado 2002; Turner 1966; Walch 2005),

and are covered by the Cochrane review relating to the use of pro-

gesterone for prevention of miscarriage (Haas 2008). One study

was excluded because progesterone was administered as an acute

tocolytic medication (Arikan 2011). A further six studies were ex-

cluded because they compared progesterone with cerclage (Abbott

2012; Chandiramani 2012; Ionescu 2012; Keeler 2009; Rust

2006) or compared cerclage with no cerclage (Berghella 2010),

and are covered by other Cochrane reviews (Alfirevic 2012; Rafael

2011).

Refer to table Characteristics of excluded studies for further details.

Studies awaiting assessment

There are 11 ongoing studies awaiting assessment (Coomarasamy

2012; Creasy 2008; Crowther 2007; Martinez 2007; Nassar 2007;

Norman 2012; Perlitz 2007; Starkey 2008; Swaby 2007; van Os

2011; Wood 2007).

Risk of bias in included studies

The overall quality of the included trials varied from good to

fair. Refer to table Characteristics of included studies for further

details and to Figure 1; Figure 2, for a summary of ’Risk of bias’

assessments.

11Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Figure 1. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as

percentages across all included studies.

12Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Figure 2. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included

study.

13Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Allocation

While all trials were stated to be randomised and placebo con-

trolled, the method of randomisation was only described in 23

trials (Borna 2008; Briery 2011; Caritis 2009; Cetingoz 2011;

Combs 2010; Combs 2011; Combs 2011a; da Fonseca 2003;

Facchinetti 2007; Glover 2011; Grobman 2012; Hassan 2011;

Lim 2011; Majhi 2009; Meis 2003; Norman 2009; O’Brien 2007;

Rai 2009; Rode 2011; Rouse 2007; Rozenberg 2012; Senat 2012;

Serra 2013). Allocation concealment was assessed as low risk of bias

in 23 trials (Aboulghar 2012; Briery 2011; Caritis 2009; Cetingoz

2011; Combs 2010; Combs 2011; Combs 2011a; da Fonseca

2003; Fonseca 2007; Glover 2011; Grobman 2012; Hassan 2011;

Johnson 1975; Lim 2011; Majhi 2009; Meis 2003; Norman 2009;

O’Brien 2007; Rai 2009; Rode 2011; Rouse 2007; Senat 2012;

Serra 2013); and unclear in 13 trials (Akbari 2009; Borna 2008;

Elsheikhah 2010; Facchinetti 2007; Hartikainen 1980; Hauth

1983; Ibrahim 2010; Moghtadaei 2008; Ndoni 2010; Papiernik

1970; Rozenberg 2012; Saghafi 2011a; Sharami 2010).

Blinding

Twenty-five of the 32 included trials were placebo controlled, with

blinding of caregivers and participants (Aboulghar 2012; Briery

2011; Caritis 2009; Cetingoz 2011; Combs 2010; Combs 2011;

Combs 2011a; da Fonseca 2003; Fonseca 2007; Glover 2011;

Grobman 2012; Hartikainen 1980; Hassan 2011; Hauth 1983;

Johnson 1975; Lim 2011; Meis 2003; Norman 2009; O’Brien

2007; Papiernik 1970; Rai 2009; Rode 2011; Rouse 2007; Serra

2013; Sharami 2010).

Blinding of outcome assessment was evident in 15 of the trials

(Aboulghar 2012; Combs 2010; da Fonseca 2003; Fonseca 2007;

Grobman 2012; Hartikainen 1980; Hauth 1983; Johnson 1975;

Lim 2011; Meis 2003; O’Brien 2007; Papiernik 1970; Rode 2011;

Rouse 2007; Serra 2013).

Four trials were assessed as high risk of bias for both blinding of

caregivers and participants and outcome assessment as no blinding

was attempted (Borna 2008; Facchinetti 2007; Rozenberg 2012;

Senat 2012).

Incomplete outcome data

Thirty-one studies were assessed as being at low risk of bias for attri-

tion bias. Thirteen studies reported no losses to follow-up (Borna

2008; Caritis 2009; Combs 2010; Combs 2011a; Facchinetti

2007; Fonseca 2007; Hartikainen 1980; Hauth 1983; Ibrahim

2010; Majhi 2009; Meis 2003; Papiernik 1970; Saghafi 2011a)

and 18 studies reported less than 20% loss to follow-up (Aboulghar

2012; Briery 2011; Cetingoz 2011; Combs 2011; da Fonseca

2003; Glover 2011; Grobman 2012; Hassan 2011; Johnson 1975;

Lim 2011; Norman 2009; O’Brien 2007; Rai 2009; Rode 2011;

Rouse 2007; Rozenberg 2012; Serra 2013; Sharami 2010). In five

studies reported only in abstract form, it was unclear whether

attrition bias was present (Elsheikhah 2010; Grobman 2012;

Moghtadaei 2008; Ndoni 2010; Senat 2012) and in one study

details were insufficient to make a judgement (Akbari 2009).

Selective reporting

Twenty-five studies were assessed as being at low risk of bias

for selective reporting (Aboulghar 2012; Akbari 2009; Borna

2008; Caritis 2009; Cetingoz 2011; Combs 2010; Combs 2011;

Combs 2011a; da Fonseca 2003; Fonseca 2007; Grobman 2012;

Hartikainen 1980; Hassan 2011; Hauth 1983; Ibrahim 2010;

Johnson 1975; Lim 2011; Majhi 2009; Meis 2003; Norman 2009;

O’Brien 2007; Rai 2009; Rode 2011; Rouse 2007; Rozenberg

2012) as all expected outcomes were reported. One study was as-

sessed as being at high risk of bias, because one of the outcomes

was incompletely reported on (Facchinetti 2007) and in one study

it was difficult to assess selective reporting based on a translation of

the original report (Papiernik 1970). In all the other study reports,

it was not possible to determine whether or not selection bias was

present (Briery 2011; Elsheikhah 2010; Glover 2011; Moghtadaei

2008; Ndoni 2010; Rozenberg 2012; Saghafi 2011a; Senat 2012;

Serra 2013; Sharami 2010).

Other potential sources of bias

Twenty-one studies were assessed as being at low risk of bias for

other potential sources of bias based on baseline characteristics

being similar between groups and no other bias apparent (Borna

2008; Briery 2011; Caritis 2009; Combs 2010; Combs 2011;

da Fonseca 2003; Facchinetti 2007; Fonseca 2007; Glover 2011;

Hassan 2011; Hauth 1983; Johnson 1975; Lim 2011; Meis 2003;

Norman 2009; O’Brien 2007; Papiernik 1970; Rai 2009; Rode

2011; Saghafi 2011a; Sharami 2010). In the remaining studies,

it was not possible to determine whether or not other sources of

bias were present (Aboulghar 2012; Akbari 2009; Cetingoz 2011;

Combs 2011a; Elsheikhah 2010; Grobman 2012; Hartikainen

1980; Ibrahim 2010; Majhi 2009; Moghtadaei 2008; Ndoni 2010;

Rouse 2007; Rozenberg 2012; Senat 2012; Serra 2013).

Assessment of studies that included multiple pregnancies

We assessed whether studies that included multiple pregnancies

accounted appropriately for non-independence of babies from

the same pregnancy in the analysis. There were 14 studies that

included a multiple pregnancy (Aboulghar 2012; Caritis 2009;

Cetingoz 2011; Combs 2010; Combs 2011; Elsheikhah 2010;

14Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Fonseca 2007; Hartikainen 1980; Lim 2011; Norman 2009;

Rode 2011; Rouse 2007; Senat 2012; Serra 2013) and in seven

studies adjustment appears to have been made in the analysis

(Caritis 2009; Combs 2010; Combs 2011; Fonseca 2007; Lim

2011; Norman 2009; Rode 2011). In the remaining seven studies

(Aboulghar 2012; Cetingoz 2011; Elsheikhah 2010; Hartikainen

1980; Rouse 2007; Senat 2012; Serra 2013), it is not clear that

any adjustment was made.

There were insufficient data presented in the trial reports to al-

low us to carry out necessary adjustment for cluster design effect

ourselves and, although in several trials results had already been

adjusted, we were not able to present these data in our data and

analyses tables because they were not reported in a consistent way.

Effects of interventions

Thirty-six randomised controlled trials (8523 women and 12,515

infants) in total were included in this review.

Data were only available in a suitable format from 30 randomised

controlled trials involving a total of 7561 women and 10,114 in-

fants. Data from these 30 trials contributed data that were included

in meta-analyses. As the aetiology of preterm birth is multifacto-

rial, results are presented according to the reason considered to be

at risk for preterm birth (past history of spontaneous preterm birth

(including preterm premature rupture of membranes), ultrasound

identified short cervical length, multiple pregnancy, prior presen-

tation with threatened preterm labour, and other reason for risk

of preterm birth).

Progesterone versus placebo/no treatment for

women with a past history of spontaneous preterm

birth

Eleven randomised controlled trials involving a total of 1899

women and infants were included in the meta-analysis.

Primary outcomes

For women administered progesterone during pregnancy, there

was a statistically significant reduction in perinatal mortality over-

all (six studies; 1453 women; risk ratio (RR) 0.50, 95% confidence

interval (CI) 0.33 to 0.75), Analysis 1.1. For the primary outcome

preterm birth less than 34 weeks’ gestation, there was also a sta-

tistically significant difference between progesterone when com-

pared with placebo (five studies; 602 women; average RR 0.31,

95% CI 0.14 to 0.69), Analysis 1.2. Substantial heterogeneity was

evident for Analysis 1.2 (heterogeneity: Tau² = 0.45, Chi² = 9.15,

df = 4 (P = 0.06), I² = 56%) and so a random-effects model was

used. Major neurodevelopmental handicap in childhood was not

reported.

Secondary infant outcomes

For women administered progesterone during pregnancy, when

compared with placebo, the results showed:

• preterm birth less than 37 weeks’ gestation (10 studies;

1750 women; average RR 0.55, 95% CI 0.42 to 0.74);

considerable heterogeneity was identified, and a random-effects

model was used (heterogeneity: Tau² = 0.11; Chi² = 29.60, df =

9 (P = 0.0005); I² = 70%), Analysis 1.3. This was also evident for

the intramuscular subgroup (four studies; 652 women; average

RR 0.62, 95% CI 0.52 to 0.75), Analysis 1.3.1. However, for the

oral subgroup, no statistically significant differences were

observed, Analysis 1.3.3. A funnel plot for this analysis (Figure

3), including the 10 studies was very asymmetrical. This suggests

that there may be some important biases or small-study effects in

the set of studies in this analysis and so these results should be

viewed with caution.

15Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Figure 3. Funnel plot of comparison: 1 Progesterone versus placebo/no treatment: previous history

spontaneous preterm birth, outcome: 1.3 Preterm birth less than 37 weeks.

There was also a statistically significant reduction in the risk of:

• infant birthweight less than 2500 g (four studies; 692

infants; RR 0.58, 95% CI 0.42 to 0.79), Analysis 1.9;

• use of assisted ventilation (three studies; 633 women; RR

0.40, 95% CI 0.18 to 0.90), Analysis 1.11;

• necrotising enterocolitis (three studies; 1170 infants; RR

0.30, 95% CI 0.10 to 0.89), Analysis 1.16;

• neonatal death (six studies; 1453 women; RR 0.45, 95% CI

0.27 to 0.76), Analysis 1.20;

• admission to neonatal intensive care unit (three studies; 389

women; RR 0.24, 95% CI 0.14 to 0.40), Analysis 1.33.

For infant outcomes Apgar score less than seven at five minutes

Analysis 1.32, respiratory distress syndrome Analysis 1.10, in-

trauterine fetal death Analysis 1.19, intraventricular haemorrhage

(all grades) Analysis 1.12, intraventricular haemorrhage (grade III

or IV) Analysis 1.13, periventricular leucomalacia Analysis 1.14,

retinopathy of prematurity Analysis 1.15, neonatal sepsis Analysis

1.17, patent ductus arteriosus Analysis 1.18, intrauterine fetal

death Analysis 1.19, or neonatal length of hospital stay Analysis

1.34, there were no statistically significant differences identified.

Secondary maternal outcomes

For women administered progesterone during pregnancy, when

compared with placebo, there was a statistically significant increase

in:

• pregnancy prolongation in weeks (one study; 148 women;

mean difference (MD) 4.47, 95% CI 2.15 to 6.79), Analysis

1.31.

There were no statistically significant differences for the outcomes

threatened preterm labour Analysis 1.4, spontaneous vaginal birth

Analysis 1.5, adverse drug reaction Analysis 1.30, caesarean birth

Analysis 1.6, use of antenatal corticosteroids Analysis 1.7, or the

use of antenatal tocolysis Analysis 1.8.

Secondary childhood outcomes

There were no statistically significant differences identified for the

outcomes developmental delay Analysis 1.21, intellectual impair-

16Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

ment Analysis 1.22, motor impairment Analysis 1.23, visual im-

pairment Analysis 1.24, hearing impairment Analysis 1.25, cere-

bral palsy Analysis 1.26, learning difficulties Analysis 1.27, height

less than fifth centile Analysis 1.28 , weight less than the fifth cen-

tile Analysis 1.29, infant weight at six, 12 and 24 months’ follow-

up Analysis 1.34; Analysis 1.35; Analysis 1.36, infant length (cm)

at six, 12 and 24 months’ follow-up Analysis 1.38; Analysis 1.39;

Analysis 1.40, and infant head circumference (cm) at six, 12 and

24 months’ follow-up Analysis 1.41; Analysis 1.42; Analysis 1.43.

Effect of route of administration, time of commencing

therapy, and dose of progesterone

We investigated statistical heterogeneity (I² > 30%) by perform-

ing subgroup analyses where possible for all outcomes and found

no differential effect on the majority of outcomes examined when

considering route of administration of progesterone (intramuscu-

lar versus vaginal versus oral). However, for respiratory distress

syndrome, the subgroup analysis indicated a differential effect be-

tween the different routes of administration (test for subgroup

differences: P = 0.001, I² = 84.8%, Analysis 1.10), although only

one trial was included in each subgroup of intramuscular versus

vaginal versus oral, Analysis 1.10.

We performed subgroup analysis to investigate the differential ef-

fect of time of commencement of supplementation (prior to 20

weeks’ gestation versus after 20 weeks’ gestation) where outcome

data allowed, and found no subgroup differences (test for sub-

group differences: P = 0.28, I² = 15.9%, Analysis 2.1).

We also performed subgroup analysis by total weekly cumulative

dose of progesterone (less than 500 mg versus greater than 500

mg) and found no differential effect for the majority of outcomes

examined: Analysis 3.1; Analysis 3.2; Analysis 3.3; Analysis 3.4;

Analysis 3.5; Analysis 3.6; Analysis 3.7; Analysis 3.9; Analysis 3.10;

Analysis 3.11; Analysis 3.12. However, for intraventricular haem-

orrhage (all grades), the subgroup analysis indicated a differential

effect between the different doses of progesterone (test for sub-

group differences: P = 0.04, I² = 76.2%, Analysis 1.38), although

only one trial was included in each subgroup of intramuscular ver-

sus vaginal versus oral, Analysis 1.10.

Progesterone versus placebo for women with a short

cervix identified on ultrasound

Four randomised controlled trials involving a total of 1556 women

and infants were included in the meta-analysis.

Primary outcomes

For women administered progesterone during pregnancy, for the

primary outcome perinatal death, there were no statistically signif-

icant differences identified when compared with placebo, Analysis

4.1. Women administered progesterone were significantly less

likely to have a preterm birth at less than 34 weeks’ gestation (two

studies; 438 women; RR 0.64, 95% CI 0.45 to 0.90), Analysis

4.2. Major neurodevelopmental handicap in childhood was not

reported.

Secondary infant outcomes

For women administered progesterone during pregnancy, for the

outcome preterm birth at less than 37 weeks’ gestation, there were

no statistically significant differences identified when compared

with placebo, Analysis 4.12. However, women administered pro-

gesterone were significantly less likely to have a preterm birth at

less than 28 weeks’ gestation (two studies; 1115 women; RR 0.59,

95% CI 0.37 to 0.93), Analysis 4.13.

For infant outcomes infant birthweight less than 2500 g Analysis

4.14, respiratory distress syndrome Analysis 4.15, Apgar score

less than seven at five minutes Analysis 4.16, need for as-

sisted ventilation Analysis 4.17, intraventricular haemorrhage (all

grades) Analysis 4.18, intraventricular haemorrhage (grades III

or IV) Analysis 4.19, periventricular leucomalacia Analysis 4.20,

retinopathy of prematurity Analysis 4.21, necrotising enterocoli-

tis Analysis 4.22, neonatal sepsis Analysis 4.23, intrauterine fetal

death Analysis 4.24, neonatal death Analysis 4.25 or admission to

neonatal intensive care unit Analysis 4.26, there were no statisti-

cally significant differences identified.

Secondary maternal outcomes

Women administered progesterone were significantly more likely

to experience the adverse drug reaction urticaria (one study; 654

women; RR 5.03, 95% CI 1.11 to 22.78), Analysis 4.7. For all

other maternal outcomes, threatened preterm labour Analysis

4.3, prelabour spontaneous rupture of membranes Analysis 4.4,

adverse drug reactions (any, injection site, nausea) Analysis 4.5;

Analysis 4.6; Analysis 4.8, pregnancy prolongation Analysis 4.9,

caesarean section Analysis 4.10, or antenatal tocolysis Analysis

4.11, there were no statistically significant differences identified.

Secondary childhood outcomes

None of the secondary childhood outcomes were reported.

Effect of route of administration, time of commencing

therapy, and dose of progesterone

We investigated statistical heterogeneity (I² > 30%) by perform-

ing subgroup analyses where possible for all outcomes and found

no differential effect on the outcomes examined when consider-

ing route of administration of progesterone (intramuscular versus

vaginal), Analysis 4.20; Analysis 4.21; Analysis 4.23. It was not

possible to assess the effect of gestational age at commencing ther-

apy.

We also performed subgroup analysis by total weekly cumulative

dose of progesterone (less than 500 mg versus greater than 500 mg)

17Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

and found no differential effect for the two outcomes examined:

Analysis 5.1; Analysis 5.2.

Progesterone versus placebo for women with a

multiple pregnancy

Ten randomised controlled trials involving a total of 3395 women

and 6178 infants were included in the meta-analysis.

One trial (Serra 2013) consisted of three groups: progesterone

200 mg versus progesterone 400 mg versus placebo. This trial

has been analysed as separate pair-wise comparisons, with separate

analyses for progesterone 200 mg versus placebo (Analysis 6.1;

Analysis 6.2; Analysis 6.3; Analysis 6.5; Analysis 6.9; Analysis 6.10;

Analysis 6.11; Analysis 6.12; Analysis 6.13; Analysis 6.14; Analysis

6.21; Analysis 6.24; Analysis 6.25; Analysis 6.26) and progesterone

400 mg versus placebo (Analysis 6.27; Analysis 6.28; Analysis

6.29; Analysis 6.30; Analysis 6.31; Analysis 6.32; Analysis 6.33;

Analysis 6.34; Analysis 6.35; Analysis 6.36; Analysis 6.37; Analysis

6.38; Analysis 6.39; Analysis 6.40; Analysis 6.41; Analysis 6.42; ;

Analysis 7.1; Analysis 7.2; Analysis 7.3).

Primary outcomes

For women administered progesterone during pregnancy, for the

primary outcomes perinatal death Analysis 6.1, Analysis 6.27, and

preterm birth less than 34 weeks’ gestation Analysis 6.2; Analysis

6.28, there were no statistically significant differences identified

when compared with placebo. Major neurodevelopmental handi-

cap in childhood was not reported.

Secondary infant outcomes

For women administered progesterone during pregnancy, when

compared with placebo, there were no statistically significant dif-

ferences identified in the risk of birth before 37 Analysis 6.11;

Analysis 6.33 or 28 weeks Analysis 6.12; Analysis 6.34, infant

birthweight less than 2500 g Analysis 6.13; Analysis 6.35, Ap-

gar score less than seven at five minutes Analysis 6.14; Analysis

6.36, respiratory distress syndrome Analysis 6.15, need for ven-

tilation Analysis 6.16; Analysis 6.37, intraventricular haemor-

rhage Analysis 6.17; Analysis 6.18, periventricular leucomalacia

Analysis 6.19, retinopathy of prematurity Analysis 6.20, chronic

lung disease Analysis 6.21, necrotising enterocolitis Analysis 6.22,

neonatal sepsis Analysis 6.23, fetal death Analysis 6.24; Analysis

6.38, neonatal death Analysis 6.25; Analysis 6.39, or admission to

neonatal intensive care unit (NICU) Analysis 6.26; Analysis 6.40.

Due to extreme heterogeneity, we did not combine data from trials

for the outcomes neonatal length of hospital stay or patent ductus

arteriosus.

Secondary maternal outcomes

For women administered progesterone during pregnancy, when

compared with placebo, there were no statistically significant dif-

ferences identified in any of the following maternal outcomes:

prelabour spontaneous rupture of membranes Analysis 6.3, ad-

verse drug reaction Analysis 6.4, caesarean section Analysis 6.5,

spontaneous birth Analysis 6.6, assisted birth Analysis 6.7, satis-

faction with the therapy Analysis 6.8, antenatal tocolysis Analysis

6.9, or antenatal corticosteroids Analysis 6.10.

Secondary childhood outcomes

None of the secondary childhood outcomes were reported.

Sensitivity analyses to account for multiple pregnancies

For multiple pregnancies we had planned to analyse neonatal

data as ’clusters’ to account for dependency between twins and

triplets. We anticipated that the degree of dependence between

twins would vary at the outcome level i.e. in the case of preterm

birth the dependency (ICC) is likely to be high, whereas in some

outcomes, such as perinatal death or morbidity, the ICC may be

much lower. However, there were insufficient data presented in

the trial reports to allow us to carry out necessary adjustment for

cluster design effect ourselves and, although in several trials results

had already been adjusted, we were not able to present these data

in our data and analyses tables because they were not reported in

a consistent way.

For the primary outcome perinatal death, we therefore carried out

a sensitivity analysis assuming two extremes. In the first we as-

sumed complete dependence between infants in multiple preg-

nancies, i.e. we assumed outcomes were the same for all infants

within that pregnancy; in this case the effective sample size for

twin pregnancies would be the total number of women rather than

infants, and for infant outcomes all event rates and sample sizes

were therefore divided by two. In the second sensitivity analyses

we assumed very limited dependence (1%) and in this case event

rates and sample sizes were divided by 1.01. Results from sensitiv-

ity analyses were very similar to those from the unadjusted analyses

although the effect estimates changed slightly due to rounding up

of event rates and sample sizes, and the 95% CIs were generally

slightly wider. Adjusted analyses showed that for women admin-

istered progesterone during pregnancy, for the primary outcome

perinatal death, there were no statistically significant differences

identified when compared with placebo. (Data not shown, avail-

able from the authors on request).

Effect of route of administration, time of commencing

therapy, and dose of progesterone

We investigated statistical heterogeneity (I² > 30%) by performing

subgroup analyses and found no differential effect on the major-

18Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

ity of outcomes examined when considering route of administra-

tion of progesterone (intramuscular versus vaginal). However, for

spontaneous birth, infant birthweight less than 2500 g and admis-

sion to NICU, the subgroup analyses indicated a differential effect

between the different routes of administration (test for subgroup

differences: P = 0.0008, I² = 91.1%, Analysis 6.6; P = 0.02, I² =

80.8% Analysis 6.13; P = 0.009, I² = 85.5%, Analysis 6.26) al-

though it must be noted that in Analysis 6.6; Analysis 6.26, some

of the subgroups contained only one trial.

We performed subgroup analysis to investigate the differential ef-

fect of time of commencement of supplementation (prior to 20

weeks’ gestation versus after 20 weeks’ gestation) where outcome

data allowed, and found no subgroup differences for the outcomes

examined, Analysis 7.1; Analysis 7.2; Analysis 7.3.

We also performed subgroup analysis by total weekly cumulative

dose of progesterone (less than 500 per week mg versus greater than

500 mg per week) and found no differential effect for the majority

of outcomes examined, Analysis 8.1; Analysis 8.2; Analysis 8.3;

Analysis 8.4; Analysis 8.5; Analysis 8.6; Analysis 8.7. However,

for infant birthweight less than 2500 g and admission to NICU,

the subgroup analyses indicated a differential effect between the

cumulative doses of progesterone (test for subgroup difference: P

= 0.02, I² = 80.8%, Analysis 8.5; P = 0.009, I² = 85.5%, Analysis

8.8).

Progesterone versus placebo/no treatment for

women following presentation with threatened

preterm labour

Five randomised controlled trials involving a total of 384 women

and infants were included in the meta-analysis.

Primary outcomes

For women administered progesterone during pregnancy, for the

primary outcomes perinatal death Analysis 9.1, and preterm birth

less than 34 weeks’ gestation Analysis 9.2, there were no statistically

significant differences identified when compared with placebo.

Major neurodevelopmental handicap in childhood was not re-

ported.

Secondary infant outcomes

For women administered progesterone during pregnancy, when

compared with placebo, there was a statistically significant reduc-

tion in the risk of:

• infant birthweight less than 2500 g (one study; 70 infants;

RR 0.52, 95% CI 0.28 to 0.98), Analysis 9.11.

There were no statistically significant differences for any of the

other outcomes analysed: preterm birth less than 37 weeks’ gesta-

tion Analysis 9.10, respiratory distress syndrome Analysis 9.12, in-

traventricular haemorrhage grade III or IV Analysis 9.13, periven-

tricular leucomalacia Analysis 9.14, needed for mechanical ventila-

tion Analysis 9.15, necrotising enterocolitis Analysis 9.16, neona-

tal sepsis Analysis 9.17, fetal death Analysis 9.18, neonatal death

Analysis 9.19, or neonatal length of hospital stay Analysis 9.20.

Secondary maternal outcomes

For women administered progesterone during pregnancy, when

compared with placebo, there were no statistically significant dif-

ferences for any of the outcomes analysed: pregnancy prolongation

Analysis 9.3; Analysis 9.4; Analysis 9.5; Analysis 9.6, spontaneous

vaginal birth Analysis 9.7, caesarean section Analysis 9.8, or use

of tocolysis Analysis 9.9.

Secondary childhood outcomes

There were no secondary childhood outcomes reported.

Effect of route of administration, time of commencing

therapy, and dose of progesterone

We investigated statistical heterogeneity (I² > 30%) by performing

subgroup analyses where possible for all outcomes and found no

differential effect on some of the outcomes examined when con-

sidering route of administration of progesterone (intramuscular

versus vaginal), Analysis 9.2; Analysis 9.9; Analysis 9.12; Analysis

9.17; Analysis 9.19. However, for pregnancy prolongation and

preterm birth less than 37 weeks’ gestation, the subgroup analyses

indicated a differential effect between the different routes of ad-

ministration (test for subgroup differences: P = 0.001, I² = 90.5%,

Analysis 9.3; P = 0.04, I² = 75.6%, Analysis 9.10), although it

must be noted that in both analyses the subgroups contained only

one trial.

It was not possible to assess the effect of gestational age at com-

mencing therapy.

We also performed subgroup analysis by total weekly cumulative

dose of progesterone (less than 500 mg versus greater than 500

mg) and found no differential effect for three outcomes examined:

Analysis 10.3; Analysis 10.4; Analysis 10.5. However, for the two

outcomes, pregnancy prolongation and preterm birth less than

37 weeks’ gestation, the subgroup analyses indicated a differential

effect between the different drug doses (test for subgroup differ-

ences: P = 0.001, I² = 90.5%, Analysis 10.1; P = 0.04, I² = 75.6%

, Analysis 10.2).

Progesterone versus placebo for women with ’other’

risk factors for preterm birth

Three randomised controlled trials involving a total of 482 women

and infants were included in the meta-analysis. Data from a fourth

study (Moghtadaei 2008), could not be included in the meta-

analysis because the number of women randomised to each group

was not reported in the brief abstract report of the study.

19Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Primary outcomes

For women administered progesterone during pregnancy, for the

primary outcomes perinatal death Analysis 11.1 and preterm birth

less than 34 weeks’ gestation Analysis 11.2, there were no sta-

tistically significant differences identified when compared with

placebo. The outcome major neurodevelopmental handicap in

childhood were not reported.

Secondary infant outcomes

For women administered progesterone during pregnancy, when

compared with placebo, there was a statistically significant reduc-

tion in the risk of:

• infant birthweight less than 2500 g (three studies; 482

infants; RR 0.48, 95% CI 0.25 to 0.91) Analysis 11.4.

In addition, for women administered progesterone who were con-

sidered to be at risk of preterm birth for ’other’ reasons, when

compared with placebo, there were no statistically significant dif-

ferences for the outcomes preterm birth less than 37 weeks’ ges-

tation Analysis 11.3., perinatal death Analysis 11.1, intrauterine

fetal death Analysis 11.5 or neonatal death Analysis 11.6.

Secondary childhood outcomes

There were no secondary childhood outcomes reported.

Effect of route of administration, time of commencing

therapy, and dose of progesterone

We investigated statistical heterogeneity (I² > 30%) by perform-

ing subgroup analysis for perinatal death Analysis 12.1, preterm

birth less than 37 weeks Analysis 12.2, and infant birthweight less

than 2500 g, Analysis 12.3, and no differential effect was observed

related for gestational age at commencing therapy, (test for sub-

group differences: P = 0.10, I² = 63.9%, Analysis 12.2; P = 0.19,

I² = 42.2%, Analysis 12.3).

D I S C U S S I O N

The randomised trials identified assessed the use of progesterone in

women considered to be at increased risk of preterm birth by virtue

of history of spontaneous preterm birth, ultrasonographic evalua-

tion of cervical length, presentation in threatened preterm labour,

multiple pregnancy, or other reasons (including ’high preterm risk

score’ and active military duty).

Summary of main results

Progesterone for women with a past history of

spontaneous preterm birth

For women with a past history of spontaneous preterm birth, there

was a statistically significant reduction in the risk of the primary

outcomes, perinatal death and in the risk of preterm birth less

than 34 weeks’ gestation. The reduction in risk of perinatal death

is confined to the subgroup of women receiving intramuscular

progesterone. There was significant heterogeneity identified for

the outcomes preterm birth before 34 and 37 weeks’ gestation,

with evidence of funnel plot asymmetry, raising questions about

potential bias and therefore caution in interpretation. For the sec-

ondary infant and maternal outcomes, the use of progesterone was

associated with a reduction in the risk of infant birthweight less

than 2500 g, use of assisted ventilation, necrotising enterocolitis,

neonatal death, admission to neonatal intensive care unit, preterm

birth less than 37 weeks’ gestation and a significant increase in

prolongation in pregnancy prolongation. There were no signifi-

cant differences identified for other secondary infant and maternal

health outcomes with the use of progesterone. Information related

to childhood health and well being is limited, with only two tri-

als reporting two-year follow-up results to date (Northen 2007;

O’Brien 2007), in which there were no documented differences

in growth or developmental outcomes between those infants ex-

posed in utero to progesterone and those to placebo. There was no

differential effect on outcomes in terms of time of commencing

therapy and dose of progesterone from the available evidence.

Further information is required about the optimal route of admin-

istration of progesterone, with the largest study to date using vagi-

nal progesterone gel suggesting no benefit in this group of women

(O’Brien 2007).

Progesterone for women with a short cervix

identified on ultrasound

In the trials to date assessing the role of progesterone in women

with a short cervix identified on ultrasound (Fonseca 2007;

Grobman 2012; Hassan 2011; Rozenberg 2012), there were no

statistically significant differences identified for the primary out-

come perinatal death. Women administered progesterone were sig-

nificantly less likely to have preterm birth less than 34 weeks’ ges-

tation. For the secondary infant outcomes, the use of progesterone

was associated with a reduction in risk of preterm birth at less than

28 weeks’ gestation. There was also a significant increase in the

risk urticaria in women receiving progesterone. Further informa-

tion is required about the risk of other infant health outcomes,

and maternal health outcomes in this group of women. Reporting

of childhood outcomes is lacking, with no trials reporting this in-

formation to date. The relative efficacy of progesterone compared

with cerclage for women with a short cervix remains uncertain,

20Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

as does the use of progesterone as an adjunct therapy following

cerclage placement (Conde-Agudelo 2013).

Progesterone for women with a multiple pregnancy

The role of progesterone in women with a multiple pregnancy

is less clear, with no identified differences in the primary out-

comes perinatal death, and preterm birth less than 34 weeks’ ges-

tation. There were also no differences identified for the other sec-

ondary infant and maternal health outcomes. Information relating

to long-term childhood health outcomes is unavailable to date.

There are several ongoing randomised trials assessing the role of in-

tramuscular (Nassar 2007) and vaginal (Wood 2007) progesterone

in women with a multiple pregnancy which will contribute infor-

mation about the role of progesterone in this group of women.

For multiple pregnancies, we had planned to analyse neonatal

data as ’clusters’ to account for dependency between twins and

triplets. We anticipated that the degree of dependence between

twins would vary at the outcome level i.e. in the case of preterm

birth the dependency (ICC) is likely to be high, whereas in some

outcomes such as perinatal death or morbidity, the ICC may be

much lower. However, there were insufficient data presented in

the trial reports to allow us to carry out necessary adjustment

for cluster design effect ourselves and, although in several trials

results had already been adjusted, we were not able to present

these data in our data and analyses tables because they were not

reported in a consistent way. In future updates, we will contact

trial authors for additional information to allow us to carry out

necessary adjustments in the analysis of the neonatal data.

Progesterone for women following presentation with

threatened preterm labour

The role of progesterone for women following presentation with

threatened preterm labour remains uncertain. The identified ran-

domised trials indicate a reduction in only the risk of infant birth-

weight less than 2500 g. However, the outcomes have been re-

ported in only five small trials (332 women), with only four con-

tributing data to meta-analysis (211 women) and are underpow-

ered to detect differences in both maternal and infant health out-

comes. There is an ongoing randomised trial assessing the role of

vaginal progesterone in women presenting with symptoms or signs

of threatened preterm labour which will contribute information

about the role of progesterone in this group of women (Martinez

2007).

Progesterone versus placebo for women with ’other’

risk factors for preterm birth

The role of progesterone in women considered to be at risk of

preterm birth for ’other reasons’ is uncertain, with the three ran-

domised trials that contributed data to the meta-analysis to date

indicating no benefit in terms of perinatal death or preterm birth

less than 37 weeks’ gestation. However, the combined sample size

of these trials is significantly underpowered to detect all but large

differences in these outcomes.

There is evidence that progesterone for women with a history of

previous preterm birth is associated with a reduction in preterm

birth before 34 and 37 weeks gestation. As indicated earlier, there

was considerable heterogeneity identified, in addition to evidence

of funnel plot asymmetry, raising concern about potential bias.

The observed reduction in perinatal mortality appears confined to

the use of intramuscular progesterone.

However, information relating to longer-term infant and child-

hood outcomes is currently insufficient, with only two randomised

trials reporting to date. Ongoing follow-up of children exposed

to progesterone in utero remains a priority. Maternal outcomes

following antenatal progesterone therapy were poorly reported in

the available literature, including treatment side-effects, prefer-

ences of mode of administration and satisfaction of care. Further

information is required on these important issues (Greene 2003;

Iams 2003). In addition, there remains uncertainty as to the op-

timal dose of progesterone to be administered, the optimal route

of administration, and the optimal gestational age at which to

commence therapy. The American College of Obstetricians and

Gynecologists have issued a committee opinion relating to the use

of progesterone for the prevention of preterm birth, indicating the

need for further information about the optimal mode of admin-

istration (ACOG 2003), including studies directly comparing the

relative efficacy of vaginal and intramuscular preparations.

Overall completeness and applicability of evidence

The majority of studies to date have reported short-term maternal

and infant outcomes, with only two studies reporting longer-term

childhood outcomes (Northen 2007; O’Brien 2007).

As outlined above, there are a number of ongoing studies which

will contribute to the evidence relating to the use of progesterone

for women considered at risk of preterm birth. The trials by

Crowther (Crowther 2007), Norman (Norman 2012), and Per-

litz (Perlitz 2007) will contribute data from women with a prior

preterm birth; van Os (van Os 2011) will contribute data from

women with a short cervix identified by ultrasound; Nassar (Nassar

2007), and Wood (Wood 2007) will contribute data from women

with a multiple pregnancy; and Martinez (Martinez 2007) will

contribute data from women who present with symptoms or signs

of threatened preterm labour.

Quality of the evidence

Overall, the trials included in this review were considered to be

of good to fair quality. Of the 36 included trials, adequate ran-

domisation methods were described in 23 (Borna 2008; Briery

21Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

2011; Caritis 2009; Cetingoz 2011; Combs 2010; Combs 2011;

Combs 2011a; da Fonseca 2003; Facchinetti 2007; Glover 2011;

Grobman 2012; Hassan 2011; Lim 2011; Majhi 2009; Meis 2003;

Norman 2009; O’Brien 2007; Rai 2009; Rode 2011; Rouse 2007;

Rozenberg 2012; Senat 2012; Serra 2013), allocation concealment

was assessed to be at low risk of bias in 23 (Aboulghar 2012;

Briery 2011; Caritis 2009; Cetingoz 2011; Combs 2010; Combs

2011; Combs 2011a; da Fonseca 2003; Fonseca 2007; Glover

2011; Grobman 2012; Hassan 2011; Johnson 1975; Lim 2011;

Majhi 2009; Meis 2003; Norman 2009; O’Brien 2007; Rai 2009;

Rode 2011; Rouse 2007; Senat 2012; Serra 2013), and blinding

was achieved with the use of a placebo agent in 25 (Aboulghar

2012; Briery 2011; Caritis 2009; Cetingoz 2011; Combs 2010;

Combs 2011; Combs 2011a; da Fonseca 2003; Fonseca 2007;

Glover 2011; Grobman 2012; Hartikainen 1980; Hassan 2011;

Hauth 1983; Johnson 1975; Lim 2011; Meis 2003; Norman 2009;

O’Brien 2007; Papiernik 1970; Rai 2009; Rode 2011; Rouse 2007;

Serra 2013; Sharami 2010).Twenty-one of the 36 included stud-

ies were assessed as being at low risk of bias for other potential

sources of bias (Borna 2008; Briery 2011; Caritis 2009; Combs

2010; Combs 2011; da Fonseca 2003; Facchinetti 2007; Fonseca

2007; Glover 2011; Hassan 2011; Hauth 1983; Johnson 1975;

Lim 2011; Meis 2003; Norman 2009; O’Brien 2007; Papiernik

1970; Rai 2009; Rode 2011; Saghafi 2011a; Sharami 2010).

We assessed whether studies that included multiple pregnancies

accounted appropriately for non-independence of babies from

the same pregnancy in the analysis. There were 14 studies that

included a multiple pregnancy (Aboulghar 2012; Caritis 2009;

Cetingoz 2011; Combs 2010; Combs 2011; Elsheikhah 2010;

Fonseca 2007; Hartikainen 1980; Lim 2011; Norman 2009;

Rode 2011; Rouse 2007; Senat 2012; Serra 2013) and in seven

studies adjustment appears to have been made in the analysis

(Caritis 2009; Combs 2010; Combs 2011; Fonseca 2007; Lim

2011; Norman 2009; Rode 2011). In the remaining seven studies

(Aboulghar 2012; Cetingoz 2011; Elsheikhah 2010; Hartikainen

1980; Rouse 2007; Senat 2012; Serra 2013), it is not clear that

any adjustment was made. There was not enough information in

the trial reports for us to carry out the necessary adjustments our-

selves in the analysis of neonatal outcomes. This information will

be sought for future updates.

Potential biases in the review process

The possibility of introducing bias was present at every stage of

the reviewing process. We attempted to minimise bias in a num-

ber of ways: two review authors assessed eligibility for inclusion,

carried out data extraction and assessed risk of bias. Each worked

independently. Nevertheless, the process of assessing risk of bias is

not an exact science and includes many personal judgements.

Agreements and disagreements with other studies or reviews

Despite the differences in methodology and included studies, our

findings of a reduction in preterm birth before 34 weeks’ and 28

weeks’ gestation for women with a short cervix identified on ul-

trasound examination, and a reduction in infant respiratory dis-

tress syndrome are consistent with those reported in an individ-

ual patient data meta-analysis by Romero and colleagues (Romero

2012). Similarly, the findings of a proposed individual patient data

meta-analysis for women with a multiple pregnancy are awaited

to evaluate if there are specific subgroups of women with a multi-

ple pregnancy who may receive benefit from progesterone therapy

(Schuit 2012).

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Summary of the available information

Progesterone for women with a past history of spontaneous

preterm birth

The use of progesterone in this group of women is associated with

a reduction in the risk of perinatal death, preterm birth before 34

weeks’ and 37 weeks’ gestation, infant birthweight less than 2500

g, use of assisted ventilation, necrotising enterocolitis, neonatal

death, admission to neonatal intensive care unit, and prolonga-

tion of pregnancy. There is limited information about longer-term

childhood health. In addition, further information is required as

to the optimal route of administration of progesterone, the op-

timal dose to be administered, and the best time to commence

therapy.

Progesterone for women with a short cervix identified on

ultrasound

The use of progesterone in this group of women is associated

with a reduction in the risk of preterm birth less than 34 and 28

weeks’ gestation, and a significant increase in the risk urticaria in

women receiving progesterone. Further information is required

about other maternal, infant and childhood health outcomes. Of

particular note, there are no comparative data reported on longer-

term childhood health from trials conducted to date. In addition,

further information is required as to the optimal route of adminis-

tration of progesterone, the optimal dose to be administered, and

the best time to commence therapy.

22Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Progesterone for women with a multiple pregnancy

The use of progesterone in this group of women is not associ-

ated with any statistically significant differences in perinatal death,

preterm birth and other maternal, infant, and childhood health

outcomes.

Progesterone for women following presentation with

threatened preterm labour

The use of progesterone in this group of women was associated

with a statistically significant reduction in the risk of infant birth-

weight less than 2500 g. However, for all other outcomes, the

role of progesterone for women presenting following symptoms

or signs of threatened preterm labour is uncertain.

Progesterone for women with ’other’ risk factors for

preterm birth

The use of progesterone in this group of women was associated

with a statistically significant reduction in the risk of infant birth-

weight less than 2500 g. However, for all other outcomes, the role

of progesterone in women considered to be at risk of preterm birth

for ’other reasons’ is uncertain.

Implications for research

Further well-designed randomised controlled trials are required

to assess the optimal timing, mode of administration and dose of

administration of progesterone when given to women considered

to be at increased risk of early birth, by virtue of previous history of

spontaneous preterm birth, short cervix identified by transvaginal

ultrasound, following arrest of symptoms or signs of threatened

preterm labour, or on the basis of ’other’ risk factors. Assessment

of longer-term infant and childhood outcomes remains a priority.

There are several randomised trials that are currently addressing

the use of progesterone for preterm birth which will contribute

data in the future - see Characteristics of ongoing studies for details.

A C K N O W L E D G E M E N T S

We thank Lynn Hampson for searching the trials register.

We would like to thank Gabriella Behzadi for the translation of

the paper by Akbari 2009 et al.

We would like to thank Therese Dowswell, Research Associate in

the Cochrane Pregnancy and Childbirth Group, for her support

and advice with the update in 2013.

As part of the pre-publication editorial process, this review has

been commented on by six peers (an editor and five referees who

are external to the editorial team), a member of the Pregnancy

and Childbirth Group’s international panel of consumers and the

Group’s Statistical Adviser.

The National Institute for Health Research (NIHR) is the largest

single funder of the Cochrane Pregnancy and Childbirth Group.

The views and opinions expressed therein are those of the authors

and do not necessarily reflect those of the NIHR, NHS or the

Department of Health.

R E F E R E N C E S

References to studies included in this review

Aboulghar 2012 {published data only}

Aboulghar MM, Aboulghar MA, Amin YM, Al-Inany

HG, Mansour RT, Serour GI. The use of vaginal natural

progesterone for prevention of preterm birth in IVF/ICSI

pregnancies. Reproductive BioMedicine Online 2012;25(2):

133–8.

Akbari 2009 {published data only}

Akbari S, Birjandi M, Mohtasham N. Evaluation of the

effect of progesterone on prevention of preterm delivery and

its complications. Scientific Journal of Kurdistan University

of Medical Sciences 2009;14(3):11–9.

Borna 2008 {published data only} ∗ Borna S, Sahabi N. Progesterone for maintenance tocolytic

therapy after threatened preterm labour: a randomised

controlled trial. Australian and New Zealand Journal of

Obstetrics and Gynaecology 2008;48(1):58–63.

Borna S, Shakoie S, Borna H. Progesterone for maintenance

tocolytic therapy after threatened preterm labor.

Randomized controlled trial. Journal of Maternal-Fetal and

Neonatal Medicine 2008; Vol. 21, issue Suppl 1:151–2.

Briery 2011 {published data only}

Briery C, Veillon E, Klauser CK, Martin R, Chauhan S,

Magann EF, et al. Women with prolonged premature

rupture of the membrane do not benefit from weekly

progesterone: a randomized clinical trial. American Journal

of Obstetrics and Gynecology 2009;201(6 Suppl 1):S189.

Briery CM, Veillon EW, Klauser CK, Martin RW, Chauhan

SP, Magann EF, et al. Progesterone does not prevent preterm

births in women with twins. Southern Medical Journal

2009;102(9):900–4. ∗ Briery CM, Veillon EW, Klauser CK, Martin RW, Magann

EF, Chauhan SP, et al. Women with preterm premature

rupture of the membranes do not benefit from weekly

progesterone. American Journal of Obstetrics and Gynecology

2011;204(1):54.e1–5.

Caritis 2009 {published data only}

Caritis SN, Rouse DJ, Peaceman AM, Sciscione A,

23Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Momirova V, Spong CY, et al. Prevention of preterm birth

in triplets using 17 alpha-hydroxyprogesterone caproate: a

randomized controlled trial. Obstetrics & Gynecology 2009;

113(2 Pt 1):285–92.

Cetingoz 2011 {published data only}

Cetingoz E, Cam C, Sakalli M, Karateke A, Celik C,

Sancak A. Progesterone effects on preterm birth in high-

risk pregnancies: a randomized placebo-controlled trial.

Archives of Gynecology and Obstetrics 2011;283(3):423–9.

Combs 2010 {published data only} ∗ Combs CA, Garite T, Maurel K, Das A, Porto M, for

the OCRN. Failure of 17-hydroxyprogesterone to reduce

neonatal morbidity or prolong triplet pregnancy: a double-

blind, randomized clinical trial. American Journal of

Obstetrics and Gynecology 2010;203(3):248.e1–9.

Combs CA, Garite T, Porto M, Maurel K, for the OCRN.

17-hydroxyprogesterone for triplet pregnancy does not

reduce prematurity or neonatal morbidity, may increase

midtrimester loss. American Journal of Obstetrics and

Gynecology 2009;201(6 Suppl 1):S168.

Heitmann E, Lu G, Combs CA, Garite TJ, Maurel K.

The impact of maternal weight upon the effectiveness

of 17-hydroxyprogesterone in preventing preterm birth

among twin gestations. American Journal of Obstetrics and

Gynecology 2012;206(Suppl 1):S98.

Maurel K, Combs A. 17OHP for reduction of neonatal

morbidity due to preterm birth (PTB) in twin and triplet

pregnancies. http://controlledtrials.com (accessed 2007).

Combs 2011 {published data only} ∗ Combs CA, Garite T, Maurel K, Das A, Porto M, for

theOCRN. 17-hydroxyprogesterone caproate for twin

pregnancy: a double-blind, randomized clinical trial.

American Journal of Obstetrics and Gynecology 2011;204:

221.e1–8.

Combs CA, Garite TJ, Maurel K, Cebrik D. 17-

hydroxyprogesterone caproate for women with history of

preterm birth in a prior pregnancy and twins in the current

pregnancy. American Journal of Obstetrics and Gynecology

2012;206(Suppl 1):S213.

Combs CA, Maurel K, Garite T, for theOCRN. 17-

hydroxyprogesterone for twin pregnancy: no reduction in

prematurity or neonatal morbidity. American Journal of

Obstetrics and Gynecology 2011;204(1 Suppl 1):S7.

Maurel K, Combs A. 17OHP for reduction of neonatal

morbidity due to preterm birth (PTB) in twin and triplet

pregnancies. http://controlledtrials.com (accessed 2007).

Combs 2011a {published data only}

Combs CA, Garite TJ, Maurel K, Mallory K, Edwards RK,

Lu G, et al. 17-Hydroxyprogesterone caproate to prolong

pregnancy after preterm rupture of the membranes: early

termination of a double-blind, randomized clinical trial.

BMC Research Notes 2011;4(1):568.

da Fonseca 2003 {published data only} ∗ da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M.

Prophylactic administration of progesterone by vaginal

suppository to reduce the incidence of spontaneous

preterm birth in women at increased risk: a randomized

placebo-controlled double-blind study. American Journal of

Obstetrics & Gynecology 2003;188(2):419–24.

da Fonseca EB, Bittar RE, Carvalho MHB, Martinelli S,

Zugaib M. Uterine contraction monitoring in pregnant

women using vaginal natural progesterone. Journal of

Perinatal Medicine 2001;29 Suppl 1(Pt 2):525.

Elsheikhah 2010 {published data only}

Elsheikhah AZ, Dahab S, Negm S, Ebrashy A. Effect of

prophylactic progesterone on incidence of preterm labour in

spontaneous twin pregnancy, randomized controlled study.

Ultrasound in Obstetrics and Gynecology 2010;36(Suppl 1):

108.

Facchinetti 2007 {published data only}

Facchinetti F, Dante G, Venturini P, Paganelli S, Volpe

A. 17alpha-hydroxy-progesterone effects on cervical

proinflammatory agents in women at risk for preterm

delivery. American Journal of Perinatology 2008;25(8):

503–6. ∗ Facchinetti F, Paganelli S, Comitinit G, Dante G,

Volpe A. Cervical length changes during preterm cervical

ripening: effects of 17-alpha-hydroxyprogesterone caproate.

American Journal of Obstetrics and Gynecology 2007;196:

453e1–453e4.

Facchinetti F, Paganelli S, Venturini P, Dante G. 17

alpha hydroxy-progesterone caproate (17P) treatment

reduced cervical shortening inhibiting cervical interleukin-

1 secretion. American Journal of Obstetrics and Gynecology

2006;195(6 Suppl 1):S5.

Fonseca 2007 {published data only}

Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH.

Progesterone and the risk of preterm birth among women

with a short cervix. New England Journal of Medicine 2007;

357:462–9.

Glover 2011 {published data only}

Glover M, Croom CS, Sonek JD, Kovac C, McKenna D.

A randomized placebo controlled trial of oral micronized

progesterone to prevent recurrent preterm birth. American

Journal of Obstetrics and Gynecology 2009;201(6 Suppl 1):

S172. ∗ Glover MM, McKenna DS, Downing CM, Smith DB,

Croom CS, Sonek JD. A randomized trial of micronized

progesterone for the prevention of recurrent preterm birth.

American Journal of Perinatology 2011;28(5):377–81.

Grobman 2012 {published data only}

Grobman W. RCT of progesterone to prevent preterm

birth in nulliparous women with a short cervix. http://

controlledtrials.com (accessed 2007).

Grobman W. Randomized controlled trial of progesterone

treatment for preterm birth prevention in nulliparous

women with cervical length less than 30 mm. American

Journal of Obstetrics and Gynecology 2012;206(Suppl 1):

S367. ∗ Grobman WA, Thom EA, Spong CY, Iams JD, Saade GR,

Mercer BM, et al. 17 alpha-hydroxyprogesterone caproate

to prevent prematurity in nulliparas with cervical length less

24Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

than 30 mm. American Journal of Obstetrics and Gynecology

2012;207(5):390.e1–8.

Hartikainen 1980 {published data only} ∗ Hartikainen-Sorri AL, Kauppila A, Tuimala R. Inefficacy

of 17 alpha-hydroxyprogesterone caproate in the prevention

of prematurity in twin pregnancy. Obstetrics & Gynecology

1980;56(6):692–5.

Hartikainen-Sorri AL, Kauppila A, Tuimala R. Management

of twin pregnancy with 17 alpha- hydroxyprogesterone

caproate [abstract]. 9th World Congress of Gynecology

and Obstetrics 1979 October 26-31; Tokyo, Japan. 1979:

298–9.

Hassan 2011 {published data only}

Hassan SS, Romero R, Vidyadhari D, Fusey S, Baxter JK,

Khandelwal M, et al. Vaginal progesterone reduces the

rate of preterm birth in women with a sonographic short

cervix: a multicenter, randomized, double-blind, placebo-

controlled trial. Ultrasound in Obstetrics & Gynecology 2011;

38(1):18–31.

Hauth 1983 {published data only}

Hauth JC, Gilstrap LC, Brekken AL, Hauth JM. The effect

of 17 alpha-hydroxyprogesterone caproate on pregnancy

outcome in an active-duty military population. American

Journal of Obstetrics and Gynecology 1983;146(2):187–90.

Ibrahim 2010 {published data only}

Ibrahim M, Mohamed Ramy AR, Younis MA-F.

Progesterone supplementation for prevention of preterm

labor: a randomized controlled trial. Middle East Fertility

Society Journal 2010;15(1):39–41.

Johnson 1975 {published data only} ∗ Johnson JWC, Austin KL, Jones GS, Davis GH, King

TM. Efficacy of 17 alpha-hydroxyprogesterone caproate in

the prevention of premature labor. New England Journal of

Medicine 1975;293(14):675–80.

Klebanoff M, for the NICHD MFMU Network. Impact

of 17alpha hydroxyprogesterone caproate administration

on salivary progesterone and estriol [abstract]. American

Journal of Obstetrics and Gynecology 2006;195(6 Suppl 1):

S140.

Lim 2011 {published data only}

Bruinse HW. 17 alpha hydroxyprogesterone in multiple

pregnancies to prevent handicapped infants (The AMPHIA

Study). http://www.controlledtrials.com (accessed 2007).

Lim AC. The effect of 17-alpha hydroxyprogesterone

caproate on cervical length in multiple pregnancies.

Reproductive Sciences 2010;17(3 Suppl 1):282A.

Lim AC, Bloemenkamp KW, Boer K, Duvekot JJ, Erwich

JJ, Hasaart TH, et al. Progesterone for the prevention of

preterm birth in women with multiple pregnancies: the

AMPHIA trial. BMC Pregnancy & Childbirth 2007; Vol.

7:7. ∗ Lim AC, Schuit E, Bloemenkamp K, Bernardus RE,

Duvekot JJ, Erwich JJ, et al. 17alpha-hydroxyprogesterone

caproate for the prevention of adverse neonatal outcome

in multiple pregnancies: A randomized controlled trial.

Obstetrics and Gynecology 2011;118(3):513–20.

Lim AC, for the ASG. Is second trimester cervical length

a predictor for an effect of 17-alpha hydroxyprogesterone

caproate on neonatal morbidity in multiple pregnancies?

Results from the AMPHIA trial (ISRCTN40512715).

Reproductive Sciences 2010;17(3 Suppl 1):282A.

Willekes C, Lim A, Vijgen S, Mol B, Papatsonis D, Hasaart

T, et al. Mid-pregnancy cervical length as a predictor of

preterm birth in multiple pregnancies. American Journal of

Obstetrics and Gynecology 2011;204(1 Suppl 1):S54.

Majhi 2009 {published data only}

Majhi P, Bagga R, Kalra J, Sharma M. Intravaginal use

of natural micronised progesterone to prevent pre-term

birth: a randomised trial in India. Journal of Obstetrics and

Gynaecology 2009;29(6):493–8.

