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Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D

Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD004661. DOI: 10.1002/14651858.CD004661.pub3.

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Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

https://doi.org/10.1002%2F14651858.CD004661.pub3

https://www.cochranelibrary.com

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

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

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

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

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

OBJECTIVES.................................................................................................................................................................................................. 3

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

RESULTS........................................................................................................................................................................................................ 6

Figure 1.................................................................................................................................................................................................. 7

Figure 2.................................................................................................................................................................................................. 8

DISCUSSION.................................................................................................................................................................................................. 12

AUTHORS' CONCLUSIONS........................................................................................................................................................................... 13

ACKNOWLEDGEMENTS................................................................................................................................................................................ 13

REFERENCES................................................................................................................................................................................................ 14

CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 18

DATA AND ANALYSES.................................................................................................................................................................................... 21

Analysis 1.1. Comparison 1 Magnesium versus no magnesium, Outcome 1 Paediatric mortality (fetal and later)......................... 25

Analysis 1.2. Comparison 1 Magnesium versus no magnesium, Outcome 2 Fetal death................................................................. 26

Analysis 1.3. Comparison 1 Magnesium versus no magnesium, Outcome 3 Livebirth deaths......................................................... 27

Analysis 1.4. Comparison 1 Magnesium versus no magnesium, Outcome 4 Cerebral palsy............................................................ 28

Analysis 1.5. Comparison 1 Magnesium versus no magnesium, Outcome 5 Any neurological impairment.................................... 30

Analysis 1.6. Comparison 1 Magnesium versus no magnesium, Outcome 6 Substantial gross motor dysfunction........................ 30

Analysis 1.7. Comparison 1 Magnesium versus no magnesium, Outcome 7 Blindness.................................................................... 31

Analysis 1.8. Comparison 1 Magnesium versus no magnesium, Outcome 8 Deafness..................................................................... 31

Analysis 1.9. Comparison 1 Magnesium versus no magnesium, Outcome 9 Developmental delay or intellectual impairment....... 32

Analysis 1.10. Comparison 1 Magnesium versus no magnesium, Outcome 10 Major neurological disability................................. 32

Analysis 1.11. Comparison 1 Magnesium versus no magnesium, Outcome 11 Death or cerebral palsy.......................................... 33

Analysis 1.12. Comparison 1 Magnesium versus no magnesium, Outcome 12 Death or any neurological impairment................. 33

Analysis 1.13. Comparison 1 Magnesium versus no magnesium, Outcome 13 Death or substantial gross motor dysfunction....... 34

Analysis 1.14. Comparison 1 Magnesium versus no magnesium, Outcome 14 Death or major neurological disability.................. 35

Analysis 1.15. Comparison 1 Magnesium versus no magnesium, Outcome 15 Maternal mortality................................................. 35

Analysis 1.16. Comparison 1 Magnesium versus no magnesium, Outcome 16 Maternal cardiac arrest.......................................... 35

Analysis 1.17. Comparison 1 Magnesium versus no magnesium, Outcome 17 Maternal respiratory arrest.................................... 36

Analysis 1.18. Comparison 1 Magnesium versus no magnesium, Outcome 18 Cessation of maternal therapy.............................. 36

Analysis 1.19. Comparison 1 Magnesium versus no magnesium, Outcome 19 Intraventricular haemorrhage............................... 36

Analysis 1.20. Comparison 1 Magnesium versus no magnesium, Outcome 20 Intraventricular haemorrhage 3/4......................... 37

Analysis 1.21. Comparison 1 Magnesium versus no magnesium, Outcome 21 Periventricular leucomalacia................................. 37

Analysis 1.22. Comparison 1 Magnesium versus no magnesium, Outcome 22 Apgar score < 7 at 5 minutes.................................. 37

Analysis 1.23. Comparison 1 Magnesium versus no magnesium, Outcome 23 Neonatal convulsions............................................ 38

Analysis 1.24. Comparison 1 Magnesium versus no magnesium, Outcome 24 Neonatal hypotonia............................................... 38

Analysis 1.25. Comparison 1 Magnesium versus no magnesium, Outcome 25 Ongoing respiratory support................................. 38

Analysis 1.26. Comparison 1 Magnesium versus no magnesium, Outcome 26 Chronic lung disease.............................................. 39

Analysis 1.27. Comparison 1 Magnesium versus no magnesium, Outcome 27 Maternal hypotension............................................ 39

Analysis 1.28. Comparison 1 Magnesium versus no magnesium, Outcome 28 Maternal tachycardia............................................. 39

Analysis 1.29. Comparison 1 Magnesium versus no magnesium, Outcome 29 Maternal respiratory depression........................... 40

Analysis 1.30. Comparison 1 Magnesium versus no magnesium, Outcome 30 Postpartum haemorrhage..................................... 40

Analysis 1.31. Comparison 1 Magnesium versus no magnesium, Outcome 31 Caesarean birth...................................................... 40

Analysis 1.32. Comparison 1 Magnesium versus no magnesium, Outcome 32 Mother admitted to intensive care unit................. 40

Analysis 1.33. Comparison 1 Magnesium versus no magnesium, Outcome 33 Duration of mother's hospital stay (days)............. 41

Analysis 1.34. Comparison 1 Magnesium versus no magnesium, Outcome 34 Duration of primary hospital stay for babies (days)......................................................................................................................................................................................................

Analysis 2.1. Comparison 2 Studies with lowest risk of bias only, Outcome 1 Paediatric mortality................................................ 42

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Analysis 2.2. Comparison 2 Studies with lowest risk of bias only, Outcome 2 Cerebral palsy.......................................................... 42

Analysis 2.3. Comparison 2 Studies with lowest risk of bias only, Outcome 3 Neurological impairment........................................ 42

Analysis 2.4. Comparison 2 Studies with lowest risk of bias only, Outcome 4 Major neurological disability................................... 43

Analysis 2.5. Comparison 2 Studies with lowest risk of bias only, Outcome 5 Death or cerebral palsy........................................... 43

Analysis 2.6. Comparison 2 Studies with lowest risk of bias only, Outcome 6 Death or neurological impairment......................... 43

Analysis 2.7. Comparison 2 Studies with lowest risk of bias only, Outcome 7 Death or major neurological disability................... 43

Analysis 3.1. Comparison 3 Single or multiple pregnancy subgroup, Outcome 1 Paediatric mortality (fetal and later)................. 45

Analysis 3.2. Comparison 3 Single or multiple pregnancy subgroup, Outcome 2 Cerebral palsy.................................................... 45

Analysis 3.3. Comparison 3 Single or multiple pregnancy subgroup, Outcome 3 Neurological impairment.................................. 46

Analysis 3.4. Comparison 3 Single or multiple pregnancy subgroup, Outcome 4 Major neurological disability............................. 46

Analysis 3.5. Comparison 3 Single or multiple pregnancy subgroup, Outcome 5 Death or cerebral palsy...................................... 47

Analysis 3.6. Comparison 3 Single or multiple pregnancy subgroup, Outcome 6 Death or neurological impairment.................... 48

Analysis 3.7. Comparison 3 Single or multiple pregnancy subgroup, Outcome 7 Death or major neurological disability.............. 48

Analysis 4.1. Comparison 4 High antenatal corticosteroids, Outcome 1 Paediatric mortality (fetal and later)............................... 49

Analysis 4.2. Comparison 4 High antenatal corticosteroids, Outcome 2 Cerebral palsy................................................................... 49

Analysis 4.3. Comparison 4 High antenatal corticosteroids, Outcome 3 Neurological impairment................................................. 50

Analysis 4.4. Comparison 4 High antenatal corticosteroids, Outcome 4 Major neurological disability........................................... 50

Analysis 4.5. Comparison 4 High antenatal corticosteroids, Outcome 5 Death or cerebral palsy.................................................... 50

Analysis 4.6. Comparison 4 High antenatal corticosteroids, Outcome 6 Death or neurological impairment.................................. 51

Analysis 4.7. Comparison 4 High antenatal corticosteroids, Outcome 7 Death or major neurological disability............................ 51

Analysis 5.1. Comparison 5 Gestational age subgroup, Outcome 1 Paediatric mortality (fetal and later)....................................... 53

Analysis 5.2. Comparison 5 Gestational age subgroup, Outcome 2 Cerebral palsy.......................................................................... 53

Analysis 5.3. Comparison 5 Gestational age subgroup, Outcome 3 Neurological impairment........................................................ 54

Analysis 5.4. Comparison 5 Gestational age subgroup, Outcome 4 Major neurological disability................................................... 54

Analysis 5.5. Comparison 5 Gestational age subgroup, Outcome 5 Death or cerebral palsy............................................................ 54

Analysis 5.6. Comparison 5 Gestational age subgroup, Outcome 6 Death or neurological impairment.......................................... 55

Analysis 5.7. Comparison 5 Gestational age subgroup, Outcome 7 Death or major neurological disability................................... 55

Analysis 6.1. Comparison 6 Dose subgroup, Outcome 1 Paediatric mortality (fetal and later)........................................................ 58

Analysis 6.2. Comparison 6 Dose subgroup, Outcome 2 Cerebral palsy........................................................................................... 59

Analysis 6.3. Comparison 6 Dose subgroup, Outcome 3 Neurological impairment......................................................................... 60

Analysis 6.4. Comparison 6 Dose subgroup, Outcome 4 Major neurological disability.................................................................... 61

Analysis 6.5. Comparison 6 Dose subgroup, Outcome 5 Death or cerebral palsy............................................................................. 61

Analysis 6.6. Comparison 6 Dose subgroup, Outcome 6 Death or neurological impairment........................................................... 62

Analysis 6.7. Comparison 6 Dose subgroup, Outcome 7 Death or major neurological disability..................................................... 62

Analysis 7.1. Comparison 7 Retreatment subgroup, Outcome 1 Paediatric mortality (fetal and later)........................................... 64

Analysis 7.2. Comparison 7 Retreatment subgroup, Outcome 2 Cerebral palsy............................................................................... 65

Analysis 7.3. Comparison 7 Retreatment subgroup, Outcome 3 Neurologic impairment................................................................ 65

Analysis 7.4. Comparison 7 Retreatment subgroup, Outcome 4 Major neurological disability........................................................ 66

Analysis 7.5. Comparison 7 Retreatment subgroup, Outcome 5 Death or cerebral palsy................................................................ 66

Analysis 7.6. Comparison 7 Retreatment subgroup, Outcome 6 Death or neurological impairment.............................................. 67

Analysis 7.7. Comparison 7 Retreatment subgroup, Outcome 7 Death or major neurological disability........................................ 67

WHAT'S NEW................................................................................................................................................................................................. 67

HISTORY........................................................................................................................................................................................................ 67

CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 68

DECLARATIONS OF INTEREST..................................................................................................................................................................... 68

SOURCES OF SUPPORT............................................................................................................................................................................... 68

DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 68

INDEX TERMS............................................................................................................................................................................................... 69

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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[Intervention Review]

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus

Lex W Doyle1, Caroline A Crowther2, Philippa Middleton2, Stephane Marret3, Dwight Rouse4

1Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Australia. 2ARCH: Australian Research Centre for

Health of Women and Babies, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Adelaide, Australia. 3Department

of Neonatal Medicine, University Hospital, Rouen, Rouen cedex, France. 4Center for Women's Reproductive Health, The University of Alabama, Birmingham, Alabama, USA

Contact address: Lex W Doyle, Department of Obstetrics and Gynaecology, University of Melbourne, The Royal Women's Hospital, Locked Bag 300, 20 Flemington Rd, Parkville, Victoria, 3052, Australia. lwd@unimelb.edu.au.

Editorial group: Cochrane Pregnancy and Childbirth Group. Publication status and date: Edited (no change to conclusions), published in Issue 1, 2010.

Citation: Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD004661. DOI: 10.1002/14651858.CD004661.pub3.

A B S T R A C T

Background

Epidemiological and basic science evidence suggests that magnesium sulphate before birth may be neuroprotective for the fetus.

Objectives

To assess the eIects of magnesium sulphate as a neuroprotective agent when given to women considered at risk of preterm birth.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2008).

Selection criteria

Randomised controlled trials of antenatal magnesium sulphate therapy in women threatening or likely to give birth at less than 37 weeks' gestational age. For one subgroup analysis, studies were broadly categorised by the primary intent of the study into "neuroprotective intent", or "other intent (maternal neuroprotective - pre-eclampsia)", or "other intent (tocolytic)".

Data collection and analysis

At least two authors assessed trial eligibility and quality, and extracted data.

Main results

Five trials (6145 babies) were eligible for this review. Antenatal magnesium sulphate therapy given to women at risk of preterm birth substantially reduced the risk of cerebral palsy in their child (relative risk (RR) 0.68; 95% Confidence interval (CI) 0.54 to 0.87; five trials; 6145 infants). There was also a significant reduction in the rate of substantial gross motor dysfunction (RR 0.61; 95% CI 0.44 to 0.85; four trials; 5980 infants). No statistically significant eIect of antenatal magnesium sulphate therapy was detected on paediatric mortality (RR 1.04; 95% CI 0.92 to 1.17; five trials; 6145 infants), or on other neurological impairments or disabilities in the first few years of life. Overall there were no significant eIects of antenatal magnesium therapy on combined rates of mortality with cerebral palsy, although there were significant reductions for the neuroprotective groups RR 0.85; 95% CI 0.74 to 0.98; four trials; 4446 infants, but not for the other intent subgroups. There were higher rates of minor maternal side eIects in the magnesium groups, but no significant eIects on major maternal complications.

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

mailto:lwd@unimelb.edu.au

https://doi.org/10.1002%2F14651858.CD004661.pub3

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Authors' conclusions

The neuroprotective role for antenatal magnesium sulphate therapy given to women at risk of preterm birth for the preterm fetus is now established. The number of women needed to be treated to benefit one baby by avoiding cerebral palsy is 63 (95% confidence interval 43 to 155). Given the beneficial eIects of magnesium sulphate on substantial gross motor function in early childhood, outcomes later in childhood should be evaluated to determine the presence or absence of later potentially important neurological eIects, particularly on motor or cognitive function.

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

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus

Magnesium sulphate given to women at risk of preterm birth helps to protect the baby's brain and improve long-term outcomes.

Babies born too early (preterm) have a higher risk of dying in the first weeks of life than babies born at term, and those who survive oNen have damage in the form of cerebral palsy (a disorder where the ability to move the arms or legs normally is reduced), blindness, deafness or physical disabilities. This can cause huge distress for parents. Magnesium is an important element essential for normal body functions. Magnesium sulphate may help to reduce damage to a preterm baby's brain. However, it has adverse eIects in the mother of flushing, sweating, nausea, vomiting, headaches and a rapid heartbeat (palpitations). This review identified five studies involving 6145 infants and shows that magnesium sulphate therapy protects the preterm baby's brain from cerebral palsy.

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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B A C K G R O U N D

Preterm birth and neurological outcome

Infants born preterm have a higher risk of dying in the first weeks of life. If they survive, they have a greater risk of neurological impairments, such as cerebral palsy, blindness, deafness, or cognitive dysfunction (either developmental delay, or intellectual impairment), and a greater risk of substantial disability as a result of these neurological impairments (Doyle 2001; VICS 1997). Moreover, as the rate of preterm birth is rising, up to 12.8% in the United States in 2006 (Martin 2007), more babies are at risk of death and adverse neurological outcomes. Cerebral palsy and cognitive dysfunction are the most frequent neurological impairments, and any therapy that can reduce their prevalence should have a substantial eIect on reducing overall neurological impairments and disabilities in surviving preterm infants.

Cerebral palsy is a term which includes a number of diIerent diseases or conditions that can arise at any time during brain development that involves a disorder of movement or posture, or both, and a disorder of motor function which is permanent but may change over time (Oxford Register 2001; SCPE 2000). The cerebral palsies remain the most frequent cause of severe motor disability in childhood with a background prevalence of two per thousand live births (Oxford Register 2001; Stanley 1994). The life expectancy shows 92% of aIected children surviving to 20 years (Hutton 1994), contributing substantially to the burden of illness into adulthood.

Very preterm birth (less than 34 weeks) and very low birthweight (less than 1500 g) are principal risk factors for cerebral palsy (Drummond 2002; Lorenz 1998; Pharoah 1998; Winter 2002) making up between 17% to 32% of all cases of cerebral palsy. Over 10% of all preterm births are from a multiple pregnancy with higher rates of cerebral palsy than singleton pregnancies. Twins have seven times and triplets 47 times the risk of cerebral palsy compared with singletons (Petterson 1993).

Evidence from population-based registries shows that the prevalence of cerebral palsy in low and very low birthweight infants is rising (Drummond 2002; Hagberg 2001; Oxford Register 2001; Stanley 1992). However, not all population-based registries have reported an increase in cerebral palsy in very low birthweight survivors; some have reported a decrease (Himmelmann 2005; Surman 2003). Although suspected from earlier birthweight analyses, Drummond's registry study confirms that the increasing prevalence of cerebral palsy is from higher rates in preterm, not term, infants (Drummond 2002). Intraventricular haemorrhage (IVH) is a known risk factor for the later development of cerebral palsy (Kuban 1994) with the risk of IVH and periventricular leucomalacia increasing the earlier the gestational age at birth (Vermeulen 2001).

In order to reduce the impact of cerebral palsy from very preterm birth, eIorts must be focused on primary prevention.

A possible role for magnesium

The first report that prenatal magnesium sulphate was associated with a reduction in risk of IVH, from 18.9% to 4.4%, in babies born with a birthweight less than 1500 g was by Kuban and colleagues in 1992 (Kuban 1992). A case-control analysis from the California Cerebral Palsy project investigated whether in utero exposure to magnesium sulphate was associated with a lower prevalence of

cerebral palsy in infants born weighing less than 1500 g (Nelson 1995). Cases were children with cerebral palsy who were singletons and whose birthweight had been less than 1500 g. Controls were randomly sampled from live births of less than 1500 g from the same birth populations. Magnesium sulphate given to the mother during labour was associated with a marked reduction in the risk of cerebral palsy (odds ratio 0.14; 95% confidence interval 0.05 to 0.51).

Other observational studies have supported a reduction in cerebral palsy in preterm infants by maternal administration of magnesium sulphate (Hauth 1995; Schendel 1996; Wiswell 1996) and some have found a reduction in the risk of IVH (Finesmith 1997; Perlman 1994; Wiswell 1996) and perinatal mortality (Grether 1998). However, not all observational studies have reported benefit for prenatal magnesium sulphate on the risk of IVH (Canterino 1999; Kimberlin 1998; Paneth 1997; Weintraub 2001), cerebral palsy (Grether 2000; O'Shea 1998; Paneth 1997) or perinatal mortality (Kimberlin 1998). However, observational studies alone cannot be the basis for changing clinical practice.

Animal studies have shown that magnesium can provide a neuroprotective eIect (McDonald 1990). It can prevent post hypoxic brain injury by blocking the excess release of glutamate in the calcium channel. Fetal and newborn brains seem to be more susceptible to damage from glutamate release. Consequently, blocking glutamate receptors through agents such as magnesium may reduce the risk of injury in the perinatal period (Espinoza 1991).

Magnesium sulphate is widely used in obstetrics as an anticonvulsant for the treatment of eclampsia (Duley 2000; Duley 2003a; Duley 2003b), prevention of eclampsia in women with pre- eclampsia (Duley 2003c; Sibai 2003); it has also been used as a tocolytic, although lacking eIicacy for inhibiting preterm labour (Crowther 2002).

Magnesium sulphate, by its peripheral vasodilator eIects when infused intravenously, produces flushing, sweating, and a sensation of warmth. Reported maternal side eIects, related to dosage and speed of infusion, include nausea, vomiting, headache, palpitations and, rarely, pulmonary oedema. Administration to levels above the recommended therapeutic range can lead to respiratory depression, respiratory arrest, cardiac arrest and death. For the neonate, hypermagnesaemia can lead to hyporeflexia, poor sucking, and, rarely, respiratory depression needing mechanical ventilation (Levene 1995; Lipsitz 1971).

This review assesses the eIectiveness and safety of magnesium sulphate given to women considered to be at risk of preterm birth, as a neuroprotective agent for their babies.

O B J E C T I V E S

To assess the eIectiveness and safety, using the best available evidence, of magnesium sulphate as a neuroprotective agent when given to women considered to be at risk of preterm birth.

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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M E T H O D S

Criteria for considering studies for this review

Types of studies

All published, unpublished and ongoing randomised trials with reported data comparing outcomes for women at risk of preterm birth given prenatal magnesium sulphate with outcomes in controls, whether treated or not with placebo. Trials were included if the primary aim of the study was to prevent neurological abnormalities in the unborn baby, or if the primary aim was otherwise but long-term neurological outcomes were reported for the infants. The trials had to use some form of random allocation and report data on one or more of the prestated outcomes. Quasi- randomised trials were excluded.

Types of participants

Women considered to be at risk of preterm birth.

Types of interventions

Magnesium sulphate given to the women at risk of preterm birth, administered intravenously, intramuscularly or orally, compared with either placebo or no placebo. Trials where magnesium sulphate was used with the prime aim of tocolysis (Crowther 2002), prevention and treatment of eclampsia (Duley 2000; Duley 2003a; Duley 2003b), maintenance therapy aNer preterm labour (Crowther 1998) or as a dietary supplement in pregnancy (Makrides 2001) were not included (unless they reported long-term neurological outcomes in the children), as those trials are covered in separate Cochrane reviews.

Types of outcome measures

We prespecified clinically relevant outcomes aNer discussion.

Primary outcomes

We chose primary outcomes to be most representative of the clinically important measures of eIectiveness and safety, including serious outcomes, for the women and their infants. We recognised that the list of outcomes was extensive and that data for some may not be available but we wanted to encapsulate the types of outcomes that may be of concern to clinicians caring for both the mother and the baby, both now and in the future. In so doing, we also recognised the increased possibility of type I errors because multiple outcomes would be evaluated. Combined outcomes were used for the main analyses, rather than all their components.

For the infants/children

• Fetal, neonatal or later death.

• Neurological impairments (developmental delay or intellectual impairment (developmental quotient or intelligence quotient less than one standard deviation (SD) below the mean), cerebral palsy (abnormality of tone with motor dysfunction), blindness (corrected visual acuity worse than 6/60 in the better eye), or deafness (hearing loss requiring amplification or worse)), or neurological disabilities (abnormal neurological function caused by any of the preceding impairments) at follow up later in childhood. Substantial gross motor dysfunction (defined as motor dysfunction such that the child was not walking at age two years or later, or the inability to grasp and release a small block with both hands).

• Major neurological disability (defined as any of: legal blindness, sensorineural deafness requiring hearing aids, moderate or severe cerebral palsy, or developmental delay/intellectual impairment (defined as developmental quotient or intelligence quotient less than two SD below the mean)).

• Paediatric mortality combined with cerebral palsy, substantial gross motor dysfunction, neurological impairment, or major neurological disability (these combined outcomes recognise the competing risks of death or survival with neurological problems).

The major paediatric outcomes were death or neurological (cerebral palsy, impairment or disability), or combinations of death with the neurological outcomes.

For the women

• Serious adverse cardiovascular/respiratory outcome (maternal death, respiratory arrest, cardiac arrest).

• Adverse eIects severe enough to stop treatment.

Secondary outcomes

These include other measures of eIectiveness, complications, satisfaction with care and health service use.

For the infant

• Any intraventricular haemorrhage (IVH).

• IVH grade 3/4.

• Periventricular leucomalacia.

• Apgar score less than seven at five minutes.

• Need for active resuscitation (assisted ventilation via an endotracheal tube) at birth.

• Neonatal convulsions.

• Neonatal hypotonia.

• Use of respiratory support (mechanical ventilation or continuous positive airways pressure, or both).

• Chronic lung disease (need for continuous, supplemental oxygen at 28 days postnatal age or 36 weeks' postmenstrual age).

• Use of postnatal corticosteroids.

For the child

• Growth assessments at childhood follow up (weight, head circumference, length/height).

• Educational achievements.

For the woman

• Blood pressure changes during infusion.

• Respiratory rate changes during infusion.

• Pulse rate at birth changes during infusion.

• Length of labour.

• Need for augmentation of labour.

• Postpartum haemorrhage.

• Mode of birth.

• Intrapartum fever requiring the use of antibiotics.

• Breastfeeding aNer hospital discharge.

• Women's satisfaction with the therapy.

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Use of health services

• Length of postnatal hospitalisation for the women.

• Admission to intensive care unit for the mother.

• Admission to neonatal intensive care.

• Length of stay in neonatal intensive care unit.

• Length of neonatal hospitalisation.

• Costs of care for mother or baby, or both.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co-ordinator (31 August 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. handsearches of 30 journals and the proceedings of major conferences;

4. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL and MEDLINE, 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.

We did not apply any language restrictions.

Data collection and analysis

At least two review authors evaluated trials under consideration for inclusion without consideration of their results. We also independently assessed the risk of bias in each included trial. We resolved diIerences of opinion by discussion. There was no blinding of authorship. We processed included trial data as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Where one of the authors was a chief investigator in a trial included in the review, at least one other author also extracted data.

Risk of bias assessment

We assessed risk of bias using the dimensions outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

In assessing selection bias, we examined the processes involved in the generation of the random sequence and the method of allocation concealment separately.

We examined performance bias as to whom was blinded in the trials. We sought details of the feasibility and appropriateness of blinding for participant, caregiver, outcome assessment and data analysis.

Analysis

We performed statistical analyses using the Review Manager soNware (RevMan 2008) and compared categorical data using relative risks and 95% confidence intervals. We tested for statistical heterogeneity between trials using the I2 statistic. If substantial heterogeneity was found (I2 greater than 50%), we used a random- eIects model, as well as exploring subgroup analyses. In addition, statistically significant diIerences between subgroups for primary outcomes were analysed by chi-squared analysis, where possible.

We analysed data extracted from the trials on an intention-to- treat basis. Where this was not done in the original report, we performed re-analysis where possible. If missing data were such that it might significantly aIect the results, we excluded these data from the analysis. This decision rested with the review authors and was clearly documented. If missing data become available subsequently, they will be included in the analyses.

Sensitivity analyses

A priori it was decided that all eligible trials would be included in the initial analysis and sensitivity analyses carried out to evaluate the eIect of trial quality, including aspects of selection, performance and attrition bias. This was done by subgrouping for quality of concealment of treatment allocation and other sensitivity analyses based on the risk of bias assessments as specified above.

Subgroup analyses

We planned subgroup analyses for:

• the major paediatric outcomes of mortality and long-term neurological morbidity according to whether the primary intention of administering magnesium sulphate was for neuroprotection of the fetus, as distinct from other indications such as prevention of eclampsia in women with pre-eclampsia or use for tocolysis.

We also planned subgroup analyses to examine separately the major paediatric outcomes of mortality and long-term neurological morbidity based on;

• the reasons the woman was considered to be at risk of preterm birth, (such as preterm labour, the presence or absence of ruptured membranes at trial entry, pre-eclampsia);

• the number of babies in utero (singleton or multiple);

• the use of prenatal corticosteroids in more than 50% of those at risk;

• the gestational age at which treatment was given;

• the type of magnesium preparation given;

• the dosage of magnesium sulphate given;

• its mode of administration;

• whether repeat treatment was permitted; and

• the time treatment was given prior to expected preterm birth.

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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We limited primary analysis to the prespecified outcomes and subgroup analyses. In the event of diIerences in outcomes not prespecified being found, we clearly identified them as such.

R E S U L T S

Description of studies

Five trials (6145 babies) qualified for inclusion in this review, one from Australia and New Zealand (Crowther 2003), two from the US (Mittendorf 2002; Rouse 2008), one from France (Marret 2006), and one that was worldwide, but predominantly from developing countries (Magpie 2006) (see 'Characteristics of included studies' table). The first four trials specifically targeted women who were likely to give birth early and magnesium was being used for neuroprotection, although one study (Mittendorf 2002) also had a tocolytic arm to the study. The fiNh study, the MAGPIE trial (Magpie 2006) was designed to evaluate whether magnesium prevented eclampsia in women with pre-eclampsia; it included women at all gestational ages. Data from the MAGPIE study relevant to women less than 37 weeks when randomised have been provided by the authors for inclusion in this review.

Crowther 2003 (neuroprotection)

A total of 1062 women with babies less than 30 weeks' gestation and in whom birth was anticipated within 24 hours were enrolled from February 1996 to September 2000 into ACTOMgSO4 (Australasian Collaborative Trial of Magnesium Sulphate). Women were excluded if birth was imminent (they were in second stage of labour), if they had already received magnesium sulphate during the pregnancy, or if there were contraindications to magnesium sulphate therapy. There were 16 collaborating centres within Australia and New Zealand. Stratification was by centre and multiple pregnancy (three groups - singleton, twin or higher order multiple). Women were randomly allocated to either intravenous magnesium sulphate (n = 535 women, 629 live babies) or an identical volume of saline placebo (n = 527 women, 626 live babies). The magnesium sulphate dose was 4 g over 20 minutes, followed by 1 g/hour for up to 24 hours or until birth, whichever came first. There were no repeat courses of treatment. The primary endpoints of the study were total paediatric mortality up to a corrected age of two years; cerebral palsy at two years' corrected age; and the combined adverse outcome of death or cerebral palsy at two year follow up.

Magpie 2006 (other intent - neuroprotection of the pre-eclamptic mother)

A total of 10,141 women who were either undelivered or within 24 hours of birth with pre-eclampsia and uncertainty about whether to use magnesium sulphate to prevent eclampsia were enrolled from July 1998 to November 2001 into the Magpie Trial - a randomised controlled trial of either magnesium sulphate or saline placebo. Women were excluded if they had hypersensitivity to magnesium, hepatic coma, or myasthenia gravis. The magnesium sulphate dose was 4 g intravenously over 10 to 15 minutes, followed by either 1 g/hour intravenously for 24 hours, or by 5 g every 4 hours intramuscularly for 24 hours. There were no repeat courses of treatment. The major endpoint of the study was neuroprotection of the mother (avoidance of eclampsia). Secondary endpoints included long-term outcome for the children. Unpublished outcome data were provided from the trial investigators on the 1544 women who were undelivered

when treated with magnesium sulphate and who were less than 37 weeks' gestational age at randomisation, as well as for the subgroups less than 34 and less than 30 weeks' gestational age at randomisation, and for the subgroups of singleton pregnancies versus multiple pregnancies. Outcome data for women from the Magpie study were included if the child was selected for follow up and outcomes for the child were known, even if the only outcome available was death.

Marret 2006 (neuroprotection)

A total of 573 women whose birth was planned or expected within 24 hours with singleton, twin or triplet less than 33 weeks' gestation were enrolled at 18 collaborating centres in France into the Premag Trial. Only data from 13 centres (564 women) were included in the final report; two of the 18 centres recruited no women and three centres enrolled fewer than five women and were excluded on the basis of a prespecified criterion for exclusion of centres. Women were not eligible when the fetus had severe malformations, chromosomal abnormalities or growth restriction, and with various maternal complications, such as pre-eclampsia, hypotension, cardiac arrhythmias, electrolyte anomalies, renal insuIiciency. Women were randomly allocated to either intravenous magnesium sulphate 4 g or an equal volume of isotonic saline placebo over 30 minutes. There were no repeat courses of treatment. The major endpoint of the study was white matter injury to the infant diagnosed by cranial ultrasound.

Mittendorf 2002 (neuroprotection/other intent: tocolysis)

A total of 149 women in preterm labour 25 to 33 weeks' gestation were enrolled from October 1995 to January 1997 at a single US centre into the MAGNET Trial. Women were excluded if there was non-reassuring fetal assessment, or clinical features of infection or pre-eclampsia, or more than twin pregnancy. Stratification was by race (black versus other), gestational age (25 to 28 weeks and 28 to 33 weeks), and, several months into the trial, plurality (singleton versus twin). There were two treatment strategies dependent upon cervical dilatation at entry: those with active labour and cervical dilatation less than 5 cm were considered candidates for tocolysis with magnesium sulphate (the 'tocolytic' arm); they were randomly allocated to receive magnesium sulphate as a 4 g bolus followed by 2 to 3 g/hour maintenance (n = 46 women, 55 babies), or an alternative tocolytic (non-blinded) (n = 46 women, 51 babies). The remainder (with cervical dilatation greater than 4 cm) were considered for the 'neuroprotective' arm of the study and were randomly allocated to either a 4 g magnesium sulphate bolus (n = 29 women, 30 babies) or saline placebo (n = 28 women, 29 babies). In the 'neuroprotective' arm no further magnesium sulphate treatment occurred. For the purposes of this review, the Mittendorf study was considered as two separate trials.

Rouse 2008 (neuroprotection)

A total of 2241 women were eligible (a singleton or twin pregnancy at least 24 weeks gestation but less than 32 weeks at high risk of spontaneous birth due to ruptured membranes at 22 to 31 weeks gestation, or advanced preterm labour with dilatation 4 to 8 cm and intact membranes; or if an indicated preterm birth was anticipated with 24 hours (e.g. due to fetal growth restriction) but not if birth was anticipated within 2 hours or if cervical dilatation exceeded 8 cm). Women were not eligible if membranes had ruptured prior to 22 weeks; the obstetrician was unwilling to

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intervene for fetal benefit; or there were major fetal anomalies or demise; presence of hypertension or pre-eclampsia; maternal contraindications to magnesium sulphate; or receipt of intravenous magnesium sulphate within the prior 12 hours.

There were 20 collaborating sites across the United States with recruitment in the BEAM Trial from December 1997 to May 2004.

Stratification was by centre, and, in twin pregnancies, gestational age below, or at, or above 28 weeks gestation. Women were "randomised in a double-blind fashion" to either intravenous magnesium sulphate (n = 1096 women, 1188 babies) or identical- appearing placebo (n = 1145 women, 1256 babies).

The magnesium sulphate dose was 6 g over 20 to 30 minutes, followed by a maintenance infusion of 2 g/hour. If delivery had not occurred aNer 12 hours and was no longer considered imminent,

the infusion was discontinued and resumed when delivery threatened. If at least 6 hours had transpired, another loading dose was given. Retreatment was withheld if: pre-eclampsia/ eclampsia developed; maternal or fetal condition deteriorated so re-treatment would be detrimental; or if the gestational age had reached 34 weeks.

The primary outcome was the composite of 1) stillbirth or infant death by one year of age, or 2) moderate or severe cerebral palsy as assessed at or beyond two years' corrected age.

Risk of bias in included studies

Overall, the methodological quality of the trials was relatively good, with a low risk of bias. However, the quality was better, and the risk of bias lower, in some studies compared with others (Figure 1; Figure 2).

Figure 1. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Figure 2. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Crowther 2003 - This was a blinded trial with randomisation performed centrally by non-clinical staI independent of the chief investigators, with random variation in block sizes of four, six or eight, and separately for singleton, twin, or higher order multiple births. Each study number was placed on a masked treatment pack. Packs were sent to individual hospitals ready for use. No one at individual study sites had access to the treatment code. Outcomes were given for all mothers and fetuses enrolled.

Follow-up component: surviving children were assessed at 24 months of age, corrected for prematurity, by paediatricians and psychologists at individual study sites who were blinded to treatment group allocation. Neurological outcomes included cerebral palsy (criteria included abnormalities of tone and motor dysfunction) and gross motor function assessed by the criteria of Palisano 1997. Substantial gross motor dysfunction comprised children who were not walking independently at two years of corrected age. Other outcomes included blindness (bilateral vision worse than 6/60), deafness requiring hearing aids, and developmental delay (defined as an Mental Developmental Index (MDI) on the Bayley Scales of Infant Development less than 85 (less than -1 SD) (Bayley 1993)). Major neurological disability was defined

as any of moderate or severe cerebral palsy, blindness, deafness or an MDI less than 70. The follow-up rate of survivors at two years was 99% (1047/1061).

Magpie 2006 - This was a blinded trial with randomisation performed centrally, independent of the clinical investigators, with balance for severity of pre-eclampsia, gestational age, undelivered or delivered, anticonvulsants prior to entry, multiple pregnancy, and country. Masked treatment packs were provided to individual hospitals ready for use. No one at individual study sites had access to the treatment code. Outcomes were given for 99.7% of mothers and 98.7% of fetuses enrolled.

Follow-up component: not all surviving children could be followed in this multinational trial for various logistical reasons. In the study overall, approximately 2/3 of surviving children were selected for follow up, and of these children outcomes were determined for 73% (n = 3283), including those who died. Children were assessed by a developmental screening questionnaire at 18 or more months of age, corrected for prematurity where appropriate, and those who failed were invited for a more formal developmental test - usually the Bayley Scales of Infant Development, either the first

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(Bayley 1969) or the second edition (Bayley 1993), or alternative tests such as the GriIiths scales. In addition, 20% of screen negative children were also assessed formally. It was intended that children would be at least 18 months old, corrected for prematurity where appropriate, but in some instances children had data only at younger ages. Major neurological disability was defined as any of moderate or severe cerebral palsy, blindness, deafness or a MDI on the Bayley Scales less than 70. Children were not routinely examined by a paediatrician or neurologist for diagnoses such as cerebral palsy. Given the lack of formal assessment of all children it is probable that diagnoses such as developmental delay (defined as a MDI on the Bayley Scales less than 85 (less than -1 SD)), or cerebral palsy were underestimated. For this review, the Magpie investigators provided data for 1593 infants whose mothers were treated at less than 37 weeks' gestational age out of the total of 3283 children with follow-up data.

Marret 2006 - This was a single-blind trial with randomisation performed centrally, with randomisation numbers generated by computer using variable block size from two to 16 depending on expected recruitment. Randomisation was independent of the clinical investigators, with balance for study centre, multiple pregnancy, and gestational age (less than 27 weeks, 27 to 29 weeks, 30 to 32 weeks). The major endpoint of the study was infant death or white matter injury detected by cranial ultrasound and defined as the presence of periventricular cavitation, intraparenchymal haemorrhage, persisting hyperechogenicity or ventricular dilatation.

Follow-up component: at two years of age. Physicians caring for the children or the study investigators, who were blinded to treatment allocation, obtained data either by clinical examination or telephone with a standardised questionnaire derived from Amiel-Tison's (Amiel-Tison 2004) and the Denver Developmental Scale. Motor and cognitive developmental scales were scored, ranging from one (normal) to four (severely impaired). Mild cognitive dysfunction was considered present if the child pointed to an article or an animal without possibility of nomination and/ or pointed to the diIerent part of the body and/or tired of quickly and/or had no symbolic games and/or had an uncertain building in and/or use of single words; a moderate cognitive dysfunction was considered if there was no preference for a toy or any activity, if the child only removed, threw out and did not put the cubes or toys in the box, if language was gibberish without identified words, if they were unable to express wish by gesture or attitude; a severe cognitive dysfunction was considered if there was no activity or stereotyped activities, no pointing with finger, no following with eyes and production of stereotyped sounds.The follow-up rate of survivors was 98%.

Mittendorf 2002 - The method of randomisation was not described. The 'tocolytic' arm was unblinded, whereas the 'neuroprotective' arm was blinded. Outcomes were given for all mothers and babies enrolled.

Follow-up component: surviving children were assessed at 4, 8, 12 and 18 months of age, corrected for prematurity, in a special follow- up clinic. Cerebral palsy (criteria not described) was diagnosed or verified at 18 months, by a developmental paediatrician who was blind to treatment allocation. Other long-term outcomes were not described. The follow-up rate of survivors was not described.

Rouse 2008 - This was a blinded trial with group allocation made according to a computer-generated random sequence. The sequence was generated centrally and given to the individual hospital pharmacies. The outcome assessors remained blinded to the treatment allocation (BEAM Study Protocol - unpublished ).

Follow-up component: Surviving children were scheduled for follow-up visits at age 6,12 and 24 months of age corrected for prematurity.

At the one year examination it was considered possible to make a definitive determination that the child did not have cerebral palsy. Infants who had a normal neurological examination and could walk 10 steps independently and had a bilateral pincer grasp, were declared free of cerebral palsy and further assessment (at two years) for cerebral palsy was not made.

Neurological outcomes included cerebral palsy, diagnosed by criteria of delay in gross motor development milestones, abnormalities of muscle tone, motor dysfunction and abnormal reflexes (persistence of primitive or absence of protective reflexes). An annually certified paediatrician or paediatric neurologist made a diagnosis of cerebral palsy if two or more of the following three features were present: a delay of 30% or more in gross motor developmental milestones (e.g., inability to sit without arm support by 9.5 months or walk by 17 months of corrected age) (Capute 1985; Blasco 1994), abnormality in muscle tone (e.g., scissoring), 4+ or absent deep-tendon reflexes, or movement abnormality (e.g., posturing or gait asymmetry); or persistence of primitive reflexes or absence of protective reflexes. The Gross Motor Function Classification Scale (Palisano 1997) was used to assess severity when cerebral palsy was diagnosed. Level one defined mild cerebral palsy, Levels two and three defined moderate, and Levels four and five defined severe. Other outcomes included scores on the Bayley Scales of Infant Development II. The follow-up rate of surviving infants was 95% (2137/2255).

EAects of interventions

This updated review includes the recently published USA study - the BEAM trial (Rouse 2008).

We included five trials with a total of 6145 babies (Crowther 2003; Magpie 2006; Marret 2006; Mittendorf 2002; Rouse 2008). The Mittendorf trial (Mittendorf 2002) has both tocolytic and neuroprotective arms. Results are presented on an 'as randomised' basis, without double counting data.

Infant mortality - fetal, neonatal and later (Graphs 1.1 to 1.3)

Antenatal magnesium sulphate treatment had no overall significant eIect on paediatric (fetal, neonatal and later) mortality (relative risk (RR) 1.04; 95% confidence interval (CI) 0.92 to 1.17; five trials; 6145 infants). While Crowther 2003; Magpie 2006; Marret 2006; and Rouse 2008 showed no significant mortality diIerences between magnesium and no magnesium groups, Mittendorf 2002 showed significantly more deaths in the magnesium group (10/85 versus 1/80). Eight of the 10 deaths in the magnesium group (and no deaths in the no magnesium group) occurred in the 'tocolytic' arms of Mittendorf 2002 compared with two deaths and one death respectively in the 'neuroprotective' arms of the trial.

There were suIicient data to permit subgroup analysis based on the primary intent for giving magnesium sulphate in the study, either

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specifically for neuroprotection of the infant (the neuroprotective intent subgroup) or for other intent subgroups of prevention of pre-eclampsia and tocolysis. The RR for the neuroprotective intent subgroup was 0.95; 95% CI 0.80 to 1.12; four trials; 4446 infants; for the other intent subgroup 'prevention of eclampsia' RR 1.11; 95% CI 0.93 to 1.31; one trial; 1593 infants; and the other intent subgroup 'tocolysis' RR 15.79; 95% CI 0.93 to 266.72; one trial; 106 infants. There was moderate heterogeneity overall (I2 = 45%) between studies, largely due to the diIerent results from the other intent subgroup 'tocolysis', from the tocolytic arm of Mittendorf 2002.

Little diIerence was seen between the magnesium and no magnesium groups for fetal deaths alone (RR 0.96; 95% CI 0.77 to 1.21; five trials; 6145 infants), in the subgroups by intent, or for deaths of liveborn infants to latest age of follow up (RR 1.06; 95% CI 0.81 to 1.40; five trials; 6145 infants). Most discrepancy between studies was seen for deaths of liveborn infants to latest age of follow up for subgroups by intent (neuroprotective intent subgroup: RR 0.96; 95% CI 0.77 to 1.18; four trials; 4446 infants; and other intent subgroup 'prevention of eclampsia': RR 1.27; 95% CI 0.96 to 1.68; one trial; 1593 infants; and other intent subgroup 'tocolysis': RR 15.79; 95% CI 0.93 to 266.72; one trial 106 infants).

Paediatric neurological outcomes (Graphs 1.4 to 1.10)

Overall antenatal magnesium sulphate treatment significantly reduced the risk for cerebral palsy (overall RR 0.68; 95% CI 0.54 to 0.87; five trials; 6145 infants);

• this remained significant within the neuroprotective intent subgroup (RR 0.71; 95% CI 0.55 to 0.91; four trials; 4446 infants);

• but not for the other intent subgroups; a. pre-eclampsia RR 0.40; 95% CI 0.08 to 2.05; one trial;1493

infants;

b. tocolysis: RR 0.13 95% CI 0.01 to 2.51; one trial; 106 infants.

There were fewer children with moderate or severe cerebral palsy in the magnesium sulphate treated group compared with placebo (overall RR 0.64; 95% CI 0.44 to 0.92; three trials; 4387 infants).

Four trials, Crowther 2003 (neuroprotective intent: 1255 infants), Marret 2006 (neuroprotective intent: 688 infants); Magpie 2006 (other intent: pre-eclampsia 1593 infants) and Rouse 2008 (neuroprotective intent: 2136 infants) reported on a number of other neurological outcomes (four trials; 5980 infants).

Substantial gross motor dysfunction was the only other outcome to show a significant diIerence between magnesium and placebo overall (RR 0.61; 95% CI 0.44 to 0.85; four trials; 5980 infants) in favour of magnesium, with the result attributable to the trials in the neuroprotective intent group (RR 0.60; 95% CI 0.43 to 0.83; three trials; 4387 children).

Combined results for the other neurological outcomes were:

• any neurological impairment: RR 1.01; 95% CI 0.86 to 1.19; two trials; 2848 infants;

• blindness: RR 0.74; 95% CI 0.17 to 3.30; three trials; 3536 infants;

• deafness: RR 0.79; 95% CI 0.24 to 2.56; three trials; 3536 infants;

• developmental delay or intellectual impairment: RR 0.99; 95% CI 0.91 to 1.09; four trials; 5980 infants;

• major neurological disability: RR 1.07; 95% CI 0.82 to 1.40; two trials; 2848 infants.

Combined paediatric mortality and neurological outcomes (Graphs 1.11 to 1.14)

There was no significant eIect of antenatal magnesium sulphate treatment on the combined rate of death or cerebral palsy overall (RR 0.94; 95% CI 0.78 to 1.12; five trials; 6145 infants). However there was a significant reduction for the neuroprotective groups RR 0.85; 95% CI 0.74 to 0.98; four trials; 4446 infants, although not for the other intent subgroups for 'prevention of eclampsia' (RR 1.09; 95% CI 0.92 to 1.29; one trial; 1593 infants, or 'tocolysis' (RR 2.47; 95% CI 0.69 to 8.81; one trial; 106 infants). The level of heterogeneity for the trials overall was I2 = 51%.