Meis 2003 {published data only}

Gyamfi C, Horton AL, Momirova V, Rouse DJ, Caritis

SN, Peaceman AM, et al. The effect of 17-alpha

hydroxyprogesterone caproate on the risk of gestational

diabetes in singleton or twin pregnancies. American Journal

of Obstetrics and Gynecology 2009;201(4):392.e1–5.

Klebanoff MA, Meis PJ, Dombrowski MP, Zhao Y,

Moawad AH, Northen A, et al. Salivary progesterone and

estriol among pregnant women treated with 17-alpha-

hydroxyprogesterone caproate or placebo. American Journal

of Obstetrics and Gynecology 2008;199(5):506.e1–7.

Koontz G. Does gestational age at randomization affect the

efficacy of alpha hydroxyprogesterone caproate (17-OHCP)

in preventing recurrent preterm delivery? [abstract].

American Journal of Obstetrics and Gynecology 2005;193(6

Suppl 1):S55.

Manuck TA, Lai Y, Meis PJ, Dombrowski MP, Sibai B,

Spong CY, et al. Progesterone receptor polymorphisms and

clinical response to 17-alpha-hydroxyprogesterone caproate.

American Journal of Obstetrics & Gynecology 2011;205(2):

135.e1–9.

Meis P, NICHD MFMU Network. More than one previous

preterm delivery and the risk of preterm birth in women

treated with 17 alpha-hydroxyprogesterone (17P) [abstract].

American Journal of Obstetrics and Gynecology 2003;189(6):

S168.

Meis PJ, Klebanoff M, Dombrowski MP, Sibai BM,

Leindecker S, Moawad AH, et al. Does progesterone

treatment influence risk factors for recurrent preterm

delivery?. Obstetrics & Gynecology 2005;106(3):557–61. ∗ Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai

B, Moawad AH, et al. Prevention of recurrent preterm

delivery by 17 alpha-hydroxyprogesterone caproate. New

England Journal of Medicine 2003;348(24):2379–85.

Meis PJ, NICHD MFMU Network. 17

alphahydroxyprogesterone caproate prevents recurrent

preterm birth [abstract]. American Journal of Obstetrics and

Gynecology 2002;187(6 Pt 2):S54.

Northen A. 4-year follow-up of children exposed to 17alpha

hydroxyprogesterone caproate (17P) in utero. American

25Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Journal of Obstetrics and Gynecology 2006;195(6 Suppl 1):

S6.

Northen AT, Norman GS, Anderson K, Moseley, L, Divito

M, Cotroneo M, et al. Follow-up of children exposed in

utero to 17 alpha-hydroxyprogesterone caproate compared

with placebo. Obstetrics & Gynecology 2007;110(4):864–72.

Sibai B. Plasma CRH levels at 16-20 weeks do not predict

preterm delivery in women at high-risk for preterm delivery

[abstract]. American Journal of Obstetrics and Gynecology

2004;191(6 Suppl 1):S114.

Sibai B, Meis PJ, Klebanoff M, Dombrowski MP, Weiner

SJ, Moawad AH, et al. Plasma CRH measurement at 16

to 20 weeks’ gestation does not predict preterm delivery in

women at high-risk for preterm delivery. American Journal

of Obstetrics and Gynecology 2005;193(3 Pt 2):1181–6.

Spong CY. Progesterone for prevention of recurrent preterm

birth: impact of gestational age at prior delivery [abstract].

American Journal of Obstetrics and Gynecology 2004;191(6

Suppl 1):S11.

Spong CY, Meis PJ, Thom EA, Sibai B, Dombrowski MP,

Moawad AH, et al. Progesterone for prevention of recurrent

preterm birth: impact of gestational age at previous delivery.

American Journal of Obstetrics and Gynecology 2005;193(3

Pt 2):1127–31.

Moghtadaei 2008 {published data only}

Moghtadaei P, Sardari F, Latifi M. Progesterone for

prevention of preterm birth and improvement in pregnancy

outcomes among primiparae of advanced maternal age.

Archives of Disease in Childhood. Fetal and Neonatal

Edition 2008; Vol. 93, issue Suppl 1:Fa71.

Moghtadei P, Sardari F, Latifi M. Progesterone for

prevention of preterm birth and improvement pregnancy

outcomes among primiparae of advanced maternal age.

Journal of Maternal-Fetal and Neonatal Medicine 2008;

Vol. 21, issue Suppl 1:122.

Ndoni 2010 {published data only}

Ndoni E, Bimbashi A, Dokle A, Kallfa E. Treatment with

different types of progesterone in prevention of preterm

delivery. Journal of Maternal-Fetal and Neonatal Medicine

2010;23(S1):305.

Norman 2009 {published data only}

Eddama O, Petrou S, Regier D, Norrie J, MacLennan G,

MacKenzie F, et al. Study of progesterone for the prevention

of preterm birth in twins (STOPPIT): findings from a trial-

based cost-effectiveness analysis. International Journal of

Technology Assessment in Health Care 2010;26(2):141–8.

Norman J. Double blind randomised placebo controlled

trial of progesterone for the prevention of preterm birth.

http://controlledtrials.com (accessed 2007). ∗ Norman JE, Mackenzie F, Owen P, Mactier H, Hanretty

K, Cooper S, et al. Progesterone for the prevention of

preterm birth in twin pregnancy (STOPPIT): a randomised,

double-blind, placebo-controlled study and meta-analysis.

Lancet 2009;373(9680):2034–40.

Norman JE, Yuan M, Anderson L, Howie F, Harold G,

Young A, et al. Effect of prolonged in vivo administration of

progesterone in pregnancy on myometrial gene expression,

peripheral blood leukocyte activation, and circulating

steroid hormone levels. Reproductive Sciences 2011;18(5):

435–46.

O’Brien 2007 {published data only}

DeFranco EA, O’Brien JM, Adair CD, Lewis DF, Hall

DR, Fusey S, et al. Vaginal progesterone is associated with

a decrease in risk for early preterm birth and improved

neonatal outcome in women with a short cervix: a

secondary analysis from a randomized, double-blind,

placebo-controlled trial. Ultrasound in Obstetrics and

Gynecology 2007; Vol. 30, issue 5:697–705.

Defranco E, O’Brien J, Adair J, Lewis DF, Hall D, Phillips

J, et al. Is there a racial disparity of progesterone to

prevent preterm birth. American Journal of Obstetrics and

Gynecology 2007; Vol. 197, issue 6 Suppl 1:S200, Abstract

no: 702.

O’Brien J, Defranco E, Adair D, Lewis DF, Hall D, Bsharat

M, et al. Progesterone reduces the rate of cervical shortening

in women at risk for preterm birth: secondary analysis

from a randomized, double-blind, placebo-controlled trial.

American Journal of Obstetrics and Gynecology 2007; Vol.

197, issue 6 Suppl 1:S7, Abstract no: 15.

O’Brien J, Defranco E, Hall D, Creasy G. Natural

progesterone administration and the risk of medical

complications of pregnancy: secondary analysis from

a multinational, randomized, double blind, placebo-

controlled trial. American Journal of Obstetrics and

Gynecology 2008; Vol. 199, issue 6 Suppl 1:S139.

O’Brien J, Defranco E, Hall D, Phillips J, Creasy G. Do

other elements of the obstetrical history provide a possible

indication for progesterone supplementation? Secondary

analysis from the progesterone vaginal gel trial. American

Journal of Obstetrics and Gynecology 2008; Vol. 199, issue

6 Suppl 1:S42. ∗ O’Brien JM, Adair CD, Lewis DF, Hall DR, Defranco EA,

Fusey S, et al. Progesterone vaginal gel for the reduction of

recurrent preterm birth: primary results from a randomized

double blind placebo controlled trial. Ultrasound in

Obstetrics and Gynecology 2007;30(5):687–96.

O’Brien JM, Defranco EA, Adair CD, Lewis DF, Hall DR,

How H, et al. Effect of progesterone on cervical shortening

in women at risk for preterm birth: secondary analysis

from a multinational, randomized, double-blind, placebo-

controlled trial. Ultrasound in Obstetrics & Gynecology 2010;

34(6):653–9.

O’Brien JM, Steichen JJ, Phillips JA, Creasy GW. Two

year infant outcomes for children exposed to supplemental

intravaginal progesterone gel in utero: secondary analysis

of a multicenter, randomized, double-blind, placebo-

controlled trial. American Journal of Obstetrics and

Gynecology 2012;206(Suppl 1):S223.

Papiernik 1970 {published data only}

Papiernik-Berkhauer E. Double blind study of an agent to

prevent preterm delivery among women at increased risk

[Etude en double aveugle d’un medicament prevenant la

survenue prematuree de l’accouchement chez les femmes a

26Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

risque eleve d’accouchement premature]. Edition Schering

Serie IV 1970; Vol. 3:65–8.

Rai 2009 {published data only}

Rai P, Rajaram S, Goel N, Ayalur Gopalakrishnan R,

Agarwal R, Mehta S. Oral micronized progesterone for

prevention of preterm birth. International Journal of

Gynecology & Obstetrics 2009;104(1):40–3.

Rode 2011 {published data only}

Klein K, Rode L, Nicolaides K, Krampl-Bettelheim E,

Larsen H, Holmskov A, et al. Vaginal progesterone and

the risk of preterm delivery in high-risk twin gestations -

secondary analysis of a placebo-controlled randomized trial.

Ultrasound in Obstetrics & Gynecology 2011;38(S1):11. ∗ Klein K, Rode L, Nicolaides KH, Krampl-Bettelheim

E, Tabor A, PREDICT Group. Vaginal micronized

progesterone and risk of preterm delivery in high-risk twin

pregnancies: secondary analysis of a placebo-controlled

randomized trial and meta-analysis. Ultrasound in Obstetrics

& Gynecology 2011;38(3):281–7.

Rode L. The PREDICT study. http://controlledtrials.com

(accessed 2007).

Rode L, Klein K, Nicolaides K, Krampl-Bettelheim E,

Vogel I, Larsen H, et al. Prevention of preterm delivery

in twin gestations (PREDICT): a multicentre randomised

placebo-controlled trial on the effect of vaginal micronised

progesterone. Ultrasound in Obstetrics & Gynecology 2011;

38(Suppl 1):1.

Rode L, Klein K, Nicolaides KH, Krampl-Bettelheim E,

Tabor A, PREDICT G. Prevention of preterm delivery in

twin gestations (PREDICT): a multicenter, randomized,

placebo-controlled trial on the effect of vaginal micronized

progesterone. Ultrasound in Obstetrics & Gynecology 2011;

38(3):272–80.

Rouse 2007 {published data only}

Caritis S, Rouse D. A randomized controlled trial of

17-hydroxyprogesterone caproate (17-OHPC) for the

prevention of preterm birth in twins. American Journal of

Obstetrics and Gynecology 2006;195(6 Suppl 1):S2.

Caritis SN, Simhan H. Relationship of 17-alpha

hydroxyprogesterone caproate (17-OHPC) concentrations

and gestational age at delivery in twins. 55th Annual

Meeting of the Society of Gynecologic Investigation; 2008

March 26-29; San Diego, USA 2008:Abstract no: 139.

Caritis SN, Simhan HN, Zhao Y, Rouse DJ, Peaceman

AM, Sciscione A, et al. Relationship between 17-

hydroxyprogesterone caproate concentrations and

gestational age at delivery in twin gestation. American

Journal of Obstetrics and Gynecology 2012;207(5):396.e1–8.

Caritis SN, Venkat R. Impact of body mass index (BMI)

on plasma concentrations of 17-alpha hydroxyprogesterone

caproate (17-OHPC). 55th Annual Meeting of the Society

of Gynecologic Investigation; 2008 March 26-29; San

Diego, USA 2008:Abstract no: 138.

Durnwald C. The impact of cervical length on risk of

preterm birth in twin gestations. American Journal of

Obstetrics and Gynecology 2008; Vol. 199, issue 6 Suppl 1:

S10.

Durnwald CP, Momirova V, Rouse DJ, Caritis SN,

Peaceman AM, Sciscione A, et al. Second trimester cervical

length and risk of preterm birth in women with twin

gestations treated with 17- hydroxyprogesterone caproate.

Journal of Maternal-Fetal and Neonatal Medicine 2010;23

(12):1360–4.

Gyamfi C, Horton AL, Momirova V, Rouse DJ, Caritis

SN, Peaceman AM, et al. The effect of 17-alpha

hydroxyprogesterone caproate on the risk of gestational

diabetes in singleton or twin pregnancies. American Journal

of Obstetrics and Gynecology 2009;201(4):392.e1–5.

Horton A, Gyamfi C. 17-alpha hydroxyprogesterone

caproate does not increase the risk of gestational diabetes

in singleton and twin pregnancies. American Journal of

Obstetrics and Gynecology 2008; Vol. 199, issue 6 Suppl 1:

S197.

Manuck T, for the Eunice Kennedy Shriver National

Institute of Child Health and Human Development

(NICHD). The relationship between polymorphisms in the

human progesterone receptor and clinical response to 17

alpha-hydroxyprogesterone caproate for the prevention of

recurrent spontaneous preterm birth. American Journal of

Obstetrics and Gynecology 2008; Vol. 199, issue 6 Suppl 1:

S18.

Refuerzo JS, Momirova V, Peaceman AM, Sciscione A,

Rouse DJ, Caritis SN, et al. Neonatal outcomes in twin

pregnancies delivered moderately preterm, late preterm, and

term. American Journal of Perinatology 2010;27(7):537–42. ∗ Rouse DJ, Caritis SN, Peaceman AM, Sciscione

A, Thom EA, Spong CY, et al. A trial of 17 Alpha-

hydroxyprogesterone caproate to prevent prematurity in

twins. New England Journal of Medicine 2007;357:454–61.

Simhan HN, Caritis SN. The effect of 17-alpha

hydroxyprogesterone caproate (17-OHPC) on maternal

plasma CRP levels in twin pregnancies. 55th Annual

Meeting of the Society of Gynecologic Investigation; 2008

March 26-29; San Diego, USA 2008:Abstract no: 140.

Rozenberg 2012 {published data only}

Rozenberg P. Efficacy of 17 alpha-hydroxyprogesterone

caproate for the prevention of preterm delivery. http://

controlledtrials.com (accessed 2007). ∗ Rozenberg P, Chauveaud A, Deruelle P, Capelle M, Winer

N, Desbriere R, et al. Prevention of preterm delivery

after successful tocolysis in preterm labor by 17 alpha-

hydroxyprogesterone caproate: a randomized controlled

trial. American Journal of Obstetrics & Gynecology 2012;206

(3):206.e1–9.

Rozenberg P, Deruelle P, Chauveaud A, Capelle M, Winer

N, Porcher R, et al. Prevention of preterm delivery

after successful tocolysis in preterm labour by 17 alpha-

hydroxyprogesterone caproate: a randomised controlled

trial. American Journal of Obstetrics and Gynecology 2012;

206(Suppl 1):S2–S3.

Saghafi 2011a {published data only}

Saghafi N, Khadem N, Mohajeri T, Shakeri MT. Efficacy

27Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

of 17alpha-hydroxyprogesterone caproate in prevention

of preterm delivery. Journal of Obstetrics and Gynaecology

Research 2011;37(10):1342–5. ∗ Saghafi N, Khadem N, Mohajeri T, Shakeri MT, Amini

M. Efficacy of 17alpha-hydroxyprogesterone caproate in

preterm delivery prevention. Iranian Journal of Obstetrics,

Gynecology and Infertility 2011;14(2):28–33.

Senat 2012 {published data only}

Senat MV, Winer N, Porcher R, Rozenberg P. Prevention

of preterm delivery in asymptomatic women with twin

pregnancy by 17 alpha-Hydroxyprogesterone caproate: A

randomised controlled trial. Journal of Maternal-Fetal and

Neonatal Medicine 2012;25(S2):14.

Serra 2013 {published data only}

Serra V. Natural progesterone and preterm birth in twins.

http://controlledtrials.com (accessed 2007).

Serra V, Perales A, Meseguer J, Parrilla J, Lara C, Bellver

J, et al. Increased doses of vaginal progesterone for

the prevention of preterm birth in twin pregnancies: a

randomised controlled double-blind multicentre trial.

BJOG: an international journal of obstetrics and gynaecology

2013;120(1):50–7.

Sharami 2010 {published data only}

Sharami SH, Zahiri Z, Shakiba M, Milani F. Maintenance

therapy by vaginal progesterone after threatened idiopathic

preterm labor: a randomized placebo-controlled double-

blind trial. International Journal of Fertility and Sterility

2010;4(2):45–50.

References to studies excluded from this review

Abbott 2012 {published data only}

Abbott D. Relationship between cervical-vaginal fluid

elafin concentrations and subsequent cervical shortening

in women at high risk of spontaneous preterm birth.

Reproductive Sciences 2012;19(3Suppl):73A.

Arikan 2011 {published data only}

Arikan I, Barut A, Harma M, Harma IM. Effect of

progesterone as a tocolytic and in maintenance therapy

during preterm labor. Gynecologic and Obstetric Investigation

2011;72(4):269–73.

Berghella 2010 {published data only}

Berghella V, Figueroa D, Szychowski JM, Owen J, Hankins

GD, Iams JD, et al. 17-alpha-hydroxyprogesterone caproate

for the prevention of preterm birth in women with prior

preterm birth and a short cervical length. American Journal

of Obstetrics and Gynecology 2010;202(4):351.e1–6.

Breart 1979 {published data only}

Breart G, Lanfranchi M, Chavigny C, Rumeau-Rouquette

C, Sureau C. A comparative study of the efficiency of

hydroxyprogesterone caproate and of chlormadinone acetate

in the prevention of premature labor. International Journal

of Gynecology & Obstetrics 1979;16(5):381–4.

Brenner 1962 {published data only}

Brenner WE, Hendricks CH. Effect of medroxyprogesterone

acetate upon the duration and characteristics of human

gestation and labor. American Journal of Obstetrics and

Gynecology 1962;83:1094–8.

Chandiramani 2012 {published data only}

Chandiramani M. Serum progesterone concentrations in

women with a previous preterm birth treated with vaginal

progesterone supplementation. Reproductive Sciences 2012;

19(3Suppl):189A.

Corrado 2002 {published data only}

Corrado F, Dugo C, Cannata M, Di Bartolo M, Scilipoti

A, Stella N. A randomised trial of progesterone prophylaxis

after midtrimester amniocentesis. European Journal of

Obstetrics & Gynecology and Reproductive Biology 2002;100

(2):196–8.

Hobel 1986 {published data only} ∗ Hobel CJ, Bemis RL. West Area Los Angeles prematurity

prevention demonstration project. In: Papiernik E, Breart

G, Spira N editor(s). Prevention of Preterm Birth. Paris:

INSERM, 1986:205–22.

Hobel CJ, Bragonier R, Ross M, Bear M, Bemis R, Mori

B. West Los Angeles premature prevention program:

significant impact. Journal of Perinatal Medicine 1987;15:

112.

Hobel CJ, Ross MG, Bemis RL, Bragonier JR, Bear M,

Mori B. West Los Angeles preterm birth prevention project

(LAPPP): program impact. American Journal of Obstetrics

and Gynecology 1992;166:363.

Hobel CJ, Ross MG, Bemis RL, Bragonier JR, Nessim S,

Sandhu M, et al. The West Los Angeles preterm birth

prevention project: I. program impact on high-risk women.

American Journal of Obstetrics and Gynecology 1994;170:

54–62.

Ionescu 2012 {published data only}

Ionescu AC, Gheorghiu D, Pacu I, Davitoiu B, Dimitriu M,

Haradja H. Randomized trial of cerclage and progesterone

to prevent spontaneous preterm brith in high-risk women

with a short cervix. Journal of Perinatal Medicine 2012;39

Suppl:Abstract no. 008.

Keeler 2009 {published data only}

Keeler SM, Kiefer D, Rochon M, Quinones JN, Novetsky

AP, Rust O. A randomized trial of cerclage vs. 17 alpha-

hydroxyprogesterone caproate for treatment of short cervix.

Journal of Perinatal Medicine 2009;37(5):473–9.

Le Vine 1964 {published data only}

Le Vine L. Habitual abortion. A controlled clinical study of

progestational therapy. Western Journal of Surgical Obstetrics

and Gynecology 1964;72:30–6.

Rust 2006 {published data only}

Rust O, Larkin R, Roberts W, Quinones J, Rochon M,

Reed J, et al. A randomized trial of cerclage versus 17

hydroxyprogesterone for the treatment of short cervix.

American Journal of Obstetrics and Gynecology 2006;195(6

Suppl 1):S112.

Suvonnakote 1986 {published data only}

Suvonnakote T. Prevention of preterm labour with

progesterone. Journal of the Medical Association of Thailand

1986;69(10):538–42.

28Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Turner 1966 {published data only}

Turner SJ, Mizock GB, Feldman GL. Prolonged gynecologic

and endocrine manifestations subsequent to administration

of medroxyprogesterone acetate during pregnancy. American

Journal of Obstetrics and Gynecology 1966;95(2):222–7.

Walch 2005 {published data only}

Walch K, Hefler L, Nagele F. Oral dydrogesterone treatment

during the first trimester of pregnancy: the prevention of

miscarriage study. A double blind, prospectively randomised

placebo controlled parallel group trial. Journal of Maternal-

Fetal and Neonatal Medicine 2005;18(4):265–9.

Yemini 1985 {published data only}

Yemini M, Borenstein R, Dreazen E, Apelman Z, Mogilner

B, Kessler I, et al. Prevention of premature labor by 17

alpha-hydroxyprogesterone caproate. American Journal of

Obstetrics and Gynecology 1985;151(5):574–7.

References to ongoing studies

Coomarasamy 2012 {published data only}

Coomarasamy A. First trimester progesterone therapy

in women with a history of unexplained recurrent

miscarriages: a randomised double-blind placebo-controlled

multi-centre trial (The PROMISE [PROgesterone in

recurrent MIScarriagE] Trial). http://www.controlled-

trials.com/ISRCTN92644181/ISRCTN92644181

(accessed 11.01.2012).

Creasy 2008 {published data only}

Creasy GW. The effect of vaginal progesterone

administration in the prevention of preterm birth in

women with a short cervix. ClinicalTrials.gov (http://

clinicaltrials.gov/) (accessed 2008).

Crowther 2007 {published data only}

Armson BA, Dodd J, for the POPPI Collaborative Trial

Group. POPPI: prevention of problems of preterm birth

with progesterone in women at increased risk: a multicentre

randomised controlled trial [abstract]. Journal of Paediatrics

and Child Health 2007;43:A29.

Ashwood P. Progesterone after previous preterm birth for

the prevention of neonatal respiratory distress syndrome.

WOMBAT Collaboration (www.wombatcollaboration.net/

trials) (accessed 4 October 2006).

Crowther CA, Dodd JM, McPhee AJ, Flenady

V. Australasian Collaborative Trial of Vaginal

Progesterone Therapy (The PROGRESS Trial). http://

controlledtrials.com (accessed 2007). ∗ Dodd JM, Crowther CA, McPhee AJ, Flenady V,

Robinson JS. Progesterone after previous preterm birth

for prevention of neonatal respiratory distress syndrome

(PROGRESS): a randomised controlled trial. BMC

Pregnancy and Childbirth 2009;9:6.

Martinez 2007 {published data only}

Matrinez de Tajada B. Vaginal progesterone to prevent

preterm delivery in women with preterm labor. http://

controlledtrials.com (accessed 2007).

Nassar 2007 {published data only}

Nassar A. Prevention of preterm delivery in twin pregnancies

by 17 alpha hydroxyprogesterone caproate. http://

controlledtrials.com (accessed 2007). ∗ Nassar A, Awwad J, Succar J, Saassouh W, Khalife T,

Hayek S, et al. Incidence of GDM in twin pregnancies

of women receiving prophylactic 17-A OH progesterone

caproate. Journal of Maternal-Fetal and Neonatal Medicine

2010;23(S1):307–8.

Norman 2012 {published data only}

Norman JE, Shennan A, Bennett P, Thornton S, Robson

S, Marlow N, et al. Trial protocol OPPTIMUM- Does

progesterone prophylaxis for the prevention of preterm

labour improve outcome?. BMC pregnancy and childbirth

2012;12(1):79. [PUBMED: 22866909]

Perlitz 2007 {published data only}

Perlitz Y. Prevention of recurrent preterm delivery by a

natural progesterone agent. http://controlledtrials.com

(accessed 2007).

Starkey 2008 {published data only}

Starkey M. Comparing IM vs. vaginal progesterone for pre-

term birth. ClinicalTrials.gov (http://clinicaltrials.gov/)

(accessed 20 April 2008).

Swaby 2007 {published data only}

Swaby C. Pilot randomized controlled trial of vaginal

progesterone to prevent preterm birth in multiple pregnancy.

JOGC: Journal of Obstetrics and Gynaecology Canada

2007; Vol. 29, issue 6 Suppl 1:S47.

van Os 2011 {published data only}

van Os MA, van der Ven JA, Kleinrouweler CE, Pajkrt E,

de Miranda E, van Wassenaer A, et al. Preventing preterm

birth with progesterone: Costs and effects of screening low

risk women with a singleton pregnancy for short cervical

length, the Triple P study. BMC Pregnancy and Childbirth

2011;11:77.

Wood 2007 {published data only}

Wood S. Vaginal progesterone versus placebo in multiple

pregnancy. http://controlledtrials.com (accessed 2007).

Additional references

ACOG 2003

American College of Obstetrics and Gynecology.

Committee opinion: use of progesterone to reduce preterm

birth. Obstetrics & Gynecology 2003;102:1115–6.

Adams 2000

Adams MM, Elam-Evans LD, Wilson HG, Gilbertz DA.

Rates and factors associated with recurrence of preterm

delivery. JAMA 2000;283(12):1591–6.

AIHW 2003

Australian Institute of Health and Welfare. Australia’s

Mothers and Babies 2000. National Perinatal Statistics Unit,

2003.

Alfirevic 2012

Alfirevic Z, Stampalija T, Roberts D, Jorgensen AL. Cervical

stitch (cerclage) for preventing preterm birth in singleton

29Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

pregnancy. Cochrane Database of Systematic Reviews 2012,

Issue 4. [DOI: 10.1002/14651858.CD008991.pub2]

Astle 2003

Astle S, Slater DM, Thornton S. The involvement of

progesterone in the onset of human labour. European

Journal of Obstetrics & Gynecology and Reproductive Biology

2003;108(2):177–81.

Bakketeig 1979

Bakketeig LS, Hoffman HJ, Harley EE. The tendency to

repeat gestational age and birth weight in successive births.

American Journal of Obstetrics and Gynecology 1979;135(8):

1086–103.

Berkowitz 1993

Berkowitz G, Papiernik E. Epidemiology of preterm birth.

Epidemiologic Reviews 1993;88:233–8.

Blencowe 2012

Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller

AB, Narwal R, et al. National, regional, and worldwide

estimates of preterm birth rates in the year 2010 with

time trends since 1990 for selected countries: a systematic

analysis and implications. Lancet 2012;379(9832):

2162–72. [PUBMED: 22682464]

Block 1984

Block BS, Liggins GC, Creasy RK. Preterm delivery is

not predicted by serial plasma estradiol or progesterone

concentration measurements. American Journal of Obstetrics

and Gynecology 1984;150(6):716–22.

Bloom 2001

Bloom SL, Yost NP, McIntire DD, Leveno KJ. Recurrence of

preterm birth in singleton and twin pregnancies. Obstetrics

& Gynecology 2001;98:379–85.

Carr-Hill 1985

Carr-Hill RA, Hall MH. The repetition of spontaneous

preterm labour. BJOG:an international journal of obstetrics

and gynaecology 1985;92(9):921–8.

Conde-Agudelo 2013

Conde-Agudelo A, Romero R, Nicolaides K,

Chaiworapongsa T, O’Brien JM, Cetingoz E, et al. Vaginal

progesterone vs. cervical cerclage for the prevention

of preterm birth in women with a sonographic short

cervix, previous preterm birth, and singleton gestation: a

systematic review and indirect comparison metaanalysis.

American Journal of Obstetrics and Gynecology 2013;208(1):

42.e1–42.e18.

Condon 2003

Condon JC, Jeyasuria P, Faust JM, Wilson JW, Mendelson

CR. A decline in the levels of progesterone receptor

coactivators in the pregnant uterus at term may antagonize

progesterone receptor function and contribute to the

initiation of parturition. Proceedings of the National Academy

of Sciences of the United States of America 2003;100(16):

9518–23.

Elder 1999

Elder DE, Haga R, Evans SF, Benninger HR, French NP.

Hospital admissions in the first year of life in very preterm

infants. Journal of Paediatrics and Child Health 1999;35(2):

145–50.

Gates 2004

Gates S, Brocklehurst P. How should randomised trial

including multiple pregnancies be analysed?. BJOG: an

international journal of obstetrics and gynaecology 2004;111:

213–9.

Goldenberg 1998

Goldenberg RL, Rouse DJ. Prevention of premature birth.

New England Journal of Medicine 1998;339:313–20.

Grazzini 1998

Grazzini E, Guillon G, Mouillac B, Zingg HH. Inhibition

of oxytocin receptor function by direct binding of

progesterone. Nature 1998;392(6675):509–12.

Greene 2003

Greene MF. Progesterone and preterm delivery - deja vu

all over again. New England Medical Journal 2003;348:

2453–5.

Haas 2008

Haas DM, Ramsey PS. Progestogen for preventing

miscarriage. Cochrane Database of Systematic Reviews 2008,

Issue 2. [DOI: 10.1002/14651858.CD003511.pub2]

Hack 1999

Hack M. Consideration of the use of health status,

functional outcome, and quality-of-life to monitor neonatal

intensive care practice. Pediatrics 1999;103(1 Suppl E):

319–28.

Haluska 1997

Haluska GJ, Cook MJ, Novy MJ. Inhibition and

augmentation of progesterone production during pregnancy:

effects on parturition in rhesus monkeys. American Journal

of Obstetrics and Gynecology 1997;176(3):682–91.

Haluska 2002

Haluska GJ, Wells TR, Hirst JJ, Brenner RM, Sadowsky

DW, Novy MJ. Progesterone receptor localisation and

isoforms in myometrium, decidua, and fetal membranes

from rhesus macaques: evidence for functional progesterone

withdrawal at parturition. Journal of the Society for

Gynecological Investigation 2002;9(3):125–36.

Hewitt 1988

Hewitt BC, Newnham JP. A review of the obstetric and

medical complications leading to the delivery of very low

birth weight infants. Medical Journal of Australia 1988;149:

234–7.

Higgins 2002

Higgins J, Thompson S. Quantifying heterogeneity in

meta-analysis. Statistics in Medicine 2002;21:1559–74.

Higgins 2008

Higgins JPT, Green S, editors. Cochrane Handbook for

Systematic Reviews of Interventions Version 5.0.0 [updated

February 2008]. The Cochrane Collaboration, 2008.

Available from www.cochrane-handbook.org.

Higgins 2011

Higgins JPT, Green S, editors. Cochrane Handbook for

Systematic Reviews of Interventions Version 5.1.0 [updated

30Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

March 2011]. The Cochrane Collaboration, 2011.

Available from www.cochrane-handbook.org.

Iams 2003

Iams JD. Supplemental progesterone to prevent preterm

birth. American Journal Obstetrics and Gynecology 2003;188

(2):303.

Kaminski 1973

Kaminski M, Goujard J, Rumeau-Rouquette C. Prediction

of low birthweight and prematurity by a multiple regression

analysis with maternal characteristics known since the

beginning of the pregnancy. International Journal of

Epidemiology 1973;2:195–204.

Kistka 2007

Kistka ZA, Palomar L, Lee KA. Racial disparity in the

frequency of recurrence of preterm birth. American Journal

of Obstetrics and Gynecology 2007;196:131.e1–131.e6.

Kramer 2000

Kramer M, Demissie K, Yang H, Platt RW, Sauve R, Liston

R. The contribution of mild and moderate preterm birth to

infant mortality. JAMA 2000;284:843–9.

Lopez-Bernal 2003

Lopez-Bernal A. Mechanism of labour - biochemical

aspects. BJOG: an international journal of obstetrics and

gynaecology 2003;110(Suppl 20):39–45.

Martin 2003

Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker

F, Munson ML. Births: final data for 2002. National Vital

Statistics Report 2003;52(10):1–113.

Mattison 2001

Mattison DR, Damus K, Fiore E, Petrini J, Alter C.

Preterm delivery: a public health perspective. Paediatric and

Perinatal Epidemiology 2001;15(Suppl. 2):7–16.

McLaughlin 2002

McLaughlin KJ, Crowther CA, Vigneswaran P, Hancock E,

Willson K. Who remains undelivered more than seven days

after a single course of prenatal corticosteroids and gives

birth at less than 34 weeks?. Australian and New Zealand

Journal of Obstetrics and Gynaecology 2002;42(4):353–7.

Mercer 1999

Mercer BM, Goldenberg RL, Moawad AH. The preterm

prediction study: effect of gestational age and cause of

preterm birth on subsequent obstetric outcomes. American

Journal of Obstetrics and Gynecology 1999;181(5 Pt 1):

1216–21.

Northen 2007

Northen AT, Norman GS, Anderson K, Moseley, L, Divito

M, Cotroneo M, et al. Follow-up of children exposed in

utero to 17 alpha-hydroxyprogesterone caproate compared

with placebo. Obstetrics & Gynecology 2007;110(4):864–72.

Papiernik 1974

Papiernik E, Kaminski M. Multifactorial study of the

risk of prematurity at 32 weeks of gestation: a study of

the frequency of 30 predictive characteristics. Journal of

Perinatal Medicine 1974;2:30–6.

Pepe 1995

Pepe GJ, Albrecht ED. Actions of placental and fetal adrenal

steroid hormones in primate pregnancy. Endocrine Review

1995;16(5):608–48.

Petrini 2005

Petrini J, Callaghan W, Klebanoff M. Estimated effect of 17

alpha hydroxyprogesterone caproate on preterm birth in the

United States. Obstetrics & Gynecology 2005;105:267–72.

Pieber 2001

Peiber D, Allport VC, Hills F, Johnson M, Bennett PR.

Interactions between progesterone receptor isoforms in

myometrial cells in human labour. Molecular Human

Reproduction 2001;7(9):875–9.

Rafael 2011

Rafael TJ, Berghella V, Alfirevic Z. Cervical stitch (cerclage)

for preventing preterm birth in multiple pregnancy.

Cochrane Database of Systematic Reviews 2011, Issue 6.

[DOI: 10.1002/14651858.CD009166]

RevMan 2008 [Computer program]

The Cochrane Collaboration. Review Manager (RevMan).

Version 5.0. Copenhagen, The Nordic Cochrane Centre:

The Cochrane Collaboration, 2008.

RevMan 2012 [Computer program]

The Nordic Cochrane Centre, The Cochrane Collaboration.

Review Manager (RevMan). Version 5.2. Copenhagen:

The Nordic Cochrane Centre, The Cochrane Collaboration,

2012.

Robinson 2001

Robinson JN, Regan JA, Norwitz ER. The epidemiology of

preterm labour. Seminars in Perinatology 2001;25:204–14.

Romero 2012

Romero R, Nicolaides K, Conde-Agudelo A, Tabor A,

O’Brien JM, Cetingoz E, et al. Vaginal progesterone in

women with an asymptomatic sonographic short cervix in

the midtrimester decreases preterm delivery and neonatal

morbidity: a systematic review and metaanalysis of

individual patient data. American Journal of Obstetrics and

Gynecology 2012;206(2):124: 1-19.

Schuit 2012

Schuit E, Stock S, Groenwold RH, Maurel K, Combs CA,

Garite T, et al. Progestogens to prevent preterm birth in

twin pregnancies: an individual participant data meta-

analysis of randomized trials. BMC Pregnancy Childbirth

2012;15(12):13.

Smit 1984

Smit DA, Essed GG, deHaan J. Predictive value of uterine

contractility and the serum levels of progesterone and

oestrogens with regard to preterm labour. Gynecologic and

Obstetric Investigation 1984;18(5):252–63.

Smith 2007

Smith V, Devane D, Begley CM, Clarke M, Higgins S.

A systematic review and quality assessment of systematic

reviews of fetal fibronectin and transvaginal length for

predicting preterm birth. European Journal of Obstetrics,

Gynecology, and Reproductive Biology 2007;133(2):134–42.

31Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Stanley 1992

Stanley F. Survival and cerebral palsy in low birthweight

infants: implications for perinatal care. Paediatric and

Perinatal Epidemiology 1992;6(2):298–310.

References to other published versions of this review

Cincotta 2004

Cincotta R, Gardener G, Duncombe G, Flenady V,

Dodd J. Antenatal administration of progesterone for

preventing spontaneous preterm birth. Cochrane Database

of Systematic Reviews 2004, Issue 4. [DOI: 10.1002/

14651858.CD004947]

Dodd 2006

Dodd JM, Flenady V, Cincotta R, Crowther CA. Prenatal

administration of progesterone for preventing preterm

birth in women considered to be at risk of preterm birth.

Cochrane Database of Systematic Reviews 2006, Issue 1.

[DOI: 10.1002/14651858.CD004947.pub2] ∗ Indicates the major publication for the study

32Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Aboulghar 2012

Methods Single-centre prospective placebo-controlled randomised clinical trial

IVF Center, Cairo, Egypt.

Participants 313 women at high risk of preterm birth with pregnancies conceived by IVF or ICSI

Inclusion criteria: Healthy pregnant women who conceived after IVF/ICSI between 18-

24 weeks of gestation, with a first pregnancy, singleton or dichorionic twins, normal

uterine and cervical anatomy, and normal fetal anatomy

Exclusion criteria: Previous pregnancy, serious fetal anomalies for which termination

may be considered such as major heart anomaly or major CNS anomaly

All women received progesterone injections as luteal phase support which they continued

if pregnant until the day of the first ultrasound

Interventions Vaginal progesterone 200 mg twice daily from randomisation until delivery or 37 weeks’

gestation. Total number randomised: n = 161 women (161 analysed, 210 babies)

Placebo vaginal suppositories from randomisation until 37 weeks’ gestation. Total num-

ber randomised: n = 152 women (145 women analysed, 187 babies)

Outcomes Primary outcomes were: preterm birth of singleton and twin pregnancies before 37

completed weeks and before 34 completed weeks

Secondary outcomes: neonatal morbidity and mortality (live-born children who died <

28 days after delivery) and take-home baby rate (live-birth rate per patient). Birthweight

> 2500 g; 1500-2500 g; < 1500 g; NICU admissions

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk States, “Dark, sealed envelopes containing

the intervention taken from a table of num-

bers” - not clear how the table of number

generated - does not state “random number

table”

Allocation concealment (selection bias) Low risk Refers to “dark, sealed, sequentially num-

bered envelopes” and the envelopes were

picked by a nurse not involved in the study.

The envelopes had been created by a third

party not involved in the allocation process

33Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Aboulghar 2012 (Continued)

Incomplete outcome data (attrition bias)

All outcomes

Low risk Study flow diagram clearly displays partic-

ipant flow in the study

410 women recruited, 313 randomised;

none lost to follow-up in progesterone

group and 6 lost to follow-up in placebo

group and 1 excluded because of termina-

tion of pregnancy after diagnosis of trisomy

21.

States “Intention-to-treat principle was fol-

lowed during data analysis.”

Selective reporting (reporting bias) Low risk All expected outcome results reported.

Other bias Unclear risk None apparent, although baseline charac-

teristics table not presented

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk States “single blinding” and that “the pa-

tient was informed about the allocated arm”

so presumably the clinician/personnel were

blinded

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Not clear, but probably low risk. Placebo-

controlled trial.

Akbari 2009

Methods Randomised.

Single centre, Lorestan.

Participants 150 women randomised: 75 to each group.

Inclusion criteria: 1. Single child pregnancy with the exact age of conception based on

LMP was determined and was verified by sonogram before reaching 20 weeks. If the LMP

was not available the exact age of pregnancy was based on 2 sonograms that were verified

on at least 2 separate weeks; 2. Women with a history of 1 or 2 previous early childbirths

before reaching 37 weeks of pregnancy or women with a history of prophylactic cervical

cerclage or uterine anomalies (unicornuate uterus, bicornuate uterus, septate uterus,

arcuate uterus, uterus didelphys); and 3. Older than 18 years, younger than 35 years

Exclusion criteria: 1. Rupture of membranes PROM; 2. Large known fetal anomalies;

3 Cervix dilatation larger than 4 cm; 4. Contraindications for tocolysis including fetal

distress, chorioamnionitis, pre-eclampsia, and haemodynamic instability; 5. Allergies

to progesterone (dizziness, mygan, visual disturbances, depression, and increased blood

sugar during previous consumption of this drug were considered allergic reactions to the

hormone.); 6. Not following up with patients; 7. Multiple pregnancies; 8.The existence

of an illness in the mother that necessitated medication, such as high blood pressure,

cancer, tension, thromboembolic disease, Kennedy’s disease, illnesses that are treated for

asthma with oral beta-adrenergic; 9. Age younger than 18 or older than 35; 10. Existence

of IUGR fetuses; 11. Unwarranted vaginal bleeding

34Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Akbari 2009 (Continued)

Interventions Experimental intervention: 100 mg of prophylactic vaginal progesterone daily between

24th and 34th week of gestation - Cyclogest.

Control/Comparison intervention: the other group received no treatment and were

monitored

Outcomes Mean gestational age at time of delivery.

Preterm delivery before 37th week gestation.

Preterm delivery before 34th week gestation.

Respiratory distress syndrome.

Low birthweight.

Birthweight.

Need for oxygen.

Infant Apgar score.

Need for mechanical ventilator.

Hospitalisation in NICU.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Not clear “150 women that had passed the en-

trance criterion to the study were divided ran-

domly into two groups of 75.”

Allocation concealment (selection bias) Unclear risk Not reported.

Incomplete outcome data (attrition bias)

All outcomes

Unclear risk 3 individuals from the control group and 4 from

the group receiving progesterone were excluded

from the study - reasons for exclusion not clear

- but in table of results - 6 people appear to be

missing from denominator for the progesterone

group (report 69) and not 4 as described?

Results presented for 69 women in progesterone

group and 72 in control

Selective reporting (reporting bias) Low risk All expected outcomes appear to have been re-

ported.

Other bias Unclear risk Unclear.

Blinding of participants and personnel

(performance bias)

All outcomes

Unclear risk Not reported.

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not reported.

35Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Borna 2008

Methods Method of randomisation: random number table.

Allocation concealment: unclear.

Blinded outcome assessment: no.

Completeness of follow-up: outcome data available for 70 women

Participants 70 women presenting between 24 and 34 weeks’ gestation with symptoms and signs of

threatened preterm labour, where acute symptoms were arrested following use of tocolytic

medication

Interventions Daily intravaginal pessary (400 mg) versus no treatment.

Outcomes Interval from randomisation to birth.

Notes Trial conducted in Tehran, Iran.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Random number table.

Allocation concealment (selection bias) Unclear risk Unclear.

Incomplete outcome data (attrition bias)

All outcomes

Low risk Complete data available.

Selective reporting (reporting bias) Low risk All prespecified outcomes reported in the

abstract appear to have been reported upon

(latency period until delivery; respiratory

distress syndrome; low birthweight; birth-

weight; recurrent preterm birth; admission

to intensive care unit; neonatal sepsis)

Other bias Low risk Baseline characteristics were similar (see ta-

ble 1, page 61)

Blinding of participants and personnel

(performance bias)

All outcomes

High risk No blinding of care givers and women.

Blinding of outcome assessment (detection

bias)

All outcomes

High risk No blinding of outcome assessment.

36Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Briery 2011

Methods Placebo-controlled double-blind randomised clinical trial.

Single site, USA.

Participants 69 women randomised: 33 to 17-OH group and 36 to placebo.

Inclusion criteria: women who presented with singleton, vertex gestations to university’s

obstetric emergency area with a diagnosis of PPROM at 20-30 weeks’ gestation, typically

dated by ultrasound, were eligible

Exclusion criteria: severe fetal or placental disease that might bias neonatal outcomes

such as intrauterine growth restriction (< 5th percentile), suspected placental abruption,

and confirmed placenta previa. Also excluded were patients already taking 17P, and some

with signs and symptoms of chorioamnionitis, non-reassuring fetal assessments or severe

medical/obstetric diseases such as sickle cell disease with the crisis, insulin-dependent

diabetes, and severe pre-eclampsia

Interventions Experimental intervention: weekly injections of 17P (250 mg) until 34 weeks or delivery,

whichever came first

Control/Comparison intervention: weekly injections of placebo until 34 weeks or deliv-

ery, whichever came first

Outcomes Gestational age at birth; route of delivery; indications for delivery; birthweight; 5-minute

Apgar score; total NICU days; significant neonatal morbidity (sepsis, seizures); respira-

tory distress syndrome; patent ductus arteriosis; intraventricular haemorrhage; necrotis-

ing enterocolitis; bronchopulmonary dysplasia; death during neonatal period

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Random number table.

Allocation concealment (selection bias) Low risk Central allocation - pharmacy-controlled.

Incomplete outcome data (attrition bias)

All outcomes

Low risk 2 patients lost - 1 person from 17P group

who was previously enrolled in another

study and 1 in placebo group refused the

injection.

“All 69 were analyzed (intention to treat).”

Selective reporting (reporting bias) Unclear risk All expected outcomes, apart from intra-

ventricular haemorrhage, are reported in

tables - although number of seizures were

recorded

37Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Briery 2011 (Continued)

Other bias Low risk No significant differences in demographic

statistics between groups.

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk “Patients, their families, research person-

nel, and physicians/nurses were not aware

of the study group assignment”. Also de-

scribed as “double-blind”

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not reported.

Caritis 2009

Methods Randomised, double-blinded, placebo-controlled trial.

14 centres, USA.

Participants 134 women randomised: 71 to 17 alph-hydroxyprogesterone caproate; 63 to placebo

Inclusion criteria: pregnant women with triplets were eligible if their gestational age was

at least 16 weeks and no more than 20 weeks

Exclusion criteria: serious fetal anomalies, 2 or more fetuses in 1 amniotic sac, sus-

pected twin-to-twin transfusion syndrome, marked ultrasonographic growth discor-

dance, planned non study progesterone therapy after 16 weeks, in-place or planned cer-

clage, major uterine anomaly, unfractionated heparin therapy at any dose, and major

chronic medical diseases

Interventions Experimental intervention: weekly injections of 17-OHPC* (250 mg in 1 mL castor oil)

starting at 16-20 weeks and ending at delivery or 35 weeks’ gestation

*17 Alpha-Hydroxyprogesterone Caproate

Control/Comparison intervention: weekly injections of placebo (1mL castor oil) starting

at 16-20 weeks and ending at delivery or 35 weeks’ gestation

Outcomes Primary outcomes: composite of delivery or fetal loss before 35 completed weeks of

gestation (245 days) - fetal loss included: miscarriage, termination, or stillbirth occurring

any time after randomisation.

Secondary outcomes: selected individual maternal and neonatal outcomes and a com-

posite of serious neonatal outcomes.

Composite serious adverse neonatal outcomes included: neonatal death, respiratory dis-

tress syndrome, culture-proven sepsis, necrotising enterocolitis stage II or III, bron-

chopulmonary dysplasia, intraventricular haemorrhage grade III or IV, or periventricular

leucomalacia or severe retinopathy of prematurity stage III or higher

Notes

Risk of bias

38Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Caritis 2009 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk “The simple urn method of randomization

with stratification according to clinical cen-

ter, was used to create a randomization se-

quence for each center.”

Allocation concealment (selection bias) Low risk The injections were prepared by a research

pharmacy and boxes of 17-OHPC and

placebo were packaged for each centre ac-

cording to randomisation sequences - so

appears to be central allocation - pharmacy-

controlled

Incomplete outcome data (attrition bias)

All outcomes

Low risk “Outcome data were available for 100% of

the assigned women, and for all of the 402

fetuses.”

No exclusions apparent.

ITT stated in statistical methods.

Selective reporting (reporting bias) Low risk All expected outcomes appear to have been

reported.

Other bias Low risk The baseline characteristics of the 2 study

groups were similar (Table 1)

This study included women with multiple

pregnancies (triplet) and there appears to be

adjustment for neonatal binary outcomes

- used log binomial regression to calculate

relative risk

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk “The participating women, their care-

givers, and the research personnel were not

aware of the study group assignment”. Also

described as “double-blinded”

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not reported.

39Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Cetingoz 2011

Methods Randomised placebo-controlled double-blind study.

Department of Obstetrics and Gynecology, Istanbul.

Participants 160 women randomised: 84 allocated to intervention and 76 allocated to placebo

Inclusion criteria: high-risk pregnant women: twin pregnancies; pregnancies with at least

1 spontaneous preterm birth; uterine malformation

Exclusion criteria: not stated.

Interventions Experimental intervention: micronized progesterone (100 mg) administered daily by

vaginal suppository between 24 and 34 weeks of gestation

Control/Comparison intervention: placebo (100 mg) administered daily by vaginal sup-

pository between 24 and 34 weeks of gestation

Outcomes Delivery < 37 weeks.

Delivery < 34 weeks.

Preterm labour admission.

NICU admission.

Neonatal death.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Computer-generated random-number list

- “Patients were allocated according to ran-

domised number table”

Allocation concealment (selection bias) Low risk Random-number list generated centrally

by research hospital pharmacy

Incomplete outcome data (attrition bias)

All outcomes

Low risk 170 high-risk women were eligible - 10

women were excluded before randomisa-

tion due to abortion (n = 2), delivery be-

tween 20 and 24 weeks (n = 7) and appli-

cation of cervical cerclage (n = 1).

160 women were randomised - 10 lost dur-

ing follow-up, 6 from the placebo group

and 4 from intervention group

150 women analysed (intervention group -

n = 80 - prior preterm birth = 37; uterine

malformation = 4; twin gestation = 39) and

(placebo group - n = 70 - prior preterm

birth = 34; uterine malformation = 8; twin

gestation = 28)

Analysis was performed according to ITT

principle.

40Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Cetingoz 2011 (Continued)

Selective reporting (reporting bias) Low risk Yes - all expected outcomes reported

Other bias Unclear risk Groups were similar in regard to age, pre-

gravid BMI, parity, abortion, and ratio

of high-risk groups according to baseline

characteristics table. There were no statisti-

cally significant differences in demograph-

ics

This study included singleton and twin

pregnancies - Odd ratio presented, but does

not state whether any adjustments made in

the analysis

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk “The participating women, their care-

givers, and the research personnel were un-

aware of the woman’s study-group assign-

ments.”

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not reported.

Combs 2010

Methods Double-blind, randomised clinical trial.

Multicentre, Obstetrix Collaborative Research Network, USA.

Participants 81 women randomised: 56 allocated to 17P and 25 to placebo.

Inclusion criteria: mothers carrying trichorionic-triamniotic triplets - confirmed at 15-

23 week detailed second-trimester ultrasound examination - showing normal amniotic

fluid volume and no major fetal anomalies

Exclusion criteria: women with symptomatic uterine contractions, rupture of fetal mem-

branes, any contraindication to interventions intended to prolong the pregnancy, a pre-

existing medical condition that might be worsened by progesterone, or a pre-existing

medical condition carrying a high risk of preterm delivery. Women less than 18 years

of age, had an allergy to 17P or the oil vehicle, had taken any progesterone-derivative

medication after 15 weeks of gestation, or had undergone placement of cervical cerclage

for treatment of cervical change in the current pregnancy

Interventions Experimental intervention: 17 alpha-hydroxyprogesterone caproate (17P) (250 mg in

1 mL castor oil) - weekly injections starting at 16-22 weeks and continued until 34

weeks or delivery. Weekly repeat injections were carried out at the site or at home

with partner administering after training. Injection diary for partner injections and

measurement of unused medication returned by patient used to assess compliance with

home administration

Control/Comparison intervention: identical appearing placebo (in 1 mL castor oil).

41Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Combs 2010 (Continued)

Outcomes Primary outcomes: composite neonatal morbidity defined as 1 or more of: perinatal

death (stillbirth, neonatal death, miscarriage); respiratory distress syndrome; use of oxy-

gen therapy at 28 days of life; neonatal sepsis proven by blood culture; pneumonia; in-

traventricular haemorrhage (grade III or IV); periventricular leucomalacia; necrotising

enterocolitis requiring surgery; retinopathy of prematurity; newborn asphyxia

Secondary outcomes: individual neonatal morbidities listed above; gestational age at

delivery; birthweight; maternal side effects

Other outcomes reported:

Mean weeks of gestation.

Delivery before 28, 32 or 35 week.

Reason for delivery before 32 weeks (spontaneous; indicated)

Reason for delivery, all deliveries (spontaneous; indicated)

Caesarean delivery.

Tocolysis used.

Antenatal corticosteroids.

Maternal complications:

Pre-eclampsia or gestational hypertension.

Gestational diabetes.

Chorioamnionitis.

Sepsis.

Postpartum endometritis.

Neonatal outcomes:

Birthweight, g.

Head circumference, cm.

Total hospital stay, days.

NICU.

Intermediate care.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Computer-generated scheme.

Allocation concealment (selection bias) Low risk Random-number generated centrally by

pharmacy. “Progesterone or identical-ap-

pearing placebo was compounded by phar-

macy and shipped in advance to each study

site in coded prenumbered kits. To ran-

domise the research nurse contacted the

central pharmacy by telephone or fax to ob-

tain the code number for the kit assigned

to that patient.”

42Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Combs 2010 (Continued)

Incomplete outcome data (attrition bias)

All outcomes

Low risk 248 women identified with triplets, 147 el-

igible for trial inclusion, of these 89 gave

consent (61%) and were given trial injec-

tion. Of these, 81 (91%) returned for ran-

domisation.

No loss - 81 women randomised and out-

come data available for all 81 mothers and

243 offspring

“Analysis was by the “intention-to-treat”

principle. Accordingly, outcomes for each

patient were tabulated according to the as-

signed group (17P vs placebo) regardless of

her compliance.”

Selective reporting (reporting bias) Low risk Yes - all expected outcomes reported.

Other bias Low risk Baseline characteristics of the participants

were similar. There were no significant dif-

ference between the groups in the percent-

age with cervix length less than 2.5 cm

17% in the 17P group versus 35% in the

placebo group or with positive fibronectin,

11% versus 9%

Mean compliance was 98.5% in the 17P

group and 96.1% in the placebo group.

There was no significant difference be-

tween groups in the percentage of injec-

tions given by clinic staff (27% versus 30%)

, by patients themselves (13% versus 15%),

or by their designated representatives (61%

versus 56%)

Included multiple pregnancies (triplet) -

adjustment made in analysis - used repeated

measures model, where each infant was

considered as a repeated measure

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk “Subjects, physicians, and study personnel

remained blinded as to group assignment

until after completion of the trial.”

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk “Data were abstracted by study personnel

who remained blinded to each subject’s

group assignment.”

43Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Combs 2011

Methods Double-blind, randomised clinical trial.

Multicentre - 18 sites, Obstetrix Collaborative Research Network, USA

Participants 240 women randomised: 160 allocated to 17Pc and 80 to placebo

Inclusion criteria: women were eligible if they had a dichorionic-diamniotic twin preg-

nancy at 15-23 weeks’ gestation and if they had completed a detailed ultrasound exam-

ination - showing no major fetal anomalies.