Crowther 2003; Magpie 2006; and Rouse 2008 reported other neurological outcomes. Results for combined death/neurological outcomes are only available from these three trials for a total of 5282 infants.

Neither death nor any neurological impairment (RR 1.00; 95% CI 0.91 to 1.11; two trials; 2848 infants), or death or major neurological disability (RR 1.02; 95% CI 0.90 to 1.15; two trials; 2848 infants) showed statistically significant diIerences between the magnesium and placebo groups overall. The combined outcome of death or substantial gross motor dysfunction was also not significantly in favour of magnesium overall (RR 0.92; 95% CI 0.75 to 1.12; 4 trials; 5980 infants) overall, but there was substantial heterogeneity in this outcome between the four studies (I2 = 65%).

Major maternal outcomes (Graphs 1.15 to 1.17)

There were no substantial diIerences between treatment groups in maternal deaths (RR 1.25; 95% CI 0.51 to 3.07; four trials; 5411 women), cardiac arrest (RR 0.34; 95% CI 0.04 to 3.26; four trials; 5411 women), or respiratory arrest (RR 1.02; 95% CI 0.06 to 16.25; four trials; 5411 women) but few women had these outcomes.

Cessation of maternal therapy (Graph 1.18)

Crowther 2003; Magpie 2006 and Rouse 2008 (three trials; 4847 women) reported on this outcome. Overall, significantly more women in the magnesium group ceased therapy because of side eIects (RR 3.26; 95% CI 2.46 to 4.31).

Secondary paediatric outcomes (Graphs 1.19 to 1.26)

The need for ongoing respiratory support was reduced in the magnesium group (borderline statistical significance): RR 0.94; 95% CI 0.89 to 1.00; three trials; 4387 infants.

There were no significant diIerences seen in any of the other secondary paediatric outcomes in all studies combined:

• intraventricular haemorrhage: RR 0.96; 95% CI 0.86 to 1.08; four trials; 4552 infants;

• intraventricular haemorrhage 3/4: RR 0.83; 95% CI 0.62 to 1.13; two trials; 3699 infants;

• periventricular leucomalacia RR 0.93; 95% CI 0.68 to 1.28; four trials; 4552 infants;

• Apgar score less than seven at five minutes: RR 1.03; 95% CI 0.90 to 1.18; three trials; 4387 infants;

• neonatal convulsions: RR 0.80; 95% CI 0.56 to 1.13; three trials; 4387 infants;

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• neonatal hypotonia: RR 1.02; 95% CI 0.77 to 1.36; one trial; 2444 infants;

• chronic lung disease (oxygen at 28 days): RR 1.07; 95% CI 0.94 to 1.22; one trial; 1255 infants;

• chronic lung disease (oxygen at 36 weeks): RR 1.12; 95% CI 0.95 to 1.32; two trials; 1943 infants.

None of the trials reported on need for active resuscitation at birth, how many babies were treated with postnatal steroids, measures of growth such as weight, height or head circumference or educational achievements.

Secondary maternal outcomes (Graphs 1.27 to 1.30)

There was significantly more maternal hypotension (RR 1.51; 95% CI 1.09 to 2.09; two trials; 1626 women) and tachycardia (RR 1.53; 95% CI 1.03 to 2.29; one trial; 1062 women) in the magnesium group than in the placebo group.

No significant diIerences between magnesium and placebo were seen for:

• maternal respiratory depression: RR 1.31; 95% CI 0.83 to 2.07; two trials; 3303 women;

• postpartum haemorrhage: RR 0.87; 95% CI 0.67 to 1.12; two trials; 1626 women;

• caesarean birth: RR 1.03; 95% CI 0.98 to 1.09; four trials; 5411 women.

Crowther 2003 reported that none of the women in the trial were admitted to the intensive care unit. There were no significant diIerences in the rates of admission to intensive care for the mother in the Magpie trial (Magpie 2006; RR 0.89; 95% CI 0.54 to 1.47; one trial; 1544 women).

None of the trials reported on length of labour, augmentation of labour, use of intrapartum antibiotics, breastfeeding, or maternal satisfaction.

Consumption of health resources (Graphs 1.31 to 1.32)

No substantial diIerences were seen between the magnesium and placebo groups for length of mother's hospital stay (mean diIerence (MD) 0.17 days; 95% CI -0.18 to 0.53; two trials; 2606 women) or infant's primary stay (MD -0.52 days; 95% CI -4.15 to 3.11; two trials; 2828 infants), but there was substantial heterogeneity in the last comparison (I2 = 52%).

No study reported the number of babies admitted to the neonatal intensive care unit (NICU), duration of any NICU stay or costs of care either for the mother or baby.

Sensitivity Analysis (Graphs 2.1 to 2.7)

Only two studies (Crowther 2003; Rouse 2008) had no major methodological issues of trial quality relating to aspects of selection, performance or attrition bias. Restricting the main paediatric analyses to these two trials at lowest risk of bias, antenatal magnesium sulphate treatment significantly reduced the risk for cerebral palsy (RR 0.68; 95% CI 0.52 to 0.91; two trials; 3699 infants), there was a borderline significant reduction in the combined outcome of death or cerebral palsy (RR 0.86; 95% CI 0.74 to 1.00; two trials; 3699 infants), but there were no statistically significant eIects on any other paediatric outcomes.

Subgroup Analysis

Neuroprotective intent only versus other intent (prevention of eclampsia, tocolysis)

This subgroup analysis is discussed in the primary analysis above.

Reasons women considered at risk of preterm birth

Preterm labour

In Crowther 2003, 63% of women in each group were in preterm labour at randomisation and, similarly for Marret 2006 84% in the magnesium group and 88% in the placebo group and for Rouse 2008 11% in the magnesium group and 10% in the placebo group. Results were not reported separately.

Preterm prelabour rupture of the membranes (PPROM) at randomisation

In Crowther 2003, 8% of women in the magnesium group and 10% in the placebo group had PPROM at randomisation, but results were not reported separately. In the study of Marret 2006, 54% of the magnesium group and 47% of the placebo group had PPROM at randomisation but the results were not reported separately for the subgroups. For Rouse 2008, 86% of the magnesium group and 87% of the placebo group had PPROM at randomisation but results were not reported separately.

Pre-eclampsia/eclampsia

In Crowther 2003, 16% of women in the magnesium group and 14% in the placebo group had pre-eclampsia or eclampsia at randomisation but results were not presented separately. Mittendorf 2002; Marret 2006; and Rouse 2008 excluded pre- eclamptic women. In the Magpie trial (Magpie 2006), all women had pre-eclampsia.

Single or multiple pregnancy (Graphs 3.1 to 3.7)

Data were available from Crowther 2003; Magpie 2006; and Rouse 2008 for single and multiple pregnancies separately, with no clear diIerences seen between any of the primary outcomes, although there was substantial heterogeneity where mortality was considered, either alone or combined with neurological outcomes.

Use of prenatal corticosteroids in more than 50% of those at risk (Graphs 4.1 to 4.7)

Corticosteroids were given to more than 50% of women in the trials of Crowther 2003; Marret 2006; and Rouse 2008 and to the tocolytic arm of the Mittendorf study (Mittendorf 2002), but the results were not reported separately for the subgroups. Analyses confined to these four studies revealed no diIerent conclusions.

Gestational age at randomisation (Graphs 5.01 to 5.07)

Although Mittendorf 2002 reported stratifying by gestational age, their results were not presented by gestational age. In Crowther 2003, all women at entry had fetuses younger than 30 weeks' gestation. In the study of Marret 2006 all fetuses were less than 33 weeks at randomisation. In the Rouse 2008 study all fetuses were less than 32 weeks at randomisation. The Magpie investigators (Magpie 2006) not only provided separate data for all infants less than 37 weeks at randomisation, they also provided separate data for infants less than 34 weeks and less than 30 weeks. There was substantial heterogeneity in most outcomes where mortality was considered, either alone or combined with neurological outcomes.

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There was a reduction in cerebral palsy for all five studies who recruited women at less than 34 weeks gestation (RR 0.69; 95% CI 0.54 to 0.88; five trials; 5357 infants). No clear diIerences were seen between treatment groups within the gestational age subgroups for other outcomes.

Type of magnesium preparation given

All four trials used magnesium sulphate.

Dose of magnesium given (Graphs 6.01 to 6.07)

Loading doses were either 4 g or 6 g, while the major protocol diIerence between studies was in the maintenance dose, ranging from nil (Marret 2006 and Mittendorf 2002 neuroprotective), to 1 g per hour (Crowther 2003 and Magpie 2006), to 2 to 3 g per hour (Mittendorf 2002 2002 tocolytic and Rouse 2008). There was a significant reduction in cerebral palsy in any loading and any maintenance subgroup (RR 0.68; 95% CI 0.51 to 0.91; three trials; 5292 infants), largely due to the results from Rouse 2008 . There were no substantial diIerences between treatment groups within these various dosing regimens for the other outcomes.

Mode of administration of magnesium sulphate

All five trials involved the use of intravenous magnesium, at least for the loading dose. Results for the subgroup of women who received intramuscular magnesium sulphate as maintenance were not reported from the Magpie study (Magpie 2006).

Retreatment with magnesium sulphate permitted (Graphs 7.01 to 7.07)

Retreatment was permitted in the Rouse 2008 trial but not in three trials (Crowther 2003; Magpie 2006 and Marret 2006) or the 'neuroprotective' arm in the Mittendorf 2002 trial. It is unclear whether retreatment was permitted in the 'tocolytic' arm in the Mittendorf 2002 trial. Cerebral palsy showed a significant reduction with magnesium from the one trial in the retreatment permitted subgroup (RR 0.59; 95% CI 0.40 to 0.85; one trial; 2444 infants).

Time prior to preterm birth magnesium sulphate given

The time prior to expected preterm birth the magnesium sulphate or placebo was stated to be given, varied in the study protocols. For Crowther 2003 and Marret 2006 the trial medication was given to women where birth was planned or expected within 24 hours. This was the same for women with an indicated preterm birth in Rouse 2008 but not for the women at high risk of spontaneous preterm birth. For Magpie 2006 and Mittendorf 2002 there was no specific time prior to anticipated birth treatment was given.

D I S C U S S I O N

In women who are at risk of preterm birth, the available evidence shows that giving antenatal magnesium sulphate therapy substantially improves their unborn baby's chance of survival, free of cerebral palsy. The five included randomised trials with 6145 infants show an absolute risk of 3.40% (104/3052) for babies exposed to antenatal magnesium sulphate therapy and 5% (154/3093) for babies unexposed, giving an absolute risk reduction of 1.60% in cerebral palsy. The number of women need to treat to benefit one baby is 63 (95% confidence interval 44 to 155), assuming an event rate of 5% in the no magnesium group.

The body of evidence available is largest where the indication for use of magnesium sulphate was for neuroprotection of the baby. The neuroprotective intent subgroup is the only one showing a statistical benefit overall in the reduction of cerebral palsy.

In keeping with the benefit seen on risk of cerebral palsy there is evidence from three trials now (Crowther 2003; Magpie 2006; Rouse 2008) of a neuroprotective benefit of antenatal magnesium sulphate therapy on the outcomes of substantial gross motor dysfunction. In the original trials this was a secondary outcome.

Overall, apart from cerebral palsy and substantial gross motor dysfunction there were no significant diIerences found in the risk of other neurological impairments (developmental delay or intellectual impairment, blindness, deafness) or major neurological disabilities.

There are limitations in this meta-analysis related to long- term neurological outcomes, in part because of methodological limitations of the included studies. Only two studies (Crowther 2003 and Rouse 2008) were designed to assess long-term eIects of magnesium sulphate as the primary outcome. Details of the diagnosis of cerebral palsy were unclear in the study of Mittendorf 2002. In the studies with the outcome of cerebral palsy, children have been assessed early in childhood, usually at two years of age or earlier, when the diagnosis is not always certain (Stanley 1992). Reassessment of neurological outcomes later in childhood, at least into school age, in all studies is desirable. Children in the Crowther 2003 study are being reassessed at eight to nine years of age; results should be available in 2009.

The meta-analysis shows no diIerence in paediatric mortality (fetal and later deaths) between the magnesium or no magnesium treatment groups. This is reassuring given the earlier reported concern about higher paediatric mortality that led to the termination of the Mittendorf study. Substantial heterogeneity between the studies is still evident for deaths of live born infants largely due to the Mittendorf study (Mittendorf 2002).

Secondary outcomes were not significantly diIerent between treatment groups, but these were not always reported and there were thus less data to examine for eIects of magnesium sulphate on these alternative outcomes. As further data become available it is hoped that the eIects, if any, of magnesium sulphate therapy on secondary outcomes will become clearer.

The expected higher rate of maternal side eIects with magnesium sulphate was observed, but major maternal complications were rare and not significantly diIerent between treatment groups. DiIerent strategies to reduce maternal side eIects during administration of magnesium sulphate therapy require evaluation.

Three trials (Crowther 2003; Magpie 2006; Rouse 2008) reported on need for cessation of maternal therapy. Significantly more women in the magnesium sulphate group had their therapy stopped compared with women in the placebo group (8.0% versus 2.4%, p <0.0001). Further studies are required that assess strategies to reduce maternal side eIects during administration of magnesium sulphate therapy.

In the prespecified subgroup analyses:

• when the intent of giving the magnesium sulphate was for neuroprotection, the magnesium group, compared with

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placebo, showed a significant reduction in the risk of death or cerebral palsy in favour of the magnesium group (RR 0.85; 95% CI 0.74 to 0.98; four trials; 4446 infants) and a significant reduction in substantial gross motor dysfunction (RR 0.60; 95% CI 0.43 to 0.83; three trials; 4387 children).

• for all five studies who recruited women at less than 34 weeks gestation there was a reduction in cerebral palsy (RR 0.69; 95% CI 0.54 to 0.88; five trials; 5357 infants).

• for studies with any loading and any maintenance, there was a significant reduction in cerebral palsy, largely due to the results from Rouse 2008.

• for the one trial where retreatment was permitted Rouse 2008 cerebral palsy showed a significant reduction with magnesium.

The five included trials show diversity in their inclusion and exclusion criteria; reasons women were at risk of preterm birth (preterm labour, preterm prelabour rupture of the membranes, preeclampsia), gestational ages when women were eligible; time of treatment prior to expected preterm birth; and drug treatment protocol (diIerences in loading dose given whether loading alone, or loading followed by maintenance, whether retreatment was permitted).

DiIerences in gestational age at birth between the magnesium and no magnesium groups are unlikely to explain the therapeutic benefits of antenatal magnesium sulphate. In the three studies where neuroprotection of the fetus was the primary aim and where data were available, there were negligible diIerences in mean gestational age at delivery between the magnesium and no magnesium groups (Crowther 2003 mean diIerence two days; Marret 2006 mean diIerence zero days; Rouse 2008 mean diIerence 0.1 weeks). In the neuroprotective arm of the fourth trial (Mittendorf 2002), the proportions delivering <28 weeks’ gestational age were 21% (6/28) in the magnesium group and 18% (5/28) in the no magnesium group.

To examine in a more powerful analysis whether antenatal magnesium sulphate treatment is more eIective in our prespecified subgroups (of reasons for preterm birth, singleton or multiple pregnancy, gestational age prior to birth treatment given, dosage, maintenance, retreatment) individual patient data meta- analysis may be helpful (Stewart 2002). Support from the individual trialists to contribute their data will need to be gained.

Given the positive findings that antenatal magnesium sulphate reduces the risk of cerebral palsy, further studies are required

to clarify how magnesium sulphate works, who should receive magnesium sulphate medication and how best the treatment should be given. Studies comparing the dose, timing of administration and whether maintenance magnesium therapy is required are needed and also whether the magnesium sulphate treatment should be repeated.

A U T H O R S ' C O N C L U S I O N S

Implications for practice

The evidence now supports a role for antenatal magnesium sulphate therapy in women at risk of preterm birth as a neuroprotective agent against cerebral palsy for their baby.

Implications for research

Given the beneficial eIects of magnesium sulphate reducing the risk of cerebral palsy and on substantial gross motor dysfunction in early childhood, the children in any randomised controlled trial (RCT) should be reassessed later in childhood to determine the presence or absence of other potentially important neurological eIects, particularly on motor or cognitive function.

DiIerent strategies to reduce maternal side eIects during administration of magnesium sulphate therapy require evaluation.

Studies comparing the dose, timing of administration and whether maintenance magnesium therapy is required are needed and whether the magnesium sulphate treatment should be repeated.

Clarification of who may benefit most may be assisted by individual patient meta-analysis of the data from the available trials.

A C K N O W L E D G E M E N T S

The Magpie Trial Investigators kindly provided subgroup data from their large randomised controlled trial for the purposes of this meta-analysis. Investigators from the PREMAG trial have kindly provided unpublished information on severity of cerebral palsy and developmental delay for inclusion in this meta-anaysis.

As part of the pre-publication editorial process, this review has been commented on by two peers (an editor and referee who is external to the editorial team), one or more members of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser.

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R E F E R E N C E S

References to studies included in this review

Crowther 2003 {published and unpublished data}

Crowther CA, Hiller JE, Doyle LW for the ACTOMgSO4 Collaborators Group. Does prenatal magnesium sulphate reduce the risk of mortality and cerebral palsy in infants born at less than 30 weeks' gestation? - The ACTOMgS04 trial. Perinatal Society of Australia and New Zealand 7th Annual Congress; 2003 March 9-12; Tasmania, Australia. 2003:A4.

Crowther CA, Hiller JE, Doyle LW, Haslam RR for the Australasian Collaborative Trial of Magnesium Sulphate (ACTOMg SO4) Collaborative Group. EIect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 2003;290(20):2669-76.

* Crowther CA, Hiller JE, Doyle LW, Haslam RR for the Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgS)4) Collaborative Group. EIect of magnesium sulfate given for neuroprotection before preterm birth. JAMA 2003;290(20):2669-76.

Paradisis M, Evans N, Osborn D, Kluckow M, ACTOMgSO4 Collaborators Group. The eIect of antenatal magnesium sulphate on early systemic blood flow in very preterm infants. Pediatric Research 2004;55 Suppl:114.

Smith CA, Crowther CA, Willson K, Hiller JE, Doyle LW. Placental transfer of magnesium sulphate: a randomised placebo controlled trial. Perinatal Society of Australia and New Zealand 7th Annual Congress; 2003 March 9-12; Tasmania, Australia. 2003:P48.

Magpie 2006 {unpublished data only}

Magpie Trial Follow Up Study Collaborative Group. The Magpie Trial: a randomised trial comparing magnesium sulphate with placebo for pre-eclampsia. Outcome for children at 18 months. BJOG: an international journal of obstetrics and gynaecology 2007;114(3):289-99.

Marret 2006 {published and unpublished data}

Marret S, Marpeau L, Astruc D, Cambonie G, Follet C, Benichou J. Prenatal magnesium sulfate (MgSO4) and follow up at two years of age in preterm infants: the randomised controlled PREMAG trial. Pediatric Academic Societies Annual Meeting; 2007 May 5-8; Toronto, Canada. 2007.

Marret S, Marpeau L, Benichou J. Benefit of magnesium sulfate given before very preterm birth to protect infant brain. Pediatrics 2008;121(1):225-6.

Marret S, Marpeau L, Follet-Bouhamed C, Cambonie G, Astruc D, Delaporte B, et al. for the PREMAG Group. EIect of magnesium sulphate on mortality and neurologic morbidity of the very=preterm newborn with two-year neurological outcome: results of the prospective PREMAG trial [EIet du sulfate de magnésium sur la mortalité et la morbidité neurologique chez le prématuré de moins de 33 semaines, avec recul è deux ans: résultats de l'essai prospectif multicentrique contre placebo PREMAG]. Gynécologie Obstétrique & Fertilité 2008;36:278-88.

* Marret S, Marpeau L, Zupan-Simunek V, Eurin D, Lévêque C, Hellot MF, et al. Magnesium sulfate given before very-preterm birth to protect infant brain: the randomized, controlled PREMAG trial. BJOG: an international journal of obstetrics and gynaecology 2007; Vol. 114, issue 3:310-8.

Marret S, Zupan V, Marpeau L, Adde-Michel C, Benichou J, the Premag Trial Group. Prenatal magnesium sulphate (MgSO4) and neuroprotection in preterm infants: a randomized controlled trial. Pediatric Academic Societies Annual Meeting; 2005 May 14-17; Washington DC, USA. 2005.

Mittendorf 2002 {published data only}

Mittendorf R, Bentz L, Borg M, Roizen N. Does exposure to antenatal magnesium sulfate prevent cerebral palsy?. American Journal of Obstetrics and Gynecology 2000;182(1 Pt 2):S20.

Mittendorf R, Bentz L, Kohn J, Covert R. Use of antenatal magnesium sulfate does not seem to prevent intraventricular hemorrhage. American Journal of Obstetrics and Gynecology 2000;182(1 Pt 2):S34.

Mittendorf R, Besinger R, Santillan M, Gianopoulos J. When used in circumstance of preterm labor, is there a paradoxical eIect of varying exposures to magnesium sulfate (MGSO4) on the developing human brain?. American Journal of Obstetrics and Gynecology 2005;193(6 Suppl):S65.

Mittendorf R, Covert R, Boman J, Khoshnood B, Lee KS, Siegler M. Is tocolytic magnesium sulphate associated with increased total paediatric mortality?. Lancet 1997;350(9090):1517-8.

Mittendorf R, Covert R, Elin R, Pryde P, Khoshnood B, Sun- Lee K. Umbilical cord serum ionized magnesium level and total pediatric mortality. Obstetrics & Gynecology 2001;98:75-8.

Mittendorf R, Dambrosia J, Dammann O, Pryde PG, Lee KS, Ben- Ami TE, et al. Association between maternal serum ionized magnesium levels at delivery and neonatal intraventricular hemorrhage. Journal of Pediatrics 2002;140(5):540-6.

Mittendorf R, Dambrosia J, Khoshnood B, Lee K-S, Pryde P, Yousefzadeh D. Magnesium sulfate is no more eIicacious than other tocolytic agents. American Journal of Obstetrics and Gynecology 2001;184(1):S188.

Mittendorf R, Dambrosia J, Khoshnood B, Lee KS, Pryde P, Yousefzadeh D. Association between magnesium and intraventricular haemorrhage. American Journal of Obstetrics and Gynecology 2001;184(1):S188.

* Mittendorf R, Dambrosia J, Pryde PG, Lee KS, Gianopoulos JG, Besinger RE, et al. Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants. American Journal of Obstetrics and Gynecology 2002;186(6):1111-8.

Mittendorf R, Janeczek S, Macmillan W, Gianopoulos J, Besinger R, Karlman R, et al. Mechanisms of mortality in the magnesium and neurologic endpoints trial (magnet trial): fetal

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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inflammatory response syndrome (firs). American Journal of Obstetrics and Gynecology 2001;185(6 Suppl):S151.

Mittendorf R, Kuban K, Pryde PG, Gianopoulos JG, Yousefzadeh D. Antenatal risk factors associated with the development of lenticulostriate vasculopathy (lsv) in neonates. Journal of Perinatology 2005;25(2):101-7.

Mittendorf R, Pryde P, Khoshnood B, Lee KS. If tocolytic magnesium sulfate is associated with excess total pediatric mortality, what is its impact?. Obstetrics & Gynecology 1998;92(2):308-11.

Mittendorf R, Pryde P, Lee K-S, Besinger R, MacMillan W, Karlman R, et al. Coagulase negative staphylococci cultured from the placental chorioamnion space at delivery are associated with lower bayley scores. American Journal of Obstetrics and Gynecology 2002;187(6 Pt 2):S131.

Mittendorf R, Pryde P, Lee KS, Besinger R, Macmillan W, Karlman R, et al. Umbilical cord serum ionized magnesium levels at delivery are not correlated with neuroprotection in childhood. American Journal of Obstetrics and Gynecology 2002;187(6 Pt 2):S74.

Santillan M, Besinger RE, Gianopoulos JG, Mittendorf R. An inverse correlation between umbilical cord blood ionized magnesium (IMG) and interleukin-6 (IL-6) levels could not be confirmed in the human. American Journal of Obstetrics and Gynecology 2005;193(6 Suppl):S183.

Rouse 2008 {published data only}

NICHD. Beneficial eIects of antenatal magnesium sulfate. ClinicalTrials.gov (http://clinicaltrials.gov/) (accessed 11 January 2007).

Rouse D. 1: A randomized controlled trial of magnesium sulfate for the prevention of cerebral palsy. American journal of obstetrics and gynecology (0002-9378) 2007;197(6):S2. [DOI: 10.1016/j.ajog.2007.10.002]

* Rouse D, Hirtz D, Thom E, Varner M, Alexander J, Spong C, Mercer B, Iams J, Wapner R, Sorokin Y, Harper M, Thorp J, Ramin S, Malone F, Carpenter M, Miodovnik A, Moawad A, O'Sullivan M, Peaceman A, Hankins G, Langer O, Caritis S, Roberts J. Magnesium sulfate for the prevention of cerebral palsy. New England Journal of Medicine 2008;359:895-905.

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* Indicates the major publication for the study

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]

Methods Randomised trial.

Participants 1062 women (1255 fetuses) < 30 weeks' gestation likely to deliver within 24 hours. Exclusions: already received magnesium sulphate or magnesium sulphate contraindicated.

Interventions Active treatment - infusion of 4 g magnesium sulphate over 20 minutes, then 1 g/hour until delivery or for 24 hours, whichever came first. Placebo group - equal volume of 0.9% saline.

Outcomes Primary outcomes: total paediatric mortality (stillbirths, deaths during the primary hospitalisation and after discharge) up to 2 years of age, cerebral palsy, and combined outcome of death or cerebral palsy. Secondary infant outcomes: major IVH, (grade 3 or 4), cystic periventricular leucomalacia, neurosenso- ry disability (severe - any of severe cerebral palsy (not likely to walk), blindness, or severe developmen- tal delay (MDI < -3 SD); moderate - moderate cerebral palsy (not walking at 2 years, but likely to do so), deafness, moderate developmental delay (MDI -3 SD to < -2 SD); mild - mild cerebral palsy (walking at 2 years) or mild developmental delay (MDI - 2 SD to < -1 SD), substantial gross motor dysfunction (not walking at 2 years of age). Maternal outcomes: adverse cardiovascular and respiratory effects of infu- sion, postpartum haemorrhage.

Notes

Risk of bias

Bias Authors' judgement Support for judgement

Adequate sequence gener- ation?

Low risk Central computer-generated randomisation.

Allocation concealment? Low risk Central telephone randomisation.

Blinding? All outcomes

Low risk Intervention and outcome assessments blinded.

Incomplete outcome data addressed? All outcomes

Low risk Complete follow up for outcomes during primary hospitalisation; 99% of sur- viving infants traced to 2 years of age.

Free of selective report- ing?

Low risk No indication of selective reporting.

Crowther 2003

Methods Randomised trial.

Participants 1544 women (1593 fetuses) < 37 weeks' gestation with severe pre-eclampsia and randomised prior to delivery. Women were excluded if they had hypersensitivity to magnesium, hepatic coma, or myasthe- nia gravis.

Magpie 2006

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Data provided by the Magpie Investigators for a subset of the women who were < 37 weeks' gestational age and undelivered at the time of randomisation.

Interventions Active treatment - magnesium sulphate dose 4 g intravenously over 10 to 15 minutes, followed by ei- ther 1 g/hour intravenously for 24 hours, or by 5 g every 4 hours intramuscularly for 24 hours.

Outcomes Primary outcomes: neuroprotection of the mother (avoidance of eclampsia). Secondary endpoints in- cluded long-term outcomes for the children.

Notes

Risk of bias

Bias Authors' judgement Support for judgement

Adequate sequence gener- ation?

Low risk Central computer-generated randomisation.

Allocation concealment? Low risk Central randomisation.

Blinding? All outcomes

Low risk Intervention and outcome assessments were blinded.

Incomplete outcome data addressed? All outcomes

Unclear risk Outcomes were given for 99.7% of mothers and 98.7% of fetuses enrolled.

Approximately 2/3 of surviving children were selected for follow up, and of these children outcomes were determined for 73% (n = 3283), including those who died.

Free of selective report- ing?

Low risk No indication of selective reporting.

Magpie 2006 (Continued)

Methods Randomised trial.

Participants 564 women (688 fetuses) in labour < 33 weeks' gestation. Exclusion criteria included fetal malforma- tions, growth restriction, or chromosomal anomalies, and various maternal reasons.

Interventions 4 g magnesium sulphate over 30 minutes (286 women; 354 infants). Placebo (isotonic 0.9% saline) (278 women; 341 infants).

Outcomes Primary outcomes: infant death or white matter injury on cranial ultrasound. Secondary outcomes included follow up of children at 2 years of age.

Notes Was stopped early due to dwindling recruitment (projected sample size was 1106 newborns)

Risk of bias

Bias Authors' judgement Support for judgement

Adequate sequence gener- ation?

Low risk Central computer-generated randomisation.

Allocation concealment? Low risk Central randomisation.

Marret 2006

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Blinding? All outcomes

Unclear risk Paediatricians who were blinded to treatment evaluated motor and cognitive functions; however, obstericians and anaesthetists were not blinded.

Incomplete outcome data addressed? All outcomes

Unclear risk 573 women were randomised; 564 women with 688 infants were analysed. Of the 616 survivors, 606 infants were followed up (472 by clinical examination and 134 through parent telephone interview); and 10 were lost to follow up.

Free of selective report- ing?

Low risk No indication of selective reporting.

Marret 2006 (Continued)

Methods Randomised trial.

Participants 149 women (165 fetuses) in preterm labour, with or without premature rupture of the membranes. Exclusion criteria: mothers with triplet or higher order gestations.

Interventions "Tandem" randomisation: 1) eligible for aggressive tocolysis (cervix < = 4 cm dilation), magnesium sulphate tocolysis (n = 46), 'other' tocolysis (n = 46); 2) not eligible for tocolysis (cervix > 4 cm dilatation) neuroprotective magnesium sulphate (n = 29), saline control (n = 28).

Outcomes Fetal and later mortality; CP; Death or CP; IVH.

Notes

Risk of bias

Bias Authors' judgement Support for judgement

Adequate sequence gener- ation?

Unclear risk Method not described.

Allocation concealment? Unclear risk Method not described.

Blinding? All outcomes

Unclear risk Intervention: neuroprotective arm was blinded, but the tocolytic arm was not blinded.

Cerebral palsy was assessed by a developmental paediatrician who was blind to the treatment allocation.

Incomplete outcome data addressed? All outcomes

Unclear risk Losses to follow up not reported.

Free of selective report- ing?

Unclear risk Some outcomes not reported in sufficient detail; some possibility of selective reporting.

Mittendorf 2002

Methods Randomised trial.

Rouse 2008

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Participants 2241 women (2444 fetuses) at least 24 weeks but less than 32 weeks' gestation, at high risk of sponta- neous birth due to ruptured membranes at 22 to 31 weeks' GA, or advanced preterm labor with dilata- tion 4 to 8 cm and intact membranes; also if an indicated preterm birth was anticipated within 24 hours (e.g. due to fetal growth restriction).

Exclusions: not eligible if birth was anticipated within 2 hours or if cervical dilatation exceeded 8 cm. Not eligible if rupture of membranes prior to 22 weeks; obstetrician unwilling to intervene for fetal ben- efit; major fetal anomalies, or demise; hypertension or pre-eclampsia; maternal contraindications to magnesium sulphate e.g. severe pulmonary disorders; and receipt of intravenous magnesium sulphate within the prior 12 hours.

Interventions Active treatment - magnesium sulphate dose 6 g intravenously over 20 to 30 minutes, followed by maintenance infusion of 2 g/hour. If delivery had not occurred after 12 hours and was no longer consid- ered imminent the infusion was discontinued and resumed when delivery threatened. If at least 6 hours had transpired another loading dose was given. Re-treatment was withheld if preeclampsia or eclamp- sia developed, if the maternal or fetal condition had deteriorated such that the delay for re-treatment would be detrimental, or if the gestational age had reached 34 weeks. The placebo group received an 'identical-appearing placebo'.

Outcomes Primary outcomes: the composite of 1) stillbirth or infant death by 1 year of age, or 2 years of age) mod- erate or severe cerebral palsy as assessed at or beyond 2 years of age (corrected). Secondary outcomes included maternal outcomes and complications, adverse events potentially attributable to the study intervention, neonatal complications, cerebral palsy at 2 years classified as mild, moderate or severe; stillbirth; infant death; and scores on the Bayley Scales of Infant development-II.

Notes

Risk of bias

Bias Authors' judgement Support for judgement

Adequate sequence gener- ation?

Low risk Central computer-generated randomisation.

Allocation concealment? Low risk Central (pharmacy) randomisation.

Blinding? All outcomes

Low risk Interventions and outcome assessments blinded.

Incomplete outcome data addressed? All outcomes

Low risk The follow-up rate of surviving infants was 95% (2137/2255).

Free of selective report- ing?

Low risk No indication of selective reporting.

Rouse 2008 (Continued)

CP: cerebral palsy IVH: intraventricular haemorrhage MDI: Mental Developmental Index SD: standard deviation GA: gestational age

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Comparison 1. Magnesium versus no magnesium

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 Paediatric mortality (fetal and later)

5 6145 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.92, 1.17]

1.1 Neuroprotective intent 4 4446 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.80, 1.12]

1.2 Other intent (maternal neu- roprotective - pre-eclampsia)

1 1593 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.93, 1.31]

1.3 Other intent (tocolytic) 1 106 Risk Ratio (M-H, Fixed, 95% CI) 15.79 [0.93, 266.72]

2 Fetal death 5 6145 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.77, 1.21]

2.1 Neuroprotective intent 4 4446 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.42, 1.46]

2.2 Other intent (maternal neu- roprotective - pre-eclampsia)

1 1593 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.78, 1.27]

2.3 Other intent (tocolytic) 1 106 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

3 Livebirth deaths 5 Risk Ratio (M-H, Random, 95% CI) Subtotals only

3.1 To latest age of follow up - neuroprotective intent

4 4446 Risk Ratio (M-H, Random, 95% CI) 0.96 [0.77, 1.18]

3.2 To latest age of follow up - other intent: maternal neuro- protective (pre-eclampsia)

1 1593 Risk Ratio (M-H, Random, 95% CI) 1.27 [0.96, 1.68]

3.3 To latest age of follow up - other intent: tocolytic

1 106 Risk Ratio (M-H, Random, 95% CI) 15.79 [0.93, 266.72]

3.4 To latest age of follow up - any intent

5 6145 Risk Ratio (M-H, Random, 95% CI) 1.06 [0.81, 1.40]

3.5 During primary hospitalisa- tion - neuroprotective intent

3 4387 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.76, 1.23]

3.6 During primary hospitali- sation - other intent: maternal neuroprotective (pre-eclamp- sia)

1 1593 Risk Ratio (M-H, Random, 95% CI) 1.27 [0.92, 1.73]

3.7 During primary hospitalisa- tion - any intent

4 5980 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.84, 1.29]

4 Cerebral palsy 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

4.1 Neuroprotective intent: any CP

4 4446 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.55, 0.91]

4.2 Neuroprotective intent: mild CP

3 4387 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.52, 1.04]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

4.3 Neuroprotective intent: moderate CP

2 1943 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.34, 1.28]

4.4 Neuroprotective intent: moderate/severe CP

3 4387 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.44, 0.92]

4.5 Neuroprotective intent: se- vere CP

2 1943 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.37, 1.82]

4.6 Other intent: maternal neu- roprotective (pre-eclampsia)

1 1593 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.08, 2.05]

4.7 Other intent: tocolytic 1 106 Risk Ratio (M-H, Fixed, 95% CI) 0.13 [0.01, 2.51]

4.8 Any CP: any intent 5 6145 Risk Ratio (M-H, Fixed, 95% CI) 0.68 [0.54, 0.87]

5 Any neurological impairment 2 2848 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.86, 1.19]

5.1 Neuroprotective intent 1 1255 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.87, 1.21]

5.2 Other intent (maternal neu- roprotective - pre-eclampsia)

1 1593 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.34, 1.74]

6 Substantial gross motor dys- function

4 5980 Risk Ratio (M-H, Fixed, 95% CI) 0.61 [0.44, 0.85]

6.1 Neuroprotective intent 3 4387 Risk Ratio (M-H, Fixed, 95% CI) 0.60 [0.43, 0.83]

6.2 Other intent: maternal neu- roprotective - pre-eclampsia)

1 1593 Risk Ratio (M-H, Fixed, 95% CI) 2.99 [0.12, 73.26]

7 Blindness 3 3536 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.17, 3.30]

7.1 Neuroprotective intent 2 1943 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.14, 6.90]

7.2 Other intent (maternal neu- roprotective - pre-eclampsia)

1 1593 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.05, 5.48]

8 Deafness 3 3536 Risk Ratio (M-H, Random, 95% CI) 0.79 [0.24, 2.56]

8.1 Neuroprotective intent 2 1943 Risk Ratio (M-H, Random, 95% CI) 0.51 [0.05, 4.96]

8.2 Other intent (maternal neu- roprotective - pre-eclampsia)

1 1593 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.06, 15.90]

9 Developmental delay or intel- lectual impairment

4 5980 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.91, 1.09]

9.1 Neuroprotective intent 3 4387 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.91, 1.09]

9.2 Other intent (maternal neu- roprotective - pre-eclampsia)

1 1593 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.32, 2.01]

10 Major neurological disability 2 2848 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.82, 1.40]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

10.1 Neuroprotective intent 1 1255 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.86, 1.51]

10.2 Other intent (maternal neu- roprotective - pre-eclampsia)

1 1593 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.30, 1.60]

11 Death or cerebral palsy 5 6145 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.78, 1.12]

11.1 Neuroprotective intent 4 4446 Risk Ratio (M-H, Random, 95% CI) 0.85 [0.74, 0.98]

11.2 Other intent (maternal neu- roprotective - pre-eclampsia)

1 1593 Risk Ratio (M-H, Random, 95% CI) 1.09 [0.92, 1.29]

11.3 Other intent (tocolytic) 1 106 Risk Ratio (M-H, Random, 95% CI) 2.47 [0.69, 8.81]

12 Death or any neurological impairment

2 2848 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.91, 1.11]

12.1 Neuroprotective intent 1 1255 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.84, 1.07]

12.2 Other intent (maternal neu- roprotective - pre-eclampsia)

1 1593 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.92, 1.28]

13 Death or substantial gross motor dysfunction

4 5980 Risk Ratio (M-H, Random, 95% CI) 0.92 [0.75, 1.12]

13.1 Neuroprotective intent 3 4387 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.71, 1.00]

13.2 Other intent (maternal neu- roprotective - pre-eclampsia)

1 1593 Risk Ratio (M-H, Random, 95% CI) 1.11 [0.94, 1.32]

14 Death or major neurological disability

2 2848 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.90, 1.15]

14.1 Neuroprotective intent 1 1255 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.80, 1.13]

14.2 Other intent (maternal neu- roprotective (pre-eclampsia)

1 1593 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.92, 1.27]

15 Maternal mortality 4 5411 Risk Ratio (M-H, Fixed, 95% CI) 1.25 [0.51, 3.07]

16 Maternal cardiac arrest 4 5411 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.04, 3.26]

17 Maternal respiratory arrest 4 5411 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.06, 16.25]

18 Cessation of maternal thera- py

3 4847 Risk Ratio (M-H, Fixed, 95% CI) 3.26 [2.46, 4.31]

19 Intraventricular haemor- rhage

4 4552 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.86, 1.08]

20 Intraventricular haemor- rhage 3/4

2 3699 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.62, 1.13]

21 Periventricular leucomalacia 4 4552 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.68, 1.28]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

22 Apgar score < 7 at 5 minutes 3 4387 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.90, 1.18]

23 Neonatal convulsions 3 4387 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.56, 1.13]

24 Neonatal hypotonia 1 2444 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.77, 1.36]

25 Ongoing respiratory support 3 4387 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.89, 1.00]

26 Chronic lung disease 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

26.1 Oxygen at 28 days 1 1255 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.94, 1.22]

26.2 Oxygen at 36 weeks 2 1943 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.95, 1.32]

27 Maternal hypotension 2 1626 Risk Ratio (M-H, Fixed, 95% CI) 1.51 [1.09, 2.09]

28 Maternal tachycardia 1 1062 Risk Ratio (M-H, Fixed, 95% CI) 1.53 [1.03, 2.29]

29 Maternal respiratory depres- sion

2 3303 Risk Ratio (M-H, Fixed, 95% CI) 1.31 [0.83, 2.07]

30 Postpartum haemorrhage 2 1626 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.67, 1.12]

31 Caesarean birth 4 5411 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.98, 1.09]

32 Mother admitted to intensive care unit

2 2606 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.54, 1.47]

33 Duration of mother's hospital stay (days)

2 2606 Mean Difference (IV, Fixed, 95% CI) 0.17 [-0.18, 0.53]

34 Duration of primary hospital stay for babies (days)

2 2828 Mean Difference (IV, Random, 95% CI) -0.52 [-4.15, 3.11]

Analysis 1.1. Comparison 1 Magnesium versus no magnesium, Outcome 1 Paediatric mortality (fetal and later).

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.1.1 Neuroprotective intent

Crowther 2003 87/629 107/626 24.98% 0.81[0.62,1.05]

Marret 2006 34/352 38/336 9.06% 0.85[0.55,1.32]

Mittendorf 2002 2/30 1/29 0.24% 1.93[0.19,20.18]

Rouse 2008 103/1188 96/1256 21.74% 1.13[0.87,1.48]

Subtotal (95% CI) 2199 2247 56.01% 0.95[0.8,1.12]

Total events: 226 (Magnesium), 242 (No magnesium)

Heterogeneity: Tau2=0; Chi2=3.73, df=3(P=0.29); I2=19.63%

Test for overall effect: Z=0.62(P=0.53)

1.1.2 Other intent (maternal neuroprotective - pre-eclampsia)

Favours magnesium 50.2 20.5 1 Favours no magnesium

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Magpie 2006 209/798 188/795 43.87% 1.11[0.93,1.31]

Subtotal (95% CI) 798 795 43.87% 1.11[0.93,1.31]

Total events: 209 (Magnesium), 188 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=1.17(P=0.24)

1.1.3 Other intent (tocolytic)

Mittendorf 2002 8/55 0/51 0.12% 15.79[0.93,266.72]

Subtotal (95% CI) 55 51 0.12% 15.79[0.93,266.72]

Total events: 8 (Magnesium), 0 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=1.91(P=0.06)

Total (95% CI) 3052 3093 100% 1.04[0.92,1.17]

Total events: 443 (Magnesium), 430 (No magnesium)

Heterogeneity: Tau2=0; Chi2=9.07, df=5(P=0.11); I2=44.89%

Test for overall effect: Z=0.57(P=0.57)

Test for subgroup differences: Not applicable

Favours magnesium 50.2 20.5 1 Favours no magnesium

Analysis 1.2. Comparison 1 Magnesium versus no magnesium, Outcome 2 Fetal death.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.2.1 Neuroprotective intent

Crowther 2003 9/629 11/626 8.25% 0.81[0.34,1.95]

Marret 2006 2/352 3/336 2.3% 0.64[0.11,3.78]

Mittendorf 2002 1/30 0/29 0.38% 2.9[0.12,68.5]

Rouse 2008 5/1188 8/1256 5.82% 0.66[0.22,2.01]

Subtotal (95% CI) 2199 2247 16.75% 0.78[0.42,1.46]

Total events: 17 (Magnesium), 22 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.81, df=3(P=0.85); I2=0%

Test for overall effect: Z=0.77(P=0.44)

1.2.2 Other intent (maternal neuroprotective - pre-eclampsia)

Magpie 2006 111/798 111/795 83.25% 1[0.78,1.27]

Subtotal (95% CI) 798 795 83.25% 1[0.78,1.27]

Total events: 111 (Magnesium), 111 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.03(P=0.98)

1.2.3 Other intent (tocolytic)

Mittendorf 2002 0/55 0/51 Not estimable

Subtotal (95% CI) 55 51 Not estimable

Total events: 0 (Magnesium), 0 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 3052 3093 100% 0.96[0.77,1.21]

Favours magnesium 200.05 50.2 1 Favours no magnesium

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 128 (Magnesium), 133 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.33, df=4(P=0.86); I2=0%

Test for overall effect: Z=0.35(P=0.73)

Test for subgroup differences: Not applicable

Favours magnesium 200.05 50.2 1 Favours no magnesium

Analysis 1.3. Comparison 1 Magnesium versus no magnesium, Outcome 3 Livebirth deaths.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

1.3.1 To latest age of follow up - neuroprotective intent

Crowther 2003 78/629 96/626 38.81% 0.81[0.61,1.07]

Marret 2006 32/352 35/336 21.44% 0.87[0.55,1.38]

Mittendorf 2002 1/30 1/29 0.83% 0.97[0.06,14.74]

Rouse 2008 98/1188 88/1256 38.92% 1.18[0.89,1.55]

Subtotal (95% CI) 2199 2247 100% 0.96[0.77,1.18]

Total events: 209 (Magnesium), 220 (No magnesium)

Heterogeneity: Tau2=0.01; Chi2=3.73, df=3(P=0.29); I2=19.58%

Test for overall effect: Z=0.41(P=0.68)

1.3.2 To latest age of follow up - other intent: maternal neuroprotec- tive (pre-eclampsia)

Magpie 2006 98/798 77/795 100% 1.27[0.96,1.68]

Subtotal (95% CI) 798 795 100% 1.27[0.96,1.68]

Total events: 98 (Magnesium), 77 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=1.65(P=0.1)

1.3.3 To latest age of follow up - other intent: tocolytic

Mittendorf 2002 8/55 0/51 100% 15.79[0.93,266.72]

Subtotal (95% CI) 55 51 100% 15.79[0.93,266.72]

Total events: 8 (Magnesium), 0 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=1.91(P=0.06)