Exclusion criteria: women were excluded if they were < 18 years old; had taken any

progestins > 15 weeks of gestation; or had symptomatic uterine contractions, rupture of

the fetal membranes, any contraindication to prolonging the pregnancy, any pre-existing

condition that might be worsened by progesterone, or a pre-existing medical condition

carrying a high risk of preterm delivery

Interventions Experimental intervention: 17 alpha-hydroxyprogesterone caproate (17P) (250 mg in

1 mL castor oil) - weekly injections starting at 16-24 weeks and continued until 34

weeks or delivery. Weekly repeat injections were carried out at the site or at home

with partner administering after training. Injection diary for partner injections and

measurement of unused medication returned by patient used to assess compliance with

home administration

Control/Comparison intervention: identical appearing placebo (in 1 mL castor oil).

Outcomes Primary outcomes: composite neonatal morbidity defined as 1 or more of: perinatal

death (stillbirth, neonatal death, miscarriage); respiratory distress syndrome; use of oxy-

gen therapy at 28 days of life; neonatal sepsis proven by blood culture; pneumonia; in-

traventricular haemorrhage (grade III or IV); periventricular leucomalacia; necrotising

enterocolitis requiring surgery; retinopathy of prematurity; newborn asphyxia

Secondary outcomes: individual neonatal morbidities listed above; gestational age at

delivery; birthweight; maternal side effects

Other outcomes reported:

Mean weeks of gestation.

Delivery before 28, 32 or 34 or 37 weeks.

Reason for delivery before 37 weeks (spontaneous; indicated)

Caesarean delivery.

Tocolysis used.

Antenatal corticosteroids.

Maternal complications:

Pre-eclampsia or gestational hypertension.

Gestational diabetes.

Chorioamnionitis.

Sepsis.

Postpartum endometritis.

Neonatal outcomes:

Birthweight, g.

Birthweight < 2500 g.

Birthweight < 1500 g.

Birthweight < 1000 g.

Small-for-gestational age.

44Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Combs 2011 (Continued)

All births.

Births < 2500 g.

Head circumference, cm.

Total hospital stay, days.

NICU.

Intermediate care.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Computer-generated scheme.

Allocation concealment (selection bias) Low risk Random-number generated centrally by

pharmacy. “Progesterone or identical-ap-

pearing placebo was compounded by phar-

macy and shipped in advance to each study

site in coded prenumbered kits. To ran-

domise the research nurse contacted the

central pharmacy by telephone or fax to ob-

tain the code number for the kit assigned

to that patient.”

Incomplete outcome data (attrition bias)

All outcomes

Low risk 1450 women identified with twin preg-

nancy, 254 eligible and consented and were

given trial injection. Of these, 240 returned

for randomisation.

No loss in progesterone group - 160 women

allocated, 160 mothers delivered and 320

perinates with known outcome. 80 women

allocated to placebo - 2 lost to follow-up

- 78 women delivered and 156 perinates

with known outcome

“Outcomes for each patient were tabulated

according to assigned group regardless of

her compliance.”

Selective reporting (reporting bias) Low risk Yes - all expected outcomes reported.

Other bias Low risk Baseline characteristics of the subjects were

similar.

Mean compliance was 96.4% in the 17P

group and 98.7% in the placebo group

Included multiple pregnancies (twin) - ad-

45Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Combs 2011 (Continued)

justment made in analysis - used repeated

measures model, where each infant was

considered as the repeated measure.

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk “Subjects, physicians, and study personnel

remained blinded as to group assignment

until after completion of the trial.”

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not reported.

Combs 2011a

Methods Double-blind, placebo-controlled randomised clinical trial.

Multicentre - 18 sites, Obstetrix Collaborative Research Network, USA

Participants 12 women randomised: 4 allocated to 17P and 8 to placebo. The trial was terminated

early because of 2 separate issues related to the supply of 17P

Inclusion criteria:women were eligible if they were at least 18 years old, had a singleton

pregnancy at 23.0 to 31.9 weeks of gestation and PROM

Exclusion criteria: women were excluded with contraindications to expectant manage-

ment; with known fetal abnormalities; with history of allergy to 17P or castor oil; with

medical conditions that might adversely interact with 17P; with medical conditions

treated with systemic steroid medications; or with a cervical cerclage present at the time

of PROM.

Interventions Experimental intervention: 17 alpha-hydroxyprogesterone caproate (17P) (250 mg in 1

mL castor oil) - weekly intramuscular injections

Control/Comparison intervention: identical appearing placebo (in 1 mL castor oil)

Outcomes Primary outcomes: prolongation of pregnancy until favourable gestational age. Compos-

ite neonatal morbidity defined as 1 or more of: stillbirth, neonatal death, infant death

before hospital discharge; respiratory distress syndrome; intracranial haemorrhage grade

III or IV; necrotising enterocolitis stage 2 or 3; culture proven sepsis within 72 hours of

birth; periventricular leucomalacia

Secondary outcomes: pregnancy prolongation (interval from randomisation to delivery)

. Individual neonatal morbidities listed above; gestational age at delivery; birthweight;

maternal side effects

Other outcomes reported:

Delivery at 34 weeks or more.

Delivery at 32-33.9 weeks with documented fetal lung maturity

Mean gestational age at delivery.

Delivery before 32 or 34 weeks.

Pulmonary maturity testing.

46Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Combs 2011a (Continued)

Latency - randomisation to delivery.

Less than 1 week.

1.0 to 1.9 weeks.

2.0 2.0 weeks or more.

Reason for delivery before 34 weeks (spontaneous; chorioamnionitis; fetal indications)

Maternal complications:

Pre-eclampsia or gestational hypertension.

Gestational diabetes.

Chorioamnionitis.

Sepsis.

Caesarean delivery.

Tocolysis in first 48 hours.

Antenatal corticosteroids.

Neonatal outcomes:

Birthweight, g.

Total hospital stay, days.

NICU stay, days.

Newborns with congenital anomaly.

Adverse events not tabulated elsewhere.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Computer-generated random number se-

quence was used by the trial statistician to

generate a randomisation code

Allocation concealment (selection bias) Low risk Random-number generated by a statisti-

cian and held centrally at each site’s inpa-

tient pharmacy

Incomplete outcome data (attrition bias)

All outcomes

Low risk No loss to follow-up - but only 12 patients

were randomised - 8 to placebo and 4 to

17P

Appears to have been ITT.

Selective reporting (reporting bias) Low risk Yes - all expected outcomes reported .

Other bias Unclear risk The trial was stopped early due to 2 separate

issues related to the supply of 17P. Only 12

patients were randomised and because of

the early termination, the trial was grossly

under-powered to make conclusions as to

the efficacy or safety of 17P in women with

PROM

47Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Combs 2011a (Continued)

Too few patients to assess baseline imbal-

ance.

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk “Participants and research personnel were

blinded to group assignment throughout.”

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not reported.

da Fonseca 2003

Methods Method of randomisation: random number table.

Allocation concealment: sequential sealed envelopes; allocation to either drug A or B;

allocation of groups revealed after last woman birthed.

Blinded outcome assessment: yes.

Completeness of follow-up: outcome data available for 142 women (15 women excluded

after randomisation)

Participants 157 women considered to be at ’high risk’ for preterm birth due to history of previous

preterm birth, cervical suture, uterine malformation

Interventions Nightly intravaginal pessary of either 100 mg progesterone or placebo from 24 weeks

until 28 weeks’ gestation, or birth if earlier

Outcomes Preterm birth before 37 weeks’ gestation; preterm birth before 34 weeks’ gestation

Notes Trial conducted in Sao Paulo, Brazil.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Random number table.

Allocation concealment (selection bias) Low risk Adequate; sequential sealed opaque en-

velopes.

Incomplete outcome data (attrition bias)

All outcomes

Low risk 15 women (less than 1%) post-randomisa-

tion exclusions.

Selective reporting (reporting bias) Low risk The published report includes all expected

outcomes (incidence of preterm delivery;

frequency of uterine contractions)

48Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

da Fonseca 2003 (Continued)

Other bias Low risk “The two groups were found similar in re-

gard to age, risk factors for preterm deliv-

ery, and obstetric history.”

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Caregivers and participants blinded.

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Outcome assessor blinded.

Elsheikhah 2010

Methods Described as “randomized controlled study” in abstract title

Single centre, Cairo, Egypt.

Participants 100 women: 50 allocated to progesterone group and 50 to placebo

Inclusion criteria: women with twin pregnancy.

Exclusion criteria: patients with anomalies were excluded.

Interventions Experimental intervention: vaginal progesterone 200 mg daily for 10 weeks from the 24 th to the 34th week of gestation.

Control/Comparison intervention: placebo for the same duration

Outcomes Mean cervical length.

Mean gestational age at delivery.

Fetal complications (not specified).

NICU admissions.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Data limited - only reported as an abstract.

Allocation concealment (selection bias) Unclear risk Data limited - only reported as an abstract.

Incomplete outcome data (attrition bias)

All outcomes

Unclear risk Data limited - only reported as an abstract.

Selective reporting (reporting bias) Unclear risk Data limited - only reported as an abstract.

49Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Elsheikhah 2010 (Continued)

Other bias Unclear risk Data limited - only reported as an abstract.

Multiple pregnancies - no adjustment ap-

parent from abstract report

Blinding of participants and personnel

(performance bias)

All outcomes

Unclear risk Data limited - only reported as an abstract.

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Data limited - only reported as an abstract.

Facchinetti 2007

Methods Method of randomisation: random number table.

Allocation concealment: randomisation list managed by senior midwife; allocation to

either progesterone or placebo.

Blinding of outcome assessment: no.

Completeness of follow-up: outcome data available for 60 women

Participants 60 women presenting between 25 and 33 + 6 weeks’ gestation with symptoms and

signs of threatened preterm labour, where acute symptoms were arrested following use

of tocolytic medication (atosiban)

Interventions 341 mg intramuscular 17OHP administered every 4 days to 36 weeks’ gestation

Outcomes Cervical length as assessed by transvaginal ultrasound. Secondary outcomes included

preterm birth < 37 weeks, and infant birthweight

Notes Trial conducted in Modena, Italy.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Random number table.

Allocation concealment (selection bias) Unclear risk Unclear; list managed by “senior midwife”

with allocation to either progesterone or

placebo

Incomplete outcome data (attrition bias)

All outcomes

Low risk Outcome data available for all women.

Selective reporting (reporting bias) High risk Cervical length was measured by transvagi-

nal ultrasound scanning at discharge and

at day 7 and 21. Results for cervical length

50Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Facchinetti 2007 (Continued)

at discharge were not fully reported. All

other outcomes appear to have been re-

ported upon (cervical length at 7 and 21

days; preterm delivery < 37 weeks and < 35

weeks; birthweight)

Other bias Low risk No differences were found between the 2

groups for baseline characteristics (see ta-

ble, page 3)

Blinding of participants and personnel

(performance bias)

All outcomes

High risk No blinding - not possible “The study was

not double blind because it was not spon-

sored; therefore, the preparation of true

placebo (same vial, same oil without active

compound) was not possible.”

Blinding of outcome assessment (detection

bias)

All outcomes

High risk No blinding of outcome assessor.

Fonseca 2007

Methods Method of randomisation: not stated.

Allocation concealment: central randomisation process; identically appearing treatment

packs.

Blinded outcome assessment: yes.

Completeness of follow-up: outcome data available for all 250 women randomised

Participants 250 women undergoing transvaginal ultrasound assessment of cervical length, where

the cervical length was measured to be 15 mm or less. Women with both singleton

and multiple pregnancies were eligible to participate (226 singleton and 24 with twin

pregnancies)

Interventions Nightly intravaginal pessary of either 200 mg micronised progesterone or placebo from

24 weeks until 33 + 6 weeks’ gestation, or birth if earlier

Outcomes Primary outcome: spontaneous preterm birth less than 34 weeks’ gestation.

Secondary outcomes: infant birthweight, fetal death, neonatal death, major adverse out-

comes (intraventricular haemorrhage, respiratory distress syndrome, retinopathy of pre-

maturity, necrotising enterocolitis), need for neonatal special care (NICU, ventilation,

phototherapy, treatment for proven or suspected sepsis, blood transfusion)

Notes Trial conducted in 5 maternity hospitals in London (UK), Santiago (Chile), Sao Paulo

(Brazil), and Greece

This data analysed in subgroup of women with short cervix - multiples only made up a

small proportion of total group

Risk of bias

51Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Fonseca 2007 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Method of randomisation generation not

stated.

Allocation concealment (selection bias) Low risk Adequate; central randomisation; identical

appearing treatment packs

Incomplete outcome data (attrition bias)

All outcomes

Low risk Complete follow-up.

Selective reporting (reporting bias) Low risk All expected outcomes are reported (spon-

taneous delivery before 34 completed

weeks; birthweight; fetal or neonatal death;

major adverse outcomes before discharge;

need for neonatal special care)

Other bias Low risk “There were no significant differences in

baseline characteristics between the placebo

and progesterone groups” (see Table 1, page

465)

Singleton and twin pregnancies - adjust-

ment made for infant outcomes, “ the anal-

yses of infant outcomes used robust stan-

dard errors and were clustered on a mater-

nal identifier to account for the non-inde-

pendence of twin pairs.”

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Blinding of participants, caregivers, out-

come assessors.

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Blinding of participants, caregivers, out-

come assessors.

Glover 2011

Methods Pilot, single-centre, randomised, double-blind, placebo-controlled trial

Single centre, Miami Valley Hospital, Ohio, USA.

Participants Inclusion criteria: women < 20 weeks’ gestation and had at least 1 prior spontaneous

preterm birth of a live-born singleton infant between 200/ 7 weeks and 36 6/

7 weeks’

gestation.

Exclusion criteria: multiple gestations, the presence of major fetal anomalies, proges-

terone use in current pregnancy, the presence of a cervical cerclage and the presence of

a placenta previa

52Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Glover 2011 (Continued)

Interventions 36 women randomised: 20 allocated to progesterone group and 16 allocated to placebo

group

Experimental intervention: 400 mg (2 200-mg capsules) of oral micronized progesterone

MP. Administration of the tables was initiated between 160/ 7 and 19 6/7 weeks and was

continued until the completion of the 33rd week of gestation.

Control/Comparison intervention: control group took 2 identical placebo capsules for

the same time period

Outcomes Rate of recurrent spontaneous preterm birth.

Serum progesterone levels.

Neonatal morbidity and mortality:

birthweight (g) mean (SD);

male gender;

5-minute Apgar (mean);

ventilator use;

neonatal length of stay (mean), days.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk “Randomization was done by the hospi-

tal’s research pharmacy using a standard

randomization table methodology for two

groups.”

Allocation concealment (selection bias) Low risk Central allocation - pharmacy controlled:

“After subjects were randomized to their re-

spective group, the research pharmacy dis-

pensed a 1-month supply of either proges-

terone or placebo tablets in identical pre-

scription bottles, which were labelled iden-

tically as “progesterone study medication.”

Incomplete outcome data (attrition bias)

All outcomes

Low risk 45 patients were eligible for randomisation

- 9 women didn’t complete the initial eval-

uation or failed to present to the pharmacy

for randomisation and were excluded

Appears that 36 were randomised, but only

33 analysed. 3 more participants were ex-

cluded - 1 from the MP group as became

apparent that she had not had previous

spontaneous preterm birth as she had been

induced for severe eclampsia; 1 from the

placebo group had a spontaneous abortion

53Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Glover 2011 (Continued)

at 14 weeks; and another from placebo

group did not complete her prenatal care

at this centre and delivered elsewhere.

3 appear to have been excluded after ran-

domisation, see above

Analysis appears to be ITT: 2 women ended

their participation in the study - but both

delivered at this institution and were in-

cluded in their respective group for all anal-

yses

Selective reporting (reporting bias) Unclear risk In methods reports that neonatal mortality

will be reported - but was not reported

Other bias Low risk Similar baseline characteristics - no statisti-

cally significant differences between groups

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk “The study subjects’ physicians were aware

of the study participation but were blinded

to the group assignment.”

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not reported.

Grobman 2012

Methods Multicentre, randomised controlled trial.

Multicentre, Maternal-Fetal Units Network, USA.

Participants 657 women recruited between April 2007 and May 2011 in various centres in the USA

657 women randomised: 327 to OHPc group and 330 to placebo.

Inclusion criteria: nulliparous women with a singleton gestation between 16 and 22 3/

7 weeks with cervical length less than 30 mm

Exclusion criteria: Women that had selective fetal reduction for multiple pregnancy, had

evidence of additional fetal pole/embryo at 12 weeks or more, vaginal bleeding, pro-

lapsed membranes, major fetal anomaly, current or planned cerclage, maternal medical

condition associated with preterm delivery (e.g. hypertension) prior cervical surgery, or

planned preterm delivery

Interventions Experimental intervention: 250 mg IM weekly 17 alpha hydroxyprogesterone caproate

(17-OHPc) given by nurse until delivery or up to 36 weeks and 6 days gestation

Control/Comparison intervention: An identical appearing placebo.Weekly IM injections

of placebo (castor oil) given by study nurse until delivery or up to 36 weeks and 6 days

gestation

54Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Grobman 2012 (Continued)

Outcomes Maternal outcomes:

Preterm birth before 37 weeks

Birth before 35 weeks

Preterm rupture of membranes

Delivery < 28 weeks

Tocolytic therapy

Caesarean delivery

Side effects (any; injection site; urticaria; nausea)

Perinatal outcomes:

Fetal death

Neonatal death

Respiratory distress syndrome

Necrotising enterocolitis grade II or III

Intraventricular haemorrhage grade II or IV

Periventricular leucomalacia

Early-onset sepsis

Retinopathy of prematurity grade III or IV

Birthweight < 2500 g

5-minute Apgar < 7

NICU admission

Length of NICU stay, days

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Data co-ordinating centre to created

the computer-generated randomisation se-

quence. Simple turn method of randomi-

sation used

Allocation concealment (selection bias) Low risk Simple randomisation method stratified

by centre. Study treatments were research

pharmacy prepared

Incomplete outcome data (attrition bias)

All outcomes

Low risk All women randomised were accounted for

in the analysis. Discontinuation of treat-

ment was greater in the placebo group 33/

330 vs 18/327 but there was an ITT anal-

ysis

Selective reporting (reporting bias) Low risk All expected outcomes reported upon.

Other bias Unclear risk Groups appeared balanced at baseline

(slightly more white Hispanic in the

55Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Grobman 2012 (Continued)

placebo group and this group were slightly

younger). The study was stopped early

as the study monitoring committee de-

cided that further recruitment after data

for 591 available for interim analysis would

be unlikely to show benefit (planned 1000

women , data for 657)

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk It was stated that neither patients nor med-

ical staff were aware of treatment group and

the study was placebo controlled. It was

stated that the IM injections appeared iden-

tical

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk It was stated that the trial was blinded to

research staff collecting outcome data. The

trial was placebo controlled

Hartikainen 1980

Methods Method of randomisation: stated to be “placebo controlled and double blind”.

Allocation concealment: not stated.

Blinded outcome assessment: yes.

Completeness of follow-up: outcome data available for 77 women

Participants 77 women with a twin pregnancy.

Interventions Weekly intramuscular injection of either 250 mg 17-hydroxyprogesterone caproate or

placebo from 28 weeks’ gestation until 37 weeks’ gestation or birth if earlier

Outcomes Perinatal death.

Notes Trial conducted in Finland.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Process of sequence generation not stated.

Allocation concealment (selection bias) Unclear risk Unclear.

Incomplete outcome data (attrition bias)

All outcomes

Low risk Outcome data available for all participants.

Selective reporting (reporting bias) Low risk All expected outcomes are reported (dura-

tion of pregnancy; spontaneous delivery be-

56Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Hartikainen 1980 (Continued)

fore 37 weeks; weights of neonates; perina-

tal mortality; neonatal morbidity (respira-

tory problems; omphalitis; pulmonary in-

fection); maternal levels of progesterone;

estradiol)

Other bias Unclear risk “The gestational age at the onset of med-

ication, the gestational age at diagnosis of

twin pregnancy and the patient’s age were

similar in both groups.” (see table 1, page

693)

“The factors commonly regarded as risk

factors for premature delivery showed no

differences between groups.” (see table 2,

page 693)

Multiple pregnancies - abstract only avail-

able - limited data - no adjustment appar-

ent

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Caregivers and participants blinded.

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Blinding of outcome assessors.

Hassan 2011

Methods Multicentre randomised double-blind placebo-controlled trial

Multicentre - 44 centres in 10 countries, USA.

Participants 465 women randomised: 236 allocated to progesterone and 229 to placebo

Inclusion criteria: singleton gestation; gestational age between 19 + 0 and 23 + 6 weeks;

transvaginal sonographic cervical length between 10 and 20 mm; without signs and

symptoms of preterm labour

Exclusion criteria: planned cerclage; acute cervical dilation; allergic reaction to proges-

terone; current or recent progestogen treatment within 4 weeks; chronic medical condi-

tions that would interfere with study participation or evaluation of the treatment; ma-

jor fetal anomaly or known chromosomal abnormality; uterine anatomic malformation;

vaginal bleeding; known or suspected clinical chorioamnionitis

Interventions Experimental intervention: daily micronised vaginal progesterone gel - women self-ad-

ministered the study drug once daily in the morning. Each applicator delivered 1.125

g gel containing 90 mg progesterone

Control/Comparison intervention: an identical appearing placebo - each applicator de-

livered 1.125 g gel containing 90 mg placebo

57Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Hassan 2011 (Continued)

Outcomes Primary outcome: preterm birth before 33 weeks.

Secondary outcomes: neonatal morbidity - respiratory distress syndrome; bronchopul-

monary dysplasia; intraventricular haemorrhage grade III or IV; periventricular leucoma-

lacia; proven sepsis; necrotising enterocolitis; perinatal mortality (fetal death or neonatal

death) - composite scores were used to assess perinatal mortality and morbidity.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Randomisation allocation was 1:1 and was

accomplished using a centralised interac-

tive voice response system. Randomisation

was stratified according to centre and risk

strata (previous preterm birth between 20

and 35 weeks or no previous preterm birth)

using a permuted blocks strategy with a

block size of 4.

Allocation concealment (selection bias) Low risk Reported that allocation concealment ac-

complished in 3 ways:

1. participant study kits at each site were

numbered independently from the treat-

ment assignments in the randomisation

blocks;

2. IVR system specified which kit number

was to be dispensed to the subject;

3. the study drug packaging , applicators

and contents were identical in appearance

Incomplete outcome data (attrition bias)

All outcomes

Low risk 733 women eligible, 268 declined, 465 ran-

domised.

1 lost to follow-up from progesterone

group and 6 from placebo group

ITT analysis performed.

Selective reporting (reporting bias) Low risk All expected outcomes reported upon.

Other bias Low risk Baseline characteristics were similar be-

tween groups.

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Described as double blind.

58Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Hassan 2011 (Continued)

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not reported.

Hauth 1983

Methods Method of randomisation: stated to be “randomised, double blind intervention”.

Allocation concealment: not stated.

Blinded outcome assessment: yes.

Completeness of follow-up: outcome data available for all women randomised

Participants 168 women on active military duty.

Interventions Weekly intramuscular injection of either 1000 mg 17-hydroxyprogesterone caproate or

placebo from 16 to 20 weeks until 36 weeks’ gestation, or birth if earlier

Outcomes Preterm birth before 37 weeks’ gestation; birthweight less than 2.5 kg; perinatal death

Notes Trial conducted in Lackland Airforce Base, Texas, USA.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Sequence generation not stated.

Allocation concealment (selection bias) Unclear risk Unclear.

Incomplete outcome data (attrition bias)

All outcomes

Low risk Outcome data available for all women re-

cruited.

Selective reporting (reporting bias) Low risk All expected outcomes were reported

(low birthweight; perinatal mortality; preg-

nancy-induced hypertension; premature

labour)

Other bias Low risk The groups were similar for parity, previ-

ous abortion, race, cigarette smoking, and

marital status

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Caregivers and participants blinded.

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Blinding of outcome assessors.

59Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Ibrahim 2010

Methods Randomised placebo-controlled trial.

Ain Shams University Maternity Hospital, Cairo, Egypt.

Participants 50 women randomised: 25 allocated to progesterone group and 25 to placebo group

Inclusion criteria: singleton pregnant women in their second trimester with a history of

preterm labour

Exclusion criteria: women with a history medical disease during pregnancy, multiple

pregnancy, abdominal or cervical cerclage, known fetal anomalies or scarred uterus

Interventions Experimental intervention: 17-α-hydoxy progesterone caproate - 1 dose of 250 mg

intramuscular progesterone- weekly until 36 weeks

Control/Comparison intervention: standard dose of placebo IM per week until 36 weeks

Outcomes Mean gestation age.

Birth < 37 weeks.

Birth > 37 weeks.

Live neonates.

Need for NICU.

Neonatal death.

Birthweight < 2500 g.

Birthweight > 2500 g.

Apgar score < 7.

Apgar score > 7.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Not reported - says women were divided

into 2 groups -but no details of method of

randomisation

Allocation concealment (selection bias) Unclear risk “Randomisation was done by the use of

sealed envelopes which were opened by the

nurse responsible for giving the injections

to all participants whether Cidolut depot

or placebo” - unclear whether the envelopes

were opaque and sequentially numbered -

so nurse may have been able to foresee as-

signment

Incomplete outcome data (attrition bias)

All outcomes

Low risk All women appear to be included in the

results - 25 in each group

Selective reporting (reporting bias) Low risk All expected outcomes reported upon.

60Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Ibrahim 2010 (Continued)

Other bias Unclear risk Baseline demographic characteristics not

fully reported.

Blinding of participants and personnel

(performance bias)

All outcomes

Unclear risk Described as double blind - but no details

described.

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not reported.

Johnson 1975

Methods Method of randomisation: stated to be “random double blind fashion”.

Allocation concealment: next of identical drug packages.

Blinded outcome assessment: yes.

Completeness of follow-up: outcome data available for 43 women (7 women excluded

after randomisation)

Participants 50 women with a history of 2 previous spontaneous abortions or previous preterm birth

before 36 weeks’ gestation

Interventions Weekly intramuscular injection of either 250 mg 17-hydroxyprogesterone caproate or

placebo from ’booking’ until 24 weeks’ gestation

Outcomes Preterm birth before 37 weeks’ gestation; birthweight less than 2.5 kg; perinatal death

Notes Trial conducted in Baltimore, USA.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Generation of sequence not stated.

Allocation concealment (selection bias) Low risk Adequate; identical appearing treatment

packs.

Incomplete outcome data (attrition bias)

All outcomes

Low risk 7 women excluded post-randomisation

(1%).

Selective reporting (reporting bias) Low risk All expected outcomes reported (premature

delivery; birthweight; perinatal mortality)

Other bias Low risk Groups were similar for baseline charac-

teristics, (see table 2, page 678), although

61Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Johnson 1975 (Continued)

placebo group included fewer smokers and

less heavy smokers than progesterone group

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Caregivers and participants blinded.

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Outcome assessors blinded.

Lim 2011

Methods Multicentre, double-bind, placebo-controlled randomised trial

Multicentre, 55 obstetric clinics in Netherland.

Participants 671 women randomised: 336 allocated to progesterone and 326 allocated to placebo

Inclusion criteria: women with a multiple pregnancy and gestational age between 15 and

19 weeks

Exclusion criteria: women with a previous spontaneous preterm birth before 34 weeks,

serious congenital defects or death of 1 or more fetuses, early signs of twin-to-twin

transfusion syndrome, or primary cerclage were excluded from participation

Interventions Experimental intervention: 1 mL 17-α-hydoxyprogesterone caproate (250 mg/mL in

castor oil) - starting between 16 and 20 weeks and continuing to 36 weeks. Injections

were administered at the clinic, by a general practitioner or, in case the patient or a family

member had a background in medical practice, at the patient’s home

Control/Comparison intervention: 1 mL placebo (castor oil) - study medication and

placebo were identical in packaging, colour and consistency

Outcomes Primary outcomes: composite adverse neonatal outcome - severe respiratory distress

syndrome; bronchopulmonary dysplasia; intraventricular haemorrhage grade II B or

worse;necrotising enterocolitis; proven sepsis; death before discharge

Secondary outcomes:

Side effects (soreness, itching, and swelling).

Gestational age at delivery.

Preterm birth before 28, 32 and 37 weeks.

Length of admission to the NICU.

Maternal morbidity.

Hospitalisation of the mother due to (threatened) preterm labour

Costs.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

62Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Lim 2011 (Continued)

Random sequence generation (selection

bias)

Low risk “An independent data manager rendered a

computer-generated list that was stratified

by chorionicity, parity, and number of mul-

tiples, using random blocks of maximum

block size.”

Allocation concealment (selection bias) Low risk Web-based randomisation - “Randomiza-

tion was accessible through a website” and

“Allocation code was known only to ACE

Pharmaceuticals”

Incomplete outcome data (attrition bias)

All outcomes

Low risk 1865 women eligible, 1194 declined par-

ticipation, 671 women entered trial

336 randomised to progesterone group

and no women lost to follow-up/326 ran-

domised to placebo and 4 lost to follow-up

681 children born to 336 women in pro-

gesterone group/ 680 children born to 331

women in placebo group

Neonatal outcome available for 681 in pro-

gesterone group and 674 in placebo group

States that “all analyses were based on the

intention-to-treat principle.”

Selective reporting (reporting bias) Low risk All expected outcomes reported upon.

Other bias Low risk Baseline characteristics similar.

Multiple pregnancies (twin, triplet and 1

quadruplet) - adjustments made for all

neonatal, delivery, pregnancy and side ef-

fect outcomes

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk “Participants, caregivers, and data collec-

tors were all blinded to allocation.”

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Participants, caregivers, and data collectors

were all blinded to allocation.”

63Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Majhi 2009

Methods Prospective randomised trial.

Department of Obstetrics and Gynaecology, Postgraduate Instistute of Medical Educa-

tion and Research (PGIMER), Chandigarh, India

Participants 50 women randomised: 50 allocated to progesterone and 50 allocate to no treatment

Inclusion criteria: women at high risk for preterm birth, having a singleton pregnancy

and current gestation 16-24 weeks. High risk was defined by history of at least once prior

spontaneous preterm birth of a singleton infant > 20 and < 37 weeks due to spontaneous

labour or preterm rupture of fetal membranes

Exclusion criteria: women with multifetal gestation, congenital malformation in the

fetus, current or planned cervical cerclage or with any associated medical disorder were

excluded

Interventions Experimental intervention: 100 mg natural micronised progesterone capsule intravagi-

nally once daily at bedtime from 20-24 weeks’ gestation until 36 weeks

Control/Comparison intervention: no placebo - just managed according to the institute

protocol

Outcomes Primary outcomes:

Preterm birth < 37 weeks.

Preterm birth ≤ 34 weeks.

Secondary outcomes:

Maternal hospitalisation.

Vaginal delivery.

LSCS.

Birthweight (Mean SD).

NICU.

Sepsis.

Hyperbilirubinaemia.

Necrotising enterocolitis.

Cord pH (Mean SD).

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Computer-generated random-number ta-

bles.

Allocation concealment (selection bias) Low risk Sequentially numbered opaque sealed en-

velopes - provided centrally by Dept Bio-

statistics and investigators were not in-

volved in the randomisation procedure

64Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Majhi 2009 (Continued)

Incomplete outcome data (attrition bias)

All outcomes

Low risk 118 women met the inclusion criteria; 100

women consented and were included - 50

assigned to each group

There was no attrition during follow-up.

Selective reporting (reporting bias) Low risk All expected outcomes reported upon.

Other bias Unclear risk Both groups were similar in all characteris-

tics except BV, which was commoner in the

study group. It was treated in both groups

Blinding of participants and personnel

(performance bias)

All outcomes

Unclear risk Not reported - no placebo used though -

so participants would have been aware of

assignment

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not reported.

Meis 2003

Methods Method of randomisation: computer-generated 2:1 random number schedule.

Allocation concealment: next of identical drug packages.

Blinded outcome assessment: yes.

Completeness of follow-up: outcome data available for 463 women

Participants 463 women with a history of previous spontaneous preterm birth; exclusion women with

multiple pregnancy, known fetal anomaly, progesterone or heparin treatment during

pregnancy, current or planned cervical cerclage, hypertension, seizure disorder

Interventions Weekly intramuscular injection of either 250 mg 17-hydroxyprogesterone caproate or

placebo from 16 to 20 weeks until 36 weeks’ gestation, or birth if earlier

Outcomes Preterm birth before 37 weeks’ gestation; birthweight less than 2.5 kg; stillbirth; neonatal

death; intraventricular haemorrhage; respiratory distress syndrome; bronchopulmonary

dysplasia; sepsis; necrotising enterocolitis; retinopathy of prematurity; patent ductus

arteriosus

Notes Trial conducted by the Maternal-Fetal Medicine Network, USA.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Computer-generated sequence.

65Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Meis 2003 (Continued)

Allocation concealment (selection bias) Low risk Adequate; identical appearing treatment

packs.

Incomplete outcome data (attrition bias)

All outcomes

Low risk Outcome data available for all 463 women

recruited.

Selective reporting (reporting bias) Low risk All expected outcomes reported (preterm

delivery < 37, < 35, < 32 weeks; preg-

nancy outcomes (e.g. caesarean delivery;

chorioamnionitis; fetal and neonatal out-

comes (e.g. birthweight; neonatal death;

ventilatory support; necrotizing enterocol-

itis; proven sepsis)

Other bias Low risk Groups were similar for baseline character-

istics, (see table 1, page 2382), although the

women in the placebo group had had more

previous preterm deliveries

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Women, caregivers and outcome assessors

blinded.

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Women, caregivers and outcome assessors

blinded.

Moghtadaei 2008

Methods Randomised, double-blind, placebo-controlled trial.

Single site, Iran.

Participants 260 women randomised to treatment - number randomised to placebo not reported

Inclusion criteria: women in advanced maternal age - primiparous aged 35 years or more

Exclusion criteria: not reported.

Interventions Experimental intervention: weekly injections of 17P (250 mg) starting at 16-20 weeks’

gestation until 34 weeks

Control/Comparison intervention: matching placebo.

Outcomes Delivery before 37 weeks.

Delivery before 35 weeks.

Delivery before 32 weeks.

Hypertension.

Diabetes.

Intrauterine growth restriction.

Side effects at injection site.

66Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Moghtadaei 2008 (Continued)

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Only abstract available - data limited.

Allocation concealment (selection bias) Unclear risk Only abstract available - data limited.

Incomplete outcome data (attrition bias)

All outcomes

Unclear risk Only abstract available - data limited.

Selective reporting (reporting bias) Unclear risk Only abstract available - data limited.

Other bias Unclear risk Only abstract available - data limited.

Blinding of participants and personnel

(performance bias)

All outcomes

Unclear risk Only abstract available - data limited - al-

though states “double blind”

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Only abstract available - data limited.

Ndoni 2010

Methods Prospective randomised placebo-controlled study.

Single centre, Albania.

Participants 121 women randomised into 3 groups: IM injection prontogest (n = 52); oral proges-

terone (n = 43); placebo (n = 26)

Inclusion criteria: 15-22 weeks’ gestation at high risk for preterm labour, hospitalised in

the pathology of pregnancy clinic

Exclusion criteria: not stated.

Interventions Experimental intervention:

Group 1: Daily intramuscular injection of 17 alpha-hydroxyprogesterone caproate (Pron-

togest) (n = 52)

Group 2: Oral progesterone (Utrogestan) (n = 43).

Control/Comparison intervention:

Group 3: Identical-looking placebo (n = 26).

Outcomes Not reported.

Notes

67Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Ndoni 2010 (Continued)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk States “The participants were separated in

three groups..”

Allocation concealment (selection bias) Unclear risk Data limited - only reported as an abstract.

Incomplete outcome data (attrition bias)

All outcomes

Unclear risk Data limited - only reported as an abstract.

Selective reporting (reporting bias) Unclear risk No outcome data was reported in the ab-

stract.

Other bias Unclear risk Data limited - only reported as an abstract.

Blinding of participants and personnel

(performance bias)

All outcomes

Unclear risk Data limited - only reported as an abstract.

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Data limited - only reported as an abstract.

Norman 2009

Methods Double-blind randomised placebo-controlled trial.

Multicentre, 9 UK NHS hospitals - STOPPIT study (Study Of Progesterone for the

Prevention of Preterm Birth In Twins), UK

Participants 500 women randomised: 250 allocated to progesterone and 250 allocated to placebo

Inclusion criteria: women with twin pregnancy, with gestation and chorionicity estab-

lished by scan before 20 weeks’ gestation and attending the antenatal clinic during the

recruitment period

Exclusion criteria: pregnancy complicated by a recognised structural or chromosomal

fetal abnormality at the time of recruitment, or if they had contraindications to proges-

terone, planned cervical suture, planned elective delivery before 34 weeks’ gestation, or

planned intervention for twin-to-twin transfusion before 22 weeks’ gestation. Women

with higher multiple pregnancy were also excluded

Interventions Experimental intervention: daily vaginal progesterone gel 90 mg starting at 24 weeks

and 0 days of gestation. Each applicator of intervention contained 1.45 g of gel and

delivered 1.125 g of gel containing 8% progesterone

Control/Comparison intervention: placebo gel - administered in the same way as active

treatment, daily from 24 weeks’ gestation. Each applicator of intervention contained 1.

45 g of gel and delivered 1.125 g of gel containing 8% excipients

68Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Norman 2009 (Continued)

Outcomes Primary:

Delivery or intrauterine death before 34 weeks.

Secondary:

Gestation at delivery.

Mode of delivery.

Duration of each stage of labour.

Safety outcomes:

Admission to neonatal unit.

Duration of neonatal unit stay.

Mother died.

Intrauterine death.

Neonatal death.

Involved or prolonged inpatient maternal hospital admission.

Involved persistent/significant maternal disability or incapacity

Life threatening.

Chorioamnionitis or intrauterine infection.

Congenital anomaly or birth defect.

Maternal symptoms.

Maternal satisfaction.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk “We used a randomisation schedule with

permuted blocks of randomly mixed sizes

to make up treatment packs (either active

or placebo) for every patient, which were

held in individual hospital pharmacies until

use.”

Allocation concealment (selection bias) Low risk Central allocation from research network

- local researcher telephoned the interac-

tive voice response randomisation applica-

tion at the UK Clinical Research Network

registered trials unit to be given a partici-

pant number that corresponded to a spe-

cific treatment pack

Incomplete outcome data (attrition bias)

All outcomes

Low risk 1483 assessed for eligibility, 983 excluded

(did not meet eligibility; declined partici-

pation), 500 enrolled and randomised

250 randomised to each group, 3 lost to

follow-up from both treatment and con-

trol groups (6 altogether) - because of with-

69Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Norman 2009 (Continued)

drawal of consent or not traceable after

moving out of study area. 3 therefore ex-

cluded from each analysis

Analysis was by ITT. 494 mothers and 988

babies remained for the per-protocol anal-

ysis

Selective reporting (reporting bias) Low risk All expected outcomes appear to have been

reported.

Other bias Low risk Baseline characteristics similar.

Multiple pregnancies - adjustment for some

neonatal outcomes - give Odds Ratios: ad-

mission to neonatal unit;

duration of neonatal unit stay.

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk “All study personnel and participants were

masked to treatment assignment for the du-

ration of the study.”

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not reported.

O’Brien 2007

Methods Method of randomisation: random number table.

Allocation concealment: identical appearing sequentially numbered treatment packs.

Blinded outcome assessment: yes.

Completeness of follow-up: outcome data available for 611 of 659 women randomised

(48 (7.3%) women lost to follow-up)

Participants 659 women with a history of prior spontaneous preterm birth.

Exclusions: adverse reaction to progesterone; progesterone treatment within 4 weeks of

randomisation; medical conditions; suspected genital tract malignancy; thromboembolic

disease; fetal anomaly; multiple pregnancy; planned cervical cerclage

Interventions Nightly vaginal progesterone gel (90 mg) versus placebo.

Outcomes Preterm birth less than 32 weeks; Apgar scores, infant birthweight, NICU admission

Secondary analysis of data from O’Brien 2012: infant weight, length and head circum-

ference at 6, 12 and 24 months

Notes Trial conducted in 53 centres worldwide.

Risk of bias

Bias Authors’ judgement Support for judgement

70Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

O’Brien 2007 (Continued)

Random sequence generation (selection

bias)

Low risk Random number table.

Allocation concealment (selection bias) Low risk Adequate; identical appearing treatment

packs.

Incomplete outcome data (attrition bias)

All outcomes

Low risk Outcome data available for 611 of 659

women randomised (7.3% women lost to

follow-up)

Selective reporting (reporting bias) Low risk All expected outcomes reported (preterm

birth; maternal, fetal and neonatal out-

comes), detailed in table 2, page 692

Other bias Low risk Baseline characteristics similar between

groups (see table 1, page 691)

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Women, caregivers and outcome assessors

blinded.

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Women, caregivers and outcome assessors

blinded.

Papiernik 1970

Methods Method of randomisation: unclear.

Allocation concealment: unclear.

Blinded outcome assessment: yes.

Completeness of follow-up: outcome data available for 99 women

Participants 99 women with a “high preterm risk score”.

Interventions Every 3 days intramuscular injection of either 250 mg 17-hydroxyprogesterone caproate

or placebo from 28 weeks’ gestation until 32 weeks’ gestation

Outcomes Preterm birth before 37 weeks’ gestation; birthweight less than 2.5 kg; perinatal death

Notes Trial conducted in Paris, France.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Not reported.

71Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Papiernik 1970 (Continued)

Allocation concealment (selection bias) Unclear risk Unclear.

Incomplete outcome data (attrition bias)

All outcomes

Low risk Outcome data available for 99 women ran-

domised.

Selective reporting (reporting bias) Unclear risk Not possible to tell from translation.

Other bias Low risk From the translation of the paper “Each

group studied was similar in age, the num-

ber of previous pregnancies, the onset of

treatment and risk of preterm birth”

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Caregivers and participants blinded.

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Outcome assessor blinded.

Rai 2009

Methods Randomised, double-blind, placebo-controlled trial.

Single centre, Dept Obstetrics & Gynaecology, University College of Medical Science

and Guru Teg Bahadur Hospital, Delhi

Participants 150 women randomised: 75 allocated to progesterone and 75 allocated to placebo

Inclusion criteria: asymptomatic women aged between 18 and 35 years who were between

18 and 24 weeks of pregnancy, with a history of at least 1 spontaneous preterm delivery

(between 20 weeks and 36 weeks plus 6 days) and with a singleton live pregnancy

Exclusion criteria: women with first trimester bleeding, PROM, multiple pregnancy,

fetal anomalies or active liver disease were excluded

Interventions Experimental intervention: 100 mg oral micronised progesterone - twice a day from

recruitment (18-24 weeks) until 36 weeks or delivery

Control/Comparison intervention: placebo - twice a day from recruitment (18-24 weeks)

until 36 weeks or delivery

Outcomes Primary:

Mean prolongation of pregnancy in weeks and days of gestation

Gestational age at delivery:

< 28.

28-31 + 6.

32-33 + 6.

34-36 + 6.

Secondary:

72Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Rai 2009 (Continued)

Use of tocolysis.

Adverse drug effects.

Neonatal outcomes:

Neonatal age at delivery, week.

Birthweight, g.

NICU stay.

< 24 hours.

24 hours - 1 week.

> 1 week.

Apgar score at 1 minute.

< 6.

> 6.

Apgar score at 10 minute.

< 6.

> 6.

Neonatal deaths.

Respiratory distress syndrome.

RDS with septicaemia.

RDS with hyperbilirubinaemia.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk “computer-generated numbers table.”

Allocation concealment (selection bias) Low risk Central allocation suggested - random

number table provided by the Department

of Biostatistics.

Incomplete outcome data (attrition bias)

All outcomes

Low risk 150 assessed for eligibility, all enrolled and

randomised.

75 randomised to each group - and 1 lost

to follow-up from each group - 74 analysed

in each group

ITT not mentioned - but 74 from each

group analysed.

Selective reporting (reporting bias) Low risk All expected outcomes appear to have been

reported .

Other bias Low risk Baseline characteristics similar.

73Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Rai 2009 (Continued)

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk “The patients and the medical staff were

blinded to the study medication allocation

until after the last patient had delivered and

the study was complete.”

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not reported.

Rode 2011

Methods Randomised, double-blind, placebo-controlled trial.

Multicentre, 17 centres in Denmark and Austria.

Participants 677 women were randomised: 334 allocated to progesterone and 343 allocated to placebo

Inclusion criteria: women with a live, diamniotic twin pregnancy and chorionicity as-

sessed by ultrasound before 16 weeks’ gestation were eligible for recruitment

Exclusion criteria: age < 18 years; known allergy to progesterone or peanuts (active

treatment contained peanuts); history of hormone-associated thromboembolic disorders;

rupture of membranes; treatment for or signs of twin-to-twin transfusion syndrome;

intentional fetal reduction; known major structural or chromosomal fetal abnormality;

known or suspected malignancy in genitals or breasts; known liver disease; women with

higher-order multiple pregnancies; women who did not speak and understand Danish

or German

Interventions Experimental intervention: vaginal micronized progesterone pessaries (200 mg) - self-

administered daily by participants - starting from 20-24 weeks until 34 weeks’ gestation

Control/Comparison intervention: vaginal placebo pessaries (200 mg) - self-adminis-

tered daily by participants - starting from 20-24 weeks until 34 weeks’ gestation

Outcomes Primary:

Incidence of delivery before 34 + 0 weeks’ gestation.

Secondary:

Delivery before 22, 28, 32, 37 weeks’ gestation.

Delivery by caesarean section (emergency and planned).

Number of liveborn infants.

Miscarriage.

Intrauterine death.

Infant death during delivery.

Neonatal death.

Death after 28 days.

Sudden infant death.

Corticosteroids for fetal lung maturation.

Tocolytic therapy.

Maternal adverse outcomes (gestational diabetes; increased liver enzymes; pre-eclampsia;

thromboembolic event)

74Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Rode 2011 (Continued)

Birthweight < 2500 g.

Birthweight < 1500 g.

Apgar score < 7 at 5 minutes.

Congenital or chromosomal anomalies.

Perinatal complication:

Hypoglycaemia.

Intraventricular haemorrhage.

Jaundice.

Necrotising enterocolitis.

Patent ductus arteriosis.

Respiratory distress syndrome.

Retinopathy of prematurity.

Septicemia.

Admission to NICU.

CPAP treatment of at least 24 hours.

Respirator treatment.

Neurophysiological development 6 and 18 months after estimated date of delivery (as-

sessed via Ages and Stages Questionnaire (ASQ)

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk “The Perinatal Epidemiology Research

Unit created a randomization sequence

with a 1:1 ratio.”

Allocation concealment (selection bias) Low risk Central allocation suggested - used an in-

teractive voice-response randomisation sys-

tem:

“We stratified by center and chorionic-

ity using an interactive voice-response ran-

domization system at the Perinatal Epi-

demiology Research Unit. Each local re-

searcher telephoned the randomization sys-

tem, was given a randomization number

that corresponded to a specific treatment

box from a given batch”

Incomplete outcome data (attrition bias)

All outcomes

Low risk 1507 assessed for eligibility, 219 excluded,

1288 informed about the trial, 526 de-

clined to participate/did not answer, 677

randomised - 343 to each group

2 from placebo group lost to follow-up -

75Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Rode 2011 (Continued)

343 included in analysis for progesterone

group and 341 in placebo group

9 women in the progesterone group and

4 in the placebo group never started treat-

ment because they changed their minds

with respect to participation (n = 8), they

miscarried or a fetus died in utero (n = 2)

or they were withdrawn from the study (n

= 3). Analyses based on 343 from proges-

terone group and 341 from placebo group.

States that all analyses were performed ac-

cording to the ITT principle

Selective reporting (reporting bias) Low risk All expected outcomes appear to have been

reported.

Other bias Low risk Baseline characteristics were comparable

for the groups but there were slightly more

monochorionic gestations in the placebo

group - but the difference was not statisti-

cally significant

Multiple pregnancies - adjustments made

for infant outcomes - present Relative Risks

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk “All participants and study personnel were

blinded to treatment assignment for the du-

ration of the trial, and the randomization

code was not broken before all data had

been collected, including the infant follow-

up at 18 months of age.”

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Appears that outcome assessment was

blinded - “Only the statistician and the

independent Data Monitoring and Safety

Committee had access to unblinded data

during the study period”

Rouse 2007

Methods Method of randomisation: the “urn” method of randomisation.

Allocation concealment: next of identical appearing treatment injections.

Blinded outcome assessment: yes.

Completeness of follow-up: 661 women randomised with outcome data available for

655 women

76Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Rouse 2007 (Continued)

Participants 661 women with a twin pregnancy; exclusion women with known fetal anomaly, spon-

taneous fetal death of a fetus after 12 weeks, presumed monoamnionic placenta, sus-

pected twin-twin transfusion syndrome, marked ultrasonographic growth discordance,

progesterone or heparin treatment during pregnancy, current or planned cervical cer-

clage, hypertension, insulin-dependent diabetes, and twin pregnancies that were the re-

sult of intentional fetal reduction

Interventions Weekly intramuscular injection of either 250 mg 17-hydroxyprogesterone caproate or

placebo (castor oil) from 16 - 20 + 3 weeks until 34 completed weeks’ gestation, or birth

if earlier

Outcomes Primary outcome: composite of delivery or death prior to 35 weeks’ gestation.

Secondary outcomes: randomisation to delivery interval; composite adverse outcomes

(retinopathy of prematurity, respiratory distress syndrome, sepsis, necrotising enterocoli-

tis, bronchopulmonary dysplasia, grade III or IV intraventricular haemorrhage, periven-

tricular leucomalacia), birthweight (less than 2500 g and less than 1500 g), 5-minute

Apgar score < 7, patent ductus arteriosus, pneumonia, mechanical ventilation, seizures

Preterm birth before 37 weeks’ gestation; birthweight less than 2.5 kg; stillbirth; neonatal

death; intraventricular haemorrhage; respiratory distress syndrome; bronchopulmonary

dysplasia; sepsis; necrotising enterocolitis; retinopathy of prematurity; patent ductus

arteriosus

Notes Trial conducted by the Maternal-Fetal Medicine Network, USA.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk “The simple urn method of randomisa-

tion with stratification according to clinical

center was used by the George Washing-

ton University Biostatistical Co-ordinating

Center to create a randomization sequence

for each center,...”

Allocation concealment (selection bias) Low risk Adequate; identical appearing treatment

packs.

Incomplete outcome data (attrition bias)

All outcomes

Low risk Outcome data available for 655 of

661women (less than 1% loss to follow-up)

Selective reporting (reporting bias) Low risk All expected outcomes reported (delivery

or fetal death before 35 weeks’ gestation;

other obstetric and neonatal outcomes) see

table 2 and 3

Other bias Unclear risk “Baseline demographic data were similar in

the two study groups” (see table 1)

Multiple pregnancies - no adjustment in

77Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Rouse 2007 (Continued)

analysis apparent.

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Women, caregivers and outcome assessors

blinded.

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Women, caregivers and outcome assessors

blinded.

Rozenberg 2012

Methods Open-label randomised controlled trial.

Multicentre, 13 French university hospitals.

Participants 188 women randomised.

Inclusion criteria: women with singleton pregnancies admitted at 24 + 0 through 31 +

6 weeks of gestation with a cervical length < 25 mm for an episode of preterm labour

that was then successfully arrested by tocolytic treatment. A course of betamethasone

12 mg, repeated after 24 hours, was given intramuscularly in all patients.

Exclusion criteria: cervical dilatation > 3cm, chorioamnionitis, fetal heart rate abnormal-

ities, placenta previa, adruptio placentae, PROM, polyhydramnios, IUGR, pregnancy-

related hypertension or pre-eclampsia, maternal or fetal condition requiring immediate

delivery, anticonvulsive treatment or participation in any other trial

Interventions Experimental intervention: 500 mg of intramuscular 17 alpha-hydroxyprogesterone

caproate (17 P) started after tocolysis ended and repeated twice weekly until 36 weeks

or until preterm delivery.

Control/Comparison intervention: no treatment with 17P. Additional management in

the 2 arms was left to the discretion of the attending physician, except that progesterone

was not allowed in the control group

Outcomes Time from randomisation to delivery, preterm delivery before 37, 34 and 32 weeks, read-

missions for preterm labour, NICU, birthweight, respiratory distress, bronchopulmonary

dysplasia, necrotising enterocolitis, periventricular leucomalacia, perinatal death, severe

maternal or neonatal adverse effect

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Centralised, computer-generated

randomisation process in a 1:1 ratio

Allocation concealment (selection bias) Unclear risk Not described.

78Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Rozenberg 2012 (Continued)

Incomplete outcome data (attrition bias)

All outcomes

Low risk A total of 188 women were randomised.

Outcome data available for 184 women.

States “assessed according to the intention-

to-treat principle”

Selective reporting (reporting bias) Low risk All expected outcome results reported.

Other bias Unclear risk A subsequent letter to the journal ques-

tioned the use of the study medication un-

less it had been tested for purity and many

samples of the medication did not meet

FDA specifications. The letter stated that

this casts doubt on the findings of any study

using 17Pc. The authors confirmed that the

study medication was not of questionable

quality

Study groups appeared similar at baseline

although 12% of the intervention group

and 24% of controls had had a previous

preterm delivery

Blinding of participants and personnel

(performance bias)

All outcomes

High risk No blinding - trial is described as “open

label”.

Blinding of outcome assessment (detection

bias)

All outcomes

High risk Not mentioned. High risk of bias (ran-

domisation to the control group may have

affected subsequent treatment and out-

come assessment)

Saghafi 2011a

Methods Described as an interventional study.

Obstetrics Clinic of Ghaem Hospital, Mashad University of Medical Sciences, Iran

Participants 100 women randomised: 50 allocated to progesterone and 50 allocated to placebo

Inclusion criteria: pregnant women with a previous history of preterm delivery who had

no contraindication for continuing pregnancy

Exclusion criteria: women who had entered the active phase of delivery, cases of preterm

PROM, pre-eclampsia, vaginal bleeding, maternal-fetal diseases for which continuation

of the pregnancy was dangerous, symptoms of distress, and fetal anomalies

79Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Saghafi 2011a (Continued)

Interventions Experimental intervention: 250 mg of intramuscular 17 alpha-hydroxyprogesterone

caproate (17 P) weekly from 16 weeks’ gestation up to a maximum of 37 weeks’ gestation.

Control/Comparison intervention: routine perinatal care.

Outcomes Preterm delivery (< 37 weeks).

Apgar score at 1 and 5 minutes (mean values given).

Newborn weight (g) mean values.

Vaginal delivery (n).

Low birthweight neonates (%) - didn’t specify what low birthweight was

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Not described - just says “They were ran-

domly divided into two groups...”

Allocation concealment (selection bias) Unclear risk Not described.

Incomplete outcome data (attrition bias)

All outcomes

Low risk Appears to be no loss.

Outcome data available for all 100 women,

50 randomised to each group

Selective reporting (reporting bias) Unclear risk Data limited - only reported as an abstract.

Other bias Low risk States that the 2 groups were similar for

age, gravidity, abortions, previous preterm

births - see table 1

Blinding of participants and personnel

(performance bias)

All outcomes

Unclear risk Not described.

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not described.

Senat 2012

Methods Open-label multicentre, randomised controlled trial in France - 13 French university

hospitals

Participants 165 women randomised and 161 followed up - it was not clear how many were ran-

domised to each group

Inclusion criteria: asymptomatic women with twin pregnancy and cervical length < 25

mm between 20 and 32 weeks of gestation

80Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Senat 2012 (Continued)

Exclusion criteria: not reported in the abstract.

Interventions Experimental intervention: 500 mg intramuscular 17 alpha-hydroxyprogesterone

caproate (17P) - twice weekly until 36 weeks or until preterm delivery

Control/Comparison intervention: no 17P.