1.3.4 To latest age of follow up - any intent

Crowther 2003 78/629 96/626 27.95% 0.81[0.61,1.07]

Marret 2006 32/352 35/336 15.44% 0.87[0.55,1.38]

Magpie 2006 98/798 77/795 27.53% 1.27[0.96,1.68]

Mittendorf 2002 9/85 1/80 1.06% 8.47[1.1,65.36]

Rouse 2008 98/1188 88/1256 28.03% 1.18[0.89,1.55]

Subtotal (95% CI) 3052 3093 100% 1.06[0.81,1.4]

Total events: 315 (Magnesium), 297 (No magnesium)

Heterogeneity: Tau2=0.05; Chi2=10.47, df=4(P=0.03); I2=61.79%

Test for overall effect: Z=0.44(P=0.66)

1.3.5 During primary hospitalisation - neuroprotective intent

Crowther 2003 76/629 92/626 40.83% 0.82[0.62,1.09]

Marret 2006 31/352 32/336 21.92% 0.92[0.58,1.48]

Favours magnesium 50.2 20.5 1 Favours no magnesium

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

Rouse 2008 80/1188 71/1256 37.25% 1.19[0.87,1.62]

Subtotal (95% CI) 2169 2218 100% 0.97[0.76,1.23]

Total events: 187 (Magnesium), 195 (No magnesium)

Heterogeneity: Tau2=0.02; Chi2=3.05, df=2(P=0.22); I2=34.32%

Test for overall effect: Z=0.26(P=0.79)

1.3.6 During primary hospitalisation - other intent: maternal neuro- protective (pre-eclampsia)

Magpie 2006 80/798 63/795 100% 1.27[0.92,1.73]

Subtotal (95% CI) 798 795 100% 1.27[0.92,1.73]

Total events: 80 (Magnesium), 63 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=1.46(P=0.14)

1.3.7 During primary hospitalisation - any intent

Rouse 2008 80/1188 71/1256 27.28% 1.19[0.87,1.62]

Crowther 2003 76/629 92/626 29.9% 0.82[0.62,1.09]

Marret 2006 31/352 32/336 16.06% 0.92[0.58,1.48]

Magpie 2006 80/798 63/795 26.76% 1.27[0.92,1.73]

Subtotal (95% CI) 2967 3013 100% 1.04[0.84,1.29]

Total events: 267 (Magnesium), 258 (No magnesium)

Heterogeneity: Tau2=0.02; Chi2=5.12, df=3(P=0.16); I2=41.37%

Test for overall effect: Z=0.36(P=0.72)

Favours magnesium 50.2 20.5 1 Favours no magnesium

Analysis 1.4. Comparison 1 Magnesium versus no magnesium, Outcome 4 Cerebral palsy.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.4.1 Neuroprotective intent: any CP

Crowther 2003 36/629 42/626 28.99% 0.85[0.55,1.31]

Marret 2006 22/352 30/336 21.13% 0.7[0.41,1.19]

Mittendorf 2002 3/30 0/29 0.35% 6.77[0.37,125.65]

Rouse 2008 41/1188 74/1256 49.53% 0.59[0.4,0.85]

Subtotal (95% CI) 2199 2247 100% 0.71[0.55,0.91]

Total events: 102 (Magnesium), 146 (No magnesium)

Heterogeneity: Tau2=0; Chi2=4.01, df=3(P=0.26); I2=25.17%

Test for overall effect: Z=2.74(P=0.01)

1.4.2 Neuroprotective intent: mild CP

Crowther 2003 21/629 21/626 28.66% 1[0.55,1.8]

Marret 2006 12/352 17/336 23.69% 0.67[0.33,1.39]

Rouse 2008 21/1188 36/1256 47.65% 0.62[0.36,1.05]

Subtotal (95% CI) 2169 2218 100% 0.74[0.52,1.04]

Total events: 54 (Magnesium), 74 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.47, df=2(P=0.48); I2=0%

Test for overall effect: Z=1.72(P=0.09)

1.4.3 Neuroprotective intent: moderate CP

Favours magnesium 10000.001 100.1 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 12/629 15/626 71.01% 0.8[0.38,1.69]

Marret 2006 2/352 6/336 28.99% 0.32[0.06,1.57]

Subtotal (95% CI) 981 962 100% 0.66[0.34,1.28]

Total events: 14 (Magnesium), 21 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.05, df=1(P=0.31); I2=4.45%

Test for overall effect: Z=1.23(P=0.22)

1.4.4 Neuroprotective intent: moderate/severe CP

Crowther 2003 15/629 21/626 29.53% 0.71[0.37,1.37]

Marret 2006 10/352 13/336 18.66% 0.73[0.33,1.65]

Rouse 2008 20/1188 38/1256 51.82% 0.56[0.33,0.95]

Subtotal (95% CI) 2169 2218 100% 0.64[0.44,0.92]

Total events: 45 (Magnesium), 72 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.47, df=2(P=0.79); I2=0%

Test for overall effect: Z=2.42(P=0.02)

1.4.5 Neuroprotective intent: severe CP

Crowther 2003 3/629 6/626 45.64% 0.5[0.13,1.98]

Marret 2006 8/352 7/336 54.36% 1.09[0.4,2.98]

Subtotal (95% CI) 981 962 100% 0.82[0.37,1.82]

Total events: 11 (Magnesium), 13 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.81, df=1(P=0.37); I2=0%

Test for overall effect: Z=0.49(P=0.63)

1.4.6 Other intent: maternal neuroprotective (pre-eclampsia)

Magpie 2006 2/798 5/795 100% 0.4[0.08,2.05]

Subtotal (95% CI) 798 795 100% 0.4[0.08,2.05]

Total events: 2 (Magnesium), 5 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=1.1(P=0.27)

1.4.7 Other intent: tocolytic

Mittendorf 2002 0/55 3/51 100% 0.13[0.01,2.51]

Subtotal (95% CI) 55 51 100% 0.13[0.01,2.51]

Total events: 0 (Magnesium), 3 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=1.35(P=0.18)

1.4.8 Any CP: any intent

Crowther 2003 36/629 42/626 27.55% 0.85[0.55,1.31]

Magpie 2006 2/798 5/795 3.28% 0.4[0.08,2.05]

Marret 2006 22/352 30/336 20.08% 0.7[0.41,1.19]

Mittendorf 2002 3/85 3/80 2.02% 0.94[0.2,4.53]

Rouse 2008 41/1188 74/1256 47.07% 0.59[0.4,0.85]

Subtotal (95% CI) 3052 3093 100% 0.68[0.54,0.87]

Total events: 104 (Magnesium), 154 (No magnesium)

Heterogeneity: Tau2=0; Chi2=2.26, df=4(P=0.69); I2=0%

Test for overall effect: Z=3.08(P=0)

Favours magnesium 10000.001 100.1 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Analysis 1.5. Comparison 1 Magnesium versus no magnesium, Outcome 5 Any neurological impairment.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.5.1 Neuroprotective intent

Crowther 2003 193/629 187/626 93.5% 1.03[0.87,1.21]

Subtotal (95% CI) 629 626 93.5% 1.03[0.87,1.21]

Total events: 193 (Magnesium), 187 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.31(P=0.75)

1.5.2 Other intent (maternal neuroprotective - pre-eclampsia)

Magpie 2006 10/798 13/795 6.5% 0.77[0.34,1.74]

Subtotal (95% CI) 798 795 6.5% 0.77[0.34,1.74]

Total events: 10 (Magnesium), 13 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.64(P=0.52)

Total (95% CI) 1427 1421 100% 1.01[0.86,1.19]

Total events: 203 (Magnesium), 200 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.48, df=1(P=0.49); I2=0%

Test for overall effect: Z=0.12(P=0.9)

Test for subgroup differences: Not applicable

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 1.6. Comparison 1 Magnesium versus no magnesium, Outcome 6 Substantial gross motor dysfunction.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.6.1 Neuroprotective intent

Crowther 2003 18/629 34/626 36.24% 0.53[0.3,0.92]

Marret 2006 18/352 22/336 23.94% 0.78[0.43,1.43]

Rouse 2008 20/1188 38/1256 39.29% 0.56[0.33,0.95]

Subtotal (95% CI) 2169 2218 99.47% 0.6[0.43,0.83]

Total events: 56 (Magnesium), 94 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.01, df=2(P=0.6); I2=0%

Test for overall effect: Z=3.08(P=0)

1.6.2 Other intent: maternal neuroprotective - pre-eclampsia)

Magpie 2006 1/798 0/795 0.53% 2.99[0.12,73.26]

Subtotal (95% CI) 798 795 0.53% 2.99[0.12,73.26]

Total events: 1 (Magnesium), 0 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.67(P=0.5)

Total (95% CI) 2967 3013 100% 0.61[0.44,0.85]

Total events: 57 (Magnesium), 94 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.96, df=3(P=0.58); I2=0%

Test for overall effect: Z=2.98(P=0)

Test for subgroup differences: Not applicable

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Analysis 1.7. Comparison 1 Magnesium versus no magnesium, Outcome 7 Blindness.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.7.1 Neuroprotective intent

Crowther 2003 1/629 1/626 24.88% 1[0.06,15.88]

Marret 2006 1/352 1/336 25.39% 0.95[0.06,15.2]

Subtotal (95% CI) 981 962 50.27% 0.97[0.14,6.9]

Total events: 2 (Magnesium), 2 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0, df=1(P=0.98); I2=0%

Test for overall effect: Z=0.03(P=0.98)

1.7.2 Other intent (maternal neuroprotective - pre-eclampsia)

Magpie 2006 1/798 2/795 49.73% 0.5[0.05,5.48]

Subtotal (95% CI) 798 795 49.73% 0.5[0.05,5.48]

Total events: 1 (Magnesium), 2 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.57(P=0.57)

Total (95% CI) 1779 1757 100% 0.74[0.17,3.3]

Total events: 3 (Magnesium), 4 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.18, df=2(P=0.91); I2=0%

Test for overall effect: Z=0.4(P=0.69)

Test for subgroup differences: Not applicable

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Analysis 1.8. Comparison 1 Magnesium versus no magnesium, Outcome 8 Deafness.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

1.8.1 Neuroprotective intent

Crowther 2003 8/629 7/626 69.21% 1.14[0.41,3.12]

Marret 2006 0/352 4/336 14.68% 0.11[0.01,1.96]

Subtotal (95% CI) 981 962 83.89% 0.51[0.05,4.96]

Total events: 8 (Magnesium), 11 (No magnesium)

Heterogeneity: Tau2=1.77; Chi2=2.42, df=1(P=0.12); I2=58.75%

Test for overall effect: Z=0.58(P=0.56)

1.8.2 Other intent (maternal neuroprotective - pre-eclampsia)

Magpie 2006 1/798 1/795 16.11% 1[0.06,15.9]

Subtotal (95% CI) 798 795 16.11% 1[0.06,15.9]

Total events: 1 (Magnesium), 1 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0(P=1)

Total (95% CI) 1779 1757 100% 0.79[0.24,2.56]

Total events: 9 (Magnesium), 12 (No magnesium)

Heterogeneity: Tau2=0.26; Chi2=2.42, df=2(P=0.3); I2=17.41%

Test for overall effect: Z=0.4(P=0.69)

Test for subgroup differences: Not applicable

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Analysis 1.9. Comparison 1 Magnesium versus no magnesium, Outcome 9 Developmental delay or intellectual impairment.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.9.1 Neuroprotective intent

Crowther 2003 176/629 170/626 25.82% 1.03[0.86,1.23]

Rouse 2008 406/1188 427/1256 62.9% 1.01[0.9,1.12]

Marret 2006 57/352 63/336 9.77% 0.86[0.62,1.2]

Subtotal (95% CI) 2169 2218 98.48% 1[0.91,1.09]

Total events: 639 (Magnesium), 660 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.9, df=2(P=0.64); I2=0%

Test for overall effect: Z=0.05(P=0.96)

1.9.2 Other intent (maternal neuroprotective - pre-eclampsia)

Magpie 2006 8/798 10/795 1.52% 0.8[0.32,2.01]

Subtotal (95% CI) 798 795 1.52% 0.8[0.32,2.01]

Total events: 8 (Magnesium), 10 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.48(P=0.63)

Total (95% CI) 2967 3013 100% 0.99[0.91,1.09]

Total events: 647 (Magnesium), 670 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.13, df=3(P=0.77); I2=0%

Test for overall effect: Z=0.11(P=0.91)

Test for subgroup differences: Not applicable

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

Analysis 1.10. Comparison 1 Magnesium versus no magnesium, Outcome 10 Major neurological disability.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.10.1 Neuroprotective intent

Crowther 2003 89/629 78/626 85.72% 1.14[0.86,1.51]

Subtotal (95% CI) 629 626 85.72% 1.14[0.86,1.51]

Total events: 89 (Magnesium), 78 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.88(P=0.38)

1.10.2 Other intent (maternal neuroprotective - pre-eclampsia)

Magpie 2006 9/798 13/795 14.28% 0.69[0.3,1.6]

Subtotal (95% CI) 798 795 14.28% 0.69[0.3,1.6]

Total events: 9 (Magnesium), 13 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%

Test for overall effect: Z=0.86(P=0.39)

Total (95% CI) 1427 1421 100% 1.07[0.82,1.4]

Total events: 98 (Magnesium), 91 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.21, df=1(P=0.27); I2=17.19%

Test for overall effect: Z=0.51(P=0.61)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Test for subgroup differences: Not applicable

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 1.11. Comparison 1 Magnesium versus no magnesium, Outcome 11 Death or cerebral palsy.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

1.11.1 Neuroprotective intent

Crowther 2003 123/629 149/626 25.34% 0.82[0.66,1.02]

Marret 2006 56/352 67/336 17.25% 0.8[0.58,1.1]

Mittendorf 2002 5/30 1/29 0.72% 4.83[0.6,38.9]

Rouse 2008 144/1188 170/1256 25.7% 0.9[0.73,1.1]

Subtotal (95% CI) 2199 2247 69.01% 0.85[0.74,0.98]

Total events: 328 (Magnesium), 387 (No magnesium)

Heterogeneity: Tau2=0; Chi2=3.17, df=3(P=0.37); I2=5.25%

Test for overall effect: Z=2.21(P=0.03)

1.11.2 Other intent (maternal neuroprotective - pre-eclampsia)

Magpie 2006 211/798 193/795 29.12% 1.09[0.92,1.29]

Subtotal (95% CI) 798 795 29.12% 1.09[0.92,1.29]

Total events: 211 (Magnesium), 193 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.99(P=0.32)

1.11.3 Other intent (tocolytic)

Mittendorf 2002 8/55 3/51 1.88% 2.47[0.69,8.81]

Subtotal (95% CI) 55 51 1.88% 2.47[0.69,8.81]

Total events: 8 (Magnesium), 3 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=1.4(P=0.16)

Total (95% CI) 3052 3093 100% 0.94[0.78,1.12]

Total events: 547 (Magnesium), 583 (No magnesium)

Heterogeneity: Tau2=0.02; Chi2=10.28, df=5(P=0.07); I2=51.34%

Test for overall effect: Z=0.7(P=0.48)

Test for subgroup differences: Not applicable

Favours magnesium 200.05 50.2 1 Favours no magnesium

Analysis 1.12. Comparison 1 Magnesium versus no magnesium, Outcome 12 Death or any neurological impairment.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.12.1 Neuroprotective intent

Crowther 2003 280/629 294/626 59.41% 0.95[0.84,1.07]

Subtotal (95% CI) 629 626 59.41% 0.95[0.84,1.07]

Total events: 280 (Magnesium), 294 (No magnesium)

Heterogeneity: Not applicable

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Test for overall effect: Z=0.87(P=0.38)

1.12.2 Other intent (maternal neuroprotective - pre-eclampsia)

Magpie 2006 219/798 201/795 40.59% 1.09[0.92,1.28]

Subtotal (95% CI) 798 795 40.59% 1.09[0.92,1.28]

Total events: 219 (Magnesium), 201 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.98(P=0.33)

Total (95% CI) 1427 1421 100% 1[0.91,1.11]

Total events: 499 (Magnesium), 495 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.74, df=1(P=0.19); I2=42.48%

Test for overall effect: Z=0.07(P=0.94)

Test for subgroup differences: Not applicable

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 1.13. Comparison 1 Magnesium versus no magnesium, Outcome 13 Death or substantial gross motor dysfunction.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

1.13.1 Neuroprotective intent

Crowther 2003 105/629 141/626 25.88% 0.74[0.59,0.93]

Marret 2006 52/352 60/336 18.14% 0.83[0.59,1.16]

Rouse 2008 123/1188 134/1256 25.53% 0.97[0.77,1.22]

Subtotal (95% CI) 2169 2218 69.55% 0.84[0.71,1]

Total events: 280 (Magnesium), 335 (No magnesium)

Heterogeneity: Tau2=0.01; Chi2=2.67, df=2(P=0.26); I2=25.15%

Test for overall effect: Z=1.95(P=0.05)

1.13.2 Other intent (maternal neuroprotective - pre-eclampsia)

Magpie 2006 210/798 188/795 30.45% 1.11[0.94,1.32]

Subtotal (95% CI) 798 795 30.45% 1.11[0.94,1.32]

Total events: 210 (Magnesium), 188 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=1.23(P=0.22)

Total (95% CI) 2967 3013 100% 0.92[0.75,1.12]

Total events: 490 (Magnesium), 523 (No magnesium)

Heterogeneity: Tau2=0.03; Chi2=8.57, df=3(P=0.04); I2=65.01%

Test for overall effect: Z=0.87(P=0.39)

Test for subgroup differences: Not applicable

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Analysis 1.14. Comparison 1 Magnesium versus no magnesium, Outcome 14 Death or major neurological disability.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.14.1 Neuroprotective intent

Crowther 2003 176/629 185/626 47.94% 0.95[0.8,1.13]

Subtotal (95% CI) 629 626 47.94% 0.95[0.8,1.13]

Total events: 176 (Magnesium), 185 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.61(P=0.54)

1.14.2 Other intent (maternal neuroprotective (pre-eclampsia)

Magpie 2006 218/798 201/795 52.06% 1.08[0.92,1.27]

Subtotal (95% CI) 798 795 52.06% 1.08[0.92,1.27]

Total events: 218 (Magnesium), 201 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.92(P=0.36)

Total (95% CI) 1427 1421 100% 1.02[0.9,1.15]

Total events: 394 (Magnesium), 386 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.17, df=1(P=0.28); I2=14.32%

Test for overall effect: Z=0.27(P=0.79)

Test for subgroup differences: Not applicable

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

Analysis 1.15. Comparison 1 Magnesium versus no magnesium, Outcome 15 Maternal mortality.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 0/535 0/527 Not estimable

Magpie 2006 10/765 7/779 82.01% 1.45[0.56,3.8]

Marret 2006 0/286 1/278 17.99% 0.32[0.01,7.92]

Rouse 2008 0/1096 0/1145 Not estimable

Total (95% CI) 2682 2729 100% 1.25[0.51,3.07]

Total events: 10 (Magnesium), 8 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.78, df=1(P=0.38); I2=0%

Test for overall effect: Z=0.49(P=0.62)

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Analysis 1.16. Comparison 1 Magnesium versus no magnesium, Outcome 16 Maternal cardiac arrest.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 0/535 0/527 Not estimable

Magpie 2006 1/765 3/779 100% 0.34[0.04,3.26]

Marret 2006 0/286 0/278 Not estimable

Rouse 2008 0/1096 0/1145 Not estimable

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total (95% CI) 2682 2729 100% 0.34[0.04,3.26]

Total events: 1 (Magnesium), 3 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.94(P=0.35)

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Analysis 1.17. Comparison 1 Magnesium versus no magnesium, Outcome 17 Maternal respiratory arrest.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 0/535 0/527 Not estimable

Magpie 2006 1/765 1/779 100% 1.02[0.06,16.25]

Marret 2006 0/286 0/278 Not estimable

Rouse 2008 0/1096 0/1145 Not estimable

Total (95% CI) 2682 2729 100% 1.02[0.06,16.25]

Total events: 1 (Magnesium), 1 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.01(P=0.99)

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Analysis 1.18. Comparison 1 Magnesium versus no magnesium, Outcome 18 Cessation of maternal therapy.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 78/535 28/527 47.39% 2.74[1.81,4.15]

Magpie 2006 11/765 1/779 1.66% 11.2[1.45,86.55]

Rouse 2008 103/1096 31/1145 50.94% 3.47[2.34,5.14]

Total (95% CI) 2396 2451 100% 3.26[2.46,4.31]

Total events: 192 (Magnesium), 60 (No magnesium)

Heterogeneity: Tau2=0; Chi2=2.16, df=2(P=0.34); I2=7.31%

Test for overall effect: Z=8.22(P<0.0001)

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Analysis 1.19. Comparison 1 Magnesium versus no magnesium, Outcome 19 Intraventricular haemorrhage.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 165/629 148/626 30.36% 1.11[0.92,1.34]

Marret 2006 71/352 82/336 17.17% 0.83[0.62,1.09]

Mittendorf 2002 13/85 11/80 2.32% 1.11[0.53,2.34]

Rouse 2008 218/1188 252/1256 50.14% 0.91[0.78,1.08]

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total (95% CI) 2254 2298 100% 0.96[0.86,1.08]

Total events: 467 (Magnesium), 493 (No magnesium)

Heterogeneity: Tau2=0; Chi2=3.75, df=3(P=0.29); I2=20.09%

Test for overall effect: Z=0.65(P=0.51)

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

Analysis 1.20. Comparison 1 Magnesium versus no magnesium, Outcome 20 Intraventricular haemorrhage 3/4.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 49/629 50/626 57.57% 0.98[0.67,1.42]

Rouse 2008 23/1188 38/1256 42.43% 0.64[0.38,1.07]

Total (95% CI) 1817 1882 100% 0.83[0.62,1.13]

Total events: 72 (Magnesium), 88 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.69, df=1(P=0.19); I2=40.79%

Test for overall effect: Z=1.18(P=0.24)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 1.21. Comparison 1 Magnesium versus no magnesium, Outcome 21 Periventricular leucomalacia.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 22/629 21/626 27.53% 1.04[0.58,1.88]

Marret 2006 27/352 28/336 37.47% 0.92[0.55,1.53]

Mittendorf 2002 1/85 0/80 0.67% 2.83[0.12,68.37]

Rouse 2008 21/1188 27/1256 34.33% 0.82[0.47,1.45]

Total (95% CI) 2254 2298 100% 0.93[0.68,1.28]

Total events: 71 (Magnesium), 76 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.8, df=3(P=0.85); I2=0%

Test for overall effect: Z=0.43(P=0.67)

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Analysis 1.22. Comparison 1 Magnesium versus no magnesium, Outcome 22 Apgar score < 7 at 5 minutes.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 94/629 91/626 26.4% 1.03[0.79,1.34]

Marret 2006 45/352 31/336 9.18% 1.39[0.9,2.14]

Rouse 2008 212/1188 229/1256 64.42% 0.98[0.83,1.16]

Total (95% CI) 2169 2218 100% 1.03[0.9,1.18]

Total events: 351 (Magnesium), 351 (No magnesium)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Tau2=0; Chi2=2.16, df=2(P=0.34); I2=7.25%

Test for overall effect: Z=0.42(P=0.68)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 1.23. Comparison 1 Magnesium versus no magnesium, Outcome 23 Neonatal convulsions.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 25/629 32/626 46.17% 0.78[0.47,1.3]

Marret 2006 7/352 9/336 13.25% 0.74[0.28,1.97]

Rouse 2008 23/1188 29/1256 40.58% 0.84[0.49,1.44]

Total (95% CI) 2169 2218 100% 0.8[0.56,1.13]

Total events: 55 (Magnesium), 70 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.06, df=2(P=0.97); I2=0%

Test for overall effect: Z=1.28(P=0.2)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 1.24. Comparison 1 Magnesium versus no magnesium, Outcome 24 Neonatal hypotonia.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Rouse 2008 85/1188 88/1256 100% 1.02[0.77,1.36]

Total (95% CI) 1188 1256 100% 1.02[0.77,1.36]

Total events: 85 (Magnesium), 88 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.14(P=0.89)

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Analysis 1.25. Comparison 1 Magnesium versus no magnesium, Outcome 25 Ongoing respiratory support.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 176/629 185/626 17.6% 0.95[0.8,1.13]

Marret 2006 191/352 175/336 16.99% 1.04[0.91,1.2]

Rouse 2008 613/1188 709/1256 65.41% 0.91[0.85,0.98]

Total (95% CI) 2169 2218 100% 0.94[0.89,1]

Total events: 980 (Magnesium), 1069 (No magnesium)

Heterogeneity: Tau2=0; Chi2=2.62, df=2(P=0.27); I2=23.76%

Test for overall effect: Z=1.91(P=0.06)

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Analysis 1.26. Comparison 1 Magnesium versus no magnesium, Outcome 26 Chronic lung disease.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.26.1 Oxygen at 28 days

Crowther 2003 280/629 260/626 100% 1.07[0.94,1.22]

Subtotal (95% CI) 629 626 100% 1.07[0.94,1.22]

Total events: 280 (Magnesium), 260 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=1.07(P=0.29)

1.26.2 Oxygen at 36 weeks

Crowther 2003 192/629 164/626 83.83% 1.17[0.98,1.39]

Marret 2006 28/352 31/336 16.17% 0.86[0.53,1.41]

Subtotal (95% CI) 981 962 100% 1.12[0.95,1.32]

Total events: 220 (Magnesium), 195 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.3, df=1(P=0.25); I2=23.07%

Test for overall effect: Z=1.29(P=0.2)

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

Analysis 1.27. Comparison 1 Magnesium versus no magnesium, Outcome 27 Maternal hypotension.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 77/535 52/527 99.04% 1.46[1.05,2.03]

Marret 2006 3/286 0/278 0.96% 6.8[0.35,131.14]

Total (95% CI) 821 805 100% 1.51[1.09,2.09]

Total events: 80 (Magnesium), 52 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.04, df=1(P=0.31); I2=3.54%

Test for overall effect: Z=2.47(P=0.01)

Favours magnesium 10000.001 100.1 1 Favours no magnesium

Analysis 1.28. Comparison 1 Magnesium versus no magnesium, Outcome 28 Maternal tachycardia.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 56/535 36/527 100% 1.53[1.03,2.29]

Total (95% CI) 535 527 100% 1.53[1.03,2.29]

Total events: 56 (Magnesium), 36 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=2.09(P=0.04)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Analysis 1.29. Comparison 1 Magnesium versus no magnesium, Outcome 29 Maternal respiratory depression.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 34/535 28/527 90.58% 1.2[0.74,1.94]

Rouse 2008 7/1096 3/1145 9.42% 2.44[0.63,9.4]

Total (95% CI) 1631 1672 100% 1.31[0.83,2.07]

Total events: 41 (Magnesium), 31 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.95, df=1(P=0.33); I2=0%

Test for overall effect: Z=1.18(P=0.24)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 1.30. Comparison 1 Magnesium versus no magnesium, Outcome 30 Postpartum haemorrhage.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 86/535 99/527 98.99% 0.86[0.66,1.11]

Marret 2006 2/286 1/278 1.01% 1.94[0.18,21.32]

Total (95% CI) 821 805 100% 0.87[0.67,1.12]

Total events: 88 (Magnesium), 100 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.45, df=1(P=0.5); I2=0%

Test for overall effect: Z=1.08(P=0.28)

Favours magnesium 50.2 20.5 1 Favours no magnesium

Analysis 1.31. Comparison 1 Magnesium versus no magnesium, Outcome 31 Caesarean birth.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 289/535 290/527 22.83% 0.98[0.88,1.1]

Magpie 2006 488/765 456/779 35.31% 1.09[1.01,1.18]

Marret 2006 116/286 96/278 7.61% 1.17[0.95,1.46]

Rouse 2008 417/1096 448/1145 34.24% 0.97[0.88,1.08]

Total (95% CI) 2682 2729 100% 1.03[0.98,1.09]

Total events: 1310 (Magnesium), 1290 (No magnesium)

Heterogeneity: Tau2=0; Chi2=5.25, df=3(P=0.15); I2=42.82%

Test for overall effect: Z=1.11(P=0.27)

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

Analysis 1.32. Comparison 1 Magnesium versus no magnesium, Outcome 32 Mother admitted to intensive care unit.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 0/535 0/527 Not estimable

Magpie 2006 28/765 32/779 100% 0.89[0.54,1.47]

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total (95% CI) 1300 1306 100% 0.89[0.54,1.47]

Total events: 28 (Magnesium), 32 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.45(P=0.65)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 1.33. Comparison 1 Magnesium versus no magnesium, Outcome 33 Duration of mother's hospital stay (days).

Study or subgroup Magnesium No magnesium Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

Crowther 2003 535 5.2 (3.6) 527 5 (2.6) 87.49% 0.2[-0.18,0.58]

Magpie 2006 765 11 (10) 779 11 (10) 12.51% 0[-1,1]

Total *** 1300 1306 100% 0.17[-0.18,0.53]

Heterogeneity: Tau2=0; Chi2=0.14, df=1(P=0.71); I2=0%

Test for overall effect: Z=0.97(P=0.33)

Favours magnesium 105-10 -5 0 Favours no magnesium

Analysis 1.34. Comparison 1 Magnesium versus no magnesium, Outcome 34 Duration of primary hospital stay for babies (days).

Study or subgroup Magnesium No magnesium Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) Random, 95% CI Random, 95% CI

Crowther 2003 620 72.9 (36.7) 615 71.1 (42.4) 38.96% 1.8[-2.62,6.22]

Magpie 2006 798 17 (19) 795 19 (34) 61.04% -2[-4.71,0.71]

Total *** 1418 1410 100% -0.52[-4.15,3.11]

Heterogeneity: Tau2=3.72; Chi2=2.06, df=1(P=0.15); I2=51.51%

Test for overall effect: Z=0.28(P=0.78)

Favours magnesium 105-10 -5 0 Favours no magnesium

Comparison 2. Studies with lowest risk of bias only

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 Paediatric mortality 2 3699 Risk Ratio (M-H, Random, 95% CI) 0.96 [0.69, 1.33]

2 Cerebral palsy 2 3699 Risk Ratio (M-H, Fixed, 95% CI) 0.68 [0.52, 0.91]

3 Neurological impairment 1 1255 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.87, 1.21]

4 Major neurological disability 1 1255 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.86, 1.51]

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

5 Death or cerebral palsy 2 3699 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.74, 1.00]

6 Death or neurological impairment 1 1255 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.84, 1.07]

7 Death or major neurological disability 1 1255 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.80, 1.13]

Analysis 2.1. Comparison 2 Studies with lowest risk of bias only, Outcome 1 Paediatric mortality.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

Crowther 2003 87/629 107/626 50.37% 0.81[0.62,1.05]

Rouse 2008 103/1188 96/1256 49.63% 1.13[0.87,1.48]

Total (95% CI) 1817 1882 100% 0.96[0.69,1.33]

Total events: 190 (Magnesium), 203 (No magnesium)

Heterogeneity: Tau2=0.04; Chi2=3.16, df=1(P=0.08); I2=68.36%

Test for overall effect: Z=0.26(P=0.79)

Favours magnesium 50.2 20.5 1 Favours no magnesium

Analysis 2.2. Comparison 2 Studies with lowest risk of bias only, Outcome 2 Cerebral palsy.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 36/629 42/626 36.92% 0.85[0.55,1.31]

Rouse 2008 41/1188 74/1256 63.08% 0.59[0.4,0.85]

Total (95% CI) 1817 1882 100% 0.68[0.52,0.91]

Total events: 77 (Magnesium), 116 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.67, df=1(P=0.2); I2=40.13%

Test for overall effect: Z=2.64(P=0.01)

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Analysis 2.3. Comparison 2 Studies with lowest risk of bias only, Outcome 3 Neurological impairment.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 193/629 187/626 100% 1.03[0.87,1.21]

Total (95% CI) 629 626 100% 1.03[0.87,1.21]

Total events: 193 (Magnesium), 187 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.31(P=0.75)

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Analysis 2.4. Comparison 2 Studies with lowest risk of bias only, Outcome 4 Major neurological disability.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 89/629 78/626 100% 1.14[0.86,1.51]

Total (95% CI) 629 626 100% 1.14[0.86,1.51]

Total events: 89 (Magnesium), 78 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.88(P=0.38)

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Analysis 2.5. Comparison 2 Studies with lowest risk of bias only, Outcome 5 Death or cerebral palsy.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 123/629 149/626 47.47% 0.82[0.66,1.02]

Rouse 2008 144/1188 170/1256 52.53% 0.9[0.73,1.1]

Total (95% CI) 1817 1882 100% 0.86[0.74,1]

Total events: 267 (Magnesium), 319 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.33, df=1(P=0.57); I2=0%

Test for overall effect: Z=1.99(P=0.05)

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Analysis 2.6. Comparison 2 Studies with lowest risk of bias only, Outcome 6 Death or neurological impairment.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 280/629 294/626 100% 0.95[0.84,1.07]

Total (95% CI) 629 626 100% 0.95[0.84,1.07]

Total events: 280 (Magnesium), 294 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.87(P=0.38)

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Analysis 2.7. Comparison 2 Studies with lowest risk of bias only, Outcome 7 Death or major neurological disability.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 176/629 185/626 100% 0.95[0.8,1.13]

Total (95% CI) 629 626 100% 0.95[0.8,1.13]

Total events: 176 (Magnesium), 185 (No magnesium)

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Not applicable

Test for overall effect: Z=0.61(P=0.54)

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Comparison 3. Single or multiple pregnancy subgroup

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 Paediatric mortality (fetal and later)

3 4984 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.85, 1.26]

1.1 Single 3 4256 Risk Ratio (M-H, Random, 95% CI) 1.01 [0.85, 1.20]

1.2 Multiple 3 728 Risk Ratio (M-H, Random, 95% CI) 1.22 [0.68, 2.18]

2 Cerebral palsy 2 2848 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.53, 1.22]

2.1 Single 2 2321 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.57, 1.49]

2.2 Multiple 2 527 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.21, 1.25]

3 Neurological impairment 2 2848 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.85, 1.19]

3.1 Single 2 2321 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.88, 1.28]

3.2 Multiple 2 527 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.61, 1.21]

4 Major neurological disability 2 2848 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.82, 1.40]

4.1 Single 2 2321 Risk Ratio (M-H, Fixed, 95% CI) 1.17 [0.87, 1.59]

4.2 Multiple 2 527 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.44, 1.37]

5 Death or cerebral palsy 2 2848 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.76, 1.24]

5.1 Single 2 2321 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.82, 1.14]

5.2 Multiple 2 527 Risk Ratio (M-H, Random, 95% CI) 1.14 [0.45, 2.92]

6 Death or neurological im- pairment

2 2848 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.86, 1.16]

6.1 Single 2 2321 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.90, 1.12]

6.2 Multiple 2 527 Risk Ratio (M-H, Random, 95% CI) 1.21 [0.56, 2.65]

7 Death or major neurological disability

2 2848 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.85, 1.22]

7.1 Single 2 2321 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.89, 1.16]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

7.2 Multiple 2 527 Risk Ratio (M-H, Random, 95% CI) 1.20 [0.53, 2.71]

Analysis 3.1. Comparison 3 Single or multiple pregnancy subgroup, Outcome 1 Paediatric mortality (fetal and later).

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

3.1.1 Single

Crowther 2003 60/447 73/438 20.16% 0.81[0.59,1.1]

Magpie 2006 186/716 179/720 30.93% 1.04[0.88,1.25]

Rouse 2008 83/950 75/985 21.22% 1.15[0.85,1.55]

Subtotal (95% CI) 2113 2143 72.32% 1.01[0.85,1.2]

Total events: 329 (Magnesium), 327 (No magnesium)

Heterogeneity: Tau2=0.01; Chi2=2.82, df=2(P=0.24); I2=29.05%

Test for overall effect: Z=0.07(P=0.94)

3.1.2 Multiple

Crowther 2003 27/182 34/188 12.71% 0.82[0.52,1.3]

Magpie 2006 23/82 9/75 6.65% 2.34[1.16,4.73]

Rouse 2008 16/91 18/110 8.33% 1.07[0.58,1.98]

Subtotal (95% CI) 355 373 27.68% 1.22[0.68,2.18]

Total events: 66 (Magnesium), 61 (No magnesium)

Heterogeneity: Tau2=0.18; Chi2=5.96, df=2(P=0.05); I2=66.47%

Test for overall effect: Z=0.65(P=0.51)

Total (95% CI) 2468 2516 100% 1.04[0.85,1.26]

Total events: 395 (Magnesium), 388 (No magnesium)

Heterogeneity: Tau2=0.02; Chi2=9.02, df=5(P=0.11); I2=44.58%

Test for overall effect: Z=0.36(P=0.72)

Test for subgroup differences: Not applicable

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

Analysis 3.2. Comparison 3 Single or multiple pregnancy subgroup, Outcome 2 Cerebral palsy.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

3.2.1 Single

Crowther 2003 29/447 28/438 60.12% 1.01[0.61,1.68]

Magpie 2006 2/716 5/720 10.6% 0.4[0.08,2.07]

Subtotal (95% CI) 1163 1158 70.72% 0.92[0.57,1.49]

Total events: 31 (Magnesium), 33 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.13, df=1(P=0.29); I2=11.23%

Test for overall effect: Z=0.33(P=0.74)

3.2.2 Multiple

Favours magnesium 1000.01 100.1 1 Favours no magnesium

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 7/182 14/188 29.28% 0.52[0.21,1.25]

Magpie 2006 0/82 0/75 Not estimable

Subtotal (95% CI) 264 263 29.28% 0.52[0.21,1.25]

Total events: 7 (Magnesium), 14 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=1.46(P=0.14)

Total (95% CI) 1427 1421 100% 0.8[0.53,1.22]

Total events: 38 (Magnesium), 47 (No magnesium)

Heterogeneity: Tau2=0; Chi2=2.48, df=2(P=0.29); I2=19.24%

Test for overall effect: Z=1.03(P=0.3)

Test for subgroup differences: Not applicable

Favours magnesium 1000.01 100.1 1 Favours no magnesium

Analysis 3.3. Comparison 3 Single or multiple pregnancy subgroup, Outcome 3 Neurological impairment.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

3.3.1 Single

Crowther 2003 149/447 136/438 68.3% 1.07[0.89,1.3]

Magpie 2006 10/716 11/720 5.45% 0.91[0.39,2.14]

Subtotal (95% CI) 1163 1158 73.76% 1.06[0.88,1.28]

Total events: 159 (Magnesium), 147 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.13, df=1(P=0.72); I2=0%

Test for overall effect: Z=0.63(P=0.53)

3.3.2 Multiple

Crowther 2003 44/182 51/188 24.94% 0.89[0.63,1.26]

Magpie 2006 0/82 2/75 1.3% 0.18[0.01,3.75]

Subtotal (95% CI) 264 263 26.24% 0.86[0.61,1.21]

Total events: 44 (Magnesium), 53 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.05, df=1(P=0.3); I2=4.99%

Test for overall effect: Z=0.88(P=0.38)

Total (95% CI) 1427 1421 100% 1.01[0.85,1.19]

Total events: 203 (Magnesium), 200 (No magnesium)

Heterogeneity: Tau2=0; Chi2=2.17, df=3(P=0.54); I2=0%

Test for overall effect: Z=0.09(P=0.93)

Test for subgroup differences: Not applicable

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

Analysis 3.4. Comparison 3 Single or multiple pregnancy subgroup, Outcome 4 Major neurological disability.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

3.4.1 Single

Crowther 2003 71/447 56/438 61.63% 1.24[0.9,1.72]

Favours magnesium 10000.001 100.1 1 Favours no magnesium

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Magpie 2006 9/716 11/720 11.95% 0.82[0.34,1.97]

Subtotal (95% CI) 1163 1158 73.58% 1.17[0.87,1.59]

Total events: 80 (Magnesium), 67 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.75, df=1(P=0.39); I2=0%

Test for overall effect: Z=1.04(P=0.3)

3.4.2 Multiple

Crowther 2003 18/182 22/188 23.58% 0.85[0.47,1.52]

Magpie 2006 0/82 2/75 2.84% 0.18[0.01,3.75]

Subtotal (95% CI) 264 263 26.42% 0.77[0.44,1.37]

Total events: 18 (Magnesium), 24 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.96, df=1(P=0.33); I2=0%

Test for overall effect: Z=0.88(P=0.38)

Total (95% CI) 1427 1421 100% 1.07[0.82,1.4]

Total events: 98 (Magnesium), 91 (No magnesium)

Heterogeneity: Tau2=0; Chi2=3.09, df=3(P=0.38); I2=2.95%

Test for overall effect: Z=0.49(P=0.63)

Test for subgroup differences: Not applicable

Favours magnesium 10000.001 100.1 1 Favours no magnesium

Analysis 3.5. Comparison 3 Single or multiple pregnancy subgroup, Outcome 5 Death or cerebral palsy.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

3.5.1 Single

Crowther 2003 89/447 101/438 30.75% 0.86[0.67,1.11]

Magpie 2006 188/716 184/720 36.97% 1.03[0.86,1.22]

Subtotal (95% CI) 1163 1158 67.72% 0.97[0.82,1.14]

Total events: 277 (Magnesium), 285 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.23, df=1(P=0.27); I2=18.77%

Test for overall effect: Z=0.42(P=0.67)

3.5.2 Multiple

Crowther 2003 34/182 48/188 21.29% 0.73[0.5,1.08]

Magpie 2006 23/82 11/75 10.99% 1.91[1,3.65]

Subtotal (95% CI) 264 263 32.28% 1.14[0.45,2.92]

Total events: 57 (Magnesium), 59 (No magnesium)

Heterogeneity: Tau2=0.39; Chi2=6.24, df=1(P=0.01); I2=83.97%

Test for overall effect: Z=0.28(P=0.78)

Total (95% CI) 1427 1421 100% 0.97[0.76,1.24]

Total events: 334 (Magnesium), 344 (No magnesium)

Heterogeneity: Tau2=0.03; Chi2=7.48, df=3(P=0.06); I2=59.88%

Test for overall effect: Z=0.24(P=0.81)

Test for subgroup differences: Not applicable

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

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Analysis 3.6. Comparison 3 Single or multiple pregnancy subgroup, Outcome 6 Death or neurological impairment.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

3.6.1 Single

Crowther 2003 209/447 209/438 38.62% 0.98[0.85,1.13]

Magpie 2006 196/716 190/720 33.12% 1.04[0.87,1.23]

Subtotal (95% CI) 1163 1158 71.73% 1[0.9,1.12]

Total events: 405 (Magnesium), 399 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.26, df=1(P=0.61); I2=0%

Test for overall effect: Z=0.04(P=0.96)

3.6.2 Multiple

Crowther 2003 71/182 85/188 23.33% 0.86[0.68,1.1]

Magpie 2006 23/82 11/75 4.94% 1.91[1,3.65]

Subtotal (95% CI) 264 263 28.27% 1.21[0.56,2.65]

Total events: 94 (Magnesium), 96 (No magnesium)

Heterogeneity: Tau2=0.26; Chi2=5.24, df=1(P=0.02); I2=80.91%

Test for overall effect: Z=0.48(P=0.63)

Total (95% CI) 1427 1421 100% 1[0.86,1.16]

Total events: 499 (Magnesium), 495 (No magnesium)

Heterogeneity: Tau2=0.01; Chi2=5.6, df=3(P=0.13); I2=46.4%

Test for overall effect: Z=0.02(P=0.98)

Test for subgroup differences: Not applicable

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

Analysis 3.7. Comparison 3 Single or multiple pregnancy subgroup, Outcome 7 Death or major neurological disability.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

3.7.1 Single

Crowther 2003 131/447 129/438 34.27% 1[0.81,1.22]

Magpie 2006 195/716 190/720 39.7% 1.03[0.87,1.22]

Subtotal (95% CI) 1163 1158 73.97% 1.02[0.89,1.16]

Total events: 326 (Magnesium), 319 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.07, df=1(P=0.79); I2=0%

Test for overall effect: Z=0.25(P=0.8)

3.7.2 Multiple

Crowther 2003 45/182 56/188 19.33% 0.83[0.59,1.16]

Magpie 2006 23/82 11/75 6.7% 1.91[1,3.65]

Subtotal (95% CI) 264 263 26.03% 1.2[0.53,2.71]

Total events: 68 (Magnesium), 67 (No magnesium)

Heterogeneity: Tau2=0.28; Chi2=5.07, df=1(P=0.02); I2=80.29%

Test for overall effect: Z=0.44(P=0.66)

Total (95% CI) 1427 1421 100% 1.02[0.85,1.22]

Total events: 394 (Magnesium), 386 (No magnesium)

Heterogeneity: Tau2=0.01; Chi2=5.15, df=3(P=0.16); I2=41.69%

Test for overall effect: Z=0.2(P=0.84)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

Test for subgroup differences: Not applicable

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Comparison 4. High antenatal corticosteroids

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 Paediatric mortality (fetal and later) 4 4493 Risk Ratio (M-H, Random, 95% CI) 0.96 [0.70, 1.32]

2 Cerebral palsy 4 4493 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.53, 0.86]

3 Neurological impairment 1 1255 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.87, 1.21]

4 Major neurological disability 1 1255 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.86, 1.51]

5 Death or cerebral palsy 4 4493 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.75, 0.99]

6 Death or neurological impairment 1 1255 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.84, 1.07]

7 Death or major neurological disabil- ity

1 1255 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.80, 1.13]

Analysis 4.1. Comparison 4 High antenatal corticosteroids, Outcome 1 Paediatric mortality (fetal and later).