Additional management in the 2 arms was left to the discretion of the attending physician,

except that progesterone was not allowed in the control group

Outcomes Median time to delivery; delivery before 32 and 34 weeks’ gestation

Notes Not able to report any outcome data because the number randomised to each group is

not stated

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Randomly assigned by computer-gener-

ated randomisation process in a 1:1 ratio

Allocation concealment (selection bias) Low risk States - central randomisation. “A cen-

tralised, computer generated randomised

process in a 1:1 ratio.”

Incomplete outcome data (attrition bias)

All outcomes

Unclear risk Unclear - limited data reported as only an

abstract.

Selective reporting (reporting bias) Unclear risk Unclear - limited data reported as only an

abstract.

Other bias Unclear risk Unclear - limited data reported as only an

abstract.

Blinding of participants and personnel

(performance bias)

All outcomes

High risk Described as an “open label trial”.

Blinding of outcome assessment (detection

bias)

All outcomes

High risk Described as an “open label trial”.

81Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Serra 2013

Methods 3-arm RCT in 5 centres in Spain, individual randomisation.

Participants 294 women attending 1 of 5 university hospital centres in Spain between December

2005 and January 2008

Inclusion criteria: women were recruited at 11-13 weeks’ gestation. If they had previously

been treated with vaginal progesterone it was stopped. Women were 18 years or more,

dichorionic, diamniotic twin pregnancy

Exclusion criteria: singleton pregnancy, mono-chorionic twin pregnancies, triplets or

higher multiple pregnancies, elective cervical cerclage before 14 weeks’ gestation, history

of hepatic problems, pregnancy cholestasis, abnormal liver or kidney function, allergy

to peanuts or study medication, recurrent vaginal bleeding or infection, fetal anomalies,

alcohol or illicit drug use and smoking more than 10 cigarettes per day

Interventions Intervention:

1. 200 mg vaginal progesterone self-inserted daily at bedtime. (98 women)

2. 400 mg vaginal progesterone self-inserted daily at bedtime (98 women)

3. (control) placebo vaginal pessaries self-inserted daily at bedtime (98 women)

All women were provided with specially manufactured identical looking pessaries, 2 to

be administered each evening

Total number randomised: n = 294.

Outcomes Preterm birth rate < 37 weeks of gestation; early preterm birth rate < 34, 32, 28 weeks

of gestation; need for tocolytic treatment; steroid treatment; rate of preterm premature

rupture of membranes < 37 weeks of gestation; cervical length measurements at 20,

24, 28 weeks of gestation; perinatal mortality and morbidity; caesarean section. Local

tolerance to the treatment; number of serious systemic adverse effects

Perinatal outcomes: short-term neonatal morbidity (respiratory distress syndrome; pneu-

monia; early onset sepsis; seizures; graded III-IV intraventricular haemorrhage; stage II-

II necrotising enterocolitis; and/or patent duct arteriosus). Long-term neonatal morbid-

ity included: broncho-pulmonary dysplasia; periventricular leucomalacia; and/or severe

retinopathy of prematurity

Birthweight < 2500 g; 5 minute Apgar score; major congenital malformation; admission

to NICU; mechanical ventilation; neonatal death

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk “Randomisation was performed by com-

puter (SPSS Random Number Generator,

using a randomisation sequence 1:1:1 ratio

(blocks of nine, with no stratification).”

Allocation concealment (selection bias) Low risk Central allocation “An external monitor-

ing centre provided a randomisation code

number for each pregnant woman” “The

medication was given at each visit by the

82Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Serra 2013 (Continued)

hospital pharmacy department.”

Incomplete outcome data (attrition bias)

All outcomes

Low risk It was stated that an ITT analysis was car-

ried out. There was very little loss to fol-

low-up

294 randomised at 20 weeks.

290 analysed - analysed as ITT.

Placebo group - n = 98, n = 10 discontinued

study, n = 2 lost to follow-up, 96 analysed

200 mg progesterone group = n = 98, n =

11 discontinued study, n = 1 lost to follow-

up, 97 analysed

400 mg progesterone group = n = 98, n =

10 discontinued study, n = 1 lost to follow-

up, 97 analysed

Selective reporting (reporting bias) Unclear risk Most expected outcomes reported upon.

However - individual outcome results for

short-term and long-term neonatal mor-

bidity were not reported, e.g. respiratory

distress syndrome, periventricular leuco-

malacia

Other bias Unclear risk Baseline characteristics similar. Manage-

ment may have differed in the 5 partici-

pating centres although this was not clear.

Groups appeared similar at baseline

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Women and staff were blinded. Medication

packs were coded and contained identical

appearing pessaries

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk It was reported that all study personnel were

blind to treatment allocation for the dura-

tion of the project

Sharami 2010

Methods Described as placebo-controlled double-blind RCT. Alzhara Hospital, Iran. Recruitment

between 2007 and 2009

Participants Inclusion criteria:173 randomised. Women with singleton pregnancies, gestational age

28-36 weeks admitted with threatened preterm labour successfully treated with tocolysis

with intact membranes and less than 2cm cervical dilatation

Exclusion criteria: patients with intrauterine infection, vaginal bleeding, pre-eclampsia,

urinary tract infection, intrauterine growth retardation, hypertension and heart disease,

dilatation ≥ 2 cm, fetal distress and fetal abnormalities

83Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Sharami 2010 (Continued)

Interventions Intervention: n = 86 women. 200 mg vaginal progesterone daily until 36 weeks’ gestation

Control/comparison intervention: n = 87 women. Placebo vaginal suppositories until

36 weeks’ gestation

All patients (in both groups) received 12 mg betamethasone and antibiotic prophylaxis

and advised to restrict physical activity

Outcomes Primary:

Time until delivery (latency time)

PTB before 34 and 37 weeks of gestation

Secondary:

Selected maternal and neonatal outcomes including nausea, headache, pre-eclampsia,

PROM, chorioamnionitis, post-partum haemorrhage for maternal complications and

birth weight, Apgar score, admission to the NICU, fetal death, neonatal death, RDS,

sepsis, and intraventricular haemorrhage (IVH)

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Just states, “Random block allocation

method” - no other details

Allocation concealment (selection bias) Unclear risk No details reported.

Incomplete outcome data (attrition bias)

All outcomes

Low risk 270 eligible, 97 women delivered within 48

hours, a total of 173 randomised

Placebo group - n = 87, n = 4 lost to follow-

up, 83 completed follow-up - 83 included

in analysis

Progesterone group = n = 86, n = 6 lost

to follow-up, 80 completed follow-up - 80

included in analysis

Selective reporting (reporting bias) Unclear risk Not clear. Several outcomes stated as sec-

ondary outcomes in the methods were not

reported (this may have been because there

were no cases but this was not stated, e.g.

fetal death, intraventricular haemorrhage)

Other bias Low risk Baseline characteristics similar.

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Both patients and physician were blinded

to the type of suppositories

84Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Sharami 2010 (Continued)

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Described as double-blind. Not clear if out-

come assessment was blind

CNS: central nervous system

CPAP: continuous positive airways pressure

ITT: intention-to-treat

ICSI: intracytoplasmic sperm injection

IUGR: intrauterine growth restriction

IVF: in vitro fertilisation

LSCS: lower segment Cesarian section

LMP: last menstrual period

NICU: neonatal intensive care unit

PROM: premature rupture of membranes

PPROM: preterm premature rupture of membranes

PTB:preterm birth

RDS: respiratory distress syndrome

SD: standard deviation

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Abbott 2012 RCT embedded in a longitudinal study, but comparison of progesterone versus cerclage, so not relevant to

this review

Arikan 2011 Acute treatment - being used as a tocolytic.

Berghella 2010 Women were randomised to cerclage versus no cerclage - not randomised to 17P use or not - stratified at

randomisation to intent to use or not use 17P

Breart 1979 Progesterone administration for prevention of miscarriage.

Brenner 1962 Progesterone administration for prevention of miscarriage.

Chandiramani 2012 Not clear that this is an RCT and also compares progesterone with cerclage, so not relevant to this review

Corrado 2002 Progesterone administered after amniocentesis for the prevention of miscarriage

Hobel 1986 Compares an oral progesterone agent with placebo but the only outcome reported is the rate of preterm birth

as a percentage (not able to determine n = in either progesterone or placebo group). Other results reported as

experimental group versus control (this allocation is not randomised but based on risk assessment at first and

second antenatal visit)

85Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

(Continued)

Ionescu 2012 Progesterone versus cerclage - so not relevant to this review

Keeler 2009 Comparison with McDonald cerclage, not placebo - topic of another review

Le Vine 1964 Quasi-randomised trial.

Rust 2006 Progesterone versus cerclage - so not relevant to this review

Suvonnakote 1986 Quasi-randomised trial - women were ’divided’ into 2 groups (trial group and control group)

Turner 1966 Progesterone administration for prevention of miscarriage.

Walch 2005 Progesterone administration for prevention of miscarriage.

Yemini 1985 Quasi-randomised trial.

RCT: randomised controlled trial

Characteristics of ongoing studies [ordered by study ID]

Coomarasamy 2012

Trial name or title Progesterone in recurrent miscarriages (PROMISE) study.

Methods

Participants 1. Women with unexplained recurrent miscarriages (3 or more consecutive first trimester miscarriages).

2. Age 18-39 years at randomisation (likelihood of miscarriages due to chromosomal aberrations is higher in

older women; such miscarriages are unlikely to be prevented by progesterone therapy).

3. Spontaneous conception (as confirmed by urinary pregnancy tests).

4. Willing and able to give informed consent.

Interventions Intervention group: progesterone pessaries (400 mg twice daily) started soon as possible after a positive

pregnancy test (and no later than 6 weeks’ gestation) and continued to 12 weeks of gestation.

Control group: placebo.

Total duration of follow-up per participant: 42 weeks.

Outcomes Primary outcome: live births beyond 24 weeks.

Secondary outcomes:

1. Gestation at delivery.

2. Clinical pregnancy at 6-8 weeks.

3. On-going pregnancy at 12 weeks (range 11-13 weeks).

4. Miscarriage rate.

86Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Coomarasamy 2012 (Continued)

5. Survival at 28 days of neonatal life.

6. Congenital abnormalities with specific examination for genital anomalies.

7. Adverse events.

Starting date 01/05/2009, anticipated end date 0105/2012.

Contact information Dr Arri Coomarasamy: [email protected]

Notes

Creasy 2008

Trial name or title The effect of vaginal progesterone administration in the prevention of preterm birth in women with a short

cervix.

NCT00615550.

Methods

Participants Women with a singleton gestation and a short cervical length by transvaginal ultrasound defined as 10-20

Interventions Progesterone 8% vaginal gel, 1.125 g once daily, beginning at 19 0/7 to 23 6/7 weeks’ gestation through 36

6/7 weeks’ gestation

Placebo vaginal gel, 1.125 g once daily, beginning at 19 0/7 to 23 6/7 weeks’ gestation through 36 6/7 weeks’

gestation

Outcomes Reduction in the frequency of preterm birth (less than or equal to 32 6/7 weeks’ gestation

Starting date March 2008.

Contact information Joseph R Parella: [email protected]

Notes

Crowther 2007

Trial name or title Progesterone for the prevention of neonatal respiratory distress syndrome (The PROGRESS Study).

ISRCTN20269066.

Methods

Participants Women with a history of previous spontaneous preterm birth.

Interventions Daily vaginal progesterone vs placebo.

Outcomes Neonatal lung disease.

Starting date October 2005.

87Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

http://mailto:jparella%40columbialabs.com

Crowther 2007 (Continued)

Contact information [email protected]

[email protected]

Notes

Martinez 2007

Trial name or title Vaginal progesterone to prevent preterm delivery in women with preterm labour.

NCT00536003.

Methods

Participants Women presenting with symptoms and signs of preterm labour, and evidence of cervical change or positive

fetal fibronectin testing

Interventions Vaginal progesterone vs placebo.

Outcomes Preterm birth less than 37 weeks.

Starting date July 2006.

Contact information Begona Martinez de Tejada: [email protected]

Notes

Nassar 2007

Trial name or title Prevention of preterm delivery in twin pregnancies by 17 alpha hydroxyprogesterone caproate.

NCT00141908.

Methods

Participants Women with a twin pregnancy.

Interventions Weekly IM 17OHP vs placebo.

Outcomes Preterm birth.

Starting date March 2006.

Contact information Anwar Nassar: [email protected]

Notes

88Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Norman 2012

Trial name or title Trial protocol OPPTIMUM - Does progesterone prophylaxis for the prevention of preterm labour improve

outcome?

ISRCTN14568373.

Methods Double-blind randomised placebo controlled trial.

Participants Women with singleton pregnancy and at high risk of preterm labour

Interventions Prophylactice vaginal natural progesterone, 200 mg daily from 22-34 weeks’ gestation vs placebo

Outcomes Incidence of preterm delivery (before 34 weeks); neonatal outcome (composite of death and major morbidity)

; childhood cognitive and neurosensory outcomes at 2 years of age

Starting date Recruitment began in 2009 and is scheduled to close in Spring 2013

Contact information Jane E Norman.

Notes

Perlitz 2007

Trial name or title Prevention of recurrent preterm delivery by a natural progesterone agent.

NCT00329316.

Methods

Participants Women with preterm labour in a prior pregnancy.

Interventions Daily vaginal progesterone gel vs placebo.

Outcomes Not specified.

Starting date Not yet recruiting.

Contact information Yuri Perlitz: [email protected]

Notes

Starkey 2008

Trial name or title Comparing intramuscular versus vaginal progesterone for prevention of preterm birth.

NCT00579553.

Methods

Participants Women with singleton pregnancies and history of prior spontaneous preterm birth

89Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Starkey 2008 (Continued)

Interventions Weekly intramuscular injection of 17 alpha hydroxylprogesterone caproate (250 mg) or daily vaginal proges-

terone (100 mg)

Outcomes Maternal, fetal and neonatal outcomes.

Starting date October 2006.

Contact information Christy Zornes: [email protected]

Notes

Swaby 2007

Trial name or title Pilot randomised controlled trial of vaginal progesterone to prevent preterm birth in multiple pregnancy

Methods

Participants Women with a multiple pregnancy.

Interventions Vaginal progesterone (90 mg) or placebo gel.

Outcomes Duration of pregnancy.

Starting date

Contact information C Swaby. University of Calgary, 1403-29 Street, Calgary, Canada

Notes

van Os 2011

Trial name or title Preventing preterm birth with progesterone: costs and effects of screening low risk women with a singleton

pregnancy for short cervical length, the Triple P study

Netherlands Trial Register (NTR): NTR207.

Methods Cohort study with a randomised placebo-controlled trial embedded

Multicentre, Dutch Obstetric Consortium.

Participants Inclusion criteria: women with low risk singleton pregnancies at 18-22 weeks’ gestation with a short cervix

<= 30 mm

Interventions Vaginal progesterone 200 mg-capsules of micronised progesterone - vs placebo, taken between 22 and 34

weeks

Outcomes Primary outcome: composite poor neonatal outcome (death or severe morbidity): severe respiratory distress

syndrome; bronchopulmonary dysplasia; periventricular leucomalacia > grade 1; intracerebral haemorrhage

> grade II; necrotising enterocolitis > stage 1; proven sepsis and death before discharge from the nursery

90Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

http://mailto:christina-zornes%40ouhsc.edu

van Os 2011 (Continued)

Secondary outcomes: time to delivery; preterm birth rate before 32, 34 and 37 weeks; days of admission in

neonatal intensive care unit; maternal morbidity; maternal admission days for preterm labour; costs; growth,

physical condition (close examination of genital tract), neurodevelopmental outcome of child at 24 month

age; cost-effectiveness of screening for short cervical length

Starting date October 2011 - not clear from paper.

Contact information Paper reporting study protocol - Melanie A van Os first author - correspondence email: [email protected]

Notes

Wood 2007

Trial name or title Vaginal progesterone versus placebo in multiple pregnancy.

NCT00343265.

Methods

Participants Women with a multiple pregnancy.

Interventions Daily vaginal progesterone gel vs placebo.

Outcomes Primary: gestational age.

Starting date June 2006.

Contact information Stephen Wood: [email protected]

Notes

IM: intramuscular

vs: versus

91Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

D A T A A N D A N A L Y S E S

Comparison 1. Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Perinatal mortality 6 1453 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.33, 0.75]

1.1 Intramuscular 3 553 Risk Ratio (M-H, Fixed, 95% CI) 0.41 [0.23, 0.73]

1.2 Vaginal 2 752 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.34, 1.29]

1.3 Oral 1 148 Risk Ratio (M-H, Fixed, 95% CI) 0.43 [0.12, 1.59]

2 Preterm birth less than 34 weeks 5 602 Risk Ratio (M-H, Random, 95% CI) 0.31 [0.14, 0.69]

2.1 Intramuscular 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]

2.2 Vaginal 4 454 Risk Ratio (M-H, Random, 95% CI) 0.21 [0.10, 0.44]

2.3 Oral 1 148 Risk Ratio (M-H, Random, 95% CI) 0.59 [0.39, 0.90]

3 Preterm birth less than 37 weeks 10 1750 Risk Ratio (M-H, Random, 95% CI) 0.55 [0.42, 0.74]

3.1 Intramuscular 4 652 Risk Ratio (M-H, Random, 95% CI) 0.62 [0.52, 0.75]

3.2 Vaginal 5 1065 Risk Ratio (M-H, Random, 95% CI) 0.52 [0.29, 0.92]

3.3 Oral 1 33 Risk Ratio (M-H, Random, 95% CI) 0.46 [0.19, 1.11]

4 Threatened preterm labour 2 601 Risk Ratio (M-H, Random, 95% CI) 0.87 [0.47, 1.62]

4.1 Intramuscular 1 459 Risk Ratio (M-H, Random, 95% CI) 1.17 [0.73, 1.87]

4.2 Vaginal 1 142 Risk Ratio (M-H, Random, 95% CI) 0.62 [0.35, 1.11]

5 Spontaneous vaginal delivery 2 200 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.97, 1.18]

5.1 Vaginal 2 200 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.97, 1.18]

6 Caesarean section 3 1170 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.81, 1.20]

6.1 Intramuscular 1 459 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.68, 1.30]

6.2 Vaginal 2 711 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.79, 1.30]

7 Antenatal corticosteroids 2 1070 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.73, 1.16]

7.1 Intramuscular 1 459 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.58, 1.30]

7.2 Vaginal 1 611 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.72, 1.26]

8 Antenatal tocolysis 4 1262 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.78, 1.35]

8.1 Intramuscular 2 503 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.73, 1.72]

8.2 Vaginal 1 611 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.70, 1.74]

8.3 Oral 1 148 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.42, 1.35]

9 Infant birthweight less than

2500 g

4 692 Risk Ratio (M-H, Random, 95% CI) 0.58 [0.42, 0.79]

9.1 Intramuscular 3 551 Risk Ratio (M-H, Random, 95% CI) 0.63 [0.49, 0.81]

9.2 Vaginal 1 141 Risk Ratio (M-H, Random, 95% CI) 0.22 [0.07, 0.74]

10 Respiratory distress syndrome 3 1217 Risk Ratio (M-H, Random, 95% CI) 0.45 [0.17, 1.16]

10.1 Intramuscular 1 458 Risk Ratio (M-H, Random, 95% CI) 0.63 [0.38, 1.04]

10.2 Vaginal 1 611 Risk Ratio (M-H, Random, 95% CI) 0.92 [0.59, 1.43]

10.3 Oral 1 148 Risk Ratio (M-H, Random, 95% CI) 0.10 [0.03, 0.30]

11 Use of assisted ventilation 3 633 Risk Ratio (M-H, Random, 95% CI) 0.40 [0.18, 0.90]

11.1 Intramuscular 1 459 Risk Ratio (M-H, Random, 95% CI) 0.59 [0.35, 1.01]

11.2 Oral 1 33 Risk Ratio (M-H, Random, 95% CI) 0.11 [0.01, 1.92]

11.3 Vaginal 1 141 Risk Ratio (M-H, Random, 95% CI) 0.24 [0.07, 0.81]

12 Intraventricular haemorrhage -

all grades

3 1211 Risk Ratio (M-H, Random, 95% CI) 0.70 [0.20, 2.46]

12.1 Intramuscular 1 459 Risk Ratio (M-H, Random, 95% CI) 0.25 [0.08, 0.82]

12.2 Vaginal 2 752 Risk Ratio (M-H, Random, 95% CI) 1.31 [0.46, 3.77]

92Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

13 Intraventricular haemorrhage -

grade III or IV

2 1069 Risk Ratio (M-H, Fixed, 95% CI) 1.59 [0.21, 11.75]

13.1 Intramuscular 1 458 Risk Ratio (M-H, Fixed, 95% CI) 2.52 [0.12, 52.09]

13.2 Vaginal 1 611 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.06, 15.55]

14 Periventricular leucomalacia 1 141 Risk Ratio (M-H, Fixed, 95% CI) 3.13 [0.13, 75.52]

14.1 Vaginal 1 141 Risk Ratio (M-H, Fixed, 95% CI) 3.13 [0.13, 75.52]

15 Retinopathy of prematurity 1 458 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.15, 1.69]

15.1 Intramuscular 1 458 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.15, 1.69]

16 Necrotising enterocolitis 3 1170 Risk Ratio (M-H, Fixed, 95% CI) 0.30 [0.10, 0.89]

16.1 Intramuscular 1 459 Risk Ratio (M-H, Fixed, 95% CI) 0.06 [0.00, 1.03]

16.2 Vaginal 2 711 Risk Ratio (M-H, Fixed, 95% CI) 0.53 [0.15, 1.92]

17 Neonatal sepsis 3 700 Risk Ratio (M-H, Random, 95% CI) 0.42 [0.08, 2.23]

17.1 Intramuscular 1 459 Risk Ratio (M-H, Random, 95% CI) 1.13 [0.35, 3.59]

17.2 Vaginal 2 241 Risk Ratio (M-H, Random, 95% CI) 0.13 [0.02, 1.01]

18 Patent ductus arteriosus 1 459 Risk Ratio (M-H, Fixed, 95% CI) 0.44 [0.16, 1.18]

18.1 Intramuscular 1 459 Risk Ratio (M-H, Fixed, 95% CI) 0.44 [0.16, 1.18]

19 Intrauterine fetal death 4 1164 Risk Ratio (M-H, Random, 95% CI) 0.66 [0.26, 1.69]

19.1 Intramuscular 3 553 Risk Ratio (M-H, Random, 95% CI) 0.49 [0.14, 1.69]

19.2 Vaginal 1 611 Risk Ratio (M-H, Random, 95% CI) 1.22 [0.33, 4.51]

20 Neonatal death 6 1453 Risk Ratio (M-H, Fixed, 95% CI) 0.45 [0.27, 0.76]

20.1 Intramuscular 3 553 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.17, 0.87]

20.2 Vaginal 2 752 Risk Ratio (M-H, Fixed, 95% CI) 0.53 [0.24, 1.18]

20.3 Oral 1 148 Risk Ratio (M-H, Fixed, 95% CI) 0.43 [0.12, 1.59]

21 Developmental delay 1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.36, 2.04]

21.1 Intramuscular 1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.36, 2.04]

22 Intellectual impairment 1 274 Risk Ratio (M-H, Fixed, 95% CI) 1.29 [0.05, 31.34]

22.1 Intramuscular 1 274 Risk Ratio (M-H, Fixed, 95% CI) 1.29 [0.05, 31.34]

23 Motor Impairment 1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.11, 3.76]

23.1 Intramuscular 1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.11, 3.76]

24 Visual Impairment 1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.16, 4.57]

24.1 Intramuscular 1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.16, 4.57]

25 Hearing Impairment 1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.09, 1.24]

25.1 Intramuscular 1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.09, 1.24]

26 Cerebral palsy 1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.14 [0.01, 3.48]

26.1 Intramuscular 1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.14 [0.01, 3.48]

27 Learning difficulties 1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.38, 1.92]

27.1 Intramuscular 1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.38, 1.92]

28 Height less than 5th centile 1 270 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.23, 2.49]

28.1 Intramuscular 1 270 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.23, 2.49]

29 Weight less than 5th centile 1 270 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.30, 2.05]

29.1 Intramuscular 1 270 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.30, 2.05]

30 Adverse drug reaction 1 148 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.24, 2.15]

30.1 Oral 1 148 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.24, 2.15]

31 Pregnancy prolongation

(weeks)

1 148 Mean Difference (IV, Fixed, 95% CI) 4.47 [2.15, 6.79]

31.1 Oral 1 148 Mean Difference (IV, Fixed, 95% CI) 4.47 [2.15, 6.79]

32 Apgar score < 7 1 50 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.24, 1.25]

32.1 Intramuscular 1 50 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.24, 1.25]

33 Admission to neonatal intensive

care unit

3 389 Risk Ratio (M-H, Fixed, 95% CI) 0.24 [0.14, 0.40]

33.1 Oral 1 148 Risk Ratio (M-H, Fixed, 95% CI) 0.26 [0.14, 0.49]

33.2 Vaginal 2 241 Risk Ratio (M-H, Fixed, 95% CI) 0.21 [0.09, 0.49]

93Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

34 Neonatal length of hospital stay

(days)

1 33 Mean Difference (IV, Fixed, 95% CI) -1.0 [-7.67, 5.67]

34.1 Oral 1 33 Mean Difference (IV, Fixed, 95% CI) -1.0 [-7.67, 5.67]

35 Infant weight at 6 months

follow-up (g)

1 436 Mean Difference (IV, Fixed, 95% CI) 29.0 [-209.62, 267.

62]

35.1 Vaginal 1 436 Mean Difference (IV, Fixed, 95% CI) 29.0 [-209.62, 267.

62]

36 Infant weight at 12 months

follow-up (g)

1 379 Mean Difference (IV, Fixed, 95% CI) -88.0 [-381.48, 205.

48]

36.1 Vaginal 1 379 Mean Difference (IV, Fixed, 95% CI) -88.0 [-381.48, 205.

48]

37 Infant weight at 24 months

follow-up (g)

1 287 Mean Difference (IV, Fixed, 95% CI) -40.0 [-482.41, 402.

41]

37.1 Vaginal 1 287 Mean Difference (IV, Fixed, 95% CI) -40.0 [-482.41, 402.

41]

38 Infant length at 6 months

follow-up (cm)

1 430 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.59, 0.79]

38.1 Vaginal 1 430 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.59, 0.79]

39 Infant length at 12 months

follow-up (cm)

1 376 Mean Difference (IV, Fixed, 95% CI) -0.10 [-0.80, 0.60]

39.1 Vaginal 1 376 Mean Difference (IV, Fixed, 95% CI) -0.10 [-0.80, 0.60]

40 Infant length at 24 months

follow-up (cm)

1 284 Mean Difference (IV, Fixed, 95% CI) -0.20 [-1.23, 0.83]

40.1 Vaginal 1 284 Mean Difference (IV, Fixed, 95% CI) -0.20 [-1.23, 0.83]

41 Infant head circumference at 6

months follow-up (cm)

1 426 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.23, 0.43]

41.1 Vaginal 1 426 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.23, 0.43]

42 Infant head circumference at

12 months follow-up (cm)

1 372 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.26, 0.46]

42.1 Vaginal 1 372 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.26, 0.46]

43 Infant head circumference at

24 months follow-up (cm)

1 264 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.21, 0.61]

43.1 Vaginal 1 264 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.21, 0.61]

Comparison 2. Progesterone versus placebo/no treatment: previous history spontaneous preterm birth, by timing

of commencement (< 20 wk v > 20 wk, singletons)

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Preterm birth less than 37 weeks 6 1360 Risk Ratio (M-H, Random, 95% CI) 0.63 [0.44, 0.89]

1.1 Therapy commences

before 20 weeks

4 1147 Risk Ratio (M-H, Random, 95% CI) 0.69 [0.46, 1.04]

1.2 Therapy commences after

20 weeks

2 213 Risk Ratio (M-H, Random, 95% CI) 0.49 [0.30, 0.78]

94Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Comparison 3. Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by cumu-

lative weekly dose (< 500 mg v >= 500 mg, singletons)

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Perinatal death 5 1403 Risk Ratio (M-H, Random, 95% CI) 0.58 [0.35, 0.97]

1.1 Dose < 500 mg per week 2 503 Risk Ratio (M-H, Random, 95% CI) 0.38 [0.07, 2.18]

1.2 Dose >= 500 mg per week 3 900 Risk Ratio (M-H, Random, 95% CI) 0.59 [0.29, 1.21]

2 Preterm birth less than 37 weeks 9 1700 Risk Ratio (M-H, Random, 95% CI) 0.54 [0.40, 0.74]

2.1 Dose < 500 mg per week 3 602 Risk Ratio (M-H, Random, 95% CI) 0.59 [0.44, 0.80]

2.2 Dose >= 500 mg per week 6 1098 Risk Ratio (M-H, Random, 95% CI) 0.51 [0.31, 0.85]

3 Threatened preterm labour 2 601 Risk Ratio (M-H, Random, 95% CI) 0.87 [0.47, 1.62]

3.1 Dose < 500 mg per week 1 459 Risk Ratio (M-H, Random, 95% CI) 1.17 [0.73, 1.87]

3.2 Dose >= 500 mg per week 1 142 Risk Ratio (M-H, Random, 95% CI) 0.62 [0.35, 1.11]

4 Caesarean section 3 1170 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.72, 1.13]

4.1 Dose < 500 mg per week 1 459 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.58, 1.30]

4.2 Dose >= 500 mg per week 2 711 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.70, 1.21]

5 Antenatal corticosteroids 2 1070 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.73, 1.16]

5.1 Dose < 500 mg per week 1 459 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.58, 1.30]

5.2 Dose >= 500 mg per week 1 611 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.72, 1.26]

6 Need for tocolysis 3 1114 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.81, 1.52]

6.1 Dose < 500 mg per week 2 503 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.73, 1.72]

6.2 Dose >= 500 mg per week 1 611 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.70, 1.74]

7 Respiratory distress syndrome 4 1359 Risk Ratio (M-H, Random, 95% CI) 0.38 [0.16, 0.89]

7.1 Dose < 500 mg per week 1 459 Risk Ratio (M-H, Random, 95% CI) 0.63 [0.38, 1.05]

7.2 Dose >= 500 mg per week 3 900 Risk Ratio (M-H, Random, 95% CI) 0.29 [0.07, 1.23]

8 Intraventricular haemorrhage -

all grades

3 1211 Risk Ratio (M-H, Random, 95% CI) 0.70 [0.20, 2.46]

8.1 Dose < 500 mg per week 1 459 Risk Ratio (M-H, Random, 95% CI) 0.25 [0.08, 0.82]

8.2 Dose >= 500 mg per week 2 752 Risk Ratio (M-H, Random, 95% CI) 1.31 [0.46, 3.77]

9 Intraventricular haemorrhage -

grade III or IV

2 1070 Risk Ratio (M-H, Fixed, 95% CI) 1.59 [0.21, 11.73]

9.1 Dose < 500 mg per week 1 459 Risk Ratio (M-H, Fixed, 95% CI) 2.51 [0.12, 51.92]

9.2 Dose >= 500 mg per week 1 611 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.06, 15.55]

10 Necrotising enterocolitis 3 1170 Risk Ratio (M-H, Random, 95% CI) 0.35 [0.10, 1.25]

10.1 Dose < 500 mg per week 1 459 Risk Ratio (M-H, Random, 95% CI) 0.06 [0.00, 1.03]

10.2 Dose >= 500 mg per

week

2 711 Risk Ratio (M-H, Random, 95% CI) 0.53 [0.15, 1.95]

11 Intrauterine fetal death 3 1114 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.32, 2.91]

11.1 Dose < 500 mg per week 2 503 Risk Ratio (M-H, Random, 95% CI) 0.58 [0.05, 6.51]

11.2 Dose >= 500 mg per

week

1 611 Risk Ratio (M-H, Random, 95% CI) 1.22 [0.33, 4.51]

12 Neonatal death 5 1403 Risk Ratio (M-H, Fixed, 95% CI) 0.47 [0.28, 0.81]

12.1 Dose < 500 mg per week 2 503 Risk Ratio (M-H, Fixed, 95% CI) 0.42 [0.17, 1.03]

12.2 Dose >= 500 mg per

week

3 900 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.26, 0.99]

95Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Comparison 4. Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Perinatal death 3 1389 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.42, 1.29]

1.1 Vaginal 2 732 Risk Ratio (M-H, Fixed, 95% CI) 0.56 [0.27, 1.17]

1.2 Intramuscular 1 657 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.46, 2.72]

2 Preterm birth less than 34 weeks 2 438 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.45, 0.90]

2.1 Vaginal 1 250 Risk Ratio (M-H, Fixed, 95% CI) 0.58 [0.38, 0.87]

2.2 Intramuscular 1 188 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.43, 1.46]

3 Preterm labour 1 188 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.63, 1.74]

3.1 Intramuscular 1 188 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.63, 1.74]

4 Prelabour spontaneous rupture

of membranes

2 845 Risk Ratio (M-H, Random, 95% CI) 1.33 [0.68, 2.62]

4.1 Intramuscular 2 845 Risk Ratio (M-H, Random, 95% CI) 1.33 [0.68, 2.62]

5 Side effects (any) 2 842 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.92, 1.13]

5.1 Intramuscular 2 842 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.92, 1.13]

6 Side effects (injection site) 1 654 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.93, 1.17]

6.1 Intramuscular 1 654 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.93, 1.17]

7 Side effects (urticaria) 1 654 Risk Ratio (M-H, Fixed, 95% CI) 5.03 [1.11, 22.78]

7.1 Intramuscular 1 654 Risk Ratio (M-H, Fixed, 95% CI) 5.03 [1.11, 22.78]

8 Side effects (nausea) 1 654 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.27, 1.83]

8.1 Intramuscular 1 654 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.27, 1.83]

9 Pregnancy prolongation (days) 1 188 Mean Difference (IV, Fixed, 95% CI) -2.0 [-10.29, 6.29]

9.1 Intramuscular 1 188 Mean Difference (IV, Fixed, 95% CI) -2.0 [-10.29, 6.29]

10 Caesarean section 2 838 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.79, 1.40]

10.1 Intramuscular 2 838 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.79, 1.40]

11 Antenatal tocolysis 2 828 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.60, 1.11]

11.1 Intramuscular 2 828 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.60, 1.11]

12 Preterm birth less than 37

weeks

3 1303 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.82, 1.15]

12.1 Vaginal 1 458 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.68, 1.16]

12.2 Intramuscular 2 845 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.83, 1.28]

13 Preterm birth less than 28

weeks

2 1115 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.37, 0.93]

13.1 Vaginal 1 458 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.25, 0.97]

13.2 Intramuscular 1 657 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.36, 1.30]

14 Infant birthweight less than

2500 g

3 1379 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.78, 1.09]

14.1 Vaginal 2 728 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.73, 1.09]

14.2 Intramuscular 1 651 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.73, 1.30]

15 Respiratory distress syndrome 4 1556 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.48, 1.00]

15.1 Vaginal 2 732 Risk Ratio (M-H, Fixed, 95% CI) 0.49 [0.29, 0.85]

15.2 Intramuscular 2 824 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.58, 1.58]

16 Apgar score < 7 1 651 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.41, 1.55]

16.1 Intramuscular 1 651 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.41, 1.55]

17 Need for assisted ventilation 1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.36, 1.16]

17.1 Vaginal 1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.36, 1.16]

18 Intraventricular haemorrhage -

all grades

1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.05, 5.53]

96Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

18.1 Vaginal 1 274 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.05, 5.53]

19 Intraventricular haemorrhage -

grades III or IV

2 1100 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.17, 5.60]

19.1 Vaginal 1 458 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.01, 7.73]

19.2 Intramuscular 1 642 Risk Ratio (M-H, Fixed, 95% CI) 2.01 [0.18, 22.08]

20 Periventricular leucomalacia 3 1282 Risk Ratio (M-H, Fixed, 95% CI) 1.78 [0.38, 8.24]

20.1 Vaginal 1 458 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

20.2 Intramuscular 2 824 Risk Ratio (M-H, Fixed, 95% CI) 1.78 [0.38, 8.24]

21 Retinopathy of prematurity 2 916 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.23, 4.42]

21.1 Vaginal 1 274 Risk Ratio (M-H, Fixed, 95% CI) 5.07 [0.25, 104.70]

21.2 Intramuscular 1 642 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.04, 3.21]

22 Necrotising enterocolitis 3 1374 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.27, 1.78]

22.1 Vaginal 2 732 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.30, 3.11]

22.2 Intramuscular 1 642 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.08, 2.06]

23 Neonatal sepsis 3 1374 Risk Ratio (M-H, Random, 95% CI) 0.46 [0.18, 1.20]

23.1 Vaginal 2 732 Risk Ratio (M-H, Random, 95% CI) 0.58 [0.15, 2.25]

23.2 Intramuscular 1 642 Risk Ratio (M-H, Random, 95% CI) 0.27 [0.08, 0.97]

24 Intrauterine fetal death 3 1389 Risk Ratio (M-H, Fixed, 95% CI) 1.21 [0.48, 3.04]

24.1 Vaginal 2 732 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.28, 2.42]

24.2 Intramuscular 1 657 Risk Ratio (M-H, Fixed, 95% CI) 4.04 [0.45, 35.92]

25 Neonatal death 4 1571 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.26, 1.13]

25.1 Vaginal 2 732 Risk Ratio (M-H, Fixed, 95% CI) 0.41 [0.15, 1.15]

25.2 Intramuscular 2 839 Risk Ratio (M-H, Fixed, 95% CI) 0.76 [0.27, 2.16]

26 Admission to neonatal intensive

care unit

2 834 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.79, 1.35]

26.1 Intramuscular 2 834 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.79, 1.35]

Comparison 5. Progesterone versus placebo: ultrasound identified short cervix, singletons by cumulative weekly

dose (<500 mg v >=500 mg)

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Periventricular leucomalacia 2 824 Risk Ratio (M-H, Random, 95% CI) 1.49 [0.13, 16.87]

1.1 Dose < 500 mg per week 1 642 Risk Ratio (M-H, Random, 95% CI) 4.03 [0.45, 35.81]

1.2 Dose >= 500 mg per week 1 182 Risk Ratio (M-H, Random, 95% CI) 0.32 [0.01, 7.73]

2 Admission to neonatal intensive

care unit

2 834 Risk Ratio (M-H, Random, 95% CI) 1.09 [0.72, 1.65]

2.1 Dose < 500 mg per week 1 651 Risk Ratio (M-H, Random, 95% CI) 0.93 [0.69, 1.27]

2.2 Dose >= 500 mg per week 1 183 Risk Ratio (M-H, Random, 95% CI) 1.45 [0.83, 2.55]

97Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Comparison 6. Progesterone versus placebo: multiple pregnancy

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Perinatal death 7 4136 Risk Ratio (M-H, Random, 95% CI) 0.93 [0.45, 1.94]

1.1 Intramuscular 4 2228 Risk Ratio (M-H, Random, 95% CI) 1.06 [0.30, 3.71]

1.2 Vaginal 3 1908 Risk Ratio (M-H, Random, 95% CI) 0.75 [0.24, 2.41]

2 Preterm birth less than 34 weeks 6 1758 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.74, 1.27]

2.1 Vaginal 5 1520 Risk Ratio (M-H, Random, 95% CI) 0.92 [0.69, 1.23]

2.2 Intramuscular 1 238 Risk Ratio (M-H, Random, 95% CI) 1.37 [0.73, 2.59]

3 Preterm PROM 3 995 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.74, 1.70]

3.1 Intramuscular 2 802 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.72, 1.71]

3.2 Vaginal 1 193 Risk Ratio (M-H, Fixed, 95% CI) 1.32 [0.30, 5.74]

4 Adverse drug reaction 2 1162 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.64, 1.19]

4.1 Intramuscular 1 668 Risk Ratio (M-H, Random, 95% CI) 0.74 [0.54, 1.01]

4.2 Vaginal 1 494 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.89, 1.08]

5 Caesarean section 8 3136 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.91, 1.02]

5.1 Intramuscular 5 1773 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.94, 1.09]

5.2 Vaginal 3 1363 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.84, 0.98]

6 Spontaneous birth 2 1168 Risk Ratio (M-H, Random, 95% CI) 1.22 [0.62, 2.38]

6.1 Intramuscular 1 668 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.75, 1.04]

6.2 Vaginal 1 500 Risk Ratio (M-H, Random, 95% CI) 1.74 [1.21, 2.49]

7 Assisted birth 2 1168 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.57, 1.76]

7.1 Intramuscular 1 668 Risk Ratio (M-H, Random, 95% CI) 1.31 [0.86, 1.99]

7.2 Vaginal 1 500 Risk Ratio (M-H, Random, 95% CI) 0.73 [0.44, 1.24]

8 Satisfaction with therapy 1 494 Mean Difference (IV, Fixed, 95% CI) 0.0 [-0.35, 0.35]

8.1 Vaginal 1 494 Mean Difference (IV, Fixed, 95% CI) 0.0 [-0.35, 0.35]

9 Antenatal tocolysis 7 2642 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.80, 1.10]

9.1 Intramuscular 5 1775 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.82, 1.17]

9.2 Vaginal 2 867 Risk Ratio (M-H, Random, 95% CI) 0.75 [0.55, 1.03]

10 Antenatal corticosteroids 2 847 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.77, 1.26]

10.1 Intramuscular 1 654 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.70, 1.17]

10.2 Vaginal 1 193 Risk Ratio (M-H, Fixed, 95% CI) 1.68 [0.81, 3.49]

11 Preterm birth less than 37

weeks

8 2674 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.95, 1.14]

11.1 Intramuscular 4 1638 Risk Ratio (M-H, Random, 95% CI) 1.09 [0.96, 1.22]

11.2 Vaginal 4 1036 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.85, 1.13]

12 Preterm birth less than 28

weeks

5 1855 Risk Ratio (M-H, Fixed, 95% CI) 1.21 [0.75, 1.95]

12.1 Intramuscular 3 987 Risk Ratio (M-H, Fixed, 95% CI) 1.19 [0.68, 2.07]

12.2 Vaginal 2 868 Risk Ratio (M-H, Fixed, 95% CI) 1.27 [0.51, 3.19]

13 Infant birthweight less than

2500 g

7 5404 Risk Ratio (M-H, Random, 95% CI) 0.95 [0.88, 1.03]

13.1 Intramuscular 4 3502 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.91, 1.14]

13.2 Vaginal 3 1902 Risk Ratio (M-H, Random, 95% CI) 0.86 [0.80, 0.94]

14 Apgar score < 7 at 5 minutes 4 3451 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.66, 1.21]

14.1 Intramuscular 2 1750 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.70, 1.38]

14.2 Vaginal 2 1701 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.28, 1.23]

15 Respiratory distress syndrome 6 5065 Risk Ratio (M-H, Random, 95% CI) 1.13 [0.94, 1.35]

15.1 Intramuscular 5 3732 Risk Ratio (M-H, Random, 95% CI) 1.13 [0.91, 1.42]

15.2 Vaginal 1 1333 Risk Ratio (M-H, Random, 95% CI) 1.08 [0.79, 1.48]

98Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

16 Use of assisted ventilation 4 3392 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.78, 1.16]

16.1 Intramuscular 2 1675 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.80, 1.22]

16.2 Vaginal 2 1717 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.45, 1.36]

17 Intraventricular haemorrhage -

grades III or IV

4 2368 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.45, 1.92]

17.1 Intramuscular 4 2368 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.45, 1.92]

18 Intraventricular haemorrhage -

all grades

2 2688 Risk Ratio (M-H, Fixed, 95% CI) 1.77 [0.75, 4.21]

18.1 Intramuscular 1 1355 Risk Ratio (M-H, Fixed, 95% CI) 1.98 [0.36, 10.77]

18.2 Vaginal 1 1333 Risk Ratio (M-H, Fixed, 95% CI) 1.70 [0.62, 4.66]

19 Periventricular leucomalacia 3 1091 Risk Ratio (M-H, Fixed, 95% CI) 0.37 [0.05, 3.02]

19.1 Intramuscular 3 1091 Risk Ratio (M-H, Fixed, 95% CI) 0.37 [0.05, 3.02]

20 Retinopathy of prematurity 5 3668 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.32, 1.91]

20.1 Intramuscular 4 2335 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.20, 2.06]

20.2 Vaginal 1 1333 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.26, 4.07]

21 Chronic lung disease 2 681 Risk Ratio (M-H, Random, 95% CI) 1.91 [0.13, 27.80]

21.1 Intramuscular 2 681 Risk Ratio (M-H, Random, 95% CI) 1.91 [0.13, 27.80]

22 Necrotising enterocolitis 6 5059 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.50, 1.75]

22.1 Intramuscular 5 3726 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.52, 1.88]

22.2 Vaginal 1 1333 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.05, 5.63]

23 Neonatal sepsis 6 5065 Risk Ratio (M-H, Fixed, 95% CI) 1.20 [0.89, 1.62]

23.1 Intramuscular 5 3732 Risk Ratio (M-H, Fixed, 95% CI) 1.22 [0.87, 1.72]

23.2 Vaginal 1 1333 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.61, 2.13]

24 Fetal death 6 4788 Risk Ratio (M-H, Fixed, 95% CI) 1.22 [0.71, 2.09]

24.1 Intramuscular 3 2074 Risk Ratio (M-H, Fixed, 95% CI) 1.55 [0.77, 3.12]

24.2 Vaginal 3 2714 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.35, 1.95]

25 Neonatal death 7 5170 Risk Ratio (M-H, Random, 95% CI) 1.01 [0.48, 2.10]

25.1 Intramuscular 4 2456 Risk Ratio (M-H, Random, 95% CI) 0.81 [0.31, 2.10]

25.2 Vaginal 3 2714 Risk Ratio (M-H, Random, 95% CI) 1.34 [0.36, 4.95]

26 Admission to NICU 5 4251 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.76, 1.18]

26.1 Vaginal 4 2896 Risk Ratio (M-H, Random, 95% CI) 0.87 [0.71, 1.07]

26.2 Intramuscular 1 1355 Risk Ratio (M-H, Random, 95% CI) 1.31 [1.05, 1.62]

27 Perinatal death 7 4133 Risk Ratio (M-H, Random, 95% CI) 1.13 [0.61, 2.08]

27.1 Intramuscular 4 2228 Risk Ratio (M-H, Random, 95% CI) 1.06 [0.30, 3.71]

27.2 Vaginal 3 1905 Risk Ratio (M-H, Random, 95% CI) 1.25 [0.67, 2.35]

28 Preterm birth less than 34

weeks

6 1758 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.71, 1.24]

28.1 Vaginal 5 1520 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.65, 1.19]

28.2 Intramuscular 1 238 Risk Ratio (M-H, Random, 95% CI) 1.37 [0.73, 2.59]

29 Preterm PROM 3 995 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.69, 1.60]

29.1 Intramuscular 2 802 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.72, 1.71]

29.2 Vaginal 1 193 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.03, 3.12]

30 Caesarean section 8 3136 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.91, 1.01]

30.1 Intramuscular 5 1773 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.94, 1.09]

30.2 Vaginal 3 1363 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.84, 0.98]

31 Antenatal tocolysis 7 2642 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.80, 1.10]

31.1 Intramuscular 5 1775 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.82, 1.17]

31.2 Vaginal 2 867 Risk Ratio (M-H, Random, 95% CI) 0.77 [0.56, 1.05]

32 Antenatal corticosteroids 2 847 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.76, 1.24]

32.1 Intramuscular 1 654 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.70, 1.17]

32.2 Vaginal 1 193 Risk Ratio (M-H, Fixed, 95% CI) 1.58 [0.76, 3.31]

99Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

33 Preterm birth less than 37

weeks

8 2674 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.95, 1.13]

33.1 Intramuscular 4 1638 Risk Ratio (M-H, Random, 95% CI) 1.09 [0.96, 1.22]

33.2 Vaginal 4 1036 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.84, 1.11]

34 Preterm birth less than 28

weeks

5 1855 Risk Ratio (M-H, Fixed, 95% CI) 1.28 [0.80, 2.04]

34.1 Intramuscular 3 987 Risk Ratio (M-H, Fixed, 95% CI) 1.19 [0.68, 2.07]

34.2 Vaginal 2 868 Risk Ratio (M-H, Fixed, 95% CI) 1.52 [0.63, 3.69]

35 Infant birthweight less than

2500 g

7 5401 Risk Ratio (M-H, Random, 95% CI) 0.96 [0.89, 1.04]

35.1 Intramuscular 4 3502 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.91, 1.14]

35.2 Vaginal 3 1899 Risk Ratio (M-H, Random, 95% CI) 0.89 [0.82, 0.96]

36 Apgar score < 7 at 5 minutes 4 3448 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.70, 1.27]

36.1 Intramuscular 2 1750 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.70, 1.38]

36.2 Vaginal 2 1698 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.41, 1.58]

37 Use of assisted ventilation 4 3389 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.81, 1.19]

37.1 Intramuscular 2 1675 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.80, 1.22]

37.2 Vaginal 2 1714 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.55, 1.59]

38 Fetal death 6 4785 Risk Ratio (M-H, Fixed, 95% CI) 1.35 [0.79, 2.29]

38.1 Intramuscular 3 2074 Risk Ratio (M-H, Fixed, 95% CI) 1.55 [0.77, 3.12]

38.2 Vaginal 3 2711 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.49, 2.48]

39 Neonatal death 7 5167 Risk Ratio (M-H, Random, 95% CI) 1.17 [0.62, 2.21]

39.1 Intramuscular 4 2456 Risk Ratio (M-H, Random, 95% CI) 0.81 [0.31, 2.10]

39.2 Vaginal 3 2711 Risk Ratio (M-H, Random, 95% CI) 1.77 [0.84, 3.72]

40 Admission to NICU 5 4248 Risk Ratio (M-H, Random, 95% CI) 0.93 [0.75, 1.17]

40.1 Vaginal 4 2893 Risk Ratio (M-H, Random, 95% CI) 0.86 [0.70, 1.07]

40.2 Intramuscular 1 1355 Risk Ratio (M-H, Random, 95% CI) 1.31 [1.05, 1.62]

41 Sensitivity analysis for

perinatal death (assuming total

non-independence)

7 2068 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.43, 1.65]

41.1 Intramuscular 4 1114 Risk Ratio (M-H, Random, 95% CI) 0.99 [0.29, 3.36]

41.2 Vaginal 3 954 Risk Ratio (M-H, Random, 95% CI) 0.77 [0.28, 2.07]

42 Sensitivity analysis for

perinatal death (assuming 1%

non-independence)

7 4091 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.44, 1.90]

42.1 Intramuscular 4 2203 Risk Ratio (M-H, Random, 95% CI) 1.03 [0.29, 3.58]

42.2 Vaginal 3 1888 Risk Ratio (M-H, Random, 95% CI) 0.75 [0.24, 2.41]

Comparison 7. Progesterone versus placebo: multiple pregnancy, by timing of commencement (< 20 wk v > 20

wk)

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Preterm birth < 37 weeks 4 1467 Risk Ratio (M-H, Random, 95% CI) 0.99 [0.82, 1.20]

1.1 Supplementation

commenced prior to 20 weeks’

gestation

2 1323 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.92, 1.17]

100Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

1.2 Supplementation

commenced after 20 weeks’

gestation

2 144 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.38, 2.54]

2 Neonatal death 3 2738 Risk Ratio (M-H, Random, 95% CI) 0.95 [0.47, 1.93]

2.1 Supplementation

commenced prior to 20 weeks’

gestation

2 1750 Risk Ratio (M-H, Random, 95% CI) 0.92 [0.29, 2.91]

2.2 Supplementation

commenced after 20 weeks’

gestation

1 988 Risk Ratio (M-H, Random, 95% CI) 1.33 [0.47, 3.81]

3 Admission to NICU 2 2343 Risk Ratio (M-H, Random, 95% CI) 1.16 [0.95, 1.43]

3.1 Supplementation

commenced prior to 20 weeks’

gestation

1 988 Risk Ratio (M-H, Random, 95% CI) 1.06 [0.88, 1.26]

3.2 Supplementation

commenced after 20 weeks’

gestation

1 1355 Risk Ratio (M-H, Random, 95% CI) 1.31 [1.05, 1.62]

Comparison 8. Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >= 500

mg)

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Perinatal death 7 4136 Risk Ratio (M-H, Random, 95% CI) 0.93 [0.45, 1.94]

1.1 Dose < 500 mg per week 4 2228 Risk Ratio (M-H, Random, 95% CI) 1.06 [0.30, 3.71]

1.2 Dose >= 500 mg per week 3 1908 Risk Ratio (M-H, Random, 95% CI) 0.75 [0.24, 2.41]

2 Preterm birth less than 34 weeks 6 1758 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.74, 1.27]

2.1 Dose < 500 mg per week 1 238 Risk Ratio (M-H, Random, 95% CI) 1.37 [0.73, 2.59]

2.2 Dose > 500 mg per week 5 1520 Risk Ratio (M-H, Random, 95% CI) 0.92 [0.69, 1.23]

3 Antenatal tocolysis 7 2642 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.80, 1.10]

3.1 Dose < 500 mg per week 5 1775 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.82, 1.17]

3.2 Dose >= 500 mg per week 2 867 Risk Ratio (M-H, Random, 95% CI) 0.75 [0.55, 1.03]

4 Preterm birth less than 37 weeks 8 3489 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.88, 1.06]

4.1 Dose < 500 mg per week 6 2380 Risk Ratio (M-H, Random, 95% CI) 1.01 [0.88, 1.15]

4.2 Dose >= 500 mg per week 4 1109 Risk Ratio (M-H, Random, 95% CI) 0.90 [0.80, 1.01]

5 Infant birthweight less than

2500 g

7 5404 Risk Ratio (M-H, Random, 95% CI) 0.95 [0.88, 1.03]

5.1 Dose < 500 mg per week 4 3502 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.91, 1.14]

5.2 Dose >= 500 mg per week 3 1902 Risk Ratio (M-H, Random, 95% CI) 0.86 [0.80, 0.94]

6 Respiratory distress syndrome 6 5065 Risk Ratio (M-H, Random, 95% CI) 1.13 [0.94, 1.35]

6.1 Dose < 500 mg per week 5 3732 Risk Ratio (M-H, Random, 95% CI) 1.13 [0.91, 1.42]

6.2 Dose >= 500 mg per week 1 1333 Risk Ratio (M-H, Random, 95% CI) 1.08 [0.79, 1.48]

7 Fetal death 6 4788 Risk Ratio (M-H, Random, 95% CI) 1.07 [0.51, 2.23]

7.1 Dose < 500 mg per week 3 2074 Risk Ratio (M-H, Random, 95% CI) 2.52 [0.19, 33.68]

7.2 Dose >= 500 mg per week 3 2714 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.36, 2.16]

8 Admission to NICU 5 4251 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.76, 1.18]

8.1 Dose < 500 mg per week 1 1355 Risk Ratio (M-H, Random, 95% CI) 1.31 [1.05, 1.62]

8.2 Dose >= 500 mg per week 4 2896 Risk Ratio (M-H, Random, 95% CI) 0.87 [0.71, 1.07]

101Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Comparison 9. Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Perinatal death 1 12 Risk Ratio (M-H, Random, 95% CI) 2.0 [0.16, 24.33]

1.1 Intramuscular 1 12 Risk Ratio (M-H, Random, 95% CI) 2.0 [0.16, 24.33]

2 Preterm birth less than 34 weeks’

gestation

2 175 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.55, 1.65]

2.1 Intramuscular 1 12 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.72, 1.39]

2.2 Vaginal 1 163 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.37, 2.27]

3 Pregnancy prolongation (days) 2 232 Mean Difference (IV, Random, 95% CI) 1.88 [-8.42, 12.17]

3.1 Intramuscular 1 69 Mean Difference (IV, Random, 95% CI) -3.30 [-7.41, 0.81]

3.2 Vaginal 1 163 Mean Difference (IV, Random, 95% CI) 7.21 [2.39, 12.03]

4 Pregnancy prolongation - less

than 1 week

1 12 Risk Ratio (M-H, Fixed, 95% CI) 0.4 [0.07, 2.37]

4.1 Intramuscular 1 12 Risk Ratio (M-H, Fixed, 95% CI) 0.4 [0.07, 2.37]

5 Pregnancy prolongation - 1.0 to

1.9 weeks

1 12 Risk Ratio (M-H, Fixed, 95% CI) 2.0 [0.16, 24.33]

5.1 Intramuscular 1 12 Risk Ratio (M-H, Fixed, 95% CI) 2.0 [0.16, 24.33]

6 Pregnancy prolongation - 2

weeks or more

1 12 Risk Ratio (M-H, Fixed, 95% CI) 2.0 [0.42, 9.42]

6.1 Intramuscular 1 12 Risk Ratio (M-H, Fixed, 95% CI) 2.0 [0.42, 9.42]

7 Spontaneous birth 1 69 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.80, 1.49]

7.1 Intramuscular 1 69 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.80, 1.49]

8 Caesarean section 2 81 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.51, 1.60]

8.1 Intramuscular 2 81 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.51, 1.60]

9 Use of tocolysis 2 205 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.58, 1.65]

9.1 Intramuscular 1 12 Risk Ratio (M-H, Fixed, 95% CI) 1.2 [0.55, 2.62]

9.2 Vaginal 1 193 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.50, 1.73]

10 Preterm birth less than 37

weeks’ gestation

2 223 Risk Ratio (M-H, Random, 95% CI) 0.51 [0.20, 1.31]

10.1 Vaginal 1 163 Risk Ratio (M-H, Random, 95% CI) 0.76 [0.55, 1.06]

10.2 Intramuscular 1 60 Risk Ratio (M-H, Random, 95% CI) 0.29 [0.12, 0.69]

11 Infant birthweight less than

2500 g

1 70 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.28, 0.98]

11.1 Vaginal 1 70 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.28, 0.98]

12 Respiratory distress syndrome 4 314 Risk Ratio (M-H, Random, 95% CI) 0.74 [0.49, 1.10]

12.1 Vaginal 2 233 Risk Ratio (M-H, Random, 95% CI) 0.48 [0.20, 1.15]

12.2 Intramuscular 2 81 Risk Ratio (M-H, Random, 95% CI) 0.86 [0.66, 1.12]

13 Intraventricular haemorrhage

grade III or IV

1 12 Risk Ratio (M-H, Fixed, 95% CI) 9.0 [0.53, 152.93]

13.1 Intramuscular 1 12 Risk Ratio (M-H, Fixed, 95% CI) 9.0 [0.53, 152.93]

14 Periventricular leucomalacia 1 12 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

14.1 Intramuscular 1 12 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

15 Use of assisted ventilation 1 70 Risk Ratio (M-H, Fixed, 95% CI) 0.30 [0.06, 1.37]

15.1 Vaginal 1 70 Risk Ratio (M-H, Fixed, 95% CI) 0.30 [0.06, 1.37]

16 Necrotizing enterocolitis 2 81 Risk Ratio (M-H, Fixed, 95% CI) 3.06 [0.50, 18.69]

16.1 Intramuscular 2 81 Risk Ratio (M-H, Fixed, 95% CI) 3.06 [0.50, 18.69]

17 Neonatal sepsis 4 314 Risk Ratio (M-H, Random, 95% CI) 0.54 [0.17, 1.68]

17.1 Vaginal 2 233 Risk Ratio (M-H, Random, 95% CI) 0.26 [0.07, 1.00]

102Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

17.2 Intramuscular 2 81 Risk Ratio (M-H, Random, 95% CI) 1.09 [0.39, 3.05]

18 Fetal death 2 81 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.07, 16.75]

18.1 Intramuscular 2 81 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.07, 16.75]

19 Neonatal death 2 175 Risk Ratio (M-H, Random, 95% CI) 0.54 [0.05, 6.24]

19.1 Intramuscular 1 12 Risk Ratio (M-H, Random, 95% CI) 2.0 [0.16, 24.33]

19.2 Vaginal 1 163 Risk Ratio (M-H, Random, 95% CI) 0.17 [0.02, 1.40]

20 Neonatal length of hospital stay

(days)

2 81 Mean Difference (IV, Fixed, 95% CI) -2.16 [-15.84, 11.