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

Marret 2006 34/352 38/336 25.32% 0.85[0.55,1.32]

Crowther 2003 87/629 107/626 36.95% 0.81[0.62,1.05]

Mittendorf 2002 8/55 0/51 1.22% 15.79[0.93,266.72]

Rouse 2008 103/1188 96/1256 36.51% 1.13[0.87,1.48]

Total (95% CI) 2224 2269 100% 0.96[0.7,1.32]

Total events: 232 (Magnesium), 241 (No magnesium)

Heterogeneity: Tau2=0.05; Chi2=7.29, df=3(P=0.06); I2=58.83%

Test for overall effect: Z=0.24(P=0.81)

Favours magnesium 10000.001 100.1 1 Favours no magnesium

Analysis 4.2. Comparison 4 High antenatal corticosteroids, Outcome 2 Cerebral palsy.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 36/629 42/626 28.38% 0.85[0.55,1.31]

Marret 2006 22/352 30/336 20.69% 0.7[0.41,1.19]

Favours magnesium 10000.001 100.1 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Mittendorf 2002 0/55 3/51 2.45% 0.13[0.01,2.51]

Rouse 2008 41/1188 74/1256 48.49% 0.59[0.4,0.85]

Total (95% CI) 2224 2269 100% 0.67[0.53,0.86]

Total events: 99 (Magnesium), 149 (No magnesium)

Heterogeneity: Tau2=0; Chi2=2.88, df=3(P=0.41); I2=0%

Test for overall effect: Z=3.13(P=0)

Favours magnesium 10000.001 100.1 1 Favours no magnesium

Analysis 4.3. Comparison 4 High antenatal corticosteroids, Outcome 3 Neurological impairment.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 193/629 187/626 100% 1.03[0.87,1.21]

Total (95% CI) 629 626 100% 1.03[0.87,1.21]

Total events: 193 (Magnesium), 187 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.31(P=0.75)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 4.4. Comparison 4 High antenatal corticosteroids, Outcome 4 Major neurological disability.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 89/629 78/626 100% 1.14[0.86,1.51]

Total (95% CI) 629 626 100% 1.14[0.86,1.51]

Total events: 89 (Magnesium), 78 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.88(P=0.38)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 4.5. Comparison 4 High antenatal corticosteroids, Outcome 5 Death or cerebral palsy.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 123/629 149/626 38.66% 0.82[0.66,1.02]

Marret 2006 56/352 67/336 17.75% 0.8[0.58,1.1]

Mittendorf 2002 8/55 3/51 0.81% 2.47[0.69,8.81]

Rouse 2008 144/1188 170/1256 42.78% 0.9[0.73,1.1]

Total (95% CI) 2224 2269 100% 0.86[0.75,0.99]

Total events: 331 (Magnesium), 389 (No magnesium)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Tau2=0; Chi2=3.19, df=3(P=0.36); I2=6.01%

Test for overall effect: Z=2.17(P=0.03)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 4.6. Comparison 4 High antenatal corticosteroids, Outcome 6 Death or neurological impairment.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 280/629 294/626 100% 0.95[0.84,1.07]

Total (95% CI) 629 626 100% 0.95[0.84,1.07]

Total events: 280 (Magnesium), 294 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.87(P=0.38)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 4.7. Comparison 4 High antenatal corticosteroids, Outcome 7 Death or major neurological disability.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Crowther 2003 176/629 185/626 100% 0.95[0.8,1.13]

Total (95% CI) 629 626 100% 0.95[0.8,1.13]

Total events: 176 (Magnesium), 185 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.61(P=0.54)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Comparison 5. Gestational age subgroup

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 Paediatric mortality (fetal and later) 5 Risk Ratio (M-H, Random, 95% CI)

Subtotals only

1.1 < 34 weeks at randomisation 5 5357 Risk Ratio (M-H, Random, 95% CI)

0.99 [0.80, 1.23]

1.2 < 30 weeks at randomisation 2 1537 Risk Ratio (M-H, Random, 95% CI)

0.97 [0.67, 1.41]

2 Cerebral palsy 5 Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

2.1 < 34 weeks at randomisation 5 5357 Risk Ratio (M-H, Fixed, 95% CI)

0.69 [0.54, 0.88]

2.2 < 30 weeks at randomisation 2 1537 Risk Ratio (M-H, Fixed, 95% CI)

0.86 [0.56, 1.31]

3 Neurological impairment 2 Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

3.1 < 34 weeks at randomisation 2 2060 Risk Ratio (M-H, Fixed, 95% CI)

1.02 [0.86, 1.20]

3.2 < 30 weeks at randomisation 2 1537 Risk Ratio (M-H, Fixed, 95% CI)

1.03 [0.87, 1.21]

4 Major neurological disability 2 Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

4.1 < 34 weeks at randomisation 2 2060 Risk Ratio (M-H, Fixed, 95% CI)

1.09 [0.83, 1.43]

4.2 < 30 weeks at randomisation 2 1537 Risk Ratio (M-H, Fixed, 95% CI)

1.12 [0.85, 1.48]

5 Death or cerebral palsy 5 Risk Ratio (M-H, Random, 95% CI)

Subtotals only

5.1 < 34 weeks at randomisation 5 5357 Risk Ratio (M-H, Random, 95% CI)

0.93 [0.78, 1.10]

5.2 < 30 weeks at randomisation 2 1537 Risk Ratio (M-H, Random, 95% CI)

0.97 [0.69, 1.38]

6 Death or neurological impairment 2 Risk Ratio (M-H, Random, 95% CI)

Subtotals only

6.1 < 34 weeks at randomisation 2 2060 Risk Ratio (M-H, Random, 95% CI)

0.98 [0.89, 1.08]

6.2 < 30 weeks at randomisation 2 1537 Risk Ratio (M-H, Random, 95% CI)

1.03 [0.86, 1.24]

7 Death or major neurological disability 2 Risk Ratio (M-H, Random, 95% CI)

Subtotals only

7.1 < 34 weeks at randomisation 2 2060 Risk Ratio (M-H, Random, 95% CI)

0.99 [0.88, 1.11]

7.2 < 30 weeks at randomisation 2 1537 Risk Ratio (M-H, Random, 95% CI)

1.04 [0.86, 1.24]

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Analysis 5.1. Comparison 5 Gestational age subgroup, Outcome 1 Paediatric mortality (fetal and later).

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

5.1.1 < 34 weeks at randomisation

Crowther 2003 87/629 107/626 25.53% 0.81[0.62,1.05]

Magpie 2006 167/404 158/401 34.46% 1.05[0.89,1.24]

Marret 2006 34/352 38/336 14.09% 0.85[0.55,1.32]

Mittendorf 2002 10/85 1/80 0.92% 9.41[1.23,71.86]

Rouse 2008 103/1188 96/1256 25% 1.13[0.87,1.48]

Subtotal (95% CI) 2658 2699 100% 0.99[0.8,1.23]

Total events: 401 (Magnesium), 400 (No magnesium)

Heterogeneity: Tau2=0.03; Chi2=8.89, df=4(P=0.06); I2=55.01%

Test for overall effect: Z=0.06(P=0.95)

5.1.2 < 30 weeks at randomisation

Crowther 2003 87/629 107/626 42.3% 0.81[0.62,1.05]

Magpie 2006 100/140 89/142 57.7% 1.14[0.97,1.34]

Subtotal (95% CI) 769 768 100% 0.97[0.67,1.41]

Total events: 187 (Magnesium), 196 (No magnesium)

Heterogeneity: Tau2=0.06; Chi2=5.87, df=1(P=0.02); I2=82.98%

Test for overall effect: Z=0.15(P=0.88)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 5.2. Comparison 5 Gestational age subgroup, Outcome 2 Cerebral palsy.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.2.1 < 34 weeks at randomisation

Crowther 2003 36/629 42/626 27.91% 0.85[0.55,1.31]

Magpie 2006 2/404 3/401 2% 0.66[0.11,3.94]

Marret 2006 22/352 30/336 20.35% 0.7[0.41,1.19]

Mittendorf 2002 3/85 3/80 2.05% 0.94[0.2,4.53]

Rouse 2008 41/1188 74/1256 47.69% 0.59[0.4,0.85]

Subtotal (95% CI) 2658 2699 100% 0.69[0.54,0.88]

Total events: 104 (Magnesium), 152 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.82, df=4(P=0.77); I2=0%

Test for overall effect: Z=2.97(P=0)

5.2.2 < 30 weeks at randomisation

Crowther 2003 36/629 42/626 97.7% 0.85[0.55,1.31]

Magpie 2006 1/140 1/142 2.3% 1.01[0.06,16.06]

Subtotal (95% CI) 769 768 100% 0.86[0.56,1.31]

Total events: 37 (Magnesium), 43 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.9); I2=0%

Test for overall effect: Z=0.71(P=0.48)

Favours magnesium 1000.01 100.1 1 Favours no magnesium

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Analysis 5.3. Comparison 5 Gestational age subgroup, Outcome 3 Neurological impairment.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.3.1 < 34 weeks at randomisation

Crowther 2003 193/629 187/626 96.39% 1.03[0.87,1.21]

Magpie 2006 5/404 7/401 3.61% 0.71[0.23,2.22]

Subtotal (95% CI) 1033 1027 100% 1.02[0.86,1.2]

Total events: 198 (Magnesium), 194 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.4, df=1(P=0.53); I2=0%

Test for overall effect: Z=0.18(P=0.85)

5.3.2 < 30 weeks at randomisation

Crowther 2003 193/629 187/626 98.44% 1.03[0.87,1.21]

Magpie 2006 3/140 3/142 1.56% 1.01[0.21,4.94]

Subtotal (95% CI) 769 768 100% 1.03[0.87,1.21]

Total events: 196 (Magnesium), 190 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0, df=1(P=0.99); I2=0%

Test for overall effect: Z=0.31(P=0.76)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 5.4. Comparison 5 Gestational age subgroup, Outcome 4 Major neurological disability.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.4.1 < 34 weeks at randomisation

Crowther 2003 89/629 78/626 91.75% 1.14[0.86,1.51]

Magpie 2006 4/404 7/401 8.25% 0.57[0.17,1.92]

Subtotal (95% CI) 1033 1027 100% 1.09[0.83,1.43]

Total events: 93 (Magnesium), 85 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.18, df=1(P=0.28); I2=15.35%

Test for overall effect: Z=0.61(P=0.54)

5.4.2 < 30 weeks at randomisation

Crowther 2003 89/629 78/626 96.33% 1.14[0.86,1.51]

Magpie 2006 2/140 3/142 3.67% 0.68[0.11,3.99]

Subtotal (95% CI) 769 768 100% 1.12[0.85,1.48]

Total events: 91 (Magnesium), 81 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.32, df=1(P=0.57); I2=0%

Test for overall effect: Z=0.79(P=0.43)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 5.5. Comparison 5 Gestational age subgroup, Outcome 5 Death or cerebral palsy.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

5.5.1 < 34 weeks at randomisation

Crowther 2003 123/629 149/626 25.27% 0.82[0.66,1.02]

Magpie 2006 169/404 161/401 29.25% 1.04[0.88,1.23]

Favours magnesium 50.2 20.5 1 Favours no magnesium

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

Marret 2006 56/352 67/336 17.27% 0.8[0.58,1.1]

Mittendorf 2002 13/85 4/80 2.58% 3.06[1.04,8.99]

Rouse 2008 144/1188 170/1256 25.63% 0.9[0.73,1.1]

Subtotal (95% CI) 2658 2699 100% 0.93[0.78,1.1]

Total events: 505 (Magnesium), 551 (No magnesium)

Heterogeneity: Tau2=0.02; Chi2=8.83, df=4(P=0.07); I2=54.69%

Test for overall effect: Z=0.87(P=0.38)

5.5.2 < 30 weeks at randomisation

Crowther 2003 123/629 149/626 46.06% 0.82[0.66,1.02]

Magpie 2006 101/140 90/142 53.94% 1.14[0.97,1.34]

Subtotal (95% CI) 769 768 100% 0.97[0.69,1.38]

Total events: 224 (Magnesium), 239 (No magnesium)

Heterogeneity: Tau2=0.05; Chi2=6.92, df=1(P=0.01); I2=85.54%

Test for overall effect: Z=0.15(P=0.88)

Favours magnesium 50.2 20.5 1 Favours no magnesium

Analysis 5.6. Comparison 5 Gestational age subgroup, Outcome 6 Death or neurological impairment.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

5.6.1 < 34 weeks at randomisation

Crowther 2003 280/629 294/626 60.43% 0.95[0.84,1.07]

Magpie 2006 172/404 165/401 39.57% 1.03[0.88,1.22]

Subtotal (95% CI) 1033 1027 100% 0.98[0.89,1.08]

Total events: 452 (Magnesium), 459 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.72, df=1(P=0.4); I2=0%

Test for overall effect: Z=0.46(P=0.65)

5.6.2 < 30 weeks at randomisation

Crowther 2003 280/629 294/626 59.02% 0.95[0.84,1.07]

Magpie 2006 103/140 92/142 40.98% 1.14[0.97,1.33]

Subtotal (95% CI) 769 768 100% 1.03[0.86,1.24]

Total events: 383 (Magnesium), 386 (No magnesium)

Heterogeneity: Tau2=0.01; Chi2=3.4, df=1(P=0.07); I2=70.59%

Test for overall effect: Z=0.32(P=0.75)

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

Analysis 5.7. Comparison 5 Gestational age subgroup, Outcome 7 Death or major neurological disability.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

5.7.1 < 34 weeks at randomisation

Crowther 2003 176/629 185/626 46.87% 0.95[0.8,1.13]

Magpie 2006 171/404 165/401 53.13% 1.03[0.87,1.21]

Subtotal (95% CI) 1033 1027 100% 0.99[0.88,1.11]

Total events: 347 (Magnesium), 350 (No magnesium)

Favours magnesium 50.2 20.5 1 Favours no magnesium

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

Heterogeneity: Tau2=0; Chi2=0.47, df=1(P=0.49); I2=0%

Test for overall effect: Z=0.17(P=0.86)

5.7.2 < 30 weeks at randomisation

Crowther 2003 176/629 185/626 45.27% 0.95[0.8,1.13]

Magpie 2006 102/140 92/142 54.73% 1.12[0.96,1.32]

Subtotal (95% CI) 769 768 100% 1.04[0.86,1.24]

Total events: 278 (Magnesium), 277 (No magnesium)

Heterogeneity: Tau2=0.01; Chi2=2.39, df=1(P=0.12); I2=58.12%

Test for overall effect: Z=0.38(P=0.71)

Favours magnesium 50.2 20.5 1 Favours no magnesium

Comparison 6. Dose subgroup

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 Paediatric mortality (fetal and later) 5 Risk Ratio (M-H, Random, 95% CI) Subtotals only

1.1 Loading dose 4 g (any or no mainte- nance)

4 3595 Risk Ratio (M-H, Random, 95% CI) 0.96 [0.78, 1.18]

1.2 Loading dose 6 g (any or no mainte- nance)

1 2444 Risk Ratio (M-H, Random, 95% CI) 1.13 [0.87, 1.48]

1.3 No maintenance: any loading dose 2 747 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.57, 1.35]

1.4 Any maintenance (high or low): any loading dose

3 5292 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.83, 1.24]

1.5 No maintenance: loading dose 4 g 2 747 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.57, 1.35]

1.6 Loading (4 g) and lower-dose main- tenance (1 g/hour)

2 2848 Risk Ratio (M-H, Random, 95% CI) 0.96 [0.71, 1.31]

1.7 Loading dose (4 g) and higher-dose maintenance (2-3 g/hour)

1 106 Risk Ratio (M-H, Random, 95% CI) 15.79 [0.93, 266.72]

1.8 Loading dose (6 g) and higher-dose maintenance (2-3 g/hour)

1 2374 Risk Ratio (M-H, Random, 95% CI) 1.21 [0.92, 1.57]

2 Cerebral palsy 5 Risk Ratio (M-H, Random, 95% CI) Subtotals only

2.1 Loading dose 4 g (any or no mainte- nance)

4 3595 Risk Ratio (M-H, Random, 95% CI) 0.79 [0.56, 1.10]

2.2 Loading dose 6 g (any or no mainte- nance)

1 2444 Risk Ratio (M-H, Random, 95% CI) 0.59 [0.40, 0.85]

2.3 No maintenance: any loading dose 2 747 Risk Ratio (M-H, Random, 95% CI) 1.37 [0.18, 10.70]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

2.4 Any maintenance (high or low): any loading dose

3 5292 Risk Ratio (M-H, Random, 95% CI) 0.68 [0.51, 0.91]

2.5 No maintenance: loading dose 4 g 2 747 Risk Ratio (M-H, Random, 95% CI) 1.37 [0.18, 10.70]

2.6 Loading dose (4 g) and lower-dose maintenance (1 g/hour)

2 2848 Risk Ratio (M-H, Random, 95% CI) 0.81 [0.54, 1.23]

2.7 Loading dose (4 g) and higher-dose maintenance (2-3 g/hour)

1 106 Risk Ratio (M-H, Random, 95% CI) 0.13 [0.01, 2.51]

2.8 Loading dose (6 g) and higher-dose maintenance (2-3 g /hour)

1 2444 Risk Ratio (M-H, Random, 95% CI) 0.59 [0.40, 0.85]

3 Neurological impairment 2 2848 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.86, 1.19]

3.1 Loading (4 g) and lower-mainte- nance dose (1 g/hour)

2 2848 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.86, 1.19]

4 Major neurological disability 2 2848 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.82, 1.40]

4.1 Loading (4 g) and lower-mainte- nance dose (1 g/hour)

2 2848 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.82, 1.40]

5 Death or cerebral palsy 5 6145 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.78, 1.12]

5.1 Loading dose (4 g) only 2 747 Risk Ratio (M-H, Random, 95% CI) 1.45 [0.27, 7.72]

5.2 Loading (4 g) and lower-mainte- nance dose (1 g/hour)

2 2848 Risk Ratio (M-H, Random, 95% CI) 0.95 [0.72, 1.26]

5.3 Loading (4 g) and higher-mainte- nance dose (2-3 g/hour): tocolytic in- tent

2 2550 Risk Ratio (M-H, Random, 95% CI) 1.22 [0.49, 3.04]

6 Death or neurological impairment 2 2848 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.91, 1.11]

6.1 Loading (4 g) and lower-mainte- nance dose (1 g/hour)

2 2848 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.91, 1.11]

7 Death or major neurological disabili- ty

2 2848 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.90, 1.15]

7.1 Loading (4 g) and lower-mainte- nance dose (1 g/hour)

2 2848 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.90, 1.15]

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Analysis 6.1. Comparison 6 Dose subgroup, Outcome 1 Paediatric mortality (fetal and later).

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

6.1.1 Loading dose 4 g (any or no maintenance)

Crowther 2003 87/629 107/626 32.3% 0.81[0.62,1.05]

Magpie 2006 209/798 188/795 52.7% 1.11[0.93,1.31]

Marret 2006 34/352 38/336 14.42% 0.85[0.55,1.32]

Mittendorf 2002 2/30 1/29 0.58% 1.93[0.19,20.18]

Subtotal (95% CI) 1809 1786 100% 0.96[0.78,1.18]

Total events: 332 (Magnesium), 334 (No magnesium)

Heterogeneity: Tau2=0.02; Chi2=4.72, df=3(P=0.19); I2=36.49%

Test for overall effect: Z=0.42(P=0.68)

6.1.2 Loading dose 6 g (any or no maintenance)

Rouse 2008 103/1188 96/1256 100% 1.13[0.87,1.48]

Subtotal (95% CI) 1188 1256 100% 1.13[0.87,1.48]

Total events: 103 (Magnesium), 96 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.93(P=0.35)

6.1.3 No maintenance: any loading dose

Marret 2006 34/352 38/336 96.11% 0.85[0.55,1.32]

Mittendorf 2002 2/30 1/29 3.89% 1.93[0.19,20.18]

Subtotal (95% CI) 382 365 100% 0.88[0.57,1.35]

Total events: 36 (Magnesium), 39 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.45, df=1(P=0.5); I2=0%

Test for overall effect: Z=0.59(P=0.55)

6.1.4 Any maintenance (high or low): any loading dose

Crowther 2003 87/629 107/626 27.78% 0.81[0.62,1.05]

Magpie 2006 209/798 188/795 45.31% 1.11[0.93,1.31]

Rouse 2008 103/1188 96/1256 26.91% 1.13[0.87,1.48]

Subtotal (95% CI) 2615 2677 100% 1.02[0.83,1.24]

Total events: 399 (Magnesium), 391 (No magnesium)

Heterogeneity: Tau2=0.02; Chi2=4.49, df=2(P=0.11); I2=55.47%

Test for overall effect: Z=0.16(P=0.87)

6.1.5 No maintenance: loading dose 4 g

Marret 2006 34/352 38/336 96.11% 0.85[0.55,1.32]

Mittendorf 2002 2/30 1/29 3.89% 1.93[0.19,20.18]

Subtotal (95% CI) 382 365 100% 0.88[0.57,1.35]

Total events: 36 (Magnesium), 39 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.45, df=1(P=0.5); I2=0%

Test for overall effect: Z=0.59(P=0.55)

6.1.6 Loading (4 g) and lower-dose maintenance (1 g/hour)

Crowther 2003 87/629 107/626 38% 0.81[0.62,1.05]

Magpie 2006 209/798 188/795 62% 1.11[0.93,1.31]

Subtotal (95% CI) 1427 1421 100% 0.96[0.71,1.31]

Total events: 296 (Magnesium), 295 (No magnesium)

Heterogeneity: Tau2=0.04; Chi2=3.91, df=1(P=0.05); I2=74.45%

Test for overall effect: Z=0.25(P=0.8)

Favours magnesium 50.2 20.5 1 Favours no magnesium

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

6.1.7 Loading dose (4 g) and higher-dose maintenance (2-3 g/hour)

Mittendorf 2002 8/55 0/51 100% 15.79[0.93,266.72]

Subtotal (95% CI) 55 51 100% 15.79[0.93,266.72]

Total events: 8 (Magnesium), 0 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=1.91(P=0.06)

6.1.8 Loading dose (6 g) and higher-dose maintenance (2-3 g/hour)

Rouse 2008 103/1118 96/1256 100% 1.21[0.92,1.57]

Subtotal (95% CI) 1118 1256 100% 1.21[0.92,1.57]

Total events: 103 (Magnesium), 96 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=1.38(P=0.17)

Favours magnesium 50.2 20.5 1 Favours no magnesium

Analysis 6.2. Comparison 6 Dose subgroup, Outcome 2 Cerebral palsy.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

6.2.1 Loading dose 4 g (any or no maintenance)

Crowther 2003 36/629 42/626 57% 0.85[0.55,1.31]

Magpie 2006 2/798 5/795 3.96% 0.4[0.08,2.05]

Marret 2006 22/352 30/336 37.81% 0.7[0.41,1.19]

Mittendorf 2002 3/30 0/29 1.24% 6.77[0.37,125.65]

Subtotal (95% CI) 1809 1786 100% 0.79[0.56,1.1]

Total events: 63 (Magnesium), 77 (No magnesium)

Heterogeneity: Tau2=0; Chi2=3.09, df=3(P=0.38); I2=2.76%

Test for overall effect: Z=1.39(P=0.16)

6.2.2 Loading dose 6 g (any or no maintenance)

Rouse 2008 41/1188 74/1256 100% 0.59[0.4,0.85]

Subtotal (95% CI) 1188 1256 100% 0.59[0.4,0.85]

Total events: 41 (Magnesium), 74 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=2.81(P=0)

6.2.3 No maintenance: any loading dose

Marret 2006 22/352 30/336 96.82% 0.7[0.41,1.19]

Mittendorf 2002 3/30 0/29 3.18% 6.77[0.37,125.65]

Subtotal (95% CI) 382 365 100% 1.37[0.18,10.7]

Total events: 25 (Magnesium), 30 (No magnesium)

Heterogeneity: Tau2=1.49; Chi2=2.3, df=1(P=0.13); I2=56.48%

Test for overall effect: Z=0.3(P=0.76)

6.2.4 Any maintenance (high or low): any loading dose

Crowther 2003 36/629 42/626 41.6% 0.85[0.55,1.31]

Magpie 2006 2/798 5/795 2.89% 0.4[0.08,2.05]

Rouse 2008 41/1188 74/1256 55.52% 0.59[0.4,0.85]

Subtotal (95% CI) 2615 2677 100% 0.68[0.51,0.91]

Favours magnesium 10000.001 100.1 1 Favours no magnesium

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

Total events: 79 (Magnesium), 121 (No magnesium)

Heterogeneity: Tau2=0; Chi2=2.09, df=2(P=0.35); I2=4.17%

Test for overall effect: Z=2.64(P=0.01)

6.2.5 No maintenance: loading dose 4 g

Marret 2006 22/352 30/336 96.82% 0.7[0.41,1.19]

Mittendorf 2002 3/30 0/29 3.18% 6.77[0.37,125.65]

Subtotal (95% CI) 382 365 100% 1.37[0.18,10.7]

Total events: 25 (Magnesium), 30 (No magnesium)

Heterogeneity: Tau2=1.49; Chi2=2.3, df=1(P=0.13); I2=56.48%

Test for overall effect: Z=0.3(P=0.76)

6.2.6 Loading dose (4 g) and lower-dose maintenance (1 g/hour)

Crowther 2003 36/629 42/626 93.51% 0.85[0.55,1.31]

Magpie 2006 2/798 5/795 6.49% 0.4[0.08,2.05]

Subtotal (95% CI) 1427 1421 100% 0.81[0.54,1.23]

Total events: 38 (Magnesium), 47 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.78, df=1(P=0.38); I2=0%

Test for overall effect: Z=0.98(P=0.33)

6.2.7 Loading dose (4 g) and higher-dose maintenance (2-3 g/hour)

Mittendorf 2002 0/55 3/51 100% 0.13[0.01,2.51]

Subtotal (95% CI) 55 51 100% 0.13[0.01,2.51]

Total events: 0 (Magnesium), 3 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=1.35(P=0.18)

6.2.8 Loading dose (6 g) and higher-dose maintenance (2-3 g /hour)

Rouse 2008 41/1188 74/1256 100% 0.59[0.4,0.85]

Subtotal (95% CI) 1188 1256 100% 0.59[0.4,0.85]

Total events: 41 (Magnesium), 74 (No magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=2.81(P=0)

Favours magnesium 10000.001 100.1 1 Favours no magnesium

Analysis 6.3. Comparison 6 Dose subgroup, Outcome 3 Neurological impairment.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.3.1 Loading (4 g) and lower-maintenance dose (1 g/hour)

Crowther 2003 193/629 187/626 93.5% 1.03[0.87,1.21]

Magpie 2006 10/798 13/795 6.5% 0.77[0.34,1.74]

Subtotal (95% CI) 1427 1421 100% 1.01[0.86,1.19]

Total events: 203 (Magnesium), 200 (No magnesium)

Heterogeneity: Tau2=0; Chi2=0.48, df=1(P=0.49); I2=0%

Test for overall effect: Z=0.12(P=0.9)

Total (95% CI) 1427 1421 100% 1.01[0.86,1.19]

Total events: 203 (Magnesium), 200 (No magnesium)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Tau2=0; Chi2=0.48, df=1(P=0.49); I2=0%

Test for overall effect: Z=0.12(P=0.9)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 6.4. Comparison 6 Dose subgroup, Outcome 4 Major neurological disability.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.4.1 Loading (4 g) and lower-maintenance dose (1 g/hour)

Crowther 2003 89/629 78/626 85.72% 1.14[0.86,1.51]

Magpie 2006 9/798 13/795 14.28% 0.69[0.3,1.6]

Subtotal (95% CI) 1427 1421 100% 1.07[0.82,1.4]

Total events: 98 (Magnesium), 91 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.21, df=1(P=0.27); I2=17.19%

Test for overall effect: Z=0.51(P=0.61)

Total (95% CI) 1427 1421 100% 1.07[0.82,1.4]

Total events: 98 (Magnesium), 91 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.21, df=1(P=0.27); I2=17.19%

Test for overall effect: Z=0.51(P=0.61)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 6.5. Comparison 6 Dose subgroup, Outcome 5 Death or cerebral palsy.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

6.5.1 Loading dose (4 g) only

Marret 2006 56/352 67/336 17.25% 0.8[0.58,1.1]

Mittendorf 2002 5/30 1/29 0.72% 4.83[0.6,38.9]

Subtotal (95% CI) 382 365 17.97% 1.45[0.27,7.72]

Total events: 61 (Magnesium), 68 (No magnesium)

Heterogeneity: Tau2=1.06; Chi2=2.83, df=1(P=0.09); I2=64.69%

Test for overall effect: Z=0.44(P=0.66)

6.5.2 Loading (4 g) and lower-maintenance dose (1 g/hour)

Crowther 2003 123/629 149/626 25.34% 0.82[0.66,1.02]

Magpie 2006 211/798 193/795 29.12% 1.09[0.92,1.29]

Subtotal (95% CI) 1427 1421 54.45% 0.95[0.72,1.26]

Total events: 334 (Magnesium), 342 (No magnesium)

Heterogeneity: Tau2=0.03; Chi2=4.17, df=1(P=0.04); I2=76.04%

Test for overall effect: Z=0.34(P=0.73)

6.5.3 Loading (4 g) and higher-maintenance dose (2-3 g/hour): tocolyt- ic intent

Mittendorf 2002 8/55 3/51 1.88% 2.47[0.69,8.81]

Rouse 2008 144/1188 170/1256 25.7% 0.9[0.73,1.1]

Subtotal (95% CI) 1243 1307 27.58% 1.22[0.49,3.04]

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

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Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

Total events: 152 (Magnesium), 173 (No magnesium)

Heterogeneity: Tau2=0.3; Chi2=2.39, df=1(P=0.12); I2=58.2%

Test for overall effect: Z=0.42(P=0.67)

Total (95% CI) 3052 3093 100% 0.94[0.78,1.12]

Total events: 547 (Magnesium), 583 (No magnesium)

Heterogeneity: Tau2=0.02; Chi2=10.28, df=5(P=0.07); I2=51.34%

Test for overall effect: Z=0.7(P=0.48)

Test for subgroup differences: Not applicable

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 6.6. Comparison 6 Dose subgroup, Outcome 6 Death or neurological impairment.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.6.1 Loading (4 g) and lower-maintenance dose (1 g/hour)

Crowther 2003 280/629 294/626 59.41% 0.95[0.84,1.07]

Magpie 2006 219/798 201/795 40.59% 1.09[0.92,1.28]

Subtotal (95% CI) 1427 1421 100% 1[0.91,1.11]

Total events: 499 (Magnesium), 495 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.74, df=1(P=0.19); I2=42.48%

Test for overall effect: Z=0.07(P=0.94)

Total (95% CI) 1427 1421 100% 1[0.91,1.11]

Total events: 499 (Magnesium), 495 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.74, df=1(P=0.19); I2=42.48%

Test for overall effect: Z=0.07(P=0.94)

Favours magnesium 50.2 20.5 1 Favours no magnesium

Analysis 6.7. Comparison 6 Dose subgroup, Outcome 7 Death or major neurological disability.

Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.7.1 Loading (4 g) and lower-maintenance dose (1 g/hour)

Crowther 2003 176/629 185/626 47.94% 0.95[0.8,1.13]

Magpie 2006 218/798 201/795 52.06% 1.08[0.92,1.27]

Subtotal (95% CI) 1427 1421 100% 1.02[0.9,1.15]

Total events: 394 (Magnesium), 386 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.17, df=1(P=0.28); I2=14.32%

Test for overall effect: Z=0.27(P=0.79)

Total (95% CI) 1427 1421 100% 1.02[0.9,1.15]

Total events: 394 (Magnesium), 386 (No magnesium)

Heterogeneity: Tau2=0; Chi2=1.17, df=1(P=0.28); I2=14.32%

Test for overall effect: Z=0.27(P=0.79)

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

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Comparison 7. Retreatment subgroup

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 Paediatric mortality (fetal and later) 5 6145 Risk Ratio (M-H, Random, 95% CI)

1.01 [0.81, 1.27]

1.1 retreatment permitted 1 2444 Risk Ratio (M-H, Random, 95% CI)

1.13 [0.87, 1.48]

1.2 retreatment not permitted 3 3536 Risk Ratio (M-H, Random, 95% CI)

0.95 [0.75, 1.19]

1.3 unclear whether retreatment permitted 1 165 Risk Ratio (M-H, Random, 95% CI)

9.41 [1.23, 71.86]

2 Cerebral palsy 5 6145 Risk Ratio (M-H, Fixed, 95% CI)

0.68 [0.54, 0.87]

2.1 retreatment permitted 1 2444 Risk Ratio (M-H, Fixed, 95% CI)

0.59 [0.40, 0.85]

2.2 retreatment not permitted 3 3536 Risk Ratio (M-H, Fixed, 95% CI)

0.76 [0.55, 1.06]

2.3 unclear whether retreatment permitted 1 165 Risk Ratio (M-H, Fixed, 95% CI)

0.94 [0.20, 4.53]

3 Neurologic impairment 2 2848 Risk Ratio (M-H, Fixed, 95% CI)

1.01 [0.86, 1.19]

3.1 retreatment not permitted 2 2848 Risk Ratio (M-H, Fixed, 95% CI)

1.01 [0.86, 1.19]

4 Major neurological disability 2 2848 Risk Ratio (M-H, Fixed, 95% CI)

1.07 [0.82, 1.40]

4.1 retreatment not permitted 2 2848 Risk Ratio (M-H, Fixed, 95% CI)

1.07 [0.82, 1.40]

5 Death or cerebral palsy 5 6145 Risk Ratio (M-H, Random, 95% CI)

0.94 [0.78, 1.13]

5.1 retreatment permitted 1 2444 Risk Ratio (M-H, Random, 95% CI)

0.90 [0.73, 1.10]

5.2 retreatment not permitted 3 3536 Risk Ratio (M-H, Random, 95% CI)

0.91 [0.74, 1.13]

5.3 unclear whether retreatment permitted 1 165 Risk Ratio (M-H, Random, 95% CI)

3.06 [1.04, 8.99]

6 Death or neurological impairment 2 2848 Risk Ratio (M-H, Fixed, 95% CI)

1.00 [0.91, 1.11]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

6.1 retreatment not permitted 2 2848 Risk Ratio (M-H, Fixed, 95% CI)

1.00 [0.91, 1.11]

7 Death or major neurological disability 2 2848 Risk Ratio (M-H, Fixed, 95% CI)

1.02 [0.90, 1.15]

7.1 retreatment not permitted 2 2848 Risk Ratio (M-H, Fixed, 95% CI)

1.02 [0.90, 1.15]

Analysis 7.1. Comparison 7 Retreatment subgroup, Outcome 1 Paediatric mortality (fetal and later).

Study or subgroup magnesium no magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

7.1.1 retreatment permitted

Rouse 2008 103/1188 96/1256 25.31% 1.13[0.87,1.48]

Subtotal (95% CI) 1188 1256 25.31% 1.13[0.87,1.48]

Total events: 103 (magnesium), 96 (no magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=0.93(P=0.35)

7.1.2 retreatment not permitted

Crowther 2003 87/629 107/626 25.72% 0.81[0.62,1.05]

Magpie 2006 209/798 188/795 32.04% 1.11[0.93,1.31]

Marret 2006 34/352 38/336 15.76% 0.85[0.55,1.32]

Subtotal (95% CI) 1779 1757 73.51% 0.95[0.75,1.19]

Total events: 330 (magnesium), 333 (no magnesium)

Heterogeneity: Tau2=0.02; Chi2=4.42, df=2(P=0.11); I2=54.71%

Test for overall effect: Z=0.48(P=0.63)

7.1.3 unclear whether retreatment permitted

Mittendorf 2002 10/85 1/80 1.18% 9.41[1.23,71.86]

Subtotal (95% CI) 85 80 1.18% 9.41[1.23,71.86]

Total events: 10 (magnesium), 1 (no magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=2.16(P=0.03)

Total (95% CI) 3052 3093 100% 1.01[0.81,1.27]

Total events: 443 (magnesium), 430 (no magnesium)

Heterogeneity: Tau2=0.03; Chi2=9.76, df=4(P=0.04); I2=59.02%

Test for overall effect: Z=0.1(P=0.92)

Test for subgroup differences: Not applicable

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

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Analysis 7.2. Comparison 7 Retreatment subgroup, Outcome 2 Cerebral palsy.

Study or subgroup magnesium no magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.2.1 retreatment permitted

Rouse 2008 41/1188 74/1256 47.07% 0.59[0.4,0.85]

Subtotal (95% CI) 1188 1256 47.07% 0.59[0.4,0.85]

Total events: 41 (magnesium), 74 (no magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=2.81(P=0)

7.2.2 retreatment not permitted

Crowther 2003 36/629 42/626 27.55% 0.85[0.55,1.31]

Magpie 2006 2/798 5/795 3.28% 0.4[0.08,2.05]

Marret 2006 22/352 30/336 20.08% 0.7[0.41,1.19]

Subtotal (95% CI) 1779 1757 50.91% 0.76[0.55,1.06]

Total events: 60 (magnesium), 77 (no magnesium)

Heterogeneity: Tau2=0; Chi2=0.96, df=2(P=0.62); I2=0%

Test for overall effect: Z=1.62(P=0.11)

7.2.3 unclear whether retreatment permitted

Mittendorf 2002 3/85 3/80 2.02% 0.94[0.2,4.53]

Subtotal (95% CI) 85 80 2.02% 0.94[0.2,4.53]

Total events: 3 (magnesium), 3 (no magnesium)

Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%

Test for overall effect: Z=0.08(P=0.94)

Total (95% CI) 3052 3093 100% 0.68[0.54,0.87]

Total events: 104 (magnesium), 154 (no magnesium)

Heterogeneity: Tau2=0; Chi2=2.26, df=4(P=0.69); I2=0%

Test for overall effect: Z=3.08(P=0)

Test for subgroup differences: Not applicable

Favours magnesium 100.1 50.2 20.5 1 Favours no magnesium

Analysis 7.3. Comparison 7 Retreatment subgroup, Outcome 3 Neurologic impairment.

Study or subgroup magnesium no magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.3.1 retreatment not permitted

Crowther 2003 193/629 187/626 93.5% 1.03[0.87,1.21]

Magpie 2006 10/798 13/795 6.5% 0.77[0.34,1.74]

Subtotal (95% CI) 1427 1421 100% 1.01[0.86,1.19]

Total events: 203 (magnesium), 200 (no magnesium)

Heterogeneity: Tau2=0; Chi2=0.48, df=1(P=0.49); I2=0%

Test for overall effect: Z=0.12(P=0.9)

Total (95% CI) 1427 1421 100% 1.01[0.86,1.19]

Total events: 203 (magnesium), 200 (no magnesium)

Heterogeneity: Tau2=0; Chi2=0.48, df=1(P=0.49); I2=0%

Test for overall effect: Z=0.12(P=0.9)

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

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Analysis 7.4. Comparison 7 Retreatment subgroup, Outcome 4 Major neurological disability.

Study or subgroup magnesium no magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.4.1 retreatment not permitted

Crowther 2003 89/629 78/626 85.72% 1.14[0.86,1.51]

Magpie 2006 9/798 13/795 14.28% 0.69[0.3,1.6]

Subtotal (95% CI) 1427 1421 100% 1.07[0.82,1.4]

Total events: 98 (magnesium), 91 (no magnesium)

Heterogeneity: Tau2=0; Chi2=1.21, df=1(P=0.27); I2=17.19%

Test for overall effect: Z=0.51(P=0.61)

Total (95% CI) 1427 1421 100% 1.07[0.82,1.4]

Total events: 98 (magnesium), 91 (no magnesium)

Heterogeneity: Tau2=0; Chi2=1.21, df=1(P=0.27); I2=17.19%

Test for overall effect: Z=0.51(P=0.61)

Favours magnesium 50.2 20.5 1 Favours no magnesium

Analysis 7.5. Comparison 7 Retreatment subgroup, Outcome 5 Death or cerebral palsy.

Study or subgroup magnesium no magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

7.5.1 retreatment permitted

Rouse 2008 144/1188 170/1256 25.57% 0.9[0.73,1.1]

Subtotal (95% CI) 1188 1256 25.57% 0.9[0.73,1.1]

Total events: 144 (magnesium), 170 (no magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=1.04(P=0.3)

7.5.2 retreatment not permitted

Crowther 2003 123/629 149/626 25.24% 0.82[0.66,1.02]

Magpie 2006 211/798 193/795 28.55% 1.09[0.92,1.29]

Marret 2006 56/352 67/336 17.81% 0.8[0.58,1.1]

Subtotal (95% CI) 1779 1757 71.6% 0.91[0.74,1.13]

Total events: 390 (magnesium), 409 (no magnesium)

Heterogeneity: Tau2=0.02; Chi2=5.47, df=2(P=0.06); I2=63.42%

Test for overall effect: Z=0.82(P=0.41)

7.5.3 unclear whether retreatment permitted

Mittendorf 2002 13/85 4/80 2.83% 3.06[1.04,8.99]

Subtotal (95% CI) 85 80 2.83% 3.06[1.04,8.99]

Total events: 13 (magnesium), 4 (no magnesium)

Heterogeneity: Not applicable

Test for overall effect: Z=2.03(P=0.04)

Total (95% CI) 3052 3093 100% 0.94[0.78,1.13]

Total events: 547 (magnesium), 583 (no magnesium)

Heterogeneity: Tau2=0.03; Chi2=10.28, df=4(P=0.04); I2=61.09%

Test for overall effect: Z=0.64(P=0.52)

Test for subgroup differences: Not applicable

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

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Analysis 7.6. Comparison 7 Retreatment subgroup, Outcome 6 Death or neurological impairment.

Study or subgroup magnesium no magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.6.1 retreatment not permitted

Crowther 2003 280/629 294/626 59.41% 0.95[0.84,1.07]

Magpie 2006 219/798 201/795 40.59% 1.09[0.92,1.28]

Subtotal (95% CI) 1427 1421 100% 1[0.91,1.11]

Total events: 499 (magnesium), 495 (no magnesium)

Heterogeneity: Tau2=0; Chi2=1.74, df=1(P=0.19); I2=42.48%

Test for overall effect: Z=0.07(P=0.94)

Total (95% CI) 1427 1421 100% 1[0.91,1.11]

Total events: 499 (magnesium), 495 (no magnesium)

Heterogeneity: Tau2=0; Chi2=1.74, df=1(P=0.19); I2=42.48%

Test for overall effect: Z=0.07(P=0.94)

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

Analysis 7.7. Comparison 7 Retreatment subgroup, Outcome 7 Death or major neurological disability.

Study or subgroup magnesium no magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.7.1 retreatment not permitted

Crowther 2003 176/629 185/626 47.94% 0.95[0.8,1.13]

Magpie 2006 218/798 201/795 52.06% 1.08[0.92,1.27]

Subtotal (95% CI) 1427 1421 100% 1.02[0.9,1.15]

Total events: 394 (magnesium), 386 (no magnesium)

Heterogeneity: Tau2=0; Chi2=1.17, df=1(P=0.28); I2=14.32%

Test for overall effect: Z=0.27(P=0.79)

Total (95% CI) 1427 1421 100% 1.02[0.9,1.15]

Total events: 394 (magnesium), 386 (no magnesium)

Heterogeneity: Tau2=0; Chi2=1.17, df=1(P=0.28); I2=14.32%

Test for overall effect: Z=0.27(P=0.79)

Favours magnesium 20.5 1.50.7 1 Favours no magnesium

W H A T ' S N E W

Date Event Description

22 September 2009 Amended Corrected error in figures reported in the first paragraph of the Discussion.

H I S T O R Y

Protocol first published: Issue 1, 2004 Review first published: Issue 3, 2007

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)

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Date Event Description

16 February 2009 Amended Error in NNT for cerebral palsy corrected.

6 November 2008 New citation required and conclusions have changed

There is now evidence that magnesium sulphate given to women at risk of preterm birth helps to protect the baby's brain and im- prove long-term outcomes.

31 August 2008 New search has been performed Search updated. One new study identified (Rouse 2008) and two additional reports of Marret 2006 added.

24 April 2008 Amended Converted to new review format.

C O N T R I B U T I O N S O F A U T H O R S

Lex Doyle and Caroline Crowther wrote the original protocol. Lex Doyle, for the first version of this review, searched the literature, reviewed all possible trials for inclusion, extracted details of the studies' methods and results, entered the data into Review Manager, wrote the initial synthesis of the results, and contributed to all versions of the original review. Caroline Crowther extracted details of the results and contributed to all versions of the original review. Philippa Middleton searched the literature, extracted details of the studies' results, and contributed to all versions of the original review. Stephane Marret searched the literature, extracted details of the studies' results, and contributed to the final version of the original review.

For this update Caroline Crowther and Philippa Middleton searched the literature, extracted details of the study methods and results, entered the data into Review Manager, wrote the initial updated synthesis of results and contributed to all versions of the review. Lex Doyle, Stephane Marret and Dwight Rouse contributed to all versions of this updated review.

D E C L A R A T I O N S O F I N T E R E S T

Two review authors (Lex Doyle and Caroline Crowther) are principal investigators in the Australasian Collaborative Trial of Magnesium Sulphate given as a neuroprotective prior to very preterm birth for the prevention of mortality and cerebral palsy in their babies (ACTOMgSO4 - Crowther 2003). This trial is funded by the Australian National Health and Medical Research Council. One review author

(Stephane Marret) is the principal investigator in the PREMAG study from France (Marret 2006).

One review author (Dwight Rouse) is protocol chairman of the "BEAM" study that was funded by the United States National Institutes of Health (Eunice Shriver Kennedy National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke) (Rouse 2008).

The results of these trials were assessed for inclusion and quality using the same criteria as all other potential studies.

S O U R C E S O F S U P P O R T

Internal sources

• Discipline of Obstetrics and Gynaecology, The University of Adelaide, Australia.

• Department of Obstetrics and Gynaecology, University of Melbourne, Australia.

External sources

• National Health and Medical Research Council, Commonwealth Department of Health and Ageing, Australia.

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

The outcome of intraventricular haemorrhage 3/4 was added at review stage.

In the 2008 update, we have added a subgroup examining the impact of permitting magnesium retreatment.

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I N D E X T E R M S

Medical Subject Headings (MeSH)

*Premature Birth; Central Nervous System Diseases [*prevention & control]; Cerebral Palsy [mortality] [prevention & control]; Fetal Death [*prevention & control]; Magnesium Sulfate [*therapeutic use]; Neuroprotective Agents [*therapeutic use]; Prenatal Care; Randomized Controlled Trials as Topic

MeSH check words

Female; Humans; Infant, Newborn; Pregnancy

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)