53]

20.1 Intramuscular 2 81 Mean Difference (IV, Fixed, 95% CI) -2.16 [-15.84, 11.

53]

21 Apgar score less than seven at

five minutes

1 163 Risk Ratio (M-H, Fixed, 95% CI) 0.26 [0.03, 2.27]

21.1 Vaginal 1 163 Risk Ratio (M-H, Fixed, 95% CI) 0.26 [0.03, 2.27]

22 Prelabour spontaneous rupture

of membranes

1 163 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.19, 1.45]

22.1 Vaginal 1 163 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.19, 1.45]

23 Preterm birth less than 28

weeks’ gestation

1 193 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.06, 15.60]

23.1 Vaginal 1 193 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.06, 15.60]

24 Apgar score less than seven at

five minutes

1 163 Risk Ratio (M-H, Fixed, 95% CI) 0.26 [0.03, 2.27]

24.1 Vaginal 1 163 Risk Ratio (M-H, Fixed, 95% CI) 0.26 [0.03, 2.27]

25 Admission to neonatal intensive

care unit

1 163 Risk Ratio (M-H, Fixed, 95% CI) 1.56 [0.27, 9.07]

25.1 Vaginal 1 163 Risk Ratio (M-H, Fixed, 95% CI) 1.56 [0.27, 9.07]

Comparison 10. Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons, by

cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Pregnancy prolongation (days) 2 232 Mean Difference (IV, Random, 95% CI) 1.88 [-8.42, 12.17]

1.1 Dose < 500 mg per week 1 69 Mean Difference (IV, Random, 95% CI) -3.30 [-7.41, 0.81]

1.2 Dose >= 500 mg per week 1 163 Mean Difference (IV, Random, 95% CI) 7.21 [2.39, 12.03]

2 Preterm birth less than 37 weeks’

gestation

2 223 Risk Ratio (M-H, Random, 95% CI) 0.51 [0.20, 1.31]

2.1 Dose >=500 mg per week 1 163 Risk Ratio (M-H, Random, 95% CI) 0.76 [0.55, 1.06]

2.2 Dose <500 mg per week 1 60 Risk Ratio (M-H, Random, 95% CI) 0.29 [0.12, 0.69]

3 Respiratory distress syndrome 4 314 Risk Ratio (M-H, Random, 95% CI) 0.74 [0.49, 1.10]

3.1 Dose >=500 mg per week 2 233 Risk Ratio (M-H, Random, 95% CI) 0.48 [0.20, 1.15]

3.2 Dose <500 mg per week 2 81 Risk Ratio (M-H, Random, 95% CI) 0.86 [0.66, 1.12]

4 Neonatal sepsis 4 314 Risk Ratio (M-H, Random, 95% CI) 0.54 [0.17, 1.68]

4.1 Dose >=500 mg per week 2 233 Risk Ratio (M-H, Random, 95% CI) 0.26 [0.07, 1.00]

4.2 Dose <500 mg per week 2 81 Risk Ratio (M-H, Random, 95% CI) 1.09 [0.39, 3.05]

5 Neonatal death 2 175 Risk Ratio (M-H, Random, 95% CI) 0.54 [0.05, 6.24]

5.1 Dose <500 mg per week 1 12 Risk Ratio (M-H, Random, 95% CI) 2.0 [0.16, 24.33]

5.2 Dose >=500 mg per week 1 163 Risk Ratio (M-H, Random, 95% CI) 0.17 [0.02, 1.40]

103Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Comparison 11. Progesterone versus placebo: other reason at risk of preterm birth, singletons

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Perinatal death 3 479 Risk Ratio (M-H, Random, 95% CI) 0.52 [0.09, 3.00]

1.1 Intramuscular 2 264 Risk Ratio (M-H, Random, 95% CI) 1.1 [0.23, 5.29]

1.2 Vaginal 1 215 Risk Ratio (M-H, Random, 95% CI) 0.18 [0.02, 1.55]

2 Preterm birth less than 34 weeks 1 215 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.16, 3.01]

2.1 Vaginal 1 215 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.16, 3.01]

3 Preterm birth less than 37 weeks 3 482 Risk Ratio (M-H, Random, 95% CI) 0.60 [0.32, 1.13]

3.1 Intramuscular 2 267 Risk Ratio (M-H, Random, 95% CI) 0.52 [0.11, 2.56]

3.2 Vaginal 1 215 Risk Ratio (M-H, Random, 95% CI) 0.63 [0.40, 0.98]

4 Infant birthweight less than

2500 g

3 482 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.25, 0.91]

4.1 Intramuscular 2 267 Risk Ratio (M-H, Fixed, 95% CI) 0.53 [0.23, 1.18]

4.2 Vaginal 1 215 Risk Ratio (M-H, Fixed, 95% CI) 0.42 [0.15, 1.16]

5 Intrauterine fetal death 1 168 Risk Ratio (M-H, Fixed, 95% CI) 0.37 [0.04, 3.45]

5.1 Intramuscular 1 168 Risk Ratio (M-H, Fixed, 95% CI) 0.37 [0.04, 3.45]

6 Neonatal death 1 168 Risk Ratio (M-H, Fixed, 95% CI) 5.49 [0.27, 112.73]

6.1 Intramuscular 1 168 Risk Ratio (M-H, Fixed, 95% CI) 5.49 [0.27, 112.73]

7 Admission to neonatal intensive

care unit

1 215 Risk Ratio (M-H, Fixed, 95% CI) 1.71 [0.71, 4.11]

7.1 Vaginal 1 215 Risk Ratio (M-H, Fixed, 95% CI) 1.71 [0.71, 4.11]

Comparison 12. Progesterone versus placebo: other reason at risk of preterm birth, by timing of commencement

(< 20 wk v > 20 wk, singletons)

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Perinatal death 2 264 Risk Ratio (M-H, Fixed, 95% CI) 1.1 [0.23, 5.29]

1.1 Supplementation

commenced prior to 20 weeks’

gestation

1 168 Risk Ratio (M-H, Fixed, 95% CI) 1.1 [0.23, 5.29]

1.2 Supplementation

commenced after 20 weeks’

gestation

1 96 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

2 Preterm birth less than 37 weeks 2 267 Risk Ratio (M-H, Random, 95% CI) 0.52 [0.11, 2.56]

2.1 Supplementation

commenced prior to 20 weeks’

gestation

1 168 Risk Ratio (M-H, Random, 95% CI) 1.1 [0.33, 3.66]

2.2 Supplementation

commenced after 20 weeks’

gestation

1 99 Risk Ratio (M-H, Random, 95% CI) 0.22 [0.05, 0.96]

3 Infant birthweight less than

2500 g

2 267 Risk Ratio (M-H, Random, 95% CI) 0.51 [0.16, 1.65]

104Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

3.1 Supplementation

commenced prior to 20 weeks’

gestation

1 168 Risk Ratio (M-H, Random, 95% CI) 0.83 [0.30, 2.27]

3.2 Supplementation

commenced after 20 weeks’

gestation

1 99 Risk Ratio (M-H, Random, 95% CI) 0.25 [0.05, 1.10]

Analysis 1.1. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 1 Perinatal mortality.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 1 Perinatal mortality

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Ibrahim 2010 4/25 13/25 21.0 % 0.31 [ 0.12, 0.81 ]

Johnson 1975 0/18 7/26 10.0 % 0.09 [ 0.01, 1.56 ]

Meis 2003 14/306 11/153 23.7 % 0.64 [ 0.30, 1.37 ]

Subtotal (95% CI) 349 204 54.8 % 0.41 [ 0.23, 0.73 ]

Total events: 18 (Progesterone), 31 (Placebo)

Heterogeneity: Chi2 = 2.65, df = 2 (P = 0.27); I2 =24%

Test for overall effect: Z = 3.01 (P = 0.0026)

2 Vaginal

Akbari 2009 3/69 10/72 15.8 % 0.31 [ 0.09, 1.09 ]

O’Brien 2007 11/309 11/302 18.0 % 0.98 [ 0.43, 2.22 ]

Subtotal (95% CI) 378 374 33.9 % 0.67 [ 0.34, 1.29 ]

Total events: 14 (Progesterone), 21 (Placebo)

Heterogeneity: Chi2 = 2.25, df = 1 (P = 0.13); I2 =55%

Test for overall effect: Z = 1.20 (P = 0.23)

3 Oral

Rai 2009 3/74 7/74 11.3 % 0.43 [ 0.12, 1.59 ]

Subtotal (95% CI) 74 74 11.3 % 0.43 [ 0.12, 1.59 ]

Total events: 3 (Progesterone), 7 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.26 (P = 0.21)

Total (95% CI) 801 652 100.0 % 0.50 [ 0.33, 0.75 ]

Total events: 35 (Progesterone), 59 (Placebo)

Heterogeneity: Chi2 = 5.85, df = 5 (P = 0.32); I2 =15%

Test for overall effect: Z = 3.31 (P = 0.00094)

Test for subgroup differences: Chi2 = 1.21, df = 2 (P = 0.55), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

105Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.2. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 2 Preterm birth less than 34 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 2 Preterm birth less than 34 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Progesterone), 0 (Placebo)

Heterogeneity: not applicable

Test for overall effect: not applicable

2 Vaginal

Akbari 2009 2/69 16/72 17.4 % 0.13 [ 0.03, 0.55 ]

Cetingoz 2011 2/37 9/34 17.0 % 0.20 [ 0.05, 0.88 ]

da Fonseca 2003 2/72 13/70 17.1 % 0.15 [ 0.04, 0.64 ]

Majhi 2009 2/50 3/50 13.8 % 0.67 [ 0.12, 3.82 ]

Subtotal (95% CI) 228 226 65.3 % 0.21 [ 0.10, 0.44 ]

Total events: 8 (Progesterone), 41 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 2.35, df = 3 (P = 0.50); I2 =0.0%

Test for overall effect: Z = 4.10 (P = 0.000042)

3 Oral

Rai 2009 22/74 37/74 34.7 % 0.59 [ 0.39, 0.90 ]

Subtotal (95% CI) 74 74 34.7 % 0.59 [ 0.39, 0.90 ]

Total events: 22 (Progesterone), 37 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.44 (P = 0.015)

Total (95% CI) 302 300 100.0 % 0.31 [ 0.14, 0.69 ]

Total events: 30 (Progesterone), 78 (Placebo)

Heterogeneity: Tau2 = 0.45; Chi2 = 9.15, df = 4 (P = 0.06); I2 =56%

Test for overall effect: Z = 2.87 (P = 0.0041)

Test for subgroup differences: Chi2 = 5.77, df = 1 (P = 0.02), I2 =83%

0.05 0.2 1 5 20

Favours progesterone Favours placebo

106Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.3. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 3 Preterm birth less than 37 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 3 Preterm birth less than 37 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Ibrahim 2010 8/25 13/25 9.0 % 0.62 [ 0.31, 1.22 ]

Johnson 1975 2/18 12/25 3.5 % 0.23 [ 0.06, 0.91 ]

Meis 2003 111/306 84/153 17.0 % 0.66 [ 0.54, 0.81 ]

Saghafi 2011a 16/50 30/50 12.5 % 0.53 [ 0.34, 0.85 ]

Subtotal (95% CI) 399 253 42.1 % 0.62 [ 0.52, 0.75 ]

Total events: 137 (Progesterone), 139 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 2.84, df = 3 (P = 0.42); I2 =0.0%

Test for overall effect: Z = 5.11 (P < 0.00001)

2 Vaginal

Akbari 2009 8/69 23/72 8.4 % 0.36 [ 0.17, 0.76 ]

Cetingoz 2011 9/37 17/34 9.3 % 0.49 [ 0.25, 0.94 ]

da Fonseca 2003 10/72 20/70 9.0 % 0.49 [ 0.25, 0.96 ]

Majhi 2009 6/50 19/50 7.2 % 0.32 [ 0.14, 0.72 ]

O’Brien 2007 129/309 123/302 17.3 % 1.03 [ 0.85, 1.24 ]

Subtotal (95% CI) 537 528 51.2 % 0.52 [ 0.29, 0.92 ]

Total events: 162 (Progesterone), 202 (Placebo)

Heterogeneity: Tau2 = 0.32; Chi2 = 20.39, df = 4 (P = 0.00042); I2 =80%

Test for overall effect: Z = 2.25 (P = 0.024)

3 Oral

Glover 2011 5/19 8/14 6.7 % 0.46 [ 0.19, 1.11 ]

Subtotal (95% CI) 19 14 6.7 % 0.46 [ 0.19, 1.11 ]

Total events: 5 (Progesterone), 8 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.73 (P = 0.084)

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

(Continued . . . )

107Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

(. . . Continued) Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

Total (95% CI) 955 795 100.0 % 0.55 [ 0.42, 0.74 ]

Total events: 304 (Progesterone), 349 (Placebo)

Heterogeneity: Tau2 = 0.11; Chi2 = 29.60, df = 9 (P = 0.00051); I2 =70%

Test for overall effect: Z = 4.08 (P = 0.000046)

Test for subgroup differences: Chi2 = 0.77, df = 2 (P = 0.68), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

Analysis 1.4. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 4 Threatened preterm labour.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 4 Threatened preterm labour

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Meis 2003 49/306 21/153 53.8 % 1.17 [ 0.73, 1.87 ]

Subtotal (95% CI) 306 153 53.8 % 1.17 [ 0.73, 1.87 ]

Total events: 49 (Progesterone), 21 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.64 (P = 0.52)

2 Vaginal

da Fonseca 2003 14/72 22/70 46.2 % 0.62 [ 0.35, 1.11 ]

Subtotal (95% CI) 72 70 46.2 % 0.62 [ 0.35, 1.11 ]

Total events: 14 (Progesterone), 22 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.61 (P = 0.11)

Total (95% CI) 378 223 100.0 % 0.87 [ 0.47, 1.62 ]

Total events: 63 (Progesterone), 43 (Placebo)

Heterogeneity: Tau2 = 0.13; Chi2 = 2.75, df = 1 (P = 0.10); I2 =64%

Test for overall effect: Z = 0.44 (P = 0.66)

Test for subgroup differences: Chi2 = 2.74, df = 1 (P = 0.10), I2 =63%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

108Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.5. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 5 Spontaneous vaginal delivery.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 5 Spontaneous vaginal delivery

Study or subgroup Progesterone Placebo/no treatment Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Majhi 2009 46/50 43/50 50.0 % 1.07 [ 0.93, 1.23 ]

Saghafi 2011a 46/50 43/50 50.0 % 1.07 [ 0.93, 1.23 ]

Total (95% CI) 100 100 100.0 % 1.07 [ 0.97, 1.18 ]

Total events: 92 (Progesterone), 86 (Placebo/no treatment)

Heterogeneity: Chi2 = 0.0, df = 1 (P = 1.00); I2 =0.0%

Test for overall effect: Z = 1.35 (P = 0.18)

Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2

Favours placebo Favours progesterone

109Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.6. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 6 Caesarean section.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 6 Caesarean section

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Meis 2003 77/306 41/153 37.5 % 0.94 [ 0.68, 1.30 ]

Subtotal (95% CI) 306 153 37.5 % 0.94 [ 0.68, 1.30 ]

Total events: 77 (Progesterone), 41 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.38 (P = 0.70)

2 Vaginal

Majhi 2009 4/50 7/50 4.8 % 0.57 [ 0.18, 1.83 ]

O’Brien 2007 89/309 83/302 57.7 % 1.05 [ 0.81, 1.35 ]

Subtotal (95% CI) 359 352 62.5 % 1.01 [ 0.79, 1.30 ]

Total events: 93 (Progesterone), 90 (Placebo)

Heterogeneity: Chi2 = 1.00, df = 1 (P = 0.32); I2 =0.0%

Test for overall effect: Z = 0.09 (P = 0.93)

Total (95% CI) 665 505 100.0 % 0.98 [ 0.81, 1.20 ]

Total events: 170 (Progesterone), 131 (Placebo)

Heterogeneity: Chi2 = 1.15, df = 2 (P = 0.56); I2 =0.0%

Test for overall effect: Z = 0.16 (P = 0.87)

Test for subgroup differences: Chi2 = 0.13, df = 1 (P = 0.72), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

110Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.7. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 7 Antenatal corticosteroids.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 7 Antenatal corticosteroids

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Meis 2003 52/306 30/153 34.8 % 0.87 [ 0.58, 1.30 ]

Subtotal (95% CI) 306 153 34.8 % 0.87 [ 0.58, 1.30 ]

Total events: 52 (Progesterone), 30 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.69 (P = 0.49)

2 Vaginal

O’Brien 2007 72/309 74/302 65.2 % 0.95 [ 0.72, 1.26 ]

Subtotal (95% CI) 309 302 65.2 % 0.95 [ 0.72, 1.26 ]

Total events: 72 (Progesterone), 74 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.35 (P = 0.73)

Total (95% CI) 615 455 100.0 % 0.92 [ 0.73, 1.16 ]

Total events: 124 (Progesterone), 104 (Placebo)

Heterogeneity: Chi2 = 0.14, df = 1 (P = 0.71); I2 =0.0%

Test for overall effect: Z = 0.69 (P = 0.49)

Test for subgroup differences: Chi2 = 0.14, df = 1 (P = 0.71), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

111Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.8. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 8 Antenatal tocolysis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 8 Antenatal tocolysis

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Johnson 1975 2/18 2/26 1.9 % 1.44 [ 0.22, 9.33 ]

Meis 2003 53/306 24/153 37.7 % 1.10 [ 0.71, 1.72 ]

Subtotal (95% CI) 324 179 39.6 % 1.12 [ 0.73, 1.72 ]

Total events: 55 (Progesterone), 26 (Placebo)

Heterogeneity: Chi2 = 0.08, df = 1 (P = 0.78); I2 =0.0%

Test for overall effect: Z = 0.52 (P = 0.60)

2 Vaginal

O’Brien 2007 35/309 31/302 36.9 % 1.10 [ 0.70, 1.74 ]

Subtotal (95% CI) 309 302 36.9 % 1.10 [ 0.70, 1.74 ]

Total events: 35 (Progesterone), 31 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.42 (P = 0.67)

3 Oral

Rai 2009 15/74 20/74 23.5 % 0.75 [ 0.42, 1.35 ]

Subtotal (95% CI) 74 74 23.5 % 0.75 [ 0.42, 1.35 ]

Total events: 15 (Progesterone), 20 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.96 (P = 0.34)

Total (95% CI) 707 555 100.0 % 1.03 [ 0.78, 1.35 ]

Total events: 105 (Progesterone), 77 (Placebo)

Heterogeneity: Chi2 = 1.43, df = 3 (P = 0.70); I2 =0.0%

Test for overall effect: Z = 0.19 (P = 0.85)

Test for subgroup differences: Chi2 = 1.35, df = 2 (P = 0.51), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

112Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.9. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 9 Infant birthweight less than 2500 g.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 9 Infant birthweight less than 2500 g

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Ibrahim 2010 5/25 10/25 10.7 % 0.50 [ 0.20, 1.25 ]

Johnson 1975 4/18 11/26 9.6 % 0.53 [ 0.20, 1.39 ]

Meis 2003 82/306 62/151 73.2 % 0.65 [ 0.50, 0.85 ]

Subtotal (95% CI) 349 202 93.5 % 0.63 [ 0.49, 0.81 ]

Total events: 91 (Progesterone), 83 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.45, df = 2 (P = 0.80); I2 =0.0%

Test for overall effect: Z = 3.65 (P = 0.00027)

2 Vaginal

Akbari 2009 3/69 14/72 6.5 % 0.22 [ 0.07, 0.74 ]

Subtotal (95% CI) 69 72 6.5 % 0.22 [ 0.07, 0.74 ]

Total events: 3 (Progesterone), 14 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.44 (P = 0.015)

Total (95% CI) 418 274 100.0 % 0.58 [ 0.42, 0.79 ]

Total events: 94 (Progesterone), 97 (Placebo)

Heterogeneity: Tau2 = 0.02; Chi2 = 3.32, df = 3 (P = 0.34); I2 =10%

Test for overall effect: Z = 3.43 (P = 0.00061)

Test for subgroup differences: Chi2 = 2.75, df = 1 (P = 0.10), I2 =64%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

113Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.10. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 10 Respiratory distress syndrome.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 10 Respiratory distress syndrome

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Meis 2003 29/306 23/152 36.6 % 0.63 [ 0.38, 1.04 ]

Subtotal (95% CI) 306 152 36.6 % 0.63 [ 0.38, 1.04 ]

Total events: 29 (Progesterone), 23 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.79 (P = 0.073)

2 Vaginal

O’Brien 2007 34/309 36/302 37.6 % 0.92 [ 0.59, 1.43 ]

Subtotal (95% CI) 309 302 37.6 % 0.92 [ 0.59, 1.43 ]

Total events: 34 (Progesterone), 36 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.36 (P = 0.72)

3 Oral

Rai 2009 3/74 31/74 25.8 % 0.10 [ 0.03, 0.30 ]

Subtotal (95% CI) 74 74 25.8 % 0.10 [ 0.03, 0.30 ]

Total events: 3 (Progesterone), 31 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 4.01 (P = 0.000060)

Total (95% CI) 689 528 100.0 % 0.45 [ 0.17, 1.16 ]

Total events: 66 (Progesterone), 90 (Placebo)

Heterogeneity: Tau2 = 0.57; Chi2 = 14.02, df = 2 (P = 0.00090); I2 =86%

Test for overall effect: Z = 1.66 (P = 0.098)

Test for subgroup differences: Chi2 = 13.15, df = 2 (P = 0.00), I2 =85%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

114Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.11. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 11 Use of assisted ventilation.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 11 Use of assisted ventilation

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Meis 2003 26/306 22/153 63.7 % 0.59 [ 0.35, 1.01 ]

Subtotal (95% CI) 306 153 63.7 % 0.59 [ 0.35, 1.01 ]

Total events: 26 (Progesterone), 22 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.93 (P = 0.053)

2 Oral

Glover 2011 0/19 3/14 7.0 % 0.11 [ 0.01, 1.92 ]

Subtotal (95% CI) 19 14 7.0 % 0.11 [ 0.01, 1.92 ]

Total events: 0 (Progesterone), 3 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.52 (P = 0.13)

3 Vaginal

Akbari 2009 3/69 13/72 29.2 % 0.24 [ 0.07, 0.81 ]

Subtotal (95% CI) 69 72 29.2 % 0.24 [ 0.07, 0.81 ]

Total events: 3 (Progesterone), 13 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.30 (P = 0.021)

Total (95% CI) 394 239 100.0 % 0.40 [ 0.18, 0.90 ]

Total events: 29 (Progesterone), 38 (Placebo)

Heterogeneity: Tau2 = 0.19; Chi2 = 2.96, df = 2 (P = 0.23); I2 =32%

Test for overall effect: Z = 2.23 (P = 0.026)

Test for subgroup differences: Chi2 = 2.86, df = 2 (P = 0.24), I2 =30%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

115Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.12. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 12 Intraventricular haemorrhage - all grades.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 12 Intraventricular haemorrhage - all grades

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Meis 2003 4/306 8/153 40.3 % 0.25 [ 0.08, 0.82 ]

Subtotal (95% CI) 306 153 40.3 % 0.25 [ 0.08, 0.82 ]

Total events: 4 (Progesterone), 8 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.29 (P = 0.022)

2 Vaginal

Akbari 2009 2/69 1/72 19.3 % 2.09 [ 0.19, 22.50 ]

O’Brien 2007 6/309 5/302 40.5 % 1.17 [ 0.36, 3.80 ]

Subtotal (95% CI) 378 374 59.7 % 1.31 [ 0.46, 3.77 ]

Total events: 8 (Progesterone), 6 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.18, df = 1 (P = 0.67); I2 =0.0%

Test for overall effect: Z = 0.51 (P = 0.61)

Total (95% CI) 684 527 100.0 % 0.70 [ 0.20, 2.46 ]

Total events: 12 (Progesterone), 14 (Placebo)

Heterogeneity: Tau2 = 0.65; Chi2 = 4.39, df = 2 (P = 0.11); I2 =54%

Test for overall effect: Z = 0.55 (P = 0.58)

Test for subgroup differences: Chi2 = 4.21, df = 1 (P = 0.04), I2 =76%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

116Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.13. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 13 Intraventricular haemorrhage - grade III or IV.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 13 Intraventricular haemorrhage - grade III or IV

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Meis 2003 2/305 0/153 39.7 % 2.52 [ 0.12, 52.09 ]

Subtotal (95% CI) 305 153 39.7 % 2.52 [ 0.12, 52.09 ]

Total events: 2 (Treatment), 0 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.60 (P = 0.55)

2 Vaginal

O’Brien 2007 1/309 1/302 60.3 % 0.98 [ 0.06, 15.55 ]

Subtotal (95% CI) 309 302 60.3 % 0.98 [ 0.06, 15.55 ]

Total events: 1 (Treatment), 1 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.02 (P = 0.99)

Total (95% CI) 614 455 100.0 % 1.59 [ 0.21, 11.75 ]

Total events: 3 (Treatment), 1 (Control)

Heterogeneity: Chi2 = 0.21, df = 1 (P = 0.65); I2 =0.0%

Test for overall effect: Z = 0.45 (P = 0.65)

Test for subgroup differences: Chi2 = 0.20, df = 1 (P = 0.65), I2 =0.0%

0.02 0.1 1 10 50

Favours progesterone Favours placebo

117Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.14. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 14 Periventricular leucomalacia.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 14 Periventricular leucomalacia

Study or subgroup Progesterone No treatment Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Akbari 2009 1/69 0/72 100.0 % 3.13 [ 0.13, 75.52 ]

Total (95% CI) 69 72 100.0 % 3.13 [ 0.13, 75.52 ]

Total events: 1 (Progesterone), 0 (No treatment)

Heterogeneity: not applicable

Test for overall effect: Z = 0.70 (P = 0.48)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours no treatment

Analysis 1.15. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 15 Retinopathy of prematurity.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 15 Retinopathy of prematurity

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Meis 2003 5/306 5/152 100.0 % 0.50 [ 0.15, 1.69 ]

Total (95% CI) 306 152 100.0 % 0.50 [ 0.15, 1.69 ]

Total events: 5 (Progesterone), 5 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.12 (P = 0.26)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

118Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.16. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 16 Necrotising enterocolitis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 16 Necrotising enterocolitis

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Meis 2003 0/306 4/153 47.8 % 0.06 [ 0.00, 1.03 ]

Subtotal (95% CI) 306 153 47.8 % 0.06 [ 0.00, 1.03 ]

Total events: 0 (Progesterone), 4 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.94 (P = 0.052)

2 Vaginal

Akbari 2009 0/50 1/50 12.0 % 0.33 [ 0.01, 7.99 ]

O’Brien 2007 3/309 5/302 40.3 % 0.59 [ 0.14, 2.43 ]

Subtotal (95% CI) 359 352 52.2 % 0.53 [ 0.15, 1.92 ]

Total events: 3 (Progesterone), 6 (Placebo)

Heterogeneity: Chi2 = 0.10, df = 1 (P = 0.75); I2 =0.0%

Test for overall effect: Z = 0.97 (P = 0.33)

Total (95% CI) 665 505 100.0 % 0.30 [ 0.10, 0.89 ]

Total events: 3 (Progesterone), 10 (Placebo)

Heterogeneity: Chi2 = 2.13, df = 2 (P = 0.35); I2 =6%

Test for overall effect: Z = 2.18 (P = 0.029)

Test for subgroup differences: Chi2 = 1.91, df = 1 (P = 0.17), I2 =48%

0.005 0.1 1 10 200

Favours progesterone Favours placebo

119Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.17. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 17 Neonatal sepsis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 17 Neonatal sepsis

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Meis 2003 9/306 4/153 54.7 % 1.13 [ 0.35, 3.59 ]

Subtotal (95% CI) 306 153 54.7 % 1.13 [ 0.35, 3.59 ]

Total events: 9 (Progesterone), 4 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.20 (P = 0.84)

2 Vaginal

Akbari 2009 0/69 4/72 22.8 % 0.12 [ 0.01, 2.11 ]

Majhi 2009 0/50 3/50 22.5 % 0.14 [ 0.01, 2.70 ]

Subtotal (95% CI) 119 122 45.3 % 0.13 [ 0.02, 1.01 ]

Total events: 0 (Progesterone), 7 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.01, df = 1 (P = 0.92); I2 =0.0%

Test for overall effect: Z = 1.95 (P = 0.051)

Total (95% CI) 425 275 100.0 % 0.42 [ 0.08, 2.23 ]

Total events: 9 (Progesterone), 11 (Placebo)

Heterogeneity: Tau2 = 0.97; Chi2 = 3.43, df = 2 (P = 0.18); I2 =42%

Test for overall effect: Z = 1.02 (P = 0.31)

Test for subgroup differences: Chi2 = 3.22, df = 1 (P = 0.07), I2 =69%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

120Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.18. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 18 Patent ductus arteriosus.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 18 Patent ductus arteriosus

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Meis 2003 7/306 8/153 100.0 % 0.44 [ 0.16, 1.18 ]

Total (95% CI) 306 153 100.0 % 0.44 [ 0.16, 1.18 ]

Total events: 7 (Progesterone), 8 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.63 (P = 0.10)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

121Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.19. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 19 Intrauterine fetal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 19 Intrauterine fetal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Ibrahim 2010 3/25 9/25 34.9 % 0.33 [ 0.10, 1.09 ]

Johnson 1975 0/18 5/26 9.7 % 0.13 [ 0.01, 2.20 ]

Meis 2003 6/306 2/153 24.2 % 1.50 [ 0.31, 7.34 ]

Subtotal (95% CI) 349 204 68.8 % 0.49 [ 0.14, 1.69 ]

Total events: 9 (Progesterone), 16 (Placebo)

Heterogeneity: Tau2 = 0.45; Chi2 = 3.17, df = 2 (P = 0.20); I2 =37%

Test for overall effect: Z = 1.13 (P = 0.26)

2 Vaginal

O’Brien 2007 5/309 4/302 31.2 % 1.22 [ 0.33, 4.51 ]

Subtotal (95% CI) 309 302 31.2 % 1.22 [ 0.33, 4.51 ]

Total events: 5 (Progesterone), 4 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.30 (P = 0.76)

Total (95% CI) 658 506 100.0 % 0.66 [ 0.26, 1.69 ]

Total events: 14 (Progesterone), 20 (Placebo)

Heterogeneity: Tau2 = 0.30; Chi2 = 4.46, df = 3 (P = 0.22); I2 =33%

Test for overall effect: Z = 0.87 (P = 0.38)

Test for subgroup differences: Chi2 = 0.98, df = 1 (P = 0.32), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

122Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.20. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 20 Neonatal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 20 Neonatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Ibrahim 2010 1/25 4/25 9.5 % 0.25 [ 0.03, 2.08 ]

Johnson 1975 0/18 2/26 4.9 % 0.28 [ 0.01, 5.59 ]

Meis 2003 8/306 9/153 28.6 % 0.44 [ 0.17, 1.13 ]

Subtotal (95% CI) 349 204 43.1 % 0.38 [ 0.17, 0.87 ]

Total events: 9 (Progesterone), 15 (Placebo)

Heterogeneity: Chi2 = 0.29, df = 2 (P = 0.86); I2 =0.0%

Test for overall effect: Z = 2.29 (P = 0.022)

2 Vaginal

Akbari 2009 3/69 10/72 23.3 % 0.31 [ 0.09, 1.09 ]

O’Brien 2007 6/309 7/302 16.9 % 0.84 [ 0.28, 2.46 ]

Subtotal (95% CI) 378 374 40.2 % 0.53 [ 0.24, 1.18 ]

Total events: 9 (Progesterone), 17 (Placebo)

Heterogeneity: Chi2 = 1.37, df = 1 (P = 0.24); I2 =27%

Test for overall effect: Z = 1.55 (P = 0.12)

3 Oral

Rai 2009 3/74 7/74 16.7 % 0.43 [ 0.12, 1.59 ]

Subtotal (95% CI) 74 74 16.7 % 0.43 [ 0.12, 1.59 ]

Total events: 3 (Progesterone), 7 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.26 (P = 0.21)

Total (95% CI) 801 652 100.0 % 0.45 [ 0.27, 0.76 ]

Total events: 21 (Progesterone), 39 (Placebo)

Heterogeneity: Chi2 = 1.99, df = 5 (P = 0.85); I2 =0.0%

Test for overall effect: Z = 2.99 (P = 0.0028)

Test for subgroup differences: Chi2 = 0.33, df = 2 (P = 0.85), I2 =0.0%

0.02 0.1 1 10 50

Favours progesterone Favours placebo

123Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.21. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 21 Developmental delay.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 21 Developmental delay

Study or subgroup Progesterone Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Meis 2003 14/192 7/82 100.0 % 0.85 [ 0.36, 2.04 ]

Total (95% CI) 192 82 100.0 % 0.85 [ 0.36, 2.04 ]

Total events: 14 (Progesterone), 7 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.36 (P = 0.72)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

Analysis 1.22. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 22 Intellectual impairment.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 22 Intellectual impairment

Study or subgroup Progesterone Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Meis 2003 1/192 0/82 100.0 % 1.29 [ 0.05, 31.34 ]

Total (95% CI) 192 82 100.0 % 1.29 [ 0.05, 31.34 ]

Total events: 1 (Progesterone), 0 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.16 (P = 0.88)

Test for subgroup differences: Not applicable

0.05 0.2 1 5 20

Favours progesterone Favours placebo

124Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.23. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 23 Motor Impairment.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 23 Motor Impairment

Study or subgroup Progesterone Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Meis 2003 3/192 2/82 100.0 % 0.64 [ 0.11, 3.76 ]

Total (95% CI) 192 82 100.0 % 0.64 [ 0.11, 3.76 ]

Total events: 3 (Progesterone), 2 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.49 (P = 0.62)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

125Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.24. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 24 Visual Impairment.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 24 Visual Impairment

Study or subgroup Progesterone Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Meis 2003 4/192 2/82 100.0 % 0.85 [ 0.16, 4.57 ]

Total (95% CI) 192 82 100.0 % 0.85 [ 0.16, 4.57 ]

Total events: 4 (Progesterone), 2 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.18 (P = 0.85)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

Analysis 1.25. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 25 Hearing Impairment.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 25 Hearing Impairment

Study or subgroup Progesterone Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Meis 2003 4/192 5/82 100.0 % 0.34 [ 0.09, 1.24 ]

Total (95% CI) 192 82 100.0 % 0.34 [ 0.09, 1.24 ]

Total events: 4 (Progesterone), 5 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 1.63 (P = 0.10)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

126Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.26. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 26 Cerebral palsy.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 26 Cerebral palsy

Study or subgroup Progesterone Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Meis 2003 0/192 1/82 100.0 % 0.14 [ 0.01, 3.48 ]

Total (95% CI) 192 82 100.0 % 0.14 [ 0.01, 3.48 ]

Total events: 0 (Progesterone), 1 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 1.19 (P = 0.23)

Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours progesterone Favours placebo

127Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.27. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 27 Learning difficulties.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 27 Learning difficulties

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Meis 2003 16/192 8/82 100.0 % 0.85 [ 0.38, 1.92 ]

Total (95% CI) 192 82 100.0 % 0.85 [ 0.38, 1.92 ]

Total events: 16 (Progesterone), 8 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.38 (P = 0.70)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

Analysis 1.28. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 28 Height less than 5th centile.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 28 Height less than 5th centile

Study or subgroup Progesterone Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Meis 2003 7/189 4/81 100.0 % 0.75 [ 0.23, 2.49 ]

Total (95% CI) 189 81 100.0 % 0.75 [ 0.23, 2.49 ]

Total events: 7 (Progesterone), 4 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.47 (P = 0.64)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

128Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.29. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 29 Weight less than 5th centile.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 29 Weight less than 5th centile

Study or subgroup Progesterone Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Meis 2003 11/189 6/81 100.0 % 0.79 [ 0.30, 2.05 ]

Total (95% CI) 189 81 100.0 % 0.79 [ 0.30, 2.05 ]

Total events: 11 (Progesterone), 6 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.49 (P = 0.62)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

129Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.30. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 30 Adverse drug reaction.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 30 Adverse drug reaction

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Oral

Rai 2009 5/74 7/74 100.0 % 0.71 [ 0.24, 2.15 ]

Total (95% CI) 74 74 100.0 % 0.71 [ 0.24, 2.15 ]

Total events: 5 (Progesterone), 7 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.60 (P = 0.55)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

Analysis 1.31. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 31 Pregnancy prolongation (weeks).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 31 Pregnancy prolongation (weeks)

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Oral

Rai 2009 74 15.57 (7.38) 74 11.1 (7.01) 100.0 % 4.47 [ 2.15, 6.79 ]

Total (95% CI) 74 74 100.0 % 4.47 [ 2.15, 6.79 ]

Heterogeneity: not applicable

Test for overall effect: Z = 3.78 (P = 0.00016)

Test for subgroup differences: Not applicable

-20 -10 0 10 20

Favours placebo Favours progesterone

130Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.32. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 32 Apgar score < 7.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 32 Apgar score < 7

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Ibrahim 2010 6/25 11/25 100.0 % 0.55 [ 0.24, 1.25 ]

Total (95% CI) 25 25 100.0 % 0.55 [ 0.24, 1.25 ]

Total events: 6 (Progesterone), 11 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.44 (P = 0.15)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

131Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.33. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 33 Admission to neonatal intensive care unit.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 33 Admission to neonatal intensive care unit

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Oral

Rai 2009 10/74 38/74 58.5 % 0.26 [ 0.14, 0.49 ]

Subtotal (95% CI) 74 74 58.5 % 0.26 [ 0.14, 0.49 ]

Total events: 10 (Progesterone), 38 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 4.24 (P = 0.000023)

2 Vaginal

Akbari 2009 5/69 23/72 34.6 % 0.23 [ 0.09, 0.56 ]

Majhi 2009 0/50 4/50 6.9 % 0.11 [ 0.01, 2.01 ]

Subtotal (95% CI) 119 122 41.5 % 0.21 [ 0.09, 0.49 ]

Total events: 5 (Progesterone), 27 (Placebo)

Heterogeneity: Chi2 = 0.22, df = 1 (P = 0.64); I2 =0.0%

Test for overall effect: Z = 3.55 (P = 0.00038)

Total (95% CI) 193 196 100.0 % 0.24 [ 0.14, 0.40 ]

Total events: 15 (Progesterone), 65 (Placebo)

Heterogeneity: Chi2 = 0.37, df = 2 (P = 0.83); I2 =0.0%

Test for overall effect: Z = 5.54 (P < 0.00001)

Test for subgroup differences: Chi2 = 0.19, df = 1 (P = 0.66), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

132Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.34. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 34 Neonatal length of hospital stay (days).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 34 Neonatal length of hospital stay (days)

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Oral

Glover 2011 19 6.5 (10.5) 14 7.5 (9) 100.0 % -1.00 [ -7.67, 5.67 ]

Total (95% CI) 19 14 100.0 % -1.00 [ -7.67, 5.67 ]

Heterogeneity: not applicable

Test for overall effect: Z = 0.29 (P = 0.77)

Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours progesterone Favours placebo

Analysis 1.35. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 35 Infant weight at 6 months follow-up (g).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 35 Infant weight at 6 months follow-up (g)

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Vaginal

O’Brien 2007 218 7491 (1285) 218 7462 (1257) 100.0 % 29.00 [ -209.62, 267.62 ]

Total (95% CI) 218 218 100.0 % 29.00 [ -209.62, 267.62 ]

Heterogeneity: not applicable

Test for overall effect: Z = 0.24 (P = 0.81)

Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours placebo Favours progesterone

133Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.36. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 36 Infant weight at 12 months follow-up (g).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 36 Infant weight at 12 months follow-up (g)

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Vaginal

O’Brien 2007 178 9315 (1379) 201 9403 (1536) 100.0 % -88.00 [ -381.48, 205.48 ]

Total (95% CI) 178 201 100.0 % -88.00 [ -381.48, 205.48 ]

Heterogeneity: not applicable

Test for overall effect: Z = 0.59 (P = 0.56)

Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours placebo Favours progesterone

134Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.37. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 37 Infant weight at 24 months follow-up (g).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 37 Infant weight at 24 months follow-up (g)

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Vaginal

O’Brien 2007 138 11705 (1838) 149 11745 (1986) 100.0 % -40.00 [ -482.41, 402.41 ]

Total (95% CI) 138 149 100.0 % -40.00 [ -482.41, 402.41 ]

Heterogeneity: not applicable

Test for overall effect: Z = 0.18 (P = 0.86)

Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours placebo Favours progesterone

Analysis 1.38. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 38 Infant length at 6 months follow-up (cm).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 38 Infant length at 6 months follow-up (cm)

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Vaginal

O’Brien 2007 216 66.2 (4) 214 66.1 (3.3) 100.0 % 0.10 [ -0.59, 0.79 ]

Total (95% CI) 216 214 100.0 % 0.10 [ -0.59, 0.79 ]

Heterogeneity: not applicable

Test for overall effect: Z = 0.28 (P = 0.78)

Test for subgroup differences: Not applicable

-4 -2 0 2 4

Favours placebo Favours progesterone

135Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.39. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 39 Infant length at 12 months follow-up (cm).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 39 Infant length at 12 months follow-up (cm)

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Vaginal

O’Brien 2007 179 74.3 (3.4) 197 74.4 (3.5) 100.0 % -0.10 [ -0.80, 0.60 ]

Total (95% CI) 179 197 100.0 % -0.10 [ -0.80, 0.60 ]

Heterogeneity: not applicable

Test for overall effect: Z = 0.28 (P = 0.78)

Test for subgroup differences: Not applicable

-10 -5 0 5 10

Favours placebo Favours progesterone

136Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.40. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 40 Infant length at 24 months follow-up (cm).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 40 Infant length at 24 months follow-up (cm)

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Vaginal

O’Brien 2007 133 84.8 (4.4) 151 85 (4.4) 100.0 % -0.20 [ -1.23, 0.83 ]

Total (95% CI) 133 151 100.0 % -0.20 [ -1.23, 0.83 ]

Heterogeneity: not applicable

Test for overall effect: Z = 0.38 (P = 0.70)

Test for subgroup differences: Not applicable

-20 -10 0 10 20

Favours placebo Favours progesterone

Analysis 1.41. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 41 Infant head circumference at 6 months follow-up (cm).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 41 Infant head circumference at 6 months follow-up (cm)

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Vaginal

O’Brien 2007 212 43.1 (1.8) 214 43 (1.7) 100.0 % 0.10 [ -0.23, 0.43 ]

Total (95% CI) 212 214 100.0 % 0.10 [ -0.23, 0.43 ]

Heterogeneity: not applicable

Test for overall effect: Z = 0.59 (P = 0.56)

Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours placebo Favours progesterone

137Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.42. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 42 Infant head circumference at 12 months follow-up (cm).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 42 Infant head circumference at 12 months follow-up (cm)

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Vaginal

O’Brien 2007 179 45.9 (1.8) 193 45.8 (1.7) 100.0 % 0.10 [ -0.26, 0.46 ]

Total (95% CI) 179 193 100.0 % 0.10 [ -0.26, 0.46 ]

Heterogeneity: not applicable

Test for overall effect: Z = 0.55 (P = 0.58)

Test for subgroup differences: Not applicable

-2 -1 0 1 2

Favours placebo Favours progesterone

138Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 1.43. Comparison 1 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth (singletons), Outcome 43 Infant head circumference at 24 months follow-up (cm).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 1 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome: 43 Infant head circumference at 24 months follow-up (cm)

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Vaginal

O’Brien 2007 128 48.1 (1.8) 136 47.9 (1.6) 100.0 % 0.20 [ -0.21, 0.61 ]

Total (95% CI) 128 136 100.0 % 0.20 [ -0.21, 0.61 ]

Heterogeneity: not applicable

Test for overall effect: Z = 0.95 (P = 0.34)

Test for subgroup differences: Not applicable

-4 -2 0 2 4

Favours placebo Favours progesterone

139Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 2.1. Comparison 2 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth, by timing of commencement (< 20 wk v > 20 wk, singletons), Outcome 1 Preterm birth less

than 37 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 2 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth, by timing of commencement (< 20 wk v > 20 wk, singletons)

Outcome: 1 Preterm birth less than 37 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Therapy commences before 20 weeks

Glover 2011 5/19 8/14 10.4 % 0.46 [ 0.19, 1.11 ]

Johnson 1975 2/18 12/26 5.3 % 0.24 [ 0.06, 0.95 ]

Meis 2003 111/306 84/153 27.7 % 0.66 [ 0.54, 0.81 ]

O’Brien 2007 129/309 123/302 28.1 % 1.03 [ 0.85, 1.24 ]

Subtotal (95% CI) 652 495 71.4 % 0.69 [ 0.46, 1.04 ]

Total events: 247 (Progesterone), 227 (Placebo)

Heterogeneity: Tau2 = 0.10; Chi2 = 14.26, df = 3 (P = 0.003); I2 =79%

Test for overall effect: Z = 1.76 (P = 0.079)

2 Therapy commences after 20 weeks

Cetingoz 2011 9/37 17/34 14.6 % 0.49 [ 0.25, 0.94 ]

da Fonseca 2003 10/72 20/70 14.0 % 0.49 [ 0.25, 0.96 ]

Subtotal (95% CI) 109 104 28.6 % 0.49 [ 0.30, 0.78 ]

Total events: 19 (Progesterone), 37 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.00, df = 1 (P = 1.00); I2 =0.0%

Test for overall effect: Z = 2.97 (P = 0.0029)

Total (95% CI) 761 599 100.0 % 0.63 [ 0.44, 0.89 ]

Total events: 266 (Progesterone), 264 (Placebo)

Heterogeneity: Tau2 = 0.10; Chi2 = 18.53, df = 5 (P = 0.002); I2 =73%

Test for overall effect: Z = 2.65 (P = 0.0081)

Test for subgroup differences: Chi2 = 1.19, df = 1 (P = 0.28), I2 =16%

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

140Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 3.1. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 1 Perinatal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons)

Outcome: 1 Perinatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Johnson 1975 0/18 7/26 3.2 % 0.09 [ 0.01, 1.56 ]

Meis 2003 14/306 11/153 35.7 % 0.64 [ 0.30, 1.37 ]

Subtotal (95% CI) 324 179 38.9 % 0.38 [ 0.07, 2.18 ]

Total events: 14 (Progesterone), 18 (Placebo)

Heterogeneity: Tau2 = 0.91; Chi2 = 1.83, df = 1 (P = 0.18); I2 =45%

Test for overall effect: Z = 1.08 (P = 0.28)

2 Dose >= 500 mg per week

Akbari 2009 3/69 10/72 15.3 % 0.31 [ 0.09, 1.09 ]

O’Brien 2007 11/309 11/302 31.9 % 0.98 [ 0.43, 2.22 ]

Rai 2009 3/74 7/74 13.9 % 0.43 [ 0.12, 1.59 ]

Subtotal (95% CI) 452 448 61.1 % 0.59 [ 0.29, 1.21 ]

Total events: 17 (Progesterone), 28 (Placebo)

Heterogeneity: Tau2 = 0.10; Chi2 = 2.65, df = 2 (P = 0.27); I2 =24%

Test for overall effect: Z = 1.44 (P = 0.15)

Total (95% CI) 776 627 100.0 % 0.58 [ 0.35, 0.97 ]

Total events: 31 (Progesterone), 46 (Placebo)

Heterogeneity: Tau2 = 0.04; Chi2 = 4.46, df = 4 (P = 0.35); I2 =10%

Test for overall effect: Z = 2.08 (P = 0.038)

Test for subgroup differences: Chi2 = 0.20, df = 1 (P = 0.66), I2 =0.0%

0.01 0.1 1 10 100

Favours treatment Favours control

141Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 3.2. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 2 Preterm birth less

than 37 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons)

Outcome: 2 Preterm birth less than 37 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Johnson 1975 2/18 12/25 4.0 % 0.23 [ 0.06, 0.91 ]

Meis 2003 111/306 84/153 18.2 % 0.66 [ 0.54, 0.81 ]

Saghafi 2011a 16/50 30/50 13.7 % 0.53 [ 0.34, 0.85 ]

Subtotal (95% CI) 374 228 36.0 % 0.59 [ 0.44, 0.80 ]

Total events: 129 (Progesterone), 126 (Placebo)

Heterogeneity: Tau2 = 0.03; Chi2 = 2.85, df = 2 (P = 0.24); I2 =30%

Test for overall effect: Z = 3.40 (P = 0.00068)

2 Dose >= 500 mg per week

Akbari 2009 8/69 23/72 9.3 % 0.36 [ 0.17, 0.76 ]

Cetingoz 2011 9/37 17/34 10.4 % 0.49 [ 0.25, 0.94 ]

da Fonseca 2003 10/72 20/70 10.0 % 0.49 [ 0.25, 0.96 ]

Glover 2011 5/19 8/14 7.6 % 0.46 [ 0.19, 1.11 ]

Majhi 2009 6/50 19/50 8.1 % 0.32 [ 0.14, 0.72 ]

O’Brien 2007 129/309 123/302 18.5 % 1.03 [ 0.85, 1.24 ]

Subtotal (95% CI) 556 542 64.0 % 0.51 [ 0.31, 0.85 ]

Total events: 167 (Progesterone), 210 (Placebo)

Heterogeneity: Tau2 = 0.29; Chi2 = 22.11, df = 5 (P = 0.00050); I2 =77%

Test for overall effect: Z = 2.57 (P = 0.010)

Total (95% CI) 930 770 100.0 % 0.54 [ 0.40, 0.74 ]

Total events: 296 (Progesterone), 336 (Placebo)

Heterogeneity: Tau2 = 0.12; Chi2 = 29.37, df = 8 (P = 0.00027); I2 =73%

Test for overall effect: Z = 3.89 (P = 0.00010)

Test for subgroup differences: Chi2 = 0.22, df = 1 (P = 0.64), I2 =0.0%

0.05 0.2 1 5 20

Favours treatment Favours control

142Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 3.3. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 3 Threatened preterm

labour.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons)

Outcome: 3 Threatened preterm labour

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Meis 2003 49/306 21/153 53.8 % 1.17 [ 0.73, 1.87 ]

Subtotal (95% CI) 306 153 53.8 % 1.17 [ 0.73, 1.87 ]

Total events: 49 (Progesterone), 21 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.64 (P = 0.52)

2 Dose >= 500 mg per week

da Fonseca 2003 14/72 22/70 46.2 % 0.62 [ 0.35, 1.11 ]

Subtotal (95% CI) 72 70 46.2 % 0.62 [ 0.35, 1.11 ]

Total events: 14 (Progesterone), 22 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.61 (P = 0.11)

Total (95% CI) 378 223 100.0 % 0.87 [ 0.47, 1.62 ]

Total events: 63 (Progesterone), 43 (Placebo)

Heterogeneity: Tau2 = 0.13; Chi2 = 2.75, df = 1 (P = 0.10); I2 =64%

Test for overall effect: Z = 0.44 (P = 0.66)

Test for subgroup differences: Chi2 = 2.74, df = 1 (P = 0.10), I2 =63%

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

143Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 3.4. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 4 Caesarean section.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons)

Outcome: 4 Caesarean section

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Dose < 500 mg per week

Meis 2003 52/306 30/153 32.8 % 0.87 [ 0.58, 1.30 ]

Subtotal (95% CI) 306 153 32.8 % 0.87 [ 0.58, 1.30 ]

Total events: 52 (Progesterone), 30 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.69 (P = 0.49)

2 Dose >= 500 mg per week

Majhi 2009 4/50 7/50 5.7 % 0.57 [ 0.18, 1.83 ]

O’Brien 2007 72/309 74/302 61.4 % 0.95 [ 0.72, 1.26 ]

Subtotal (95% CI) 359 352 67.2 % 0.92 [ 0.70, 1.21 ]

Total events: 76 (Progesterone), 81 (Placebo)

Heterogeneity: Chi2 = 0.70, df = 1 (P = 0.40); I2 =0.0%

Test for overall effect: Z = 0.61 (P = 0.54)

Total (95% CI) 665 505 100.0 % 0.90 [ 0.72, 1.13 ]

Total events: 128 (Progesterone), 111 (Placebo)

Heterogeneity: Chi2 = 0.76, df = 2 (P = 0.68); I2 =0.0%

Test for overall effect: Z = 0.89 (P = 0.37)

Test for subgroup differences: Chi2 = 0.05, df = 1 (P = 0.82), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

144Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 3.5. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 5 Antenatal

corticosteroids.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons)

Outcome: 5 Antenatal corticosteroids

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Dose < 500 mg per week

Meis 2003 52/306 30/153 34.8 % 0.87 [ 0.58, 1.30 ]

Subtotal (95% CI) 306 153 34.8 % 0.87 [ 0.58, 1.30 ]

Total events: 52 (Progesterone), 30 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.69 (P = 0.49)

2 Dose >= 500 mg per week

O’Brien 2007 72/309 74/302 65.2 % 0.95 [ 0.72, 1.26 ]

Subtotal (95% CI) 309 302 65.2 % 0.95 [ 0.72, 1.26 ]

Total events: 72 (Progesterone), 74 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.35 (P = 0.73)

Total (95% CI) 615 455 100.0 % 0.92 [ 0.73, 1.16 ]

Total events: 124 (Progesterone), 104 (Placebo)

Heterogeneity: Chi2 = 0.14, df = 1 (P = 0.71); I2 =0.0%

Test for overall effect: Z = 0.69 (P = 0.49)

Test for subgroup differences: Chi2 = 0.14, df = 1 (P = 0.71), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

145Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 3.6. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 6 Need for tocolysis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons)

Outcome: 6 Need for tocolysis

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Dose < 500 mg per week

Johnson 1975 2/18 2/26 2.5 % 1.44 [ 0.22, 9.33 ]

Meis 2003 53/306 24/153 49.2 % 1.10 [ 0.71, 1.72 ]

Subtotal (95% CI) 324 179 51.8 % 1.12 [ 0.73, 1.72 ]

Total events: 55 (Progesterone), 26 (Placebo)

Heterogeneity: Chi2 = 0.08, df = 1 (P = 0.78); I2 =0.0%

Test for overall effect: Z = 0.52 (P = 0.60)

2 Dose >= 500 mg per week

O’Brien 2007 35/309 31/302 48.2 % 1.10 [ 0.70, 1.74 ]

Subtotal (95% CI) 309 302 48.2 % 1.10 [ 0.70, 1.74 ]

Total events: 35 (Progesterone), 31 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.42 (P = 0.67)

Total (95% CI) 633 481 100.0 % 1.11 [ 0.81, 1.52 ]

Total events: 90 (Progesterone), 57 (Placebo)

Heterogeneity: Chi2 = 0.08, df = 2 (P = 0.96); I2 =0.0%

Test for overall effect: Z = 0.67 (P = 0.50)

Test for subgroup differences: Chi2 = 0.00, df = 1 (P = 0.96), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

146Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 3.7. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 7 Respiratory distress

syndrome.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons)

Outcome: 7 Respiratory distress syndrome

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Meis 2003 29/306 23/153 28.1 % 0.63 [ 0.38, 1.05 ]

Subtotal (95% CI) 306 153 28.1 % 0.63 [ 0.38, 1.05 ]

Total events: 29 (Progesterone), 23 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.77 (P = 0.077)

2 Dose >= 500 mg per week

Akbari 2009 5/69 23/72 23.0 % 0.23 [ 0.09, 0.56 ]

O’Brien 2007 34/309 36/302 28.9 % 0.92 [ 0.59, 1.43 ]

Rai 2009 3/74 31/74 20.0 % 0.10 [ 0.03, 0.30 ]

Subtotal (95% CI) 452 448 71.9 % 0.29 [ 0.07, 1.23 ]

Total events: 42 (Progesterone), 90 (Placebo)

Heterogeneity: Tau2 = 1.42; Chi2 = 18.98, df = 2 (P = 0.00008); I2 =89%

Test for overall effect: Z = 1.68 (P = 0.093)

Total (95% CI) 758 601 100.0 % 0.38 [ 0.16, 0.89 ]

Total events: 71 (Progesterone), 113 (Placebo)

Heterogeneity: Tau2 = 0.59; Chi2 = 18.91, df = 3 (P = 0.00028); I2 =84%

Test for overall effect: Z = 2.23 (P = 0.026)

Test for subgroup differences: Chi2 = 0.98, df = 1 (P = 0.32), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

147Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 3.8. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 8 Intraventricular

haemorrhage - all grades.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons)

Outcome: 8 Intraventricular haemorrhage - all grades

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Meis 2003 4/306 8/153 40.3 % 0.25 [ 0.08, 0.82 ]

Subtotal (95% CI) 306 153 40.3 % 0.25 [ 0.08, 0.82 ]

Total events: 4 (Progesterone), 8 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.29 (P = 0.022)

2 Dose >= 500 mg per week

Akbari 2009 2/69 1/72 19.3 % 2.09 [ 0.19, 22.50 ]

O’Brien 2007 6/309 5/302 40.5 % 1.17 [ 0.36, 3.80 ]

Subtotal (95% CI) 378 374 59.7 % 1.31 [ 0.46, 3.77 ]

Total events: 8 (Progesterone), 6 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.18, df = 1 (P = 0.67); I2 =0.0%

Test for overall effect: Z = 0.51 (P = 0.61)

Total (95% CI) 684 527 100.0 % 0.70 [ 0.20, 2.46 ]

Total events: 12 (Progesterone), 14 (Placebo)

Heterogeneity: Tau2 = 0.65; Chi2 = 4.39, df = 2 (P = 0.11); I2 =54%

Test for overall effect: Z = 0.55 (P = 0.58)

Test for subgroup differences: Chi2 = 4.21, df = 1 (P = 0.04), I2 =76%

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

148Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 3.9. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 9 Intraventricular

haemorrhage - grade III or IV.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons)

Outcome: 9 Intraventricular haemorrhage - grade III or IV

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Dose < 500 mg per week

Meis 2003 2/306 0/153 39.7 % 2.51 [ 0.12, 51.92 ]

Subtotal (95% CI) 306 153 39.7 % 2.51 [ 0.12, 51.92 ]

Total events: 2 (Progesterone), 0 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.59 (P = 0.55)

2 Dose >= 500 mg per week

O’Brien 2007 1/309 1/302 60.3 % 0.98 [ 0.06, 15.55 ]

Subtotal (95% CI) 309 302 60.3 % 0.98 [ 0.06, 15.55 ]

Total events: 1 (Progesterone), 1 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.02 (P = 0.99)

Total (95% CI) 615 455 100.0 % 1.59 [ 0.21, 11.73 ]

Total events: 3 (Progesterone), 1 (Placebo)

Heterogeneity: Chi2 = 0.21, df = 1 (P = 0.65); I2 =0.0%

Test for overall effect: Z = 0.45 (P = 0.65)

Test for subgroup differences: Chi2 = 0.20, df = 1 (P = 0.65), I2 =0.0%

0.02 0.1 1 10 50

Favours treatment Favours control

149Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 3.10. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 10 Necrotising

enterocolitis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons)

Outcome: 10 Necrotising enterocolitis

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Meis 2003 0/306 4/153 18.1 % 0.06 [ 0.00, 1.03 ]

Subtotal (95% CI) 306 153 18.1 % 0.06 [ 0.00, 1.03 ]

Total events: 0 (Progesterone), 4 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.94 (P = 0.052)

2 Dose >= 500 mg per week

Akbari 2009 0/50 1/50 15.3 % 0.33 [ 0.01, 7.99 ]

O’Brien 2007 3/309 5/302 66.6 % 0.59 [ 0.14, 2.43 ]

Subtotal (95% CI) 359 352 81.9 % 0.53 [ 0.15, 1.95 ]

Total events: 3 (Progesterone), 6 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.10, df = 1 (P = 0.75); I2 =0.0%

Test for overall effect: Z = 0.95 (P = 0.34)

Total (95% CI) 665 505 100.0 % 0.35 [ 0.10, 1.25 ]

Total events: 3 (Progesterone), 10 (Placebo)

Heterogeneity: Tau2 = 0.10; Chi2 = 2.13, df = 2 (P = 0.35); I2 =6%

Test for overall effect: Z = 1.62 (P = 0.11)

Test for subgroup differences: Chi2 = 1.92, df = 1 (P = 0.17), I2 =48%

0.005 0.1 1 10 200

Favours treatment Favours control

150Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 3.11. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 11 Intrauterine fetal

death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons)

Outcome: 11 Intrauterine fetal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Johnson 1975 0/18 5/26 13.8 % 0.13 [ 0.01, 2.20 ]

Meis 2003 6/306 2/153 37.0 % 1.50 [ 0.31, 7.34 ]

Subtotal (95% CI) 324 179 50.8 % 0.58 [ 0.05, 6.51 ]

Total events: 6 (Progesterone), 7 (Placebo)

Heterogeneity: Tau2 = 1.83; Chi2 = 2.33, df = 1 (P = 0.13); I2 =57%

Test for overall effect: Z = 0.44 (P = 0.66)

2 Dose >= 500 mg per week

O’Brien 2007 5/309 4/302 49.2 % 1.22 [ 0.33, 4.51 ]

Subtotal (95% CI) 309 302 49.2 % 1.22 [ 0.33, 4.51 ]

Total events: 5 (Progesterone), 4 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.30 (P = 0.76)

Total (95% CI) 633 481 100.0 % 0.97 [ 0.32, 2.91 ]

Total events: 11 (Progesterone), 11 (Placebo)

Heterogeneity: Tau2 = 0.20; Chi2 = 2.49, df = 2 (P = 0.29); I2 =20%

Test for overall effect: Z = 0.06 (P = 0.95)

Test for subgroup differences: Chi2 = 0.28, df = 1 (P = 0.59), I2 =0.0%

0.01 0.1 1 10 100

Favours treatment Favours control

151Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 3.12. Comparison 3 Progesterone versus placebo/no treatment: previous history spontaneous

preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons), Outcome 12 Neonatal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 3 Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons)

Outcome: 12 Neonatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Dose < 500 mg per week

Johnson 1975 0/18 2/26 5.4 % 0.28 [ 0.01, 5.59 ]

Meis 2003 8/306 9/153 31.6 % 0.44 [ 0.17, 1.13 ]

Subtotal (95% CI) 324 179 37.1 % 0.42 [ 0.17, 1.03 ]

Total events: 8 (Progesterone), 11 (Placebo)

Heterogeneity: Chi2 = 0.08, df = 1 (P = 0.78); I2 =0.0%

Test for overall effect: Z = 1.90 (P = 0.058)

2 Dose >= 500 mg per week

Akbari 2009 3/69 10/72 25.8 % 0.31 [ 0.09, 1.09 ]

O’Brien 2007 6/309 7/302 18.7 % 0.84 [ 0.28, 2.46 ]

Rai 2009 3/74 7/74 18.5 % 0.43 [ 0.12, 1.59 ]

Subtotal (95% CI) 452 448 62.9 % 0.50 [ 0.26, 0.99 ]

Total events: 12 (Progesterone), 24 (Placebo)

Heterogeneity: Chi2 = 1.47, df = 2 (P = 0.48); I2 =0.0%

Test for overall effect: Z = 1.99 (P = 0.047)

Total (95% CI) 776 627 100.0 % 0.47 [ 0.28, 0.81 ]

Total events: 20 (Progesterone), 35 (Placebo)

Heterogeneity: Chi2 = 1.65, df = 4 (P = 0.80); I2 =0.0%

Test for overall effect: Z = 2.72 (P = 0.0065)

Test for subgroup differences: Chi2 = 0.10, df = 1 (P = 0.76), I2 =0.0%

0.02 0.1 1 10 50

Favours treatment Favours control

152Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.1. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 1 Perinatal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 1 Perinatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Fonseca 2007 3/136 8/138 28.2 % 0.38 [ 0.10, 1.40 ]

Hassan 2011 8/235 11/223 40.0 % 0.69 [ 0.28, 1.68 ]

Subtotal (95% CI) 371 361 68.2 % 0.56 [ 0.27, 1.17 ]

Total events: 11 (Progesterone), 19 (Placebo)

Heterogeneity: Chi2 = 0.55, df = 1 (P = 0.46); I2 =0.0%

Test for overall effect: Z = 1.55 (P = 0.12)

2 Intramuscular

Grobman 2012 10/327 9/330 31.8 % 1.12 [ 0.46, 2.72 ]

Subtotal (95% CI) 327 330 31.8 % 1.12 [ 0.46, 2.72 ]

Total events: 10 (Progesterone), 9 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.25 (P = 0.80)

Total (95% CI) 698 691 100.0 % 0.74 [ 0.42, 1.29 ]

Total events: 21 (Progesterone), 28 (Placebo)

Heterogeneity: Chi2 = 1.86, df = 2 (P = 0.39); I2 =0.0%

Test for overall effect: Z = 1.06 (P = 0.29)

Test for subgroup differences: Chi2 = 1.39, df = 1 (P = 0.24), I2 =28%

0.2 0.5 1 2 5

Favours progesterone Favours placebo

153Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.2. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 2 Preterm birth less than 34 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 2 Preterm birth less than 34 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Fonseca 2007 26/125 45/125 70.3 % 0.58 [ 0.38, 0.87 ]

Subtotal (95% CI) 125 125 70.3 % 0.58 [ 0.38, 0.87 ]

Total events: 26 (Progesterone), 45 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.60 (P = 0.0095)

2 Intramuscular

Rozenberg 2012 15/94 19/94 29.7 % 0.79 [ 0.43, 1.46 ]

Subtotal (95% CI) 94 94 29.7 % 0.79 [ 0.43, 1.46 ]

Total events: 15 (Progesterone), 19 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.76 (P = 0.45)

Total (95% CI) 219 219 100.0 % 0.64 [ 0.45, 0.90 ]

Total events: 41 (Progesterone), 64 (Placebo)

Heterogeneity: Chi2 = 0.68, df = 1 (P = 0.41); I2 =0.0%

Test for overall effect: Z = 2.55 (P = 0.011)

Test for subgroup differences: Chi2 = 0.68, df = 1 (P = 0.41), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

154Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.3. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 3 Preterm labour.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 3 Preterm labour

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Rozenberg 2012 23/94 22/94 100.0 % 1.05 [ 0.63, 1.74 ]

Total (95% CI) 94 94 100.0 % 1.05 [ 0.63, 1.74 ]

Total events: 23 (Progesterone), 22 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.17 (P = 0.86)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

155Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.4. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 4 Prelabour spontaneous rupture of membranes.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 4 Prelabour spontaneous rupture of membranes

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Grobman 2012 25/327 24/330 67.8 % 1.05 [ 0.61, 1.80 ]

Rozenberg 2012 11/94 5/94 32.2 % 2.20 [ 0.80, 6.09 ]

Total (95% CI) 421 424 100.0 % 1.33 [ 0.68, 2.62 ]

Total events: 36 (Progesterone), 29 (Placebo)

Heterogeneity: Tau2 = 0.10; Chi2 = 1.58, df = 1 (P = 0.21); I2 =37%

Test for overall effect: Z = 0.83 (P = 0.40)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

156Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.5. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 5 Side effects (any).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 5 Side effects (any)

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Grobman 2012 223/326 220/328 100.0 % 1.02 [ 0.92, 1.13 ]

Rozenberg 2012 0/94 0/94 Not estimable

Total (95% CI) 420 422 100.0 % 1.02 [ 0.92, 1.13 ]

Total events: 223 (Progesterone), 220 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.36 (P = 0.72)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

157Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.6. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 6 Side effects (injection site).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 6 Side effects (injection site)

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Grobman 2012 217/326 209/328 100.0 % 1.04 [ 0.93, 1.17 ]

Total (95% CI) 326 328 100.0 % 1.04 [ 0.93, 1.17 ]

Total events: 217 (Progesterone), 209 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.76 (P = 0.45)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

Analysis 4.7. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 7 Side effects (urticaria).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 7 Side effects (urticaria)

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Grobman 2012 10/326 2/328 100.0 % 5.03 [ 1.11, 22.78 ]

Total (95% CI) 326 328 100.0 % 5.03 [ 1.11, 22.78 ]

Total events: 10 (Progesterone), 2 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.10 (P = 0.036)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

158Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.8. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 8 Side effects (nausea).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 8 Side effects (nausea)

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Grobman 2012 7/326 10/328 100.0 % 0.70 [ 0.27, 1.83 ]

Total (95% CI) 326 328 100.0 % 0.70 [ 0.27, 1.83 ]

Total events: 7 (Progesterone), 10 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.72 (P = 0.47)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

159Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.9. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 9 Pregnancy prolongation (days).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 9 Pregnancy prolongation (days)

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Intramuscular

Rozenberg 2012 94 61 (29) 94 63 (29) 100.0 % -2.00 [ -10.29, 6.29 ]

Total (95% CI) 94 94 100.0 % -2.00 [ -10.29, 6.29 ]

Heterogeneity: not applicable

Test for overall effect: Z = 0.47 (P = 0.64)

Test for subgroup differences: Not applicable

-20 -10 0 10 20

Favours placebo Favours progesterone

Analysis 4.10. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 10 Caesarean section.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 10 Caesarean section

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Grobman 2012 67/327 63/329 82.7 % 1.07 [ 0.79, 1.46 ]

Rozenberg 2012 13/92 13/90 17.3 % 0.98 [ 0.48, 1.99 ]

Total (95% CI) 419 419 100.0 % 1.05 [ 0.79, 1.40 ]

Total events: 80 (Progesterone), 76 (Placebo)

Heterogeneity: Chi2 = 0.05, df = 1 (P = 0.82); I2 =0.0%

Test for overall effect: Z = 0.37 (P = 0.71)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

160Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.11. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 11 Antenatal tocolysis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 11 Antenatal tocolysis

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Grobman 2012 35/321 42/325 57.4 % 0.84 [ 0.55, 1.29 ]

Rozenberg 2012 24/91 31/91 42.6 % 0.77 [ 0.50, 1.21 ]

Total (95% CI) 412 416 100.0 % 0.81 [ 0.60, 1.11 ]

Total events: 59 (Progesterone), 73 (Placebo)

Heterogeneity: Chi2 = 0.08, df = 1 (P = 0.78); I2 =0.0%

Test for overall effect: Z = 1.31 (P = 0.19)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

161Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.12. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 12 Preterm birth less than 37 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 12 Preterm birth less than 37 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Hassan 2011 71/235 76/223 40.3 % 0.89 [ 0.68, 1.16 ]

Subtotal (95% CI) 235 223 40.3 % 0.89 [ 0.68, 1.16 ]

Total events: 71 (Progesterone), 76 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.89 (P = 0.38)

2 Intramuscular

Grobman 2012 82/327 80/330 41.1 % 1.03 [ 0.79, 1.35 ]

Rozenberg 2012 37/94 36/94 18.6 % 1.03 [ 0.72, 1.47 ]

Subtotal (95% CI) 421 424 59.7 % 1.03 [ 0.83, 1.28 ]

Total events: 119 (Progesterone), 116 (Placebo)

Heterogeneity: Chi2 = 0.00, df = 1 (P = 0.98); I2 =0.0%

Test for overall effect: Z = 0.29 (P = 0.77)

Total (95% CI) 656 647 100.0 % 0.97 [ 0.82, 1.15 ]

Total events: 190 (Progesterone), 192 (Placebo)

Heterogeneity: Chi2 = 0.76, df = 2 (P = 0.68); I2 =0.0%

Test for overall effect: Z = 0.31 (P = 0.75)

Test for subgroup differences: Chi2 = 0.76, df = 1 (P = 0.38), I2 =0.0%

0.2 0.5 1 2 5

Favours progesterone Favours placebo

162Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.13. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 13 Preterm birth less than 28 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 13 Preterm birth less than 28 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Hassan 2011 12/235 23/223 51.9 % 0.50 [ 0.25, 0.97 ]

Subtotal (95% CI) 235 223 51.9 % 0.50 [ 0.25, 0.97 ]

Total events: 12 (Progesterone), 23 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.05 (P = 0.041)

2 Intramuscular

Grobman 2012 15/327 22/330 48.1 % 0.69 [ 0.36, 1.30 ]

Subtotal (95% CI) 327 330 48.1 % 0.69 [ 0.36, 1.30 ]

Total events: 15 (Progesterone), 22 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.15 (P = 0.25)

Total (95% CI) 562 553 100.0 % 0.59 [ 0.37, 0.93 ]

Total events: 27 (Progesterone), 45 (Placebo)

Heterogeneity: Chi2 = 0.48, df = 1 (P = 0.49); I2 =0.0%

Test for overall effect: Z = 2.25 (P = 0.024)

Test for subgroup differences: Chi2 = 0.48, df = 1 (P = 0.49), I2 =0.0%

0.2 0.5 1 2 5

Favours progesterone Favours placebo

163Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.14. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 14 Infant birthweight less than 2500 g.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 14 Infant birthweight less than 2500 g

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Fonseca 2007 56/136 59/138 28.8 % 0.96 [ 0.73, 1.27 ]

Hassan 2011 60/234 68/220 34.5 % 0.83 [ 0.62, 1.11 ]

Subtotal (95% CI) 370 358 63.4 % 0.89 [ 0.73, 1.09 ]

Total events: 116 (Progesterone), 127 (Placebo)

Heterogeneity: Chi2 = 0.53, df = 1 (P = 0.47); I2 =0.0%

Test for overall effect: Z = 1.12 (P = 0.26)

2 Intramuscular

Grobman 2012 72/323 75/328 36.6 % 0.97 [ 0.73, 1.30 ]

Subtotal (95% CI) 323 328 36.6 % 0.97 [ 0.73, 1.30 ]

Total events: 72 (Progesterone), 75 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.18 (P = 0.86)

Total (95% CI) 693 686 100.0 % 0.92 [ 0.78, 1.09 ]

Total events: 188 (Progesterone), 202 (Placebo)

Heterogeneity: Chi2 = 0.74, df = 2 (P = 0.69); I2 =0.0%

Test for overall effect: Z = 0.97 (P = 0.33)

Test for subgroup differences: Chi2 = 0.26, df = 1 (P = 0.61), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

164Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.15. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 15 Respiratory distress syndrome.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 15 Respiratory distress syndrome

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Fonseca 2007 11/136 19/138 29.3 % 0.59 [ 0.29, 1.19 ]

Hassan 2011 7/235 17/223 27.1 % 0.39 [ 0.17, 0.92 ]

Subtotal (95% CI) 371 361 56.3 % 0.49 [ 0.29, 0.85 ]

Total events: 18 (Progesterone), 36 (Placebo)

Heterogeneity: Chi2 = 0.52, df = 1 (P = 0.47); I2 =0.0%

Test for overall effect: Z = 2.55 (P = 0.011)

2 Intramuscular

Grobman 2012 13/320 16/323 24.7 % 0.82 [ 0.40, 1.68 ]

Rozenberg 2012 14/92 12/89 18.9 % 1.13 [ 0.55, 2.30 ]

Subtotal (95% CI) 412 412 43.7 % 0.95 [ 0.58, 1.58 ]

Total events: 27 (Progesterone), 28 (Placebo)

Heterogeneity: Chi2 = 0.38, df = 1 (P = 0.54); I2 =0.0%

Test for overall effect: Z = 0.18 (P = 0.85)

Total (95% CI) 783 773 100.0 % 0.69 [ 0.48, 1.00 ]

Total events: 45 (Progesterone), 64 (Placebo)

Heterogeneity: Chi2 = 3.92, df = 3 (P = 0.27); I2 =23%

Test for overall effect: Z = 1.96 (P = 0.050)

Test for subgroup differences: Chi2 = 3.05, df = 1 (P = 0.08), I2 =67%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

165Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.16. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 16 Apgar score < 7.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 16 Apgar score < 7

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Grobman 2012 15/323 19/328 100.0 % 0.80 [ 0.41, 1.55 ]

Total (95% CI) 323 328 100.0 % 0.80 [ 0.41, 1.55 ]

Total events: 15 (Progesterone), 19 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.66 (P = 0.51)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

Analysis 4.17. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 17 Need for assisted ventilation.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 17 Need for assisted ventilation

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Fonseca 2007 16/136 25/138 100.0 % 0.65 [ 0.36, 1.16 ]

Total (95% CI) 136 138 100.0 % 0.65 [ 0.36, 1.16 ]

Total events: 16 (Progesterone), 25 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.46 (P = 0.15)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

166Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.18. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 18 Intraventricular haemorrhage - all grades.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 18 Intraventricular haemorrhage - all grades

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Fonseca 2007 1/136 2/138 100.0 % 0.51 [ 0.05, 5.53 ]

Total (95% CI) 136 138 100.0 % 0.51 [ 0.05, 5.53 ]

Total events: 1 (Progesterone), 2 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.56 (P = 0.58)

Test for subgroup differences: Not applicable

0.05 0.2 1 5 20

Favours progesterone Favours placebo

167Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.19. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 19 Intraventricular haemorrhage - grades III or IV.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 19 Intraventricular haemorrhage - grades III or IV

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Hassan 2011 0/235 1/223 60.7 % 0.32 [ 0.01, 7.73 ]

Subtotal (95% CI) 235 223 60.7 % 0.32 [ 0.01, 7.73 ]

Total events: 0 (Progesterone), 1 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.71 (P = 0.48)

2 Intramuscular

Grobman 2012 2/320 1/322 39.3 % 2.01 [ 0.18, 22.08 ]

Subtotal (95% CI) 320 322 39.3 % 2.01 [ 0.18, 22.08 ]

Total events: 2 (Progesterone), 1 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.57 (P = 0.57)

Total (95% CI) 555 545 100.0 % 0.98 [ 0.17, 5.60 ]

Total events: 2 (Progesterone), 2 (Placebo)

Heterogeneity: Chi2 = 0.83, df = 1 (P = 0.36); I2 =0.0%

Test for overall effect: Z = 0.02 (P = 0.98)

Test for subgroup differences: Chi2 = 0.82, df = 1 (P = 0.36), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

168Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.20. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 20 Periventricular leucomalacia.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 20 Periventricular leucomalacia

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Hassan 2011 0/235 0/223 Not estimable

Subtotal (95% CI) 235 223 Not estimable

Total events: 0 (Progesterone), 0 (Placebo)

Heterogeneity: not applicable

Test for overall effect: not applicable

2 Intramuscular

Grobman 2012 4/320 1/322 39.4 % 4.03 [ 0.45, 35.81 ]

Rozenberg 2012 0/93 1/89 60.6 % 0.32 [ 0.01, 7.73 ]

Subtotal (95% CI) 413 411 100.0 % 1.78 [ 0.38, 8.24 ]

Total events: 4 (Progesterone), 2 (Placebo)

Heterogeneity: Chi2 = 1.65, df = 1 (P = 0.20); I2 =39%

Test for overall effect: Z = 0.74 (P = 0.46)

Total (95% CI) 648 634 100.0 % 1.78 [ 0.38, 8.24 ]

Total events: 4 (Progesterone), 2 (Placebo)

Heterogeneity: Chi2 = 1.65, df = 1 (P = 0.20); I2 =39%

Test for overall effect: Z = 0.74 (P = 0.46)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

169Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.21. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 21 Retinopathy of prematurity.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 21 Retinopathy of prematurity

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Fonseca 2007 2/136 0/138 14.2 % 5.07 [ 0.25, 104.70 ]

Subtotal (95% CI) 136 138 14.2 % 5.07 [ 0.25, 104.70 ]

Total events: 2 (Progesterone), 0 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.05 (P = 0.29)

2 Intramuscular

Grobman 2012 1/320 3/322 85.8 % 0.34 [ 0.04, 3.21 ]

Subtotal (95% CI) 320 322 85.8 % 0.34 [ 0.04, 3.21 ]

Total events: 1 (Progesterone), 3 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.95 (P = 0.34)

Total (95% CI) 456 460 100.0 % 1.01 [ 0.23, 4.42 ]

Total events: 3 (Progesterone), 3 (Placebo)

Heterogeneity: Chi2 = 2.01, df = 1 (P = 0.16); I2 =50%

Test for overall effect: Z = 0.01 (P = 0.99)

Test for subgroup differences: Chi2 = 1.99, df = 1 (P = 0.16), I2 =50%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

170Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.22. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 22 Necrotising enterocolitis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 22 Necrotising enterocolitis

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Fonseca 2007 0/136 1/138 14.1 % 0.34 [ 0.01, 8.23 ]

Hassan 2011 5/235 4/223 38.8 % 1.19 [ 0.32, 4.36 ]

Subtotal (95% CI) 371 361 52.9 % 0.96 [ 0.30, 3.11 ]

Total events: 5 (Progesterone), 5 (Placebo)

Heterogeneity: Chi2 = 0.51, df = 1 (P = 0.47); I2 =0.0%

Test for overall effect: Z = 0.07 (P = 0.95)

2 Intramuscular

Grobman 2012 2/320 5/322 47.1 % 0.40 [ 0.08, 2.06 ]

Subtotal (95% CI) 320 322 47.1 % 0.40 [ 0.08, 2.06 ]

Total events: 2 (Progesterone), 5 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.09 (P = 0.27)

Total (95% CI) 691 683 100.0 % 0.70 [ 0.27, 1.78 ]

Total events: 7 (Progesterone), 10 (Placebo)

Heterogeneity: Chi2 = 1.27, df = 2 (P = 0.53); I2 =0.0%

Test for overall effect: Z = 0.76 (P = 0.45)

Test for subgroup differences: Chi2 = 0.72, df = 1 (P = 0.40), I2 =0.0%

0.02 0.1 1 10 50

Favours progesterone Favours placebo

171Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.23. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 23 Neonatal sepsis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 23 Neonatal sepsis

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Vaginal

Fonseca 2007 3/136 11/138 31.7 % 0.28 [ 0.08, 0.97 ]

Hassan 2011 7/235 6/223 37.0 % 1.11 [ 0.38, 3.24 ]

Subtotal (95% CI) 371 361 68.7 % 0.58 [ 0.15, 2.25 ]

Total events: 10 (Progesterone), 17 (Placebo)

Heterogeneity: Tau2 = 0.61; Chi2 = 2.73, df = 1 (P = 0.10); I2 =63%

Test for overall effect: Z = 0.79 (P = 0.43)

2 Intramuscular

Grobman 2012 3/320 11/322 31.3 % 0.27 [ 0.08, 0.97 ]

Subtotal (95% CI) 320 322 31.3 % 0.27 [ 0.08, 0.97 ]

Total events: 3 (Progesterone), 11 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.00 (P = 0.046)

Total (95% CI) 691 683 100.0 % 0.46 [ 0.18, 1.20 ]

Total events: 13 (Progesterone), 28 (Placebo)

Heterogeneity: Tau2 = 0.34; Chi2 = 3.84, df = 2 (P = 0.15); I2 =48%

Test for overall effect: Z = 1.59 (P = 0.11)

Test for subgroup differences: Chi2 = 0.61, df = 1 (P = 0.44), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

172Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.24. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 24 Intrauterine fetal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 24 Intrauterine fetal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Fonseca 2007 1/136 1/138 12.2 % 1.01 [ 0.06, 16.06 ]

Hassan 2011 5/235 6/223 75.6 % 0.79 [ 0.24, 2.55 ]

Subtotal (95% CI) 371 361 87.8 % 0.82 [ 0.28, 2.42 ]

Total events: 6 (Progesterone), 7 (Placebo)

Heterogeneity: Chi2 = 0.03, df = 1 (P = 0.87); I2 =0.0%

Test for overall effect: Z = 0.36 (P = 0.72)

2 Intramuscular

Grobman 2012 4/327 1/330 12.2 % 4.04 [ 0.45, 35.92 ]

Subtotal (95% CI) 327 330 12.2 % 4.04 [ 0.45, 35.92 ]

Total events: 4 (Progesterone), 1 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.25 (P = 0.21)

Total (95% CI) 698 691 100.0 % 1.21 [ 0.48, 3.04 ]

Total events: 10 (Progesterone), 8 (Placebo)

Heterogeneity: Chi2 = 1.69, df = 2 (P = 0.43); I2 =0.0%

Test for overall effect: Z = 0.42 (P = 0.68)

Test for subgroup differences: Chi2 = 1.64, df = 1 (P = 0.20), I2 =39%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

173Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.25. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 25 Neonatal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 25 Neonatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Fonseca 2007 2/136 7/138 34.7 % 0.29 [ 0.06, 1.37 ]

Hassan 2011 3/235 5/223 25.6 % 0.57 [ 0.14, 2.35 ]

Subtotal (95% CI) 371 361 60.3 % 0.41 [ 0.15, 1.15 ]

Total events: 5 (Progesterone), 12 (Placebo)

Heterogeneity: Chi2 = 0.40, df = 1 (P = 0.53); I2 =0.0%

Test for overall effect: Z = 1.69 (P = 0.090)

2 Intramuscular

Grobman 2012 6/327 8/330 39.7 % 0.76 [ 0.27, 2.16 ]

Rozenberg 2012 0/93 0/89 Not estimable

Subtotal (95% CI) 420 419 39.7 % 0.76 [ 0.27, 2.16 ]

Total events: 6 (Progesterone), 8 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.52 (P = 0.60)

Total (95% CI) 791 780 100.0 % 0.55 [ 0.26, 1.13 ]

Total events: 11 (Progesterone), 20 (Placebo)

Heterogeneity: Chi2 = 1.01, df = 2 (P = 0.60); I2 =0.0%

Test for overall effect: Z = 1.62 (P = 0.10)

Test for subgroup differences: Chi2 = 0.67, df = 1 (P = 0.41), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

174Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 4.26. Comparison 4 Progesterone versus placebo: ultrasound identified short cervix, singletons,

Outcome 26 Admission to neonatal intensive care unit.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 4 Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome: 26 Admission to neonatal intensive care unit

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Grobman 2012 63/322 69/329 80.8 % 0.93 [ 0.69, 1.27 ]

Rozenberg 2012 24/93 16/90 19.2 % 1.45 [ 0.83, 2.55 ]

Total (95% CI) 415 419 100.0 % 1.03 [ 0.79, 1.35 ]

Total events: 87 (Progesterone), 85 (Placebo)

Heterogeneity: Chi2 = 1.84, df = 1 (P = 0.18); I2 =46%

Test for overall effect: Z = 0.24 (P = 0.81)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

175Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 5.1. Comparison 5 Progesterone versus placebo: ultrasound identified short cervix, singletons by

cumulative weekly dose (<500 mg v >=500 mg), Outcome 1 Periventricular leucomalacia.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 5 Progesterone versus placebo: ultrasound identified short cervix, singletons by cumulative weekly dose (<500 mg v >=500 mg)

Outcome: 1 Periventricular leucomalacia

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Grobman 2012 4/320 1/322 60.9 % 4.03 [ 0.45, 35.81 ]

Subtotal (95% CI) 320 322 60.9 % 4.03 [ 0.45, 35.81 ]

Total events: 4 (Progesterone), 1 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.25 (P = 0.21)

2 Dose >= 500 mg per week

Rozenberg 2012 0/93 1/89 39.1 % 0.32 [ 0.01, 7.73 ]

Subtotal (95% CI) 93 89 39.1 % 0.32 [ 0.01, 7.73 ]

Total events: 0 (Progesterone), 1 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.70 (P = 0.48)

Total (95% CI) 413 411 100.0 % 1.49 [ 0.13, 16.87 ]

Total events: 4 (Progesterone), 2 (Placebo)

Heterogeneity: Tau2 = 1.27; Chi2 = 1.65, df = 1 (P = 0.20); I2 =39%

Test for overall effect: Z = 0.32 (P = 0.75)

Test for subgroup differences: Chi2 = 1.65, df = 1 (P = 0.20), I2 =39%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

176Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 5.2. Comparison 5 Progesterone versus placebo: ultrasound identified short cervix, singletons by

cumulative weekly dose (<500 mg v >=500 mg), Outcome 2 Admission to neonatal intensive care unit.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 5 Progesterone versus placebo: ultrasound identified short cervix, singletons by cumulative weekly dose (<500 mg v >=500 mg)

Outcome: 2 Admission to neonatal intensive care unit

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Grobman 2012 63/322 69/329 64.9 % 0.93 [ 0.69, 1.27 ]

Subtotal (95% CI) 322 329 64.9 % 0.93 [ 0.69, 1.27 ]

Total events: 63 (Progesterone), 69 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.45 (P = 0.66)

2 Dose >= 500 mg per week

Rozenberg 2012 24/93 16/90 35.1 % 1.45 [ 0.83, 2.55 ]

Subtotal (95% CI) 93 90 35.1 % 1.45 [ 0.83, 2.55 ]

Total events: 24 (Progesterone), 16 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.30 (P = 0.19)

Total (95% CI) 415 419 100.0 % 1.09 [ 0.72, 1.65 ]

Total events: 87 (Progesterone), 85 (Placebo)

Heterogeneity: Tau2 = 0.04; Chi2 = 1.84, df = 1 (P = 0.18); I2 =46%

Test for overall effect: Z = 0.41 (P = 0.68)

Test for subgroup differences: Chi2 = 1.84, df = 1 (P = 0.18), I2 =46%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

177Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.1. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 1 Perinatal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 1 Perinatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Combs 2010 19/168 2/75 14.3 % 4.24 [ 1.01, 17.75 ]

Combs 2011 0/320 3/156 5.1 % 0.07 [ 0.00, 1.34 ]

Hartikainen 1980 4/78 2/76 11.9 % 1.95 [ 0.37, 10.33 ]

Lim 2011 23/681 34/674 27.0 % 0.67 [ 0.40, 1.12 ]

Subtotal (95% CI) 1247 981 58.3 % 1.06 [ 0.30, 3.71 ]

Total events: 46 (Progesterone), 41 (Placebo)

Heterogeneity: Tau2 = 1.02; Chi2 = 9.42, df = 3 (P = 0.02); I2 =68%

Test for overall effect: Z = 0.09 (P = 0.93)

2 Vaginal

Aboulghar 2012 4/98 5/84 16.0 % 0.69 [ 0.19, 2.47 ]

Rode 2011 10/664 7/678 20.3 % 1.46 [ 0.56, 3.81 ]

Serra 2013 0/194 5/190 5.3 % 0.09 [ 0.00, 1.60 ]

Subtotal (95% CI) 956 952 41.7 % 0.75 [ 0.24, 2.41 ]

Total events: 14 (Progesterone), 17 (Placebo)

Heterogeneity: Tau2 = 0.49; Chi2 = 3.78, df = 2 (P = 0.15); I2 =47%

Test for overall effect: Z = 0.48 (P = 0.63)

Total (95% CI) 2203 1933 100.0 % 0.93 [ 0.45, 1.94 ]

Total events: 60 (Progesterone), 58 (Placebo)

Heterogeneity: Tau2 = 0.45; Chi2 = 13.01, df = 6 (P = 0.04); I2 =54%

Test for overall effect: Z = 0.19 (P = 0.85)

Test for subgroup differences: Chi2 = 0.15, df = 1 (P = 0.70), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

178Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.2. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 2 Preterm birth

less than 34 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 2 Preterm birth less than 34 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Vaginal

Aboulghar 2012 8/49 10/42 8.7 % 0.69 [ 0.30, 1.58 ]

Cetingoz 2011 4/39 7/28 5.1 % 0.41 [ 0.13, 1.27 ]

Norman 2009 55/247 44/247 29.7 % 1.25 [ 0.88, 1.78 ]

Rode 2011 51/334 63/341 31.4 % 0.83 [ 0.59, 1.16 ]

Serra 2013 13/97 13/96 11.3 % 0.99 [ 0.48, 2.02 ]

Subtotal (95% CI) 766 754 86.2 % 0.92 [ 0.69, 1.23 ]

Total events: 131 (Progesterone), 137 (Placebo)

Heterogeneity: Tau2 = 0.03; Chi2 = 5.68, df = 4 (P = 0.22); I2 =30%

Test for overall effect: Z = 0.59 (P = 0.56)

2 Intramuscular

Combs 2011 31/160 11/78 13.8 % 1.37 [ 0.73, 2.59 ]

Subtotal (95% CI) 160 78 13.8 % 1.37 [ 0.73, 2.59 ]

Total events: 31 (Progesterone), 11 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.98 (P = 0.32)

Total (95% CI) 926 832 100.0 % 0.97 [ 0.74, 1.27 ]

Total events: 162 (Progesterone), 148 (Placebo)

Heterogeneity: Tau2 = 0.03; Chi2 = 6.88, df = 5 (P = 0.23); I2 =27%

Test for overall effect: Z = 0.22 (P = 0.83)

Test for subgroup differences: Chi2 = 1.30, df = 1 (P = 0.25), I2 =23%

0.05 0.2 1 5 20

Favours progesterone Favours placebo

179Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.3. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 3 Preterm PROM.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 3 Preterm PROM

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Caritis 2009 6/71 7/63 19.2 % 0.76 [ 0.27, 2.14 ]

Lim 2011 34/336 28/332 73.0 % 1.20 [ 0.74, 1.93 ]

Subtotal (95% CI) 407 395 92.2 % 1.11 [ 0.72, 1.71 ]

Total events: 40 (Progesterone), 35 (Placebo)

Heterogeneity: Chi2 = 0.61, df = 1 (P = 0.43); I2 =0.0%

Test for overall effect: Z = 0.47 (P = 0.64)

2 Vaginal

Serra 2013 4/97 3/96 7.8 % 1.32 [ 0.30, 5.74 ]

Subtotal (95% CI) 97 96 7.8 % 1.32 [ 0.30, 5.74 ]

Total events: 4 (Progesterone), 3 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.37 (P = 0.71)

Total (95% CI) 504 491 100.0 % 1.12 [ 0.74, 1.70 ]

Total events: 44 (Progesterone), 38 (Placebo)

Heterogeneity: Chi2 = 0.66, df = 2 (P = 0.72); I2 =0.0%

Test for overall effect: Z = 0.56 (P = 0.58)

Test for subgroup differences: Chi2 = 0.05, df = 1 (P = 0.82), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

180Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.4. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 4 Adverse drug

reaction.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 4 Adverse drug reaction

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Lim 2011 57/336 76/332 39.3 % 0.74 [ 0.54, 1.01 ]

Subtotal (95% CI) 336 332 39.3 % 0.74 [ 0.54, 1.01 ]

Total events: 57 (Progesterone), 76 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.91 (P = 0.057)

2 Vaginal

Norman 2009 187/247 191/247 60.7 % 0.98 [ 0.89, 1.08 ]

Subtotal (95% CI) 247 247 60.7 % 0.98 [ 0.89, 1.08 ]

Total events: 187 (Progesterone), 191 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.42 (P = 0.67)

Total (95% CI) 583 579 100.0 % 0.88 [ 0.64, 1.19 ]

Total events: 244 (Progesterone), 267 (Placebo)

Heterogeneity: Tau2 = 0.04; Chi2 = 3.81, df = 1 (P = 0.05); I2 =74%

Test for overall effect: Z = 0.83 (P = 0.41)

Test for subgroup differences: Chi2 = 2.85, df = 1 (P = 0.09), I2 =65%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

181Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.5. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 5 Caesarean

section.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 5 Caesarean section

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Caritis 2009 71/71 62/63 6.8 % 1.02 [ 0.97, 1.06 ]

Combs 2010 52/56 25/25 3.6 % 0.94 [ 0.86, 1.03 ]

Combs 2011 122/160 59/78 8.1 % 1.01 [ 0.87, 1.17 ]

Lim 2011 146/336 136/332 14.0 % 1.06 [ 0.89, 1.27 ]

Rouse 2007 200/324 204/328 20.7 % 0.99 [ 0.88, 1.12 ]

Subtotal (95% CI) 947 826 53.1 % 1.01 [ 0.94, 1.09 ]

Total events: 591 (Progesterone), 486 (Placebo)

Heterogeneity: Chi2 = 2.91, df = 4 (P = 0.57); I2 =0.0%

Test for overall effect: Z = 0.34 (P = 0.74)

2 Vaginal

Norman 2009 148/250 161/250 16.4 % 0.92 [ 0.80, 1.06 ]

Rode 2011 207/332 232/338 23.5 % 0.91 [ 0.81, 1.01 ]

Serra 2013 61/97 68/96 7.0 % 0.89 [ 0.73, 1.08 ]

Subtotal (95% CI) 679 684 46.9 % 0.91 [ 0.84, 0.98 ]

Total events: 416 (Progesterone), 461 (Placebo)

Heterogeneity: Chi2 = 0.08, df = 2 (P = 0.96); I2 =0.0%

Test for overall effect: Z = 2.36 (P = 0.018)

Total (95% CI) 1626 1510 100.0 % 0.96 [ 0.91, 1.02 ]

Total events: 1007 (Progesterone), 947 (Placebo)

Heterogeneity: Chi2 = 10.25, df = 7 (P = 0.17); I2 =32%

Test for overall effect: Z = 1.36 (P = 0.17)

Test for subgroup differences: Chi2 = 3.92, df = 1 (P = 0.05), I2 =74%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

182Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.6. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 6 Spontaneous

birth.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 6 Spontaneous birth

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Lim 2011 143/336 160/332 52.8 % 0.88 [ 0.75, 1.04 ]

Subtotal (95% CI) 336 332 52.8 % 0.88 [ 0.75, 1.04 ]

Total events: 143 (Progesterone), 160 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.46 (P = 0.14)

2 Vaginal

Norman 2009 66/250 38/250 47.2 % 1.74 [ 1.21, 2.49 ]

Subtotal (95% CI) 250 250 47.2 % 1.74 [ 1.21, 2.49 ]

Total events: 66 (Progesterone), 38 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 3.02 (P = 0.0025)

Total (95% CI) 586 582 100.0 % 1.22 [ 0.62, 2.38 ]

Total events: 209 (Progesterone), 198 (Placebo)

Heterogeneity: Tau2 = 0.22; Chi2 = 11.64, df = 1 (P = 0.00065); I2 =91%

Test for overall effect: Z = 0.57 (P = 0.57)

Test for subgroup differences: Chi2 = 11.23, df = 1 (P = 0.00), I2 =91%

0.01 0.1 1 10 100

Favours placebo Favours progesterone

183Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.7. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 7 Assisted birth.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 7 Assisted birth

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Lim 2011 45/336 34/332 53.8 % 1.31 [ 0.86, 1.99 ]

Subtotal (95% CI) 336 332 53.8 % 1.31 [ 0.86, 1.99 ]

Total events: 45 (Progesterone), 34 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.26 (P = 0.21)

2 Vaginal

Norman 2009 22/250 30/250 46.2 % 0.73 [ 0.44, 1.24 ]

Subtotal (95% CI) 250 250 46.2 % 0.73 [ 0.44, 1.24 ]

Total events: 22 (Progesterone), 30 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.17 (P = 0.24)

Total (95% CI) 586 582 100.0 % 1.00 [ 0.57, 1.76 ]

Total events: 67 (Progesterone), 64 (Placebo)

Heterogeneity: Tau2 = 0.11; Chi2 = 2.87, df = 1 (P = 0.09); I2 =65%

Test for overall effect: Z = 0.00 (P = 1.0)

Test for subgroup differences: Chi2 = 2.87, df = 1 (P = 0.09), I2 =65%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

184Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.8. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 8 Satisfaction with

therapy.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 8 Satisfaction with therapy

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Vaginal

Norman 2009 247 2.8 (2.1) 247 2.8 (1.9) 100.0 % 0.0 [ -0.35, 0.35 ]

Total (95% CI) 247 247 100.0 % 0.0 [ -0.35, 0.35 ]

Heterogeneity: not applicable

Test for overall effect: Z = 0.0 (P = 1.0)

Test for subgroup differences: Not applicable

-2 -1 0 1 2

Favours progesterone Favours placebo

185Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.9. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 9 Antenatal

tocolysis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 9 Antenatal tocolysis

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Caritis 2009 33/71 28/63 12.8 % 1.05 [ 0.72, 1.52 ]

Combs 2010 44/56 17/25 16.8 % 1.16 [ 0.85, 1.56 ]

Combs 2011 62/160 32/78 15.1 % 0.94 [ 0.68, 1.31 ]

Lim 2011 73/336 64/332 17.0 % 1.13 [ 0.84, 1.52 ]

Rouse 2007 71/324 97/330 19.5 % 0.75 [ 0.57, 0.97 ]

Subtotal (95% CI) 947 828 81.2 % 0.98 [ 0.82, 1.17 ]

Total events: 283 (Progesterone), 238 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 6.38, df = 4 (P = 0.17); I2 =37%

Test for overall effect: Z = 0.22 (P = 0.83)

2 Vaginal

Rode 2011 41/333 60/341 13.1 % 0.70 [ 0.48, 1.01 ]

Serra 2013 16/97 17/96 5.7 % 0.93 [ 0.50, 1.73 ]

Subtotal (95% CI) 430 437 18.8 % 0.75 [ 0.55, 1.03 ]

Total events: 57 (Progesterone), 77 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.60, df = 1 (P = 0.44); I2 =0.0%

Test for overall effect: Z = 1.75 (P = 0.079)

Total (95% CI) 1377 1265 100.0 % 0.94 [ 0.80, 1.10 ]

Total events: 340 (Progesterone), 315 (Placebo)

Heterogeneity: Tau2 = 0.02; Chi2 = 9.23, df = 6 (P = 0.16); I2 =35%

Test for overall effect: Z = 0.81 (P = 0.42)

Test for subgroup differences: Chi2 = 2.04, df = 1 (P = 0.15), I2 =51%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

186Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.10. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 10 Antenatal

corticosteroids.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 10 Antenatal corticosteroids

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Rouse 2007 80/324 90/330 89.9 % 0.91 [ 0.70, 1.17 ]

Subtotal (95% CI) 324 330 89.9 % 0.91 [ 0.70, 1.17 ]

Total events: 80 (Progesterone), 90 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.75 (P = 0.45)

2 Vaginal

Serra 2013 17/97 10/96 10.1 % 1.68 [ 0.81, 3.49 ]

Subtotal (95% CI) 97 96 10.1 % 1.68 [ 0.81, 3.49 ]

Total events: 17 (Progesterone), 10 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.40 (P = 0.16)

Total (95% CI) 421 426 100.0 % 0.98 [ 0.77, 1.26 ]

Total events: 97 (Progesterone), 100 (Placebo)

Heterogeneity: Chi2 = 2.48, df = 1 (P = 0.12); I2 =60%

Test for overall effect: Z = 0.13 (P = 0.90)

Test for subgroup differences: Chi2 = 2.47, df = 1 (P = 0.12), I2 =59%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

187Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.11. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 11 Preterm birth

less than 37 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 11 Preterm birth less than 37 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Combs 2011 113/160 46/78 12.3 % 1.20 [ 0.97, 1.48 ]

Hartikainen 1980 15/39 9/38 1.5 % 1.62 [ 0.81, 3.25 ]

Lim 2011 186/336 165/332 19.6 % 1.11 [ 0.96, 1.29 ]

Rouse 2007 226/325 232/330 27.2 % 0.99 [ 0.89, 1.09 ]

Subtotal (95% CI) 860 778 60.6 % 1.09 [ 0.96, 1.22 ]

Total events: 540 (Progesterone), 452 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 5.20, df = 3 (P = 0.16); I2 =42%

Test for overall effect: Z = 1.35 (P = 0.18)

2 Vaginal

Aboulghar 2012 31/49 28/42 7.0 % 0.95 [ 0.70, 1.28 ]

Cetingoz 2011 29/39 22/38 6.1 % 1.28 [ 0.93, 1.78 ]

Rode 2011 158/334 179/341 18.6 % 0.90 [ 0.77, 1.05 ]

Serra 2013 48/97 47/96 7.6 % 1.01 [ 0.76, 1.35 ]

Subtotal (95% CI) 519 517 39.4 % 0.98 [ 0.85, 1.13 ]

Total events: 266 (Progesterone), 276 (Placebo)

Heterogeneity: Tau2 = 0.00; Chi2 = 3.85, df = 3 (P = 0.28); I2 =22%

Test for overall effect: Z = 0.25 (P = 0.80)

Total (95% CI) 1379 1295 100.0 % 1.04 [ 0.95, 1.14 ]

Total events: 806 (Progesterone), 728 (Placebo)

Heterogeneity: Tau2 = 0.00; Chi2 = 10.39, df = 7 (P = 0.17); I2 =33%

Test for overall effect: Z = 0.91 (P = 0.36)

Test for subgroup differences: Chi2 = 1.14, df = 1 (P = 0.29), I2 =12%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

188Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.12. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 12 Preterm birth

less than 28 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 12 Preterm birth less than 28 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Combs 2010 9/56 2/25 9.2 % 2.01 [ 0.47, 8.63 ]

Combs 2011 3/160 1/78 4.5 % 1.46 [ 0.15, 13.83 ]

Lim 2011 19/336 18/332 60.1 % 1.04 [ 0.56, 1.95 ]

Subtotal (95% CI) 552 435 73.7 % 1.19 [ 0.68, 2.07 ]

Total events: 31 (Progesterone), 21 (Placebo)

Heterogeneity: Chi2 = 0.70, df = 2 (P = 0.71); I2 =0.0%

Test for overall effect: Z = 0.61 (P = 0.54)

2 Vaginal

Rode 2011 9/334 7/341 23.0 % 1.31 [ 0.49, 3.48 ]

Serra 2013 1/97 1/96 3.3 % 0.99 [ 0.06, 15.60 ]

Subtotal (95% CI) 431 437 26.3 % 1.27 [ 0.51, 3.19 ]

Total events: 10 (Progesterone), 8 (Placebo)

Heterogeneity: Chi2 = 0.04, df = 1 (P = 0.85); I2 =0.0%

Test for overall effect: Z = 0.51 (P = 0.61)

Total (95% CI) 983 872 100.0 % 1.21 [ 0.75, 1.95 ]

Total events: 41 (Progesterone), 29 (Placebo)

Heterogeneity: Chi2 = 0.76, df = 4 (P = 0.94); I2 =0.0%

Test for overall effect: Z = 0.79 (P = 0.43)

Test for subgroup differences: Chi2 = 0.02, df = 1 (P = 0.90), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

189Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.13. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 13 Infant

birthweight less than 2500 g.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 13 Infant birthweight less than 2500 g

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Caritis 2009 191/212 175/183 20.6 % 0.94 [ 0.89, 0.99 ]

Combs 2011 195/320 70/156 9.4 % 1.36 [ 1.12, 1.65 ]

Lim 2011 363/681 355/674 16.6 % 1.01 [ 0.92, 1.12 ]

Rouse 2007 377/628 415/648 17.9 % 0.94 [ 0.86, 1.02 ]

Subtotal (95% CI) 1841 1661 64.6 % 1.02 [ 0.91, 1.14 ]

Total events: 1126 (Progesterone), 1015 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 16.56, df = 3 (P = 0.00087); I2 =82%

Test for overall effect: Z = 0.30 (P = 0.76)

2 Vaginal

Aboulghar 2012 58/98 62/84 8.7 % 0.80 [ 0.65, 0.99 ]

Rode 2011 306/659 357/677 15.9 % 0.88 [ 0.79, 0.98 ]

Serra 2013 104/194 117/190 10.8 % 0.87 [ 0.73, 1.03 ]

Subtotal (95% CI) 951 951 35.4 % 0.86 [ 0.80, 0.94 ]

Total events: 468 (Progesterone), 536 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.63, df = 2 (P = 0.73); I2 =0.0%

Test for overall effect: Z = 3.38 (P = 0.00071)

Total (95% CI) 2792 2612 100.0 % 0.95 [ 0.88, 1.03 ]

Total events: 1594 (Progesterone), 1551 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 20.29, df = 6 (P = 0.002); I2 =70%

Test for overall effect: Z = 1.19 (P = 0.23)

Test for subgroup differences: Chi2 = 5.22, df = 1 (P = 0.02), I2 =81%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

190Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.14. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 14 Apgar score <

7 at 5 minutes.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 14 Apgar score < 7 at 5 minutes

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Caritis 2009 10/212 10/183 13.1 % 0.86 [ 0.37, 2.03 ]

Lim 2011 53/681 52/674 63.9 % 1.01 [ 0.70, 1.46 ]

Subtotal (95% CI) 893 857 77.0 % 0.98 [ 0.70, 1.38 ]

Total events: 63 (Progesterone), 62 (Placebo)

Heterogeneity: Chi2 = 0.11, df = 1 (P = 0.74); I2 =0.0%

Test for overall effect: Z = 0.09 (P = 0.93)

2 Vaginal

Rode 2011 10/648 14/669 16.8 % 0.74 [ 0.33, 1.65 ]

Serra 2013 1/194 5/190 6.2 % 0.20 [ 0.02, 1.66 ]

Subtotal (95% CI) 842 859 23.0 % 0.59 [ 0.28, 1.23 ]

Total events: 11 (Progesterone), 19 (Placebo)

Heterogeneity: Chi2 = 1.31, df = 1 (P = 0.25); I2 =24%

Test for overall effect: Z = 1.40 (P = 0.16)

Total (95% CI) 1735 1716 100.0 % 0.89 [ 0.66, 1.21 ]

Total events: 74 (Progesterone), 81 (Placebo)

Heterogeneity: Chi2 = 2.58, df = 3 (P = 0.46); I2 =0.0%

Test for overall effect: Z = 0.72 (P = 0.47)

Test for subgroup differences: Chi2 = 1.52, df = 1 (P = 0.22), I2 =34%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

191Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.15. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 15 Respiratory

distress syndrome.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 15 Respiratory distress syndrome

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Caritis 2009 65/212 50/183 18.6 % 1.12 [ 0.82, 1.53 ]

Combs 2010 44/155 28/75 14.3 % 0.76 [ 0.52, 1.12 ]

Combs 2011 44/319 18/153 9.4 % 1.17 [ 0.70, 1.96 ]

Lim 2011 82/681 51/674 17.2 % 1.59 [ 1.14, 2.22 ]

Rouse 2007 96/632 87/648 21.8 % 1.13 [ 0.86, 1.48 ]

Subtotal (95% CI) 1999 1733 81.4 % 1.13 [ 0.91, 1.42 ]

Total events: 331 (Progesterone), 234 (Placebo)

Heterogeneity: Tau2 = 0.03; Chi2 = 8.22, df = 4 (P = 0.08); I2 =51%

Test for overall effect: Z = 1.10 (P = 0.27)

2 Vaginal

Rode 2011 73/659 69/674 18.6 % 1.08 [ 0.79, 1.48 ]

Subtotal (95% CI) 659 674 18.6 % 1.08 [ 0.79, 1.48 ]

Total events: 73 (Progesterone), 69 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.50 (P = 0.62)

Total (95% CI) 2658 2407 100.0 % 1.13 [ 0.94, 1.35 ]

Total events: 404 (Progesterone), 303 (Placebo)

Heterogeneity: Tau2 = 0.02; Chi2 = 8.29, df = 5 (P = 0.14); I2 =40%

Test for overall effect: Z = 1.30 (P = 0.19)

Test for subgroup differences: Chi2 = 0.06, df = 1 (P = 0.81), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

192Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.16. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 16 Use of assisted

ventilation.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 16 Use of assisted ventilation

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Caritis 2009 70/212 57/183 37.3 % 1.06 [ 0.79, 1.41 ]

Rouse 2007 70/632 77/648 46.3 % 0.93 [ 0.69, 1.26 ]

Subtotal (95% CI) 844 831 83.5 % 0.99 [ 0.80, 1.22 ]

Total events: 140 (Progesterone), 134 (Placebo)

Heterogeneity: Chi2 = 0.37, df = 1 (P = 0.54); I2 =0.0%

Test for overall effect: Z = 0.10 (P = 0.92)

2 Vaginal

Rode 2011 12/659 12/674 7.2 % 1.02 [ 0.46, 2.26 ]

Serra 2013 9/194 15/190 9.2 % 0.59 [ 0.26, 1.31 ]

Subtotal (95% CI) 853 864 16.5 % 0.78 [ 0.45, 1.36 ]

Total events: 21 (Progesterone), 27 (Placebo)

Heterogeneity: Chi2 = 0.93, df = 1 (P = 0.34); I2 =0.0%

Test for overall effect: Z = 0.88 (P = 0.38)

Total (95% CI) 1697 1695 100.0 % 0.95 [ 0.78, 1.16 ]

Total events: 161 (Progesterone), 161 (Placebo)

Heterogeneity: Chi2 = 1.97, df = 3 (P = 0.58); I2 =0.0%

Test for overall effect: Z = 0.46 (P = 0.64)

Test for subgroup differences: Chi2 = 0.62, df = 1 (P = 0.43), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

193Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.17. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 17

Intraventricular haemorrhage - grades III or IV.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 17 Intraventricular haemorrhage - grades III or IV

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Caritis 2009 2/212 4/183 28.8 % 0.43 [ 0.08, 2.33 ]

Combs 2010 4/150 3/75 26.9 % 0.67 [ 0.15, 2.90 ]

Combs 2011 3/316 0/152 4.5 % 3.38 [ 0.18, 65.00 ]

Rouse 2007 7/632 6/648 39.8 % 1.20 [ 0.40, 3.54 ]

Total (95% CI) 1310 1058 100.0 % 0.93 [ 0.45, 1.92 ]

Total events: 16 (Progesterone), 13 (Placebo)

Heterogeneity: Chi2 = 1.93, df = 3 (P = 0.59); I2 =0.0%

Test for overall effect: Z = 0.19 (P = 0.85)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

194Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.18. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 18

Intraventricular haemorrhage - all grades.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 18 Intraventricular haemorrhage - all grades

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Lim 2011 4/681 2/674 25.3 % 1.98 [ 0.36, 10.77 ]

Subtotal (95% CI) 681 674 25.3 % 1.98 [ 0.36, 10.77 ]

Total events: 4 (Progesterone), 2 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.79 (P = 0.43)

2 Vaginal

Rode 2011 10/659 6/674 74.7 % 1.70 [ 0.62, 4.66 ]

Subtotal (95% CI) 659 674 74.7 % 1.70 [ 0.62, 4.66 ]

Total events: 10 (Progesterone), 6 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.04 (P = 0.30)

Total (95% CI) 1340 1348 100.0 % 1.77 [ 0.75, 4.21 ]

Total events: 14 (Progesterone), 8 (Placebo)

Heterogeneity: Chi2 = 0.02, df = 1 (P = 0.88); I2 =0.0%

Test for overall effect: Z = 1.30 (P = 0.19)

Test for subgroup differences: Chi2 = 0.02, df = 1 (P = 0.88), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

195Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.19. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 19 Periventricular

leucomalacia.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 19 Periventricular leucomalacia

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Caritis 2009 0/212 1/183 54.3 % 0.29 [ 0.01, 7.03 ]

Combs 2010 0/154 0/75 Not estimable

Combs 2011 1/316 1/151 45.7 % 0.48 [ 0.03, 7.59 ]

Total (95% CI) 682 409 100.0 % 0.37 [ 0.05, 3.02 ]

Total events: 1 (Progesterone), 2 (Placebo)

Heterogeneity: Chi2 = 0.06, df = 1 (P = 0.81); I2 =0.0%

Test for overall effect: Z = 0.92 (P = 0.36)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

196Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.20. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 20 Retinopathy of

prematurity.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 20 Retinopathy of prematurity

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Caritis 2009 0/212 0/183 Not estimable

Combs 2010 4/145 4/62 54.7 % 0.43 [ 0.11, 1.66 ]

Combs 2011 2/308 0/145 6.6 % 2.36 [ 0.11, 48.90 ]

Rouse 2007 0/632 0/648 Not estimable

Subtotal (95% CI) 1297 1038 61.4 % 0.64 [ 0.20, 2.06 ]

Total events: 6 (Progesterone), 4 (Placebo)

Heterogeneity: Chi2 = 1.05, df = 1 (P = 0.31); I2 =5%

Test for overall effect: Z = 0.75 (P = 0.45)

2 Vaginal

Rode 2011 4/659 4/674 38.6 % 1.02 [ 0.26, 4.07 ]

Subtotal (95% CI) 659 674 38.6 % 1.02 [ 0.26, 4.07 ]

Total events: 4 (Progesterone), 4 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.03 (P = 0.97)

Total (95% CI) 1956 1712 100.0 % 0.79 [ 0.32, 1.91 ]

Total events: 10 (Progesterone), 8 (Placebo)

Heterogeneity: Chi2 = 1.42, df = 2 (P = 0.49); I2 =0.0%

Test for overall effect: Z = 0.53 (P = 0.60)

Test for subgroup differences: Chi2 = 0.26, df = 1 (P = 0.61), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

197Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.21. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 21 Chronic lung

disease.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 21 Chronic lung disease

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Combs 2010 11/153 7/70 61.9 % 0.72 [ 0.29, 1.78 ]

Combs 2011 9/308 0/150 38.1 % 9.28 [ 0.54, 158.46 ]

Total (95% CI) 461 220 100.0 % 1.91 [ 0.13, 27.80 ]

Total events: 20 (Progesterone), 7 (Placebo)

Heterogeneity: Tau2 = 2.81; Chi2 = 3.43, df = 1 (P = 0.06); I2 =71%

Test for overall effect: Z = 0.47 (P = 0.64)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

198Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.22. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 22 Necrotising

enterocolitis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 22 Necrotising enterocolitis

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Caritis 2009 2/212 5/183 26.4 % 0.35 [ 0.07, 1.76 ]

Combs 2010 8/154 3/75 19.8 % 1.30 [ 0.35, 4.76 ]

Combs 2011 0/315 0/152 Not estimable

Lim 2011 8/681 5/674 24.7 % 1.58 [ 0.52, 4.82 ]

Rouse 2007 3/632 4/648 19.4 % 0.77 [ 0.17, 3.42 ]

Subtotal (95% CI) 1994 1732 90.3 % 0.98 [ 0.52, 1.88 ]

Total events: 21 (Progesterone), 17 (Placebo)

Heterogeneity: Chi2 = 2.57, df = 3 (P = 0.46); I2 =0.0%

Test for overall effect: Z = 0.05 (P = 0.96)

2 Vaginal

Rode 2011 1/659 2/674 9.7 % 0.51 [ 0.05, 5.63 ]

Subtotal (95% CI) 659 674 9.7 % 0.51 [ 0.05, 5.63 ]

Total events: 1 (Progesterone), 2 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.55 (P = 0.58)

Total (95% CI) 2653 2406 100.0 % 0.94 [ 0.50, 1.75 ]

Total events: 22 (Progesterone), 19 (Placebo)

Heterogeneity: Chi2 = 2.85, df = 4 (P = 0.58); I2 =0.0%

Test for overall effect: Z = 0.20 (P = 0.84)

Test for subgroup differences: Chi2 = 0.27, df = 1 (P = 0.61), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

199Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.23. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 23 Neonatal

sepsis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 23 Neonatal sepsis

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Caritis 2009 20/212 13/183 18.6 % 1.33 [ 0.68, 2.59 ]

Combs 2010 4/154 4/75 7.2 % 0.49 [ 0.13, 1.89 ]

Combs 2011 3/319 1/154 1.8 % 1.45 [ 0.15, 13.81 ]

Lim 2011 23/681 11/674 14.7 % 2.07 [ 1.02, 4.21 ]

Rouse 2007 24/632 26/648 34.1 % 0.95 [ 0.55, 1.63 ]

Subtotal (95% CI) 1998 1734 76.3 % 1.22 [ 0.87, 1.72 ]

Total events: 74 (Progesterone), 55 (Placebo)

Heterogeneity: Chi2 = 4.80, df = 4 (P = 0.31); I2 =17%

Test for overall effect: Z = 1.16 (P = 0.24)

2 Vaginal

Rode 2011 20/659 18/674 23.7 % 1.14 [ 0.61, 2.13 ]

Subtotal (95% CI) 659 674 23.7 % 1.14 [ 0.61, 2.13 ]

Total events: 20 (Progesterone), 18 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.40 (P = 0.69)

Total (95% CI) 2657 2408 100.0 % 1.20 [ 0.89, 1.62 ]

Total events: 94 (Progesterone), 73 (Placebo)

Heterogeneity: Chi2 = 4.83, df = 5 (P = 0.44); I2 =0.0%

Test for overall effect: Z = 1.21 (P = 0.23)

Test for subgroup differences: Chi2 = 0.04, df = 1 (P = 0.84), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

200Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.24. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 24 Fetal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 24 Fetal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Combs 2010 13/168 0/75 2.7 % 12.14 [ 0.73, 201.61 ]

Combs 2011 0/320 0/156 Not estimable

Lim 2011 13/681 13/674 51.8 % 0.99 [ 0.46, 2.12 ]

Subtotal (95% CI) 1169 905 54.5 % 1.55 [ 0.77, 3.12 ]

Total events: 26 (Progesterone), 13 (Placebo)

Heterogeneity: Chi2 = 3.39, df = 1 (P = 0.07); I2 =71%

Test for overall effect: Z = 1.23 (P = 0.22)

2 Vaginal

Norman 2009 6/494 4/494 15.9 % 1.50 [ 0.43, 5.28 ]

Rode 2011 3/664 5/678 19.6 % 0.61 [ 0.15, 2.55 ]

Serra 2013 0/194 2/190 10.0 % 0.20 [ 0.01, 4.05 ]

Subtotal (95% CI) 1352 1362 45.5 % 0.83 [ 0.35, 1.95 ]

Total events: 9 (Progesterone), 11 (Placebo)

Heterogeneity: Chi2 = 1.89, df = 2 (P = 0.39); I2 =0.0%

Test for overall effect: Z = 0.43 (P = 0.67)

Total (95% CI) 2521 2267 100.0 % 1.22 [ 0.71, 2.09 ]

Total events: 35 (Progesterone), 24 (Placebo)

Heterogeneity: Chi2 = 5.26, df = 4 (P = 0.26); I2 =24%

Test for overall effect: Z = 0.73 (P = 0.46)

Test for subgroup differences: Chi2 = 1.22, df = 1 (P = 0.27), I2 =18%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

201Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.25. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 25 Neonatal

death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 25 Neonatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Caritis 2009 5/212 2/183 13.1 % 2.16 [ 0.42, 10.99 ]

Combs 2010 6/155 2/75 13.7 % 1.45 [ 0.30, 7.02 ]

Combs 2011 0/320 3/156 5.3 % 0.07 [ 0.00, 1.34 ]

Lim 2011 13/681 21/674 27.9 % 0.61 [ 0.31, 1.21 ]

Subtotal (95% CI) 1368 1088 60.0 % 0.81 [ 0.31, 2.10 ]

Total events: 24 (Progesterone), 28 (Placebo)

Heterogeneity: Tau2 = 0.39; Chi2 = 5.12, df = 3 (P = 0.16); I2 =41%

Test for overall effect: Z = 0.43 (P = 0.67)

2 Vaginal

Norman 2009 8/494 6/494 21.0 % 1.33 [ 0.47, 3.81 ]

Rode 2011 7/664 2/678 13.7 % 3.57 [ 0.75, 17.14 ]

Serra 2013 0/194 3/190 5.3 % 0.14 [ 0.01, 2.69 ]

Subtotal (95% CI) 1352 1362 40.0 % 1.34 [ 0.36, 4.95 ]

Total events: 15 (Progesterone), 11 (Placebo)

Heterogeneity: Tau2 = 0.62; Chi2 = 3.74, df = 2 (P = 0.15); I2 =47%

Test for overall effect: Z = 0.43 (P = 0.67)

Total (95% CI) 2720 2450 100.0 % 1.01 [ 0.48, 2.10 ]

Total events: 39 (Progesterone), 39 (Placebo)

Heterogeneity: Tau2 = 0.38; Chi2 = 10.60, df = 6 (P = 0.10); I2 =43%

Test for overall effect: Z = 0.02 (P = 0.99)

Test for subgroup differences: Chi2 = 0.36, df = 1 (P = 0.55), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

202Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.26. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 26 Admission to

NICU.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 26 Admission to NICU

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Vaginal

Aboulghar 2012 12/98 22/84 8.7 % 0.47 [ 0.25, 0.89 ]

Norman 2009 167/494 158/494 26.3 % 1.06 [ 0.88, 1.26 ]

Rode 2011 307/664 354/678 29.4 % 0.89 [ 0.79, 0.99 ]

Serra 2013 21/194 28/190 11.3 % 0.73 [ 0.43, 1.25 ]

Subtotal (95% CI) 1450 1446 75.7 % 0.87 [ 0.71, 1.07 ]

Total events: 507 (Progesterone), 562 (Placebo)

Heterogeneity: Tau2 = 0.02; Chi2 = 7.74, df = 3 (P = 0.05); I2 =61%

Test for overall effect: Z = 1.27 (P = 0.20)

2 Intramuscular

Lim 2011 153/681 116/674 24.3 % 1.31 [ 1.05, 1.62 ]

Subtotal (95% CI) 681 674 24.3 % 1.31 [ 1.05, 1.62 ]

Total events: 153 (Progesterone), 116 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.41 (P = 0.016)

Total (95% CI) 2131 2120 100.0 % 0.94 [ 0.76, 1.18 ]

Total events: 660 (Progesterone), 678 (Placebo)

Heterogeneity: Tau2 = 0.04; Chi2 = 16.95, df = 4 (P = 0.002); I2 =76%

Test for overall effect: Z = 0.51 (P = 0.61)

Test for subgroup differences: Chi2 = 6.89, df = 1 (P = 0.01), I2 =85%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

203Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.27. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 27 Perinatal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 27 Perinatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Combs 2010 19/168 2/75 11.8 % 4.24 [ 1.01, 17.75 ]

Combs 2011 0/320 3/156 3.8 % 0.07 [ 0.00, 1.34 ]

Hartikainen 1980 4/78 2/76 9.6 % 1.95 [ 0.37, 10.33 ]

Lim 2011 23/681 34/674 26.9 % 0.67 [ 0.40, 1.12 ]

Subtotal (95% CI) 1247 981 52.1 % 1.06 [ 0.30, 3.71 ]

Total events: 46 (Progesterone), 41 (Placebo)

Heterogeneity: Tau2 = 1.02; Chi2 = 9.42, df = 3 (P = 0.02); I2 =68%

Test for overall effect: Z = 0.09 (P = 0.93)

2 Vaginal

Aboulghar 2012 4/98 5/84 13.5 % 0.69 [ 0.19, 2.47 ]

Rode 2011 10/664 7/678 18.3 % 1.46 [ 0.56, 3.81 ]

Serra 2013 8/191 5/190 16.1 % 1.59 [ 0.53, 4.78 ]

Subtotal (95% CI) 953 952 47.9 % 1.25 [ 0.67, 2.35 ]

Total events: 22 (Progesterone), 17 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 1.13, df = 2 (P = 0.57); I2 =0.0%

Test for overall effect: Z = 0.70 (P = 0.49)

Total (95% CI) 2200 1933 100.0 % 1.13 [ 0.61, 2.08 ]

Total events: 68 (Progesterone), 58 (Placebo)

Heterogeneity: Tau2 = 0.29; Chi2 = 11.54, df = 6 (P = 0.07); I2 =48%

Test for overall effect: Z = 0.38 (P = 0.70)

Test for subgroup differences: Chi2 = 0.05, df = 1 (P = 0.81), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

204Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.28. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 28 Preterm birth

less than 34 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 28 Preterm birth less than 34 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Vaginal

Aboulghar 2012 8/49 10/42 9.3 % 0.69 [ 0.30, 1.58 ]

Cetingoz 2011 4/39 7/28 5.5 % 0.41 [ 0.13, 1.27 ]

Norman 2009 55/247 44/247 29.4 % 1.25 [ 0.88, 1.78 ]

Rode 2011 51/334 63/341 30.9 % 0.83 [ 0.59, 1.16 ]

Serra 2013 10/97 13/96 10.5 % 0.76 [ 0.35, 1.65 ]

Subtotal (95% CI) 766 754 85.6 % 0.88 [ 0.65, 1.19 ]

Total events: 128 (Progesterone), 137 (Placebo)

Heterogeneity: Tau2 = 0.04; Chi2 = 5.93, df = 4 (P = 0.20); I2 =33%

Test for overall effect: Z = 0.81 (P = 0.42)

2 Intramuscular

Combs 2011 31/160 11/78 14.4 % 1.37 [ 0.73, 2.59 ]

Subtotal (95% CI) 160 78 14.4 % 1.37 [ 0.73, 2.59 ]

Total events: 31 (Progesterone), 11 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.98 (P = 0.32)

Total (95% CI) 926 832 100.0 % 0.94 [ 0.71, 1.24 ]

Total events: 159 (Progesterone), 148 (Placebo)

Heterogeneity: Tau2 = 0.04; Chi2 = 7.26, df = 5 (P = 0.20); I2 =31%

Test for overall effect: Z = 0.42 (P = 0.67)

Test for subgroup differences: Chi2 = 1.53, df = 1 (P = 0.22), I2 =35%

0.05 0.2 1 5 20

Favours progesterone Favours placebo

205Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.29. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 29 Preterm

PROM.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 29 Preterm PROM

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Caritis 2009 6/71 7/63 19.2 % 0.76 [ 0.27, 2.14 ]

Lim 2011 34/336 28/332 73.0 % 1.20 [ 0.74, 1.93 ]

Subtotal (95% CI) 407 395 92.2 % 1.11 [ 0.72, 1.71 ]

Total events: 40 (Progesterone), 35 (Placebo)

Heterogeneity: Chi2 = 0.61, df = 1 (P = 0.43); I2 =0.0%

Test for overall effect: Z = 0.47 (P = 0.64)

2 Vaginal

Serra 2013 1/97 3/96 7.8 % 0.33 [ 0.03, 3.12 ]

Subtotal (95% CI) 97 96 7.8 % 0.33 [ 0.03, 3.12 ]

Total events: 1 (Progesterone), 3 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.97 (P = 0.33)

Total (95% CI) 504 491 100.0 % 1.05 [ 0.69, 1.60 ]

Total events: 41 (Progesterone), 38 (Placebo)

Heterogeneity: Chi2 = 1.70, df = 2 (P = 0.43); I2 =0.0%

Test for overall effect: Z = 0.22 (P = 0.83)

Test for subgroup differences: Chi2 = 1.08, df = 1 (P = 0.30), I2 =7%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

206Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.30. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 30 Caesarean

section.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 30 Caesarean section

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Caritis 2009 71/71 62/63 6.8 % 1.02 [ 0.97, 1.06 ]

Combs 2010 52/56 25/25 3.6 % 0.94 [ 0.86, 1.03 ]

Combs 2011 122/160 59/78 8.1 % 1.01 [ 0.87, 1.17 ]

Lim 2011 146/336 136/332 14.0 % 1.06 [ 0.89, 1.27 ]

Rouse 2007 200/324 204/328 20.7 % 0.99 [ 0.88, 1.12 ]

Subtotal (95% CI) 947 826 53.1 % 1.01 [ 0.94, 1.09 ]

Total events: 591 (Progesterone), 486 (Placebo)

Heterogeneity: Chi2 = 2.91, df = 4 (P = 0.57); I2 =0.0%

Test for overall effect: Z = 0.34 (P = 0.74)

2 Vaginal

Norman 2009 148/250 161/250 16.4 % 0.92 [ 0.80, 1.06 ]

Rode 2011 207/332 232/338 23.5 % 0.91 [ 0.81, 1.01 ]

Serra 2013 59/97 68/96 7.0 % 0.86 [ 0.70, 1.05 ]

Subtotal (95% CI) 679 684 46.9 % 0.90 [ 0.84, 0.98 ]

Total events: 414 (Progesterone), 461 (Placebo)

Heterogeneity: Chi2 = 0.31, df = 2 (P = 0.86); I2 =0.0%

Test for overall effect: Z = 2.46 (P = 0.014)

Total (95% CI) 1626 1510 100.0 % 0.96 [ 0.91, 1.01 ]

Total events: 1005 (Progesterone), 947 (Placebo)

Heterogeneity: Chi2 = 11.21, df = 7 (P = 0.13); I2 =38%

Test for overall effect: Z = 1.44 (P = 0.15)

Test for subgroup differences: Chi2 = 4.26, df = 1 (P = 0.04), I2 =77%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

207Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.31. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 31 Antenatal

tocolysis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 31 Antenatal tocolysis

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Caritis 2009 33/71 28/63 12.8 % 1.05 [ 0.72, 1.52 ]

Combs 2010 44/56 17/25 16.8 % 1.16 [ 0.85, 1.56 ]

Combs 2011 62/160 32/78 15.0 % 0.94 [ 0.68, 1.31 ]

Lim 2011 73/336 64/332 16.9 % 1.13 [ 0.84, 1.52 ]

Rouse 2007 71/324 97/330 19.4 % 0.75 [ 0.57, 0.97 ]

Subtotal (95% CI) 947 828 81.0 % 0.98 [ 0.82, 1.17 ]

Total events: 283 (Progesterone), 238 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 6.38, df = 4 (P = 0.17); I2 =37%

Test for overall effect: Z = 0.22 (P = 0.83)

2 Vaginal

Rode 2011 41/333 60/341 13.0 % 0.70 [ 0.48, 1.01 ]

Serra 2013 17/97 17/96 5.9 % 0.99 [ 0.54, 1.82 ]

Subtotal (95% CI) 430 437 19.0 % 0.77 [ 0.56, 1.05 ]

Total events: 58 (Progesterone), 77 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.91, df = 1 (P = 0.34); I2 =0.0%

Test for overall effect: Z = 1.65 (P = 0.099)

Total (95% CI) 1377 1265 100.0 % 0.94 [ 0.80, 1.10 ]

Total events: 341 (Progesterone), 315 (Placebo)

Heterogeneity: Tau2 = 0.02; Chi2 = 9.25, df = 6 (P = 0.16); I2 =35%

Test for overall effect: Z = 0.77 (P = 0.44)

Test for subgroup differences: Chi2 = 1.78, df = 1 (P = 0.18), I2 =44%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

208Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.32. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 32 Antenatal

corticosteroids.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 32 Antenatal corticosteroids

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Rouse 2007 80/324 90/330 89.9 % 0.91 [ 0.70, 1.17 ]

Subtotal (95% CI) 324 330 89.9 % 0.91 [ 0.70, 1.17 ]

Total events: 80 (Progesterone), 90 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.75 (P = 0.45)

2 Vaginal

Serra 2013 16/97 10/96 10.1 % 1.58 [ 0.76, 3.31 ]

Subtotal (95% CI) 97 96 10.1 % 1.58 [ 0.76, 3.31 ]

Total events: 16 (Progesterone), 10 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.22 (P = 0.22)

Total (95% CI) 421 426 100.0 % 0.97 [ 0.76, 1.24 ]

Total events: 96 (Progesterone), 100 (Placebo)

Heterogeneity: Chi2 = 1.97, df = 1 (P = 0.16); I2 =49%

Test for overall effect: Z = 0.21 (P = 0.83)

Test for subgroup differences: Chi2 = 1.96, df = 1 (P = 0.16), I2 =49%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

209Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.33. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 33 Preterm birth

less than 37 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 33 Preterm birth less than 37 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Combs 2011 113/160 46/78 12.5 % 1.20 [ 0.97, 1.48 ]

Hartikainen 1980 15/39 9/38 1.6 % 1.62 [ 0.81, 3.25 ]

Lim 2011 186/336 165/332 19.6 % 1.11 [ 0.96, 1.29 ]

Rouse 2007 226/325 232/330 26.6 % 0.99 [ 0.89, 1.09 ]

Subtotal (95% CI) 860 778 60.3 % 1.09 [ 0.96, 1.22 ]

Total events: 540 (Progesterone), 452 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 5.20, df = 3 (P = 0.16); I2 =42%

Test for overall effect: Z = 1.35 (P = 0.18)

2 Vaginal

Aboulghar 2012 31/49 28/42 7.3 % 0.95 [ 0.70, 1.28 ]

Cetingoz 2011 29/39 22/38 6.3 % 1.28 [ 0.93, 1.78 ]

Rode 2011 158/334 179/341 18.7 % 0.90 [ 0.77, 1.05 ]

Serra 2013 44/97 47/96 7.4 % 0.93 [ 0.69, 1.25 ]

Subtotal (95% CI) 519 517 39.7 % 0.97 [ 0.84, 1.11 ]

Total events: 262 (Progesterone), 276 (Placebo)

Heterogeneity: Tau2 = 0.00; Chi2 = 3.78, df = 3 (P = 0.29); I2 =21%

Test for overall effect: Z = 0.49 (P = 0.63)

Total (95% CI) 1379 1295 100.0 % 1.04 [ 0.95, 1.13 ]

Total events: 802 (Progesterone), 728 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 10.81, df = 7 (P = 0.15); I2 =35%

Test for overall effect: Z = 0.78 (P = 0.44)

Test for subgroup differences: Chi2 = 1.56, df = 1 (P = 0.21), I2 =36%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

210Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.34. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 34 Preterm birth

less than 28 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 34 Preterm birth less than 28 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Combs 2010 9/56 2/25 9.2 % 2.01 [ 0.47, 8.63 ]

Combs 2011 3/160 1/78 4.5 % 1.46 [ 0.15, 13.83 ]

Lim 2011 19/336 18/332 60.1 % 1.04 [ 0.56, 1.95 ]

Subtotal (95% CI) 552 435 73.7 % 1.19 [ 0.68, 2.07 ]

Total events: 31 (Progesterone), 21 (Placebo)

Heterogeneity: Chi2 = 0.70, df = 2 (P = 0.71); I2 =0.0%

Test for overall effect: Z = 0.61 (P = 0.54)

2 Vaginal

Rode 2011 9/334 7/341 23.0 % 1.31 [ 0.49, 3.48 ]

Serra 2013 3/97 1/96 3.3 % 2.97 [ 0.31, 28.04 ]

Subtotal (95% CI) 431 437 26.3 % 1.52 [ 0.63, 3.69 ]

Total events: 12 (Progesterone), 8 (Placebo)

Heterogeneity: Chi2 = 0.43, df = 1 (P = 0.51); I2 =0.0%

Test for overall effect: Z = 0.93 (P = 0.35)

Total (95% CI) 983 872 100.0 % 1.28 [ 0.80, 2.04 ]

Total events: 43 (Progesterone), 29 (Placebo)

Heterogeneity: Chi2 = 1.33, df = 4 (P = 0.86); I2 =0.0%

Test for overall effect: Z = 1.02 (P = 0.31)

Test for subgroup differences: Chi2 = 0.22, df = 1 (P = 0.64), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

211Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.35. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 35 Infant

birthweight less than 2500 g.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 35 Infant birthweight less than 2500 g

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Caritis 2009 191/212 175/183 20.8 % 0.94 [ 0.89, 0.99 ]

Combs 2011 195/320 70/156 9.2 % 1.36 [ 1.12, 1.65 ]

Lim 2011 363/681 355/674 16.6 % 1.01 [ 0.92, 1.12 ]

Rouse 2007 377/628 415/648 17.9 % 0.94 [ 0.86, 1.02 ]

Subtotal (95% CI) 1841 1661 64.5 % 1.02 [ 0.91, 1.14 ]

Total events: 1126 (Progesterone), 1015 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 16.56, df = 3 (P = 0.00087); I2 =82%

Test for overall effect: Z = 0.30 (P = 0.76)

2 Vaginal

Aboulghar 2012 58/98 62/84 8.5 % 0.80 [ 0.65, 0.99 ]

Rode 2011 306/659 357/677 15.8 % 0.88 [ 0.79, 0.98 ]

Serra 2013 113/191 117/190 11.3 % 0.96 [ 0.82, 1.13 ]

Subtotal (95% CI) 948 951 35.5 % 0.89 [ 0.82, 0.96 ]

Total events: 477 (Progesterone), 536 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 1.85, df = 2 (P = 0.40); I2 =0.0%

Test for overall effect: Z = 2.82 (P = 0.0047)

Total (95% CI) 2789 2612 100.0 % 0.96 [ 0.89, 1.04 ]

Total events: 1603 (Progesterone), 1551 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 19.50, df = 6 (P = 0.003); I2 =69%

Test for overall effect: Z = 0.96 (P = 0.34)

Test for subgroup differences: Chi2 = 3.74, df = 1 (P = 0.05), I2 =73%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

212Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.36. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 36 Apgar score <

7 at 5 minutes.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 36 Apgar score < 7 at 5 minutes

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Caritis 2009 10/212 10/183 13.1 % 0.86 [ 0.37, 2.03 ]

Lim 2011 53/681 52/674 63.9 % 1.01 [ 0.70, 1.46 ]

Subtotal (95% CI) 893 857 77.0 % 0.98 [ 0.70, 1.38 ]

Total events: 63 (Progesterone), 62 (Placebo)

Heterogeneity: Chi2 = 0.11, df = 1 (P = 0.74); I2 =0.0%

Test for overall effect: Z = 0.09 (P = 0.93)

2 Vaginal

Rode 2011 10/648 14/669 16.8 % 0.74 [ 0.33, 1.65 ]

Serra 2013 5/191 5/190 6.1 % 0.99 [ 0.29, 3.38 ]

Subtotal (95% CI) 839 859 23.0 % 0.81 [ 0.41, 1.58 ]

Total events: 15 (Progesterone), 19 (Placebo)

Heterogeneity: Chi2 = 0.16, df = 1 (P = 0.69); I2 =0.0%

Test for overall effect: Z = 0.63 (P = 0.53)

Total (95% CI) 1732 1716 100.0 % 0.94 [ 0.70, 1.27 ]

Total events: 78 (Progesterone), 81 (Placebo)

Heterogeneity: Chi2 = 0.54, df = 3 (P = 0.91); I2 =0.0%

Test for overall effect: Z = 0.38 (P = 0.70)

Test for subgroup differences: Chi2 = 0.27, df = 1 (P = 0.60), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

213Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.37. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 37 Use of assisted

ventilation.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 37 Use of assisted ventilation

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Caritis 2009 70/212 57/183 37.3 % 1.06 [ 0.79, 1.41 ]

Rouse 2007 70/632 77/648 46.3 % 0.93 [ 0.69, 1.26 ]

Subtotal (95% CI) 844 831 83.6 % 0.99 [ 0.80, 1.22 ]

Total events: 140 (Progesterone), 134 (Placebo)

Heterogeneity: Chi2 = 0.37, df = 1 (P = 0.54); I2 =0.0%

Test for overall effect: Z = 0.10 (P = 0.92)

2 Vaginal

Rode 2011 12/659 12/674 7.2 % 1.02 [ 0.46, 2.26 ]

Serra 2013 13/191 15/190 9.2 % 0.86 [ 0.42, 1.76 ]

Subtotal (95% CI) 850 864 16.4 % 0.93 [ 0.55, 1.59 ]

Total events: 25 (Progesterone), 27 (Placebo)

Heterogeneity: Chi2 = 0.10, df = 1 (P = 0.75); I2 =0.0%

Test for overall effect: Z = 0.26 (P = 0.80)

Total (95% CI) 1694 1695 100.0 % 0.98 [ 0.81, 1.19 ]

Total events: 165 (Progesterone), 161 (Placebo)

Heterogeneity: Chi2 = 0.52, df = 3 (P = 0.91); I2 =0.0%

Test for overall effect: Z = 0.20 (P = 0.84)

Test for subgroup differences: Chi2 = 0.04, df = 1 (P = 0.84), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

214Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.38. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 38 Fetal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 38 Fetal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Combs 2010 13/168 0/75 2.8 % 12.14 [ 0.73, 201.61 ]

Combs 2011 0/320 0/156 Not estimable

Lim 2011 13/681 13/674 52.9 % 0.99 [ 0.46, 2.12 ]

Subtotal (95% CI) 1169 905 55.7 % 1.55 [ 0.77, 3.12 ]

Total events: 26 (Progesterone), 13 (Placebo)

Heterogeneity: Chi2 = 3.39, df = 1 (P = 0.07); I2 =71%

Test for overall effect: Z = 1.23 (P = 0.22)

2 Vaginal

Norman 2009 6/494 4/494 16.2 % 1.50 [ 0.43, 5.28 ]

Rode 2011 3/664 5/678 20.0 % 0.61 [ 0.15, 2.55 ]

Serra 2013 3/191 2/190 8.1 % 1.49 [ 0.25, 8.83 ]

Subtotal (95% CI) 1349 1362 44.3 % 1.10 [ 0.49, 2.48 ]

Total events: 12 (Progesterone), 11 (Placebo)

Heterogeneity: Chi2 = 0.99, df = 2 (P = 0.61); I2 =0.0%

Test for overall effect: Z = 0.22 (P = 0.82)

Total (95% CI) 2518 2267 100.0 % 1.35 [ 0.79, 2.29 ]

Total events: 38 (Progesterone), 24 (Placebo)

Heterogeneity: Chi2 = 4.20, df = 4 (P = 0.38); I2 =5%

Test for overall effect: Z = 1.11 (P = 0.27)

Test for subgroup differences: Chi2 = 0.39, df = 1 (P = 0.53), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

215Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.39. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 39 Neonatal

death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 39 Neonatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Caritis 2009 5/212 2/183 11.2 % 2.16 [ 0.42, 10.99 ]

Combs 2010 6/155 2/75 11.7 % 1.45 [ 0.30, 7.02 ]

Combs 2011 0/320 3/156 4.2 % 0.07 [ 0.00, 1.34 ]

Lim 2011 13/681 21/674 28.1 % 0.61 [ 0.31, 1.21 ]

Subtotal (95% CI) 1368 1088 55.2 % 0.81 [ 0.31, 2.10 ]

Total events: 24 (Progesterone), 28 (Placebo)

Heterogeneity: Tau2 = 0.39; Chi2 = 5.12, df = 3 (P = 0.16); I2 =41%

Test for overall effect: Z = 0.43 (P = 0.67)

2 Vaginal

Norman 2009 8/494 6/494 19.5 % 1.33 [ 0.47, 3.81 ]

Rode 2011 7/664 2/678 11.8 % 3.57 [ 0.75, 17.14 ]

Serra 2013 5/191 3/190 13.6 % 1.66 [ 0.40, 6.84 ]

Subtotal (95% CI) 1349 1362 44.8 % 1.77 [ 0.84, 3.72 ]

Total events: 20 (Progesterone), 11 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 1.07, df = 2 (P = 0.59); I2 =0.0%

Test for overall effect: Z = 1.50 (P = 0.13)

Total (95% CI) 2717 2450 100.0 % 1.17 [ 0.62, 2.21 ]

Total events: 44 (Progesterone), 39 (Placebo)

Heterogeneity: Tau2 = 0.25; Chi2 = 9.46, df = 6 (P = 0.15); I2 =37%

Test for overall effect: Z = 0.48 (P = 0.63)

Test for subgroup differences: Chi2 = 1.59, df = 1 (P = 0.21), I2 =37%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

216Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.40. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 40 Admission to

NICU.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 40 Admission to NICU

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Vaginal

Aboulghar 2012 12/98 22/84 9.0 % 0.47 [ 0.25, 0.89 ]

Norman 2009 167/494 158/494 26.3 % 1.06 [ 0.88, 1.26 ]

Rode 2011 307/664 354/678 29.3 % 0.89 [ 0.79, 0.99 ]

Serra 2013 19/191 28/190 11.1 % 0.68 [ 0.39, 1.17 ]

Subtotal (95% CI) 1447 1446 75.6 % 0.86 [ 0.70, 1.07 ]

Total events: 505 (Progesterone), 562 (Placebo)

Heterogeneity: Tau2 = 0.02; Chi2 = 8.26, df = 3 (P = 0.04); I2 =64%

Test for overall effect: Z = 1.35 (P = 0.18)

2 Intramuscular

Lim 2011 153/681 116/674 24.4 % 1.31 [ 1.05, 1.62 ]

Subtotal (95% CI) 681 674 24.4 % 1.31 [ 1.05, 1.62 ]

Total events: 153 (Progesterone), 116 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.41 (P = 0.016)

Total (95% CI) 2128 2120 100.0 % 0.93 [ 0.75, 1.17 ]

Total events: 658 (Progesterone), 678 (Placebo)

Heterogeneity: Tau2 = 0.04; Chi2 = 17.55, df = 4 (P = 0.002); I2 =77%

Test for overall effect: Z = 0.59 (P = 0.56)

Test for subgroup differences: Chi2 = 7.07, df = 1 (P = 0.01), I2 =86%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

217Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.41. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 41 Sensitivity

analysis for perinatal death (assuming total non-independence).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 41 Sensitivity analysis for perinatal death (assuming total non-independence)

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Combs 2010 10/84 1/38 9.7 % 4.52 [ 0.60, 34.09 ]

Combs 2011 0/160 2/78 4.7 % 0.10 [ 0.00, 2.02 ]

Hartikainen 1980 2/39 1/38 7.4 % 1.95 [ 0.18, 20.61 ]

Lim 2011 12/340 17/337 40.9 % 0.70 [ 0.34, 1.44 ]

Subtotal (95% CI) 623 491 62.7 % 0.99 [ 0.29, 3.36 ]

Total events: 24 (Progesterone), 21 (Placebo)

Heterogeneity: Tau2 = 0.68; Chi2 = 5.39, df = 3 (P = 0.15); I2 =44%

Test for overall effect: Z = 0.01 (P = 0.99)

2 Vaginal

Aboulghar 2012 2/49 3/42 12.6 % 0.57 [ 0.10, 3.26 ]

Rode 2011 5/332 4/339 19.8 % 1.28 [ 0.35, 4.71 ]

Serra 2013 0/97 3/95 4.9 % 0.14 [ 0.01, 2.67 ]

Subtotal (95% CI) 478 476 37.3 % 0.77 [ 0.28, 2.07 ]

Total events: 7 (Progesterone), 10 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 2.02, df = 2 (P = 0.36); I2 =1%

Test for overall effect: Z = 0.52 (P = 0.60)

Total (95% CI) 1101 967 100.0 % 0.84 [ 0.43, 1.65 ]

Total events: 31 (Progesterone), 31 (Placebo)

Heterogeneity: Tau2 = 0.15; Chi2 = 7.33, df = 6 (P = 0.29); I2 =18%

Test for overall effect: Z = 0.51 (P = 0.61)

Test for subgroup differences: Chi2 = 0.10, df = 1 (P = 0.75), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

218Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 6.42. Comparison 6 Progesterone versus placebo: multiple pregnancy, Outcome 42 Sensitivity

analysis for perinatal death (assuming 1% non-independence).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 6 Progesterone versus placebo: multiple pregnancy

Outcome: 42 Sensitivity analysis for perinatal death (assuming 1% non-independence)

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Combs 2010 18/166 2/74 14.2 % 4.01 [ 0.96, 16.85 ]

Combs 2011 0/316 3/154 5.1 % 0.07 [ 0.00, 1.34 ]

Hartikainen 1980 4/77 2/75 12.0 % 1.95 [ 0.37, 10.32 ]

Lim 2011 22/674 34/667 26.9 % 0.64 [ 0.38, 1.08 ]

Subtotal (95% CI) 1233 970 58.3 % 1.03 [ 0.29, 3.58 ]

Total events: 44 (Progesterone), 41 (Placebo)

Heterogeneity: Tau2 = 1.00; Chi2 = 9.31, df = 3 (P = 0.03); I2 =68%

Test for overall effect: Z = 0.04 (P = 0.97)

2 Vaginal

Aboulghar 2012 4/97 5/83 16.0 % 0.68 [ 0.19, 2.47 ]

Rode 2011 10/657 7/671 20.4 % 1.46 [ 0.56, 3.81 ]

Serra 2013 0/192 5/188 5.4 % 0.09 [ 0.00, 1.60 ]

Subtotal (95% CI) 946 942 41.7 % 0.75 [ 0.24, 2.41 ]

Total events: 14 (Progesterone), 17 (Placebo)

Heterogeneity: Tau2 = 0.49; Chi2 = 3.78, df = 2 (P = 0.15); I2 =47%

Test for overall effect: Z = 0.48 (P = 0.63)

Total (95% CI) 2179 1912 100.0 % 0.91 [ 0.44, 1.90 ]

Total events: 58 (Progesterone), 58 (Placebo)

Heterogeneity: Tau2 = 0.45; Chi2 = 12.97, df = 6 (P = 0.04); I2 =54%

Test for overall effect: Z = 0.25 (P = 0.80)

Test for subgroup differences: Chi2 = 0.13, df = 1 (P = 0.72), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

219Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 7.1. Comparison 7 Progesterone versus placebo: multiple pregnancy, by timing of commencement

(< 20 wk v > 20 wk), Outcome 1 Preterm birth < 37 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 7 Progesterone versus placebo: multiple pregnancy, by timing of commencement (< 20 wk v > 20 wk)

Outcome: 1 Preterm birth < 37 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Supplementation commenced prior to 20 weeks’ gestation

Lim 2011 186/336 165/332 35.9 % 1.11 [ 0.96, 1.29 ]

Rouse 2007 226/325 232/330 40.1 % 0.99 [ 0.89, 1.09 ]

Subtotal (95% CI) 661 662 76.0 % 1.04 [ 0.92, 1.17 ]

Total events: 412 (Progesterone), 397 (Placebo)

Heterogeneity: Tau2 = 0.00; Chi2 = 1.84, df = 1 (P = 0.18); I2 =46%

Test for overall effect: Z = 0.62 (P = 0.53)

2 Supplementation commenced after 20 weeks’ gestation

Cetingoz 2011 20/39 22/28 17.4 % 0.65 [ 0.45, 0.94 ]

Hartikainen 1980 15/39 9/38 6.6 % 1.62 [ 0.81, 3.25 ]

Subtotal (95% CI) 78 66 24.0 % 0.98 [ 0.38, 2.54 ]

Total events: 35 (Progesterone), 31 (Placebo)

Heterogeneity: Tau2 = 0.39; Chi2 = 5.88, df = 1 (P = 0.02); I2 =83%

Test for overall effect: Z = 0.03 (P = 0.97)

Total (95% CI) 739 728 100.0 % 0.99 [ 0.82, 1.20 ]

Total events: 447 (Progesterone), 428 (Placebo)

Heterogeneity: Tau2 = 0.02; Chi2 = 9.51, df = 3 (P = 0.02); I2 =68%

Test for overall effect: Z = 0.08 (P = 0.93)

Test for subgroup differences: Chi2 = 0.01, df = 1 (P = 0.91), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

220Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 7.2. Comparison 7 Progesterone versus placebo: multiple pregnancy, by timing of commencement

(< 20 wk v > 20 wk), Outcome 2 Neonatal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 7 Progesterone versus placebo: multiple pregnancy, by timing of commencement (< 20 wk v > 20 wk)

Outcome: 2 Neonatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Supplementation commenced prior to 20 weeks’ gestation

Caritis 2009 5/212 2/183 15.8 % 2.16 [ 0.42, 10.99 ]

Lim 2011 13/681 21/674 52.8 % 0.61 [ 0.31, 1.21 ]

Subtotal (95% CI) 893 857 68.6 % 0.92 [ 0.29, 2.91 ]

Total events: 18 (Progesterone), 23 (Placebo)

Heterogeneity: Tau2 = 0.39; Chi2 = 1.96, df = 1 (P = 0.16); I2 =49%

Test for overall effect: Z = 0.15 (P = 0.88)

2 Supplementation commenced after 20 weeks’ gestation

Norman 2009 8/494 6/494 31.4 % 1.33 [ 0.47, 3.81 ]

Subtotal (95% CI) 494 494 31.4 % 1.33 [ 0.47, 3.81 ]

Total events: 8 (Progesterone), 6 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.54 (P = 0.59)

Total (95% CI) 1387 1351 100.0 % 0.95 [ 0.47, 1.93 ]

Total events: 26 (Progesterone), 29 (Placebo)

Heterogeneity: Tau2 = 0.12; Chi2 = 2.84, df = 2 (P = 0.24); I2 =30%

Test for overall effect: Z = 0.13 (P = 0.90)

Test for subgroup differences: Chi2 = 0.22, df = 1 (P = 0.64), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

221Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 7.3. Comparison 7 Progesterone versus placebo: multiple pregnancy, by timing of commencement

(< 20 wk v > 20 wk), Outcome 3 Admission to NICU.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 7 Progesterone versus placebo: multiple pregnancy, by timing of commencement (< 20 wk v > 20 wk)

Outcome: 3 Admission to NICU

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Supplementation commenced prior to 20 weeks’ gestation

Norman 2009 167/494 158/494 54.4 % 1.06 [ 0.88, 1.26 ]

Subtotal (95% CI) 494 494 54.4 % 1.06 [ 0.88, 1.26 ]

Total events: 167 (Progesterone), 158 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.61 (P = 0.54)

2 Supplementation commenced after 20 weeks’ gestation

Lim 2011 153/681 116/674 45.6 % 1.31 [ 1.05, 1.62 ]

Subtotal (95% CI) 681 674 45.6 % 1.31 [ 1.05, 1.62 ]

Total events: 153 (Progesterone), 116 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.41 (P = 0.016)

Total (95% CI) 1175 1168 100.0 % 1.16 [ 0.95, 1.43 ]

Total events: 320 (Progesterone), 274 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 2.20, df = 1 (P = 0.14); I2 =54%

Test for overall effect: Z = 1.44 (P = 0.15)

Test for subgroup differences: Chi2 = 2.18, df = 1 (P = 0.14), I2 =54%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

222Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 8.1. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (<

500 mg v >= 500 mg), Outcome 1 Perinatal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome: 1 Perinatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Combs 2010 19/168 2/75 14.3 % 4.24 [ 1.01, 17.75 ]

Combs 2011 0/320 3/156 5.1 % 0.07 [ 0.00, 1.34 ]

Hartikainen 1980 4/78 2/76 11.9 % 1.95 [ 0.37, 10.33 ]

Lim 2011 23/681 34/674 27.0 % 0.67 [ 0.40, 1.12 ]

Subtotal (95% CI) 1247 981 58.3 % 1.06 [ 0.30, 3.71 ]

Total events: 46 (Progesterone), 41 (Placebo)

Heterogeneity: Tau2 = 1.02; Chi2 = 9.42, df = 3 (P = 0.02); I2 =68%

Test for overall effect: Z = 0.09 (P = 0.93)

2 Dose >= 500 mg per week

Aboulghar 2012 4/98 5/84 16.0 % 0.69 [ 0.19, 2.47 ]

Rode 2011 10/664 7/678 20.3 % 1.46 [ 0.56, 3.81 ]

Serra 2013 0/194 5/190 5.3 % 0.09 [ 0.00, 1.60 ]

Subtotal (95% CI) 956 952 41.7 % 0.75 [ 0.24, 2.41 ]

Total events: 14 (Progesterone), 17 (Placebo)

Heterogeneity: Tau2 = 0.49; Chi2 = 3.78, df = 2 (P = 0.15); I2 =47%

Test for overall effect: Z = 0.48 (P = 0.63)

Total (95% CI) 2203 1933 100.0 % 0.93 [ 0.45, 1.94 ]

Total events: 60 (Progesterone), 58 (Placebo)

Heterogeneity: Tau2 = 0.45; Chi2 = 13.01, df = 6 (P = 0.04); I2 =54%

Test for overall effect: Z = 0.19 (P = 0.85)

Test for subgroup differences: Chi2 = 0.15, df = 1 (P = 0.70), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

223Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 8.2. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (<

500 mg v >= 500 mg), Outcome 2 Preterm birth less than 34 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome: 2 Preterm birth less than 34 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Combs 2011 31/160 11/78 13.8 % 1.37 [ 0.73, 2.59 ]

Subtotal (95% CI) 160 78 13.8 % 1.37 [ 0.73, 2.59 ]

Total events: 31 (Progesterone), 11 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.98 (P = 0.32)

2 Dose > 500 mg per week

Aboulghar 2012 8/49 10/42 8.7 % 0.69 [ 0.30, 1.58 ]

Cetingoz 2011 4/39 7/28 5.1 % 0.41 [ 0.13, 1.27 ]

Norman 2009 55/247 44/247 29.7 % 1.25 [ 0.88, 1.78 ]

Rode 2011 51/334 63/341 31.4 % 0.83 [ 0.59, 1.16 ]

Serra 2013 13/97 13/96 11.3 % 0.99 [ 0.48, 2.02 ]

Subtotal (95% CI) 766 754 86.2 % 0.92 [ 0.69, 1.23 ]

Total events: 131 (Progesterone), 137 (Placebo)

Heterogeneity: Tau2 = 0.03; Chi2 = 5.68, df = 4 (P = 0.22); I2 =30%

Test for overall effect: Z = 0.59 (P = 0.56)

Total (95% CI) 926 832 100.0 % 0.97 [ 0.74, 1.27 ]

Total events: 162 (Progesterone), 148 (Placebo)

Heterogeneity: Tau2 = 0.03; Chi2 = 6.88, df = 5 (P = 0.23); I2 =27%

Test for overall effect: Z = 0.22 (P = 0.83)

Test for subgroup differences: Chi2 = 1.30, df = 1 (P = 0.25), I2 =23%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

224Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 8.3. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (<

500 mg v >= 500 mg), Outcome 3 Antenatal tocolysis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome: 3 Antenatal tocolysis

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Caritis 2009 33/71 28/63 12.8 % 1.05 [ 0.72, 1.52 ]

Combs 2010 44/56 17/25 16.8 % 1.16 [ 0.85, 1.56 ]

Combs 2011 62/160 32/78 15.1 % 0.94 [ 0.68, 1.31 ]

Lim 2011 73/336 64/332 17.0 % 1.13 [ 0.84, 1.52 ]

Rouse 2007 71/324 97/330 19.5 % 0.75 [ 0.57, 0.97 ]

Subtotal (95% CI) 947 828 81.2 % 0.98 [ 0.82, 1.17 ]

Total events: 283 (Progesterone), 238 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 6.38, df = 4 (P = 0.17); I2 =37%

Test for overall effect: Z = 0.22 (P = 0.83)

2 Dose >= 500 mg per week

Rode 2011 41/333 60/341 13.1 % 0.70 [ 0.48, 1.01 ]

Serra 2013 16/97 17/96 5.7 % 0.93 [ 0.50, 1.73 ]

Subtotal (95% CI) 430 437 18.8 % 0.75 [ 0.55, 1.03 ]

Total events: 57 (Progesterone), 77 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.60, df = 1 (P = 0.44); I2 =0.0%

Test for overall effect: Z = 1.75 (P = 0.079)

Total (95% CI) 1377 1265 100.0 % 0.94 [ 0.80, 1.10 ]

Total events: 340 (Progesterone), 315 (Placebo)

Heterogeneity: Tau2 = 0.02; Chi2 = 9.23, df = 6 (P = 0.16); I2 =35%

Test for overall effect: Z = 0.81 (P = 0.42)

Test for subgroup differences: Chi2 = 2.04, df = 1 (P = 0.15), I2 =51%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

225Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 8.4. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (<

500 mg v >= 500 mg), Outcome 4 Preterm birth less than 37 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome: 4 Preterm birth less than 37 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Cetingoz 2011 20/39 22/28 5.5 % 0.65 [ 0.45, 0.94 ]

Combs 2011 113/160 46/78 10.9 % 1.20 [ 0.97, 1.48 ]

Hartikainen 1980 15/39 9/38 1.8 % 1.62 [ 0.81, 3.25 ]

Lim 2011 186/336 165/332 14.8 % 1.11 [ 0.96, 1.29 ]

Rode 2011 158/334 179/341 14.3 % 0.90 [ 0.77, 1.05 ]

Rouse 2007 226/325 232/330 17.7 % 0.99 [ 0.89, 1.09 ]

Subtotal (95% CI) 1233 1147 64.9 % 1.01 [ 0.88, 1.15 ]

Total events: 718 (Progesterone), 653 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 14.01, df = 5 (P = 0.02); I2 =64%

Test for overall effect: Z = 0.08 (P = 0.93)

2 Dose >= 500 mg per week

Aboulghar 2012 31/49 28/42 7.1 % 0.95 [ 0.70, 1.28 ]

Cetingoz 2011 32/80 40/70 6.1 % 0.70 [ 0.50, 0.98 ]

Rode 2011 158/334 179/341 14.3 % 0.90 [ 0.77, 1.05 ]

Serra 2013 48/97 47/96 7.6 % 1.01 [ 0.76, 1.35 ]

Subtotal (95% CI) 560 549 35.1 % 0.90 [ 0.80, 1.01 ]

Total events: 269 (Progesterone), 294 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 2.89, df = 3 (P = 0.41); I2 =0.0%

Test for overall effect: Z = 1.83 (P = 0.067)

Total (95% CI) 1793 1696 100.0 % 0.97 [ 0.88, 1.06 ]

Total events: 987 (Progesterone), 947 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 19.68, df = 9 (P = 0.02); I2 =54%

Test for overall effect: Z = 0.71 (P = 0.48)

Test for subgroup differences: Chi2 = 1.60, df = 1 (P = 0.21), I2 =38%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

226Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 8.5. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (<

500 mg v >= 500 mg), Outcome 5 Infant birthweight less than 2500 g.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome: 5 Infant birthweight less than 2500 g

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Caritis 2009 191/212 175/183 20.6 % 0.94 [ 0.89, 0.99 ]

Combs 2011 195/320 70/156 9.4 % 1.36 [ 1.12, 1.65 ]

Lim 2011 363/681 355/674 16.6 % 1.01 [ 0.92, 1.12 ]

Rouse 2007 377/628 415/648 17.9 % 0.94 [ 0.86, 1.02 ]

Subtotal (95% CI) 1841 1661 64.6 % 1.02 [ 0.91, 1.14 ]

Total events: 1126 (Progesterone), 1015 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 16.56, df = 3 (P = 0.00087); I2 =82%

Test for overall effect: Z = 0.30 (P = 0.76)

2 Dose >= 500 mg per week

Aboulghar 2012 58/98 62/84 8.7 % 0.80 [ 0.65, 0.99 ]

Rode 2011 306/659 357/677 15.9 % 0.88 [ 0.79, 0.98 ]

Serra 2013 104/194 117/190 10.8 % 0.87 [ 0.73, 1.03 ]

Subtotal (95% CI) 951 951 35.4 % 0.86 [ 0.80, 0.94 ]

Total events: 468 (Progesterone), 536 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.63, df = 2 (P = 0.73); I2 =0.0%

Test for overall effect: Z = 3.38 (P = 0.00071)

Total (95% CI) 2792 2612 100.0 % 0.95 [ 0.88, 1.03 ]

Total events: 1594 (Progesterone), 1551 (Placebo)

Heterogeneity: Tau2 = 0.01; Chi2 = 20.29, df = 6 (P = 0.002); I2 =70%

Test for overall effect: Z = 1.19 (P = 0.23)

Test for subgroup differences: Chi2 = 5.22, df = 1 (P = 0.02), I2 =81%

0.5 0.7 1 1.5 2

Favours progesterone Favours placebo

227Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 8.6. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (<

500 mg v >= 500 mg), Outcome 6 Respiratory distress syndrome.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome: 6 Respiratory distress syndrome

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Caritis 2009 65/212 50/183 18.6 % 1.12 [ 0.82, 1.53 ]

Combs 2010 44/155 28/75 14.3 % 0.76 [ 0.52, 1.12 ]

Combs 2011 44/319 18/153 9.4 % 1.17 [ 0.70, 1.96 ]

Lim 2011 82/681 51/674 17.2 % 1.59 [ 1.14, 2.22 ]

Rouse 2007 96/632 87/648 21.8 % 1.13 [ 0.86, 1.48 ]

Subtotal (95% CI) 1999 1733 81.4 % 1.13 [ 0.91, 1.42 ]

Total events: 331 (Progesterone), 234 (Placebo)

Heterogeneity: Tau2 = 0.03; Chi2 = 8.22, df = 4 (P = 0.08); I2 =51%

Test for overall effect: Z = 1.10 (P = 0.27)

2 Dose >= 500 mg per week

Rode 2011 73/659 69/674 18.6 % 1.08 [ 0.79, 1.48 ]

Subtotal (95% CI) 659 674 18.6 % 1.08 [ 0.79, 1.48 ]

Total events: 73 (Progesterone), 69 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.50 (P = 0.62)

Total (95% CI) 2658 2407 100.0 % 1.13 [ 0.94, 1.35 ]

Total events: 404 (Progesterone), 303 (Placebo)

Heterogeneity: Tau2 = 0.02; Chi2 = 8.29, df = 5 (P = 0.14); I2 =40%

Test for overall effect: Z = 1.30 (P = 0.19)

Test for subgroup differences: Chi2 = 0.06, df = 1 (P = 0.81), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

228Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 8.7. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (<

500 mg v >= 500 mg), Outcome 7 Fetal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome: 7 Fetal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Combs 2010 13/168 0/75 6.4 % 12.14 [ 0.73, 201.61 ]

Combs 2011 0/320 0/156 Not estimable

Lim 2011 13/681 13/674 43.8 % 0.99 [ 0.46, 2.12 ]

Subtotal (95% CI) 1169 905 50.1 % 2.52 [ 0.19, 33.68 ]

Total events: 26 (Progesterone), 13 (Placebo)

Heterogeneity: Tau2 = 2.64; Chi2 = 3.39, df = 1 (P = 0.07); I2 =71%

Test for overall effect: Z = 0.70 (P = 0.48)

2 Dose >= 500 mg per week

Norman 2009 6/494 4/494 24.2 % 1.50 [ 0.43, 5.28 ]

Rode 2011 3/664 5/678 20.2 % 0.61 [ 0.15, 2.55 ]

Serra 2013 0/194 2/190 5.5 % 0.20 [ 0.01, 4.05 ]

Subtotal (95% CI) 1352 1362 49.9 % 0.88 [ 0.36, 2.16 ]

Total events: 9 (Progesterone), 11 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 1.89, df = 2 (P = 0.39); I2 =0.0%

Test for overall effect: Z = 0.29 (P = 0.77)

Total (95% CI) 2521 2267 100.0 % 1.07 [ 0.51, 2.23 ]

Total events: 35 (Progesterone), 24 (Placebo)

Heterogeneity: Tau2 = 0.17; Chi2 = 5.26, df = 4 (P = 0.26); I2 =24%

Test for overall effect: Z = 0.17 (P = 0.87)

Test for subgroup differences: Chi2 = 0.57, df = 1 (P = 0.45), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

229Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 8.8. Comparison 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (<

500 mg v >= 500 mg), Outcome 8 Admission to NICU.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 8 Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome: 8 Admission to NICU

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose < 500 mg per week

Lim 2011 153/681 116/674 24.3 % 1.31 [ 1.05, 1.62 ]

Subtotal (95% CI) 681 674 24.3 % 1.31 [ 1.05, 1.62 ]

Total events: 153 (Progesterone), 116 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.41 (P = 0.016)

2 Dose >= 500 mg per week

Aboulghar 2012 12/98 22/84 8.7 % 0.47 [ 0.25, 0.89 ]

Norman 2009 167/494 158/494 26.3 % 1.06 [ 0.88, 1.26 ]

Rode 2011 307/664 354/678 29.4 % 0.89 [ 0.79, 0.99 ]

Serra 2013 21/194 28/190 11.3 % 0.73 [ 0.43, 1.25 ]

Subtotal (95% CI) 1450 1446 75.7 % 0.87 [ 0.71, 1.07 ]

Total events: 507 (Progesterone), 562 (Placebo)

Heterogeneity: Tau2 = 0.02; Chi2 = 7.74, df = 3 (P = 0.05); I2 =61%

Test for overall effect: Z = 1.27 (P = 0.20)

Total (95% CI) 2131 2120 100.0 % 0.94 [ 0.76, 1.18 ]

Total events: 660 (Progesterone), 678 (Placebo)

Heterogeneity: Tau2 = 0.04; Chi2 = 16.95, df = 4 (P = 0.002); I2 =76%

Test for overall effect: Z = 0.51 (P = 0.61)

Test for subgroup differences: Chi2 = 6.89, df = 1 (P = 0.01), I2 =85%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

230Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.1. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 1 Perinatal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 1 Perinatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Combs 2011a 1/4 1/8 100.0 % 2.00 [ 0.16, 24.33 ]

Total (95% CI) 4 8 100.0 % 2.00 [ 0.16, 24.33 ]

Total events: 1 (Progesterone), 1 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.54 (P = 0.59)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

231Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.2. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 2 Preterm birth less than 34 weeks’ gestation.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 2 Preterm birth less than 34 weeks’ gestation

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Combs 2011a 4/4 8/8 40.7 % 1.00 [ 0.72, 1.39 ]

Subtotal (95% CI) 4 8 40.7 % 1.00 [ 0.72, 1.39 ]

Total events: 4 (Progesterone), 8 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.0 (P = 1.0)

2 Vaginal

Sharami 2010 8/80 9/83 59.3 % 0.92 [ 0.37, 2.27 ]

Subtotal (95% CI) 80 83 59.3 % 0.92 [ 0.37, 2.27 ]

Total events: 8 (Progesterone), 9 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.18 (P = 0.86)

Total (95% CI) 84 91 100.0 % 0.95 [ 0.55, 1.65 ]

Total events: 12 (Progesterone), 17 (Placebo)

Heterogeneity: Chi2 = 0.08, df = 1 (P = 0.77); I2 =0.0%

Test for overall effect: Z = 0.17 (P = 0.87)

Test for subgroup differences: Chi2 = 0.03, df = 1 (P = 0.87), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

232Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.3. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 3 Pregnancy prolongation (days).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 3 Pregnancy prolongation (days)

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 Intramuscular

Briery 2011 33 11.2 (7.3) 36 14.5 (10) 50.8 % -3.30 [ -7.41, 0.81 ]

Subtotal (95% CI) 33 36 50.8 % -3.30 [ -7.41, 0.81 ]

Heterogeneity: not applicable

Test for overall effect: Z = 1.57 (P = 0.12)

2 Vaginal

Sharami 2010 80 23.88 (18.01) 83 16.67 (12.9) 49.2 % 7.21 [ 2.39, 12.03 ]

Subtotal (95% CI) 80 83 49.2 % 7.21 [ 2.39, 12.03 ]

Heterogeneity: not applicable

Test for overall effect: Z = 2.93 (P = 0.0034)

Total (95% CI) 113 119 100.0 % 1.88 [ -8.42, 12.17 ]

Heterogeneity: Tau2 = 50.00; Chi2 = 10.57, df = 1 (P = 0.001); I2 =91%

Test for overall effect: Z = 0.36 (P = 0.72)

Test for subgroup differences: Chi2 = 10.57, df = 1 (P = 0.00), I2 =91%

-100 -50 0 50 100

Favours placebo Favours progesterone

233Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.4. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 4 Pregnancy prolongation - less than 1 week.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 4 Pregnancy prolongation - less than 1 week

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Combs 2011a 1/4 5/8 100.0 % 0.40 [ 0.07, 2.37 ]

Total (95% CI) 4 8 100.0 % 0.40 [ 0.07, 2.37 ]

Total events: 1 (Progesterone), 5 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.01 (P = 0.31)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours placebo Favours progesterone

Analysis 9.5. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 5 Pregnancy prolongation - 1.0 to 1.9 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 5 Pregnancy prolongation - 1.0 to 1.9 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Combs 2011a 1/4 1/8 100.0 % 2.00 [ 0.16, 24.33 ]

Total (95% CI) 4 8 100.0 % 2.00 [ 0.16, 24.33 ]

Total events: 1 (Progesterone), 1 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.54 (P = 0.59)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours placebo Favours progesterone

234Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.6. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 6 Pregnancy prolongation - 2 weeks or more.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 6 Pregnancy prolongation - 2 weeks or more

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Combs 2011a 2/4 2/8 100.0 % 2.00 [ 0.42, 9.42 ]

Total (95% CI) 4 8 100.0 % 2.00 [ 0.42, 9.42 ]

Total events: 2 (Progesterone), 2 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.88 (P = 0.38)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours placebo Favours progesterone

235Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.7. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 7 Spontaneous birth.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 7 Spontaneous birth

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Briery 2011 24/33 24/36 100.0 % 1.09 [ 0.80, 1.49 ]

Total (95% CI) 33 36 100.0 % 1.09 [ 0.80, 1.49 ]

Total events: 24 (Progesterone), 24 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.55 (P = 0.58)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours placebo Favours progesterone

Analysis 9.8. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 8 Caesarean section.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 8 Caesarean section

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Briery 2011 9/33 12/36 77.5 % 0.82 [ 0.40, 1.69 ]

Combs 2011a 3/4 5/8 22.5 % 1.20 [ 0.55, 2.62 ]

Total (95% CI) 37 44 100.0 % 0.90 [ 0.51, 1.60 ]

Total events: 12 (Progesterone), 17 (Placebo)

Heterogeneity: Chi2 = 0.58, df = 1 (P = 0.45); I2 =0.0%

Test for overall effect: Z = 0.35 (P = 0.73)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

236Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.9. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 9 Use of tocolysis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 9 Use of tocolysis

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Combs 2011a 3/4 5/8 16.3 % 1.20 [ 0.55, 2.62 ]

Subtotal (95% CI) 4 8 16.3 % 1.20 [ 0.55, 2.62 ]

Total events: 3 (Progesterone), 5 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.46 (P = 0.65)

2 Vaginal

Sharami 2010 16/97 17/96 83.7 % 0.93 [ 0.50, 1.73 ]

Subtotal (95% CI) 97 96 83.7 % 0.93 [ 0.50, 1.73 ]

Total events: 16 (Progesterone), 17 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.22 (P = 0.82)

Total (95% CI) 101 104 100.0 % 0.98 [ 0.58, 1.65 ]

Total events: 19 (Progesterone), 22 (Placebo)

Heterogeneity: Chi2 = 0.29, df = 1 (P = 0.59); I2 =0.0%

Test for overall effect: Z = 0.09 (P = 0.93)

Test for subgroup differences: Chi2 = 0.25, df = 1 (P = 0.62), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

237Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.10. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 10 Preterm birth less than 37 weeks’ gestation.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 10 Preterm birth less than 37 weeks’ gestation

Study or subgroup Progesterone No Treatment Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Vaginal

Sharami 2010 33/80 45/83 58.7 % 0.76 [ 0.55, 1.06 ]

Subtotal (95% CI) 80 83 58.7 % 0.76 [ 0.55, 1.06 ]

Total events: 33 (Progesterone), 45 (No Treatment)

Heterogeneity: not applicable

Test for overall effect: Z = 1.63 (P = 0.10)

2 Intramuscular

Facchinetti 2007 5/30 17/30 41.3 % 0.29 [ 0.12, 0.69 ]

Subtotal (95% CI) 30 30 41.3 % 0.29 [ 0.12, 0.69 ]

Total events: 5 (Progesterone), 17 (No Treatment)

Heterogeneity: not applicable

Test for overall effect: Z = 2.79 (P = 0.0052)

Total (95% CI) 110 113 100.0 % 0.51 [ 0.20, 1.31 ]

Total events: 38 (Progesterone), 62 (No Treatment)

Heterogeneity: Tau2 = 0.36; Chi2 = 4.28, df = 1 (P = 0.04); I2 =77%

Test for overall effect: Z = 1.39 (P = 0.16)

Test for subgroup differences: Chi2 = 4.10, df = 1 (P = 0.04), I2 =76%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

238Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.11. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 11 Infant birthweight less than 2500 g.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 11 Infant birthweight less than 2500 g

Study or subgroup Progesterone No treatment Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Borna 2008 10/37 17/33 100.0 % 0.52 [ 0.28, 0.98 ]

Total (95% CI) 37 33 100.0 % 0.52 [ 0.28, 0.98 ]

Total events: 10 (Progesterone), 17 (No treatment)

Heterogeneity: not applicable

Test for overall effect: Z = 2.02 (P = 0.043)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

239Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.12. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 12 Respiratory distress syndrome.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 12 Respiratory distress syndrome

Study or subgroup Progesterone No treatment Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Vaginal

Borna 2008 4/37 12/33 12.2 % 0.30 [ 0.11, 0.83 ]

Sharami 2010 7/80 10/83 14.7 % 0.73 [ 0.29, 1.81 ]

Subtotal (95% CI) 117 116 26.9 % 0.48 [ 0.20, 1.15 ]

Total events: 11 (Progesterone), 22 (No treatment)

Heterogeneity: Tau2 = 0.15; Chi2 = 1.61, df = 1 (P = 0.20); I2 =38%

Test for overall effect: Z = 1.65 (P = 0.099)

2 Intramuscular

Briery 2011 22/33 28/36 48.0 % 0.86 [ 0.64, 1.15 ]

Combs 2011a 3/4 7/8 25.2 % 0.86 [ 0.46, 1.60 ]

Subtotal (95% CI) 37 44 73.1 % 0.86 [ 0.66, 1.12 ]

Total events: 25 (Progesterone), 35 (No treatment)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.00, df = 1 (P = 1.00); I2 =0.0%

Test for overall effect: Z = 1.12 (P = 0.26)

Total (95% CI) 154 160 100.0 % 0.74 [ 0.49, 1.10 ]

Total events: 36 (Progesterone), 57 (No treatment)

Heterogeneity: Tau2 = 0.06; Chi2 = 4.81, df = 3 (P = 0.19); I2 =38%

Test for overall effect: Z = 1.51 (P = 0.13)

Test for subgroup differences: Chi2 = 1.55, df = 1 (P = 0.21), I2 =35%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

240Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.13. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 13 Intraventricular haemorrhage grade III or IV.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 13 Intraventricular haemorrhage grade III or IV

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Combs 2011a 2/4 0/8 100.0 % 9.00 [ 0.53, 152.93 ]

Total (95% CI) 4 8 100.0 % 9.00 [ 0.53, 152.93 ]

Total events: 2 (Progesterone), 0 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.52 (P = 0.13)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

Analysis 9.14. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 14 Periventricular leucomalacia.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 14 Periventricular leucomalacia

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Combs 2011a 0/4 0/8 Not estimable

Total (95% CI) 4 8 Not estimable

Total events: 0 (Progesterone), 0 (Placebo)

Heterogeneity: not applicable

Test for overall effect: not applicable

Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

241Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.15. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 15 Use of assisted ventilation.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 15 Use of assisted ventilation

Study or subgroup Progesterone No treatment Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Borna 2008 2/37 6/33 100.0 % 0.30 [ 0.06, 1.37 ]

Total (95% CI) 37 33 100.0 % 0.30 [ 0.06, 1.37 ]

Total events: 2 (Progesterone), 6 (No treatment)

Heterogeneity: not applicable

Test for overall effect: Z = 1.55 (P = 0.12)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

242Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.16. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 16 Necrotizing enterocolitis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 16 Necrotizing enterocolitis

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Briery 2011 2/33 1/36 72.8 % 2.18 [ 0.21, 22.96 ]

Combs 2011a 1/4 0/8 27.2 % 5.40 [ 0.27, 109.35 ]

Total (95% CI) 37 44 100.0 % 3.06 [ 0.50, 18.69 ]

Total events: 3 (Progesterone), 1 (Placebo)

Heterogeneity: Chi2 = 0.22, df = 1 (P = 0.64); I2 =0.0%

Test for overall effect: Z = 1.21 (P = 0.23)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

243Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.17. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 17 Neonatal sepsis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 17 Neonatal sepsis

Study or subgroup Progesterone No treatment Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Vaginal

Borna 2008 2/37 6/33 34.6 % 0.30 [ 0.06, 1.37 ]

Sharami 2010 0/80 3/83 12.8 % 0.15 [ 0.01, 2.82 ]

Subtotal (95% CI) 117 116 47.4 % 0.26 [ 0.07, 1.00 ]

Total events: 2 (Progesterone), 9 (No treatment)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.17, df = 1 (P = 0.68); I2 =0.0%

Test for overall effect: Z = 1.96 (P = 0.050)

2 Intramuscular

Briery 2011 6/33 6/36 52.6 % 1.09 [ 0.39, 3.05 ]

Combs 2011a 0/4 0/8 Not estimable

Subtotal (95% CI) 37 44 52.6 % 1.09 [ 0.39, 3.05 ]

Total events: 6 (Progesterone), 6 (No treatment)

Heterogeneity: not applicable

Test for overall effect: Z = 0.17 (P = 0.87)

Total (95% CI) 154 160 100.0 % 0.54 [ 0.17, 1.68 ]

Total events: 8 (Progesterone), 15 (No treatment)

Heterogeneity: Tau2 = 0.37; Chi2 = 3.06, df = 2 (P = 0.22); I2 =35%

Test for overall effect: Z = 1.07 (P = 0.29)

Test for subgroup differences: Chi2 = 2.78, df = 1 (P = 0.10), I2 =64%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

244Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.18. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 18 Fetal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 18 Fetal death

Study or subgroup Progesterone Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Briery 2011 1/33 1/36 100.0 % 1.09 [ 0.07, 16.75 ]

Combs 2011a 0/4 0/8 Not estimable

Total (95% CI) 37 44 100.0 % 1.09 [ 0.07, 16.75 ]

Total events: 1 (Progesterone), 1 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.06 (P = 0.95)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

245Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.19. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 19 Neonatal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 19 Neonatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Combs 2011a 1/4 1/8 46.2 % 2.00 [ 0.16, 24.33 ]

Subtotal (95% CI) 4 8 46.2 % 2.00 [ 0.16, 24.33 ]

Total events: 1 (Progesterone), 1 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.54 (P = 0.59)

2 Vaginal

Sharami 2010 1/80 6/83 53.8 % 0.17 [ 0.02, 1.40 ]

Subtotal (95% CI) 80 83 53.8 % 0.17 [ 0.02, 1.40 ]

Total events: 1 (Progesterone), 6 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.64 (P = 0.10)

Total (95% CI) 84 91 100.0 % 0.54 [ 0.05, 6.24 ]

Total events: 2 (Progesterone), 7 (Placebo)

Heterogeneity: Tau2 = 1.78; Chi2 = 2.28, df = 1 (P = 0.13); I2 =56%

Test for overall effect: Z = 0.50 (P = 0.62)

Test for subgroup differences: Chi2 = 2.17, df = 1 (P = 0.14), I2 =54%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

246Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.20. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 20 Neonatal length of hospital stay (days).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 20 Neonatal length of hospital stay (days)

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Intramuscular

Briery 2011 33 36.4 (31.3) 36 37 (30.3) 88.4 % -0.60 [ -15.16, 13.96 ]

Combs 2011a 4 42 (23) 8 56 (48) 11.6 % -14.00 [ -54.18, 26.18 ]

Total (95% CI) 37 44 100.0 % -2.16 [ -15.84, 11.53 ]

Heterogeneity: Chi2 = 0.38, df = 1 (P = 0.54); I2 =0.0%

Test for overall effect: Z = 0.31 (P = 0.76)

Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours progesterone Favours placebo

Analysis 9.21. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 21 Apgar score less than seven at five minutes.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 21 Apgar score less than seven at five minutes

Study or subgroup Progesterone Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Sharami 2010 1/80 4/83 100.0 % 0.26 [ 0.03, 2.27 ]

Total (95% CI) 80 83 100.0 % 0.26 [ 0.03, 2.27 ]

Total events: 1 (Progesterone), 4 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 1.22 (P = 0.22)

Test for subgroup differences: Not applicable

0.2 0.5 1 2 5

Favours progesterone Favours control

247Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.22. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 22 Prelabour spontaneous rupture of membranes.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 22 Prelabour spontaneous rupture of membranes

Study or subgroup Progesterone Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Sharami 2010 5/80 10/83 100.0 % 0.52 [ 0.19, 1.45 ]

Total (95% CI) 80 83 100.0 % 0.52 [ 0.19, 1.45 ]

Total events: 5 (Progesterone), 10 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 1.25 (P = 0.21)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours control

248Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.23. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 23 Preterm birth less than 28 weeks’ gestation.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 23 Preterm birth less than 28 weeks’ gestation

Study or subgroup Progesterone Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Sharami 2010 1/97 1/96 100.0 % 0.99 [ 0.06, 15.60 ]

Total (95% CI) 97 96 100.0 % 0.99 [ 0.06, 15.60 ]

Total events: 1 (Progesterone), 1 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.01 (P = 0.99)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours control

Analysis 9.24. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 24 Apgar score less than seven at five minutes.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 24 Apgar score less than seven at five minutes

Study or subgroup Progesterone Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Sharami 2010 1/80 4/83 100.0 % 0.26 [ 0.03, 2.27 ]

Total (95% CI) 80 83 100.0 % 0.26 [ 0.03, 2.27 ]

Total events: 1 (Progesterone), 4 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 1.22 (P = 0.22)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours control

249Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 9.25. Comparison 9 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, Outcome 25 Admission to neonatal intensive care unit.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 9 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome: 25 Admission to neonatal intensive care unit

Study or subgroup Progesterone Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Sharami 2010 3/80 2/83 100.0 % 1.56 [ 0.27, 9.07 ]

Total (95% CI) 80 83 100.0 % 1.56 [ 0.27, 9.07 ]

Total events: 3 (Progesterone), 2 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.49 (P = 0.62)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours control

250Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 10.1. Comparison 10 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, by cumulative weekly dose (< 500 mg v >= 500 mg), Outcome 1 Pregnancy prolongation (days).

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 10 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons, by cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome: 1 Pregnancy prolongation (days)

Study or subgroup Progesterone Placebo Mean

Difference Weight Mean

Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 Dose < 500 mg per week

Briery 2011 33 11.2 (7.3) 36 14.5 (10) 50.8 % -3.30 [ -7.41, 0.81 ]

Subtotal (95% CI) 33 36 50.8 % -3.30 [ -7.41, 0.81 ]

Heterogeneity: not applicable

Test for overall effect: Z = 1.57 (P = 0.12)

2 Dose >= 500 mg per week

Sharami 2010 80 23.88 (18.01) 83 16.67 (12.9) 49.2 % 7.21 [ 2.39, 12.03 ]

Subtotal (95% CI) 80 83 49.2 % 7.21 [ 2.39, 12.03 ]

Heterogeneity: not applicable

Test for overall effect: Z = 2.93 (P = 0.0034)

Total (95% CI) 113 119 100.0 % 1.88 [ -8.42, 12.17 ]

Heterogeneity: Tau2 = 50.00; Chi2 = 10.57, df = 1 (P = 0.001); I2 =91%

Test for overall effect: Z = 0.36 (P = 0.72)

Test for subgroup differences: Chi2 = 10.57, df = 1 (P = 0.00), I2 =91%

-100 -50 0 50 100

Favours placebo Favours progesterone

251Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 10.2. Comparison 10 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, by cumulative weekly dose (< 500 mg v >= 500 mg), Outcome 2 Preterm birth less than 37 weeks’

gestation.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 10 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons, by cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome: 2 Preterm birth less than 37 weeks’ gestation

Study or subgroup Progesterone No Treatment Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose >=500 mg per week

Sharami 2010 33/80 45/83 58.7 % 0.76 [ 0.55, 1.06 ]

Subtotal (95% CI) 80 83 58.7 % 0.76 [ 0.55, 1.06 ]

Total events: 33 (Progesterone), 45 (No Treatment)

Heterogeneity: not applicable

Test for overall effect: Z = 1.63 (P = 0.10)

2 Dose <500 mg per week

Facchinetti 2007 5/30 17/30 41.3 % 0.29 [ 0.12, 0.69 ]

Subtotal (95% CI) 30 30 41.3 % 0.29 [ 0.12, 0.69 ]

Total events: 5 (Progesterone), 17 (No Treatment)

Heterogeneity: not applicable

Test for overall effect: Z = 2.79 (P = 0.0052)

Total (95% CI) 110 113 100.0 % 0.51 [ 0.20, 1.31 ]

Total events: 38 (Progesterone), 62 (No Treatment)

Heterogeneity: Tau2 = 0.36; Chi2 = 4.28, df = 1 (P = 0.04); I2 =77%

Test for overall effect: Z = 1.39 (P = 0.16)

Test for subgroup differences: Chi2 = 4.10, df = 1 (P = 0.04), I2 =76%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

252Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 10.3. Comparison 10 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, by cumulative weekly dose (< 500 mg v >= 500 mg), Outcome 3 Respiratory distress syndrome.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 10 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons, by cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome: 3 Respiratory distress syndrome

Study or subgroup Progesterone No treatment Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose >=500 mg per week

Borna 2008 4/37 12/33 12.2 % 0.30 [ 0.11, 0.83 ]

Sharami 2010 7/80 10/83 14.7 % 0.73 [ 0.29, 1.81 ]

Subtotal (95% CI) 117 116 26.9 % 0.48 [ 0.20, 1.15 ]

Total events: 11 (Progesterone), 22 (No treatment)

Heterogeneity: Tau2 = 0.15; Chi2 = 1.61, df = 1 (P = 0.20); I2 =38%

Test for overall effect: Z = 1.65 (P = 0.099)

2 Dose <500 mg per week

Briery 2011 22/33 28/36 48.0 % 0.86 [ 0.64, 1.15 ]

Combs 2011a 3/4 7/8 25.2 % 0.86 [ 0.46, 1.60 ]

Subtotal (95% CI) 37 44 73.1 % 0.86 [ 0.66, 1.12 ]

Total events: 25 (Progesterone), 35 (No treatment)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.00, df = 1 (P = 1.00); I2 =0.0%

Test for overall effect: Z = 1.12 (P = 0.26)

Total (95% CI) 154 160 100.0 % 0.74 [ 0.49, 1.10 ]

Total events: 36 (Progesterone), 57 (No treatment)

Heterogeneity: Tau2 = 0.06; Chi2 = 4.81, df = 3 (P = 0.19); I2 =38%

Test for overall effect: Z = 1.51 (P = 0.13)

Test for subgroup differences: Chi2 = 1.55, df = 1 (P = 0.21), I2 =35%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

253Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 10.4. Comparison 10 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, by cumulative weekly dose (< 500 mg v >= 500 mg), Outcome 4 Neonatal sepsis.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 10 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons, by cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome: 4 Neonatal sepsis

Study or subgroup Progesterone No treatment Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose >=500 mg per week

Borna 2008 2/37 6/33 34.6 % 0.30 [ 0.06, 1.37 ]

Sharami 2010 0/80 3/83 12.8 % 0.15 [ 0.01, 2.82 ]

Subtotal (95% CI) 117 116 47.4 % 0.26 [ 0.07, 1.00 ]

Total events: 2 (Progesterone), 9 (No treatment)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.17, df = 1 (P = 0.68); I2 =0.0%

Test for overall effect: Z = 1.96 (P = 0.050)

2 Dose <500 mg per week

Briery 2011 6/33 6/36 52.6 % 1.09 [ 0.39, 3.05 ]

Combs 2011a 0/4 0/8 Not estimable

Subtotal (95% CI) 37 44 52.6 % 1.09 [ 0.39, 3.05 ]

Total events: 6 (Progesterone), 6 (No treatment)

Heterogeneity: not applicable

Test for overall effect: Z = 0.17 (P = 0.87)

Total (95% CI) 154 160 100.0 % 0.54 [ 0.17, 1.68 ]

Total events: 8 (Progesterone), 15 (No treatment)

Heterogeneity: Tau2 = 0.37; Chi2 = 3.06, df = 2 (P = 0.22); I2 =35%

Test for overall effect: Z = 1.07 (P = 0.29)

Test for subgroup differences: Chi2 = 2.78, df = 1 (P = 0.10), I2 =64%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

254Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 10.5. Comparison 10 Progesterone versus placebo/no treatment: prior threatened preterm labour,

singletons, by cumulative weekly dose (< 500 mg v >= 500 mg), Outcome 5 Neonatal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 10 Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons, by cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome: 5 Neonatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Dose <500 mg per week

Combs 2011a 1/4 1/8 46.2 % 2.00 [ 0.16, 24.33 ]

Subtotal (95% CI) 4 8 46.2 % 2.00 [ 0.16, 24.33 ]

Total events: 1 (Progesterone), 1 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.54 (P = 0.59)

2 Dose >=500 mg per week

Sharami 2010 1/80 6/83 53.8 % 0.17 [ 0.02, 1.40 ]

Subtotal (95% CI) 80 83 53.8 % 0.17 [ 0.02, 1.40 ]

Total events: 1 (Progesterone), 6 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.64 (P = 0.10)

Total (95% CI) 84 91 100.0 % 0.54 [ 0.05, 6.24 ]

Total events: 2 (Progesterone), 7 (Placebo)

Heterogeneity: Tau2 = 1.78; Chi2 = 2.28, df = 1 (P = 0.13); I2 =56%

Test for overall effect: Z = 0.50 (P = 0.62)

Test for subgroup differences: Chi2 = 2.17, df = 1 (P = 0.14), I2 =54%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

255Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 11.1. Comparison 11 Progesterone versus placebo: other reason at risk of preterm birth,

singletons, Outcome 1 Perinatal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 11 Progesterone versus placebo: other reason at risk of preterm birth, singletons

Outcome: 1 Perinatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Hauth 1983 3/80 3/88 58.2 % 1.10 [ 0.23, 5.29 ]

Papiernik 1970 0/49 0/47 Not estimable

Subtotal (95% CI) 129 135 58.2 % 1.10 [ 0.23, 5.29 ]

Total events: 3 (Progesterone), 3 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.12 (P = 0.91)

2 Vaginal

Aboulghar 2012 1/112 5/103 41.8 % 0.18 [ 0.02, 1.55 ]

Subtotal (95% CI) 112 103 41.8 % 0.18 [ 0.02, 1.55 ]

Total events: 1 (Progesterone), 5 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.56 (P = 0.12)

Total (95% CI) 241 238 100.0 % 0.52 [ 0.09, 3.00 ]

Total events: 4 (Progesterone), 8 (Placebo)

Heterogeneity: Tau2 = 0.73; Chi2 = 1.80, df = 1 (P = 0.18); I2 =44%

Test for overall effect: Z = 0.73 (P = 0.47)

Test for subgroup differences: Chi2 = 1.75, df = 1 (P = 0.19), I2 =43%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

256Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 11.2. Comparison 11 Progesterone versus placebo: other reason at risk of preterm birth,

singletons, Outcome 2 Preterm birth less than 34 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 11 Progesterone versus placebo: other reason at risk of preterm birth, singletons

Outcome: 2 Preterm birth less than 34 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Aboulghar 2012 3/112 4/103 100.0 % 0.69 [ 0.16, 3.01 ]

Total (95% CI) 112 103 100.0 % 0.69 [ 0.16, 3.01 ]

Total events: 3 (Progesterone), 4 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.49 (P = 0.62)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

257Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 11.3. Comparison 11 Progesterone versus placebo: other reason at risk of preterm birth,

singletons, Outcome 3 Preterm birth less than 37 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 11 Progesterone versus placebo: other reason at risk of preterm birth, singletons

Outcome: 3 Preterm birth less than 37 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Intramuscular

Hauth 1983 5/80 5/88 21.1 % 1.10 [ 0.33, 3.66 ]

Papiernik 1970 2/50 9/49 15.1 % 0.22 [ 0.05, 0.96 ]

Subtotal (95% CI) 130 137 36.2 % 0.52 [ 0.11, 2.56 ]

Total events: 7 (Progesterone), 14 (Placebo)

Heterogeneity: Tau2 = 0.86; Chi2 = 2.82, df = 1 (P = 0.09); I2 =65%

Test for overall effect: Z = 0.80 (P = 0.42)

2 Vaginal

Aboulghar 2012 24/112 35/103 63.8 % 0.63 [ 0.40, 0.98 ]

Subtotal (95% CI) 112 103 63.8 % 0.63 [ 0.40, 0.98 ]

Total events: 24 (Progesterone), 35 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.03 (P = 0.042)

Total (95% CI) 242 240 100.0 % 0.60 [ 0.32, 1.13 ]

Total events: 31 (Progesterone), 49 (Placebo)

Heterogeneity: Tau2 = 0.11; Chi2 = 2.82, df = 2 (P = 0.24); I2 =29%

Test for overall effect: Z = 1.58 (P = 0.12)

Test for subgroup differences: Chi2 = 0.05, df = 1 (P = 0.82), I2 =0.0%

0.05 0.2 1 5 20

Favours progesterone Favours placebo

258Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 11.4. Comparison 11 Progesterone versus placebo: other reason at risk of preterm birth,

singletons, Outcome 4 Infant birthweight less than 2500 g.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 11 Progesterone versus placebo: other reason at risk of preterm birth, singletons

Outcome: 4 Infant birthweight less than 2500 g

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Hauth 1983 6/80 8/88 28.1 % 0.83 [ 0.30, 2.27 ]

Papiernik 1970 2/50 8/49 29.8 % 0.25 [ 0.05, 1.10 ]

Subtotal (95% CI) 130 137 57.8 % 0.53 [ 0.23, 1.18 ]

Total events: 8 (Progesterone), 16 (Placebo)

Heterogeneity: Chi2 = 1.75, df = 1 (P = 0.19); I2 =43%

Test for overall effect: Z = 1.55 (P = 0.12)

2 Vaginal

Aboulghar 2012 5/112 11/103 42.2 % 0.42 [ 0.15, 1.16 ]

Subtotal (95% CI) 112 103 42.2 % 0.42 [ 0.15, 1.16 ]

Total events: 5 (Progesterone), 11 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.67 (P = 0.095)

Total (95% CI) 242 240 100.0 % 0.48 [ 0.25, 0.91 ]

Total events: 13 (Progesterone), 27 (Placebo)

Heterogeneity: Chi2 = 1.94, df = 2 (P = 0.38); I2 =0.0%

Test for overall effect: Z = 2.26 (P = 0.024)

Test for subgroup differences: Chi2 = 0.12, df = 1 (P = 0.73), I2 =0.0%

0.1 0.2 0.5 1 2 5 10

Favours progesterone Favours placebo

259Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 11.5. Comparison 11 Progesterone versus placebo: other reason at risk of preterm birth,

singletons, Outcome 5 Intrauterine fetal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 11 Progesterone versus placebo: other reason at risk of preterm birth, singletons

Outcome: 5 Intrauterine fetal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Hauth 1983 1/80 3/88 100.0 % 0.37 [ 0.04, 3.45 ]

Total (95% CI) 80 88 100.0 % 0.37 [ 0.04, 3.45 ]

Total events: 1 (Progesterone), 3 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.88 (P = 0.38)

Test for subgroup differences: Not applicable

0.05 0.2 1 5 20

Favours progesterone Favours placebo

Analysis 11.6. Comparison 11 Progesterone versus placebo: other reason at risk of preterm birth,

singletons, Outcome 6 Neonatal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 11 Progesterone versus placebo: other reason at risk of preterm birth, singletons

Outcome: 6 Neonatal death

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intramuscular

Hauth 1983 2/80 0/88 100.0 % 5.49 [ 0.27, 112.73 ]

Total (95% CI) 80 88 100.0 % 5.49 [ 0.27, 112.73 ]

Total events: 2 (Progesterone), 0 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.11 (P = 0.27)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

260Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 11.7. Comparison 11 Progesterone versus placebo: other reason at risk of preterm birth,

singletons, Outcome 7 Admission to neonatal intensive care unit.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 11 Progesterone versus placebo: other reason at risk of preterm birth, singletons

Outcome: 7 Admission to neonatal intensive care unit

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Vaginal

Aboulghar 2012 13/112 7/103 100.0 % 1.71 [ 0.71, 4.11 ]

Total (95% CI) 112 103 100.0 % 1.71 [ 0.71, 4.11 ]

Total events: 13 (Progesterone), 7 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.19 (P = 0.23)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours progesterone Favours placebo

261Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 12.1. Comparison 12 Progesterone versus placebo: other reason at risk of preterm birth, by timing

of commencement (< 20 wk v > 20 wk, singletons), Outcome 1 Perinatal death.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 12 Progesterone versus placebo: other reason at risk of preterm birth, by timing of commencement (< 20 wk v > 20 wk, singletons)

Outcome: 1 Perinatal death

Study or subgroup Progesterone Placbeo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Supplementation commenced prior to 20 weeks’ gestation

Hauth 1983 3/80 3/88 100.0 % 1.10 [ 0.23, 5.29 ]

Subtotal (95% CI) 80 88 100.0 % 1.10 [ 0.23, 5.29 ]

Total events: 3 (Progesterone), 3 (Placbeo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.12 (P = 0.91)

2 Supplementation commenced after 20 weeks’ gestation

Papiernik 1970 0/49 0/47 Not estimable

Subtotal (95% CI) 49 47 Not estimable

Total events: 0 (Progesterone), 0 (Placbeo)

Heterogeneity: not applicable

Test for overall effect: not applicable

Total (95% CI) 129 135 100.0 % 1.10 [ 0.23, 5.29 ]

Total events: 3 (Progesterone), 3 (Placbeo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.12 (P = 0.91)

Test for subgroup differences: Not applicable

0.001 0.01 0.1 1 10 100 1000

Favours progesterone Favours placebo

262Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 12.2. Comparison 12 Progesterone versus placebo: other reason at risk of preterm birth, by timing

of commencement (< 20 wk v > 20 wk, singletons), Outcome 2 Preterm birth less than 37 weeks.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 12 Progesterone versus placebo: other reason at risk of preterm birth, by timing of commencement (< 20 wk v > 20 wk, singletons)

Outcome: 2 Preterm birth less than 37 weeks

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Supplementation commenced prior to 20 weeks’ gestation

Hauth 1983 5/80 5/88 53.6 % 1.10 [ 0.33, 3.66 ]

Subtotal (95% CI) 80 88 53.6 % 1.10 [ 0.33, 3.66 ]

Total events: 5 (Progesterone), 5 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.16 (P = 0.88)

2 Supplementation commenced after 20 weeks’ gestation

Papiernik 1970 2/50 9/49 46.4 % 0.22 [ 0.05, 0.96 ]

Subtotal (95% CI) 50 49 46.4 % 0.22 [ 0.05, 0.96 ]

Total events: 2 (Progesterone), 9 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.02 (P = 0.044)

Total (95% CI) 130 137 100.0 % 0.52 [ 0.11, 2.56 ]

Total events: 7 (Progesterone), 14 (Placebo)

Heterogeneity: Tau2 = 0.86; Chi2 = 2.82, df = 1 (P = 0.09); I2 =65%

Test for overall effect: Z = 0.80 (P = 0.42)

Test for subgroup differences: Chi2 = 2.77, df = 1 (P = 0.10), I2 =64%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

263Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Analysis 12.3. Comparison 12 Progesterone versus placebo: other reason at risk of preterm birth, by timing

of commencement (< 20 wk v > 20 wk, singletons), Outcome 3 Infant birthweight less than 2500 g.

Review: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

Comparison: 12 Progesterone versus placebo: other reason at risk of preterm birth, by timing of commencement (< 20 wk v > 20 wk, singletons)

Outcome: 3 Infant birthweight less than 2500 g

Study or subgroup Progesterone Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M- H,Random,95%

1 Supplementation commenced prior to 20 weeks’ gestation

Hauth 1983 6/80 8/88 60.6 % 0.83 [ 0.30, 2.27 ]

Subtotal (95% CI) 80 88 60.6 % 0.83 [ 0.30, 2.27 ]

Total events: 6 (Progesterone), 8 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.37 (P = 0.71)

2 Supplementation commenced after 20 weeks’ gestation

Papiernik 1970 2/50 8/49 39.4 % 0.25 [ 0.05, 1.10 ]

Subtotal (95% CI) 50 49 39.4 % 0.25 [ 0.05, 1.10 ]

Total events: 2 (Progesterone), 8 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.84 (P = 0.066)

Total (95% CI) 130 137 100.0 % 0.51 [ 0.16, 1.65 ]

Total events: 8 (Progesterone), 16 (Placebo)

Heterogeneity: Tau2 = 0.32; Chi2 = 1.75, df = 1 (P = 0.19); I2 =43%

Test for overall effect: Z = 1.12 (P = 0.26)

Test for subgroup differences: Chi2 = 1.73, df = 1 (P = 0.19), I2 =42%

0.01 0.1 1 10 100

Favours progesterone Favours placebo

264Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

A P P E N D I C E S

Appendix 1. Search methods used for previous version of this review

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co-ordinator (December

2008).

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials

identified from:

1. quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

2. weekly searches of MEDLINE;

3. weekly searches of EMBASE;

4. handsearches of 30 journals and the proceedings of major conferences;

5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and EMBASE, the list of handsearched journals and conference proceedings,

and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial

information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-

ordinator searches the register for each review using the topic list rather than keywords.

In addition, we searched CENTRAL (The Cochrane LIbrary 2008, Issue 1). See below for search terms. We did not apply any language restrictions.

Searching other resources

We also manually cross referenced key publications.

We did not apply any language restrictions.

We searched the International Clinical Trials Register (using the terms pregnancy, progesterone and ante/prenatal) to identify ongoing

registered clinical trials.

Search terms for CENTRAL

Search terms included free text terms pregnancy, preterm birth, progesterone, progestogen, intramuscular, vaginal, oral, perinatal

morbidity, perinatal mortality, and randomis(z)ed controlled trial. Please contact review author for exact strategy.

Appendix 2. Methods for the previous version of this review

We used the standard methods of The Cochrane Collaboration (Higgins 2008). Review authors independently assessed trials for

inclusion in the review and extracted the data. Any differences were resolved by discussion with all co-authors.

Assessment of risk of bias in included studies

The methodology used to assess risk of bias of studies included in the previous version of this review is given in Appendix 2.

For this update, the following methods were used.

Two review authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Any disagreement was resolved by discussion or by involving a third assessor.

(1) Sequence generation (checking for possible selection bias)

We describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of

whether it should produce comparable groups.

We assessed the method as:

• adequate (any truly random process, e.g., random number table; computer random number generator);

• inadequate (any non random process, e.g.„ odd or even date of birth; hospital or clinic record number);

• unclear.

265Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/preg/frame.html

(2) Allocation concealment (checking for possible selection bias)

We describe for each included study the method used to conceal the allocation sequence in sufficient detail and determine whether

intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We assessed the methods as:

• adequate (e.g., telephone or central randomisation; consecutively numbered sealed opaque envelopes);

• inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);

• unclear.

(3) Blinding (checking for possible performance bias)

We describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which

intervention a participant received. Studies will be judged at low risk of bias if they were blinded, or if we judge that the lack of blinding

could not have affected the results. Blinding will be assessed separately for different outcomes or classes of outcomes.

We assessed the methods as:

• adequate, inadequate or unclear for participants;

• adequate, inadequate or unclear for personnel;

• adequate, inadequate or unclear for outcome assessors.

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

We describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and

exclusions from the analysis. We state whether attrition and exclusions were reported, the numbers included in the analysis at each stage

(compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were

balanced across groups or were related to outcomes. Where sufficient information was reported, or was supplied by the trial authors,

we re-included missing data in the analyses which we undertook. We assessed methods as:

• adequate;

• inadequate:

• unclear;

where ’adequate’ is less than 20% losses to follow-up.

(5) Selective reporting bias

We describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

• adequate (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have

been reported);

• inadequate (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were

not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome

that would have been expected to have been reported);

• unclear.

(6) Other sources of bias

We describe for each included study any important concerns we have about other possible sources of bias.

We assessed whether each study was free of other problems that could put it at risk of bias:

• yes;

• no;

• unclear.

266Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

(7) Overall risk of bias

We made explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook (Higgins 2008). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered

it was likely to impact on the findings. We explored the impact of the level of bias through undertaking sensitivity analyses.

Data management and analysis

We conducted data management and analysis using RevMan software (RevMan 2008). V Flenady, R Cincotta and J Dodd independently

extracted data. Results are reported as mean differences for continuous variables, and risk ratios for categorical outcomes, both with

95% confidence intervals.

We conducted the meta-analysis using the fixed-effect model, and assessed heterogeneity by visual inspection of the outcomes tables

and by using two statistics (H and I2 test) of heterogeneity (Higgins 2002). Where we discovered statistical heterogeneity, this was

explored.

Results are presented by reason women were considered to be at risk of preterm birth, including:

• past history of spontaneous preterm birth (including preterm premature rupture of membranes);

• multiple pregnancy;

• ultrasound identified short cervical length;

• fetal fibronectin testing;

• presentation with symptoms or signs of threatened preterm labour;

• other reason for risk of preterm birth.

Planned subgroup analyses included an assessment of the effect of: (1) time of treatment commencing (before 20 weeks’ gestation

versus after 20 weeks’ gestation); (2) route of administration (intramuscular, intravaginal, oral, intravenous); and (3) different dosage

regimens (divided arbitrarily into a cumulative dose of less than 500 mg per week and a dose of greater than or equal to 500 mg per

week). To evaluate the effect of subgroup comparisons, we considered confidence intervals (where non-overlap was taken to indicate a

statistically significant difference).

W H A T ’ S N E W

Last assessed as up-to-date: 14 January 2013.

Date Event Description

27 July 2015 Amended Corrected spelling of included study Fonseca 2007 (was previously listed as Fonesca 2007).

Text has been added to Published notes about this review being split into two reviews following two new

protocols

H I S T O R Y

Protocol first published: Issue 4, 2004

Review first published: Issue 1, 2006

267Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

Date Event Description

13 August 2013 Amended Robert Cincotta added to the byline. Contribution to

this update added

5 August 2013 Amended Contact details amended for Caroline Crowther.

12 June 2013 New citation required and conclusions have changed This updated review is now comprised of 36 included

studies (involving 8523 women and 12,515 infants)

. There are now 11 ongoing studies. The results and

conclusions have changed:

Progesterone versus placebo for women with a history

of preterm birth: now significant findings for perinatal

mortality; significant findings for additional infant and

maternal secondary outcomes

Progesterone versus placebo for women with a short

cervix: significant findings now identified for sec-

ondary infant outcome (preterm birth less than 28

weeks’ gestation) and secondary maternal outcome

(adverse drug reaction (urticaria); now no significant

findings for neonatal sepsis

Progesterone versus placebo for women with a multiple

pregnancy: now no significant findings for any of the

reported outcomes

Progesterone versus no treatment/placebo for women

following presentation with threatened preterm

labour: now no significant findings for two secondary

infant outcomes (preterm birth less than 37 weeks’ ges-

tation; respiratory distress syndrome (RDS))

Progesterone versus placebo for women with ’other’

risk factors for preterm birth: now significant findings

for one secondary infant outcome (infant birthweight

less than 2500 g)

14 January 2013 New search has been performed Search updated.

Data from 25 new trials incorporated into this update.

27 January 2012 Amended Fifty-two reports for 44 trials added to Studies awaiting

classification

31 December 2008 New search has been performed Search updated. A search in October 2007 identi-

fied 17 new trials. We included five (Borna 2008;

Facchinetti 2007; Fonseca 2007; O’Brien 2007; Rouse

2007); added a follow-up report to Meis 2003; and ex-

cluded one (Walch 2005). Ten trials are ongoing (Bru-

inse 2007; Maurel 2007; Grobman 2007; Martinez

2007; Nassar 2007; Perlitz 2007; Rode 2007; Rozen-

berg 2007; Serra 2007; Wood 2007).

A further updated search in December 2008 identified

268Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

(Continued)

one more report of Borna 2008; five more reports of

O’Brien 2007; six more reports of Rouse 2007; one

more report of Crowther 2007; one more report of

Bruinse 2007; three ongoing studies (Creasy 2008;

Starkey 2008; Swaby 2007); and one study which is

awaiting classification (Moghtadaei 2008a)

The review’s conclusions have not changed.

5 November 2008 Amended Converted to new review format.

31 March 2005 New search has been performed Search updated and new studies found and included

or excluded

C O N T R I B U T I O N S O F A U T H O R S

For the update in 2013, J Dodd and L Jones assessed studies, extracted data and entered it into RevMan. L Jones wrote the first version

of the results. J Dodd revised the review, discussion and conclusions. V Flenady, CA Crowther and R Cincotta commented on all drafts

of the update (2013).

D E C L A R A T I O N S O F I N T E R E S T

J Dodd, V Flenady and C Crowther are investigators in a randomised trial assessing the use of progesterone for prevention of respiratory

distress syndrome (The PROGRESS Trial).

S O U R C E S O F S U P P O R T

Internal sources

• Mater Research Support Centre, Mater Health Services Brisbane, South Brisbane, Queensland, Australia.

• Department of Maternal Fetal Medicine, Mater Mothers’ Hospital, South Brisbane, Queensland, Australia.

• The University of Adelaide, Discipline of Obstetrics and Gynaecology, Australia.

External sources

• National Institute for Health Research, UK.

NIHR Programme of centrally-managed pregnancy and childbirth systematic reviews of priority to the NHS and users of the NHS:

10/4001/02

269Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

In view of the increase in the number of trials published, along with the huge variation in the patient populations recruited, we

have decided to categorise the studies by the reason women were considered to be at increased risk of preterm birth. We have also

included longer-term childhood health outcomes, in recognition of the need for ongoing follow-up of children exposed antenatally to

progesterone (Update 2008), and maternal quality of life (Update 2013).

N O T E S

This review examines prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm

birth. Women considered in this review includes women considered at high risk because of multiple pregnancy as well as women with

singleton pregnancies considered at high risk for various clinical reasons (history of preterm birth, short cervix, threatened preterm

labour and other risk factors). This review included 36 trials with several trials recruiting only women with multiple pregnancies.

The results of this review may be easier to interpret and more clinically relevant if the results for women with multiple and singleton

pregnancy are assessed and reported separately.

Consequently, this review will no longer be updated in it’s current form but will be split into two separate reviews:

• Prenatal administration of progesterone for preventing preterm birth in women with a multiple pregnancy

• Prenatal administration of progesterone for preventing preterm birth in women with a singleton pregnancy

Each of these reviews will be prepared following publication of a new protocol.

I N D E X T E R M S

Medical Subject Headings (MeSH)

17-alpha-Hydroxyprogesterone [administration & dosage; adverse effects]; Pregnancy, High-Risk; Premature Birth [∗prevention &

control]; Prenatal Care [methods]; Progesterone [∗administration & dosage; adverse effects]; Randomized Controlled Trials as Topic

MeSH check words

Female; Humans; Pregnancy

270Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth (Review)