Evidence-based practice inquiry

Advanced maternal age increases the risk of very preterm birth, irrespective of parity: a population-based register study U Waldenstr€om,a S Cnattingius,b L Vixner,c M Normand,e

a Division of Reproductive Health, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden b Clinical

Epidemiology Unit, Department of Medicine Solna, Karolinska University Hospital, Stockholm, Sweden c School of Health and Social Studies,

Dalarna University, Falun, Sweden d Division of Paediatrics, Department of Clinical Science, Intervention and Technology, Karolinska

Institutet, Stockholm, Sweden e Department of Neonatal Medicine K78, Karolinska University Hospital, Stockholm, Sweden

Correspondence: Professor U Waldenstr€om, Division of Reproductive Health, Department of Women’s and Children’s Health, Karolinska

Institutet, Bastugatan 42, 118 25 Stockholm, Sweden. Email [email protected]

Accepted 20 August 2016. Published Online 21 October 2016.

Objective To investigate whether advanced maternal age is

associated with preterm birth, irrespective of parity.

Design Population-based registry study.

Setting Swedish Medical Birth Register.

Population First, second, and third live singleton births to

women aged 20 years or older in Sweden, from 1990 to 2011

(n = 2 009 068).

Methods Logistic regression analysis was used in each parity group

to estimate risks of very and moderately preterm births to women

at 20–24, 25–29, 30–34, 35–39, and 40 years or older, using 25– 29 years as the reference group. Odds ratios (ORs) were adjusted for

year of birth, education, country of birth, smoking, body mass index,

and history of preterm birth. Age-related risks of spontaneous and

medically indicated preterm births were also investigated.

Main outcome measures Very preterm (22–31 weeks of gestation) and moderately preterm (32–36 weeks) births.

Results Risks of very preterm birth increased with maternal age,

irrespective of parity: adjusted ORs in first, second, and third

births ranged from 1.18 to 1.28 at 30–34 years, from 1.59 to 1.70 at 35–39 years, and from 1.97 to 2.40 at ≥40 years. In moderately preterm births, age-related associations were weaker, but were

statistically significant from 35–39 years in all parity groups. Advanced maternal age increased the risks of both spontaneous

and medically indicated preterm births.

Conclusions Advanced maternal age is associated with an

increased risk of preterm birth, irrespective of parity, especially

very preterm birth. Women aged 35 years and older, expecting

their first, second, or third births, should be regarded as a risk

group for very preterm birth.

Keywords Maternal age, parity, preterm birth.

Tweetable abstract Women aged 35 years and older should be

regarded as a risk group for very preterm birth, irrespective of

parity.

Linked article This article is commented on by KY Eichelberger,

p. 1245 in this issue. To view this mini commentary visit http://

dx.doi.org/10.1111/1471-0528.14464.

Please cite this paper as: Waldenstr€om U, Cnattingius S, Vixner L, Norman M. Advanced maternal age increases the risk of very preterm birth, irrespective

of parity: a population-based register study. BJOG 2017;124:1235–1244.

Introduction

So far, it has not been possible to prevent preterm birth,

mostly because the specific causes are complex and difficult

to establish in individual patients. Spontaneous preterm

birth is regarded as a syndrome initiated by multiple mech-

anisms, such as infection and inflammation, uteroplacental

ischaemia and haemorrhage, uterine overdistension, cervical

insufficiency, hormonal disorders, stress, or other immuno-

logically mediated processes.1

Targeting maternal risk factors for preterm birth in epi-

demiological studies might provide clues to the mecha-

nisms leading to preterm birth, and help to identify

women at risk.2 Low or advanced maternal ages have been

established as important risk factors for preterm birth,

along with socio-economic factors, smoking, low or high

body mass index (BMI), and an obstetric history of previ-

ous adverse events. 3–7

Whereas socio-economic confound-

ing may largely explain the increased risk of preterm birth

at young maternal age, this explanation seems less obvious

1235ª 2016 Royal College of Obstetricians and Gynaecologists

DOI: 10.1111/1471-0528.14368

www.bjog.org General obstetrics

in relation to advanced maternal age. 8 Parity is another fac-

tor associated with preterm birth, with the highest rates

reported in nulliparous women and the lowest rates

reported in second births.5,6,9 The combined effect of

advanced maternal age and parity has been less explored,

as most studies have included nulliparous women

alone,10–15 or have treated parity as a covariate in the sta-

tistical analyses. 16–23

A limited number of studies compar-

ing nulliparous and parous women, 24,25

and studies

comparing first and second births,26,27 suggest that

advanced maternal age influences the risk of preterm birth

risk, regardless of parity. A review of studies from low- and

middle-income countries reported an increased risk of pre-

term birth in older women (≥35 years) expecting their third birth or more, however.28

Considering maternal age and parity as two interrelated

risk factors that may affect pregnancy in different ways, it

is important to study their combined effect on the risk of

preterm birth. The principal aim of the present study was

to investigate associations between advanced maternal age

and risks of very preterm and moderately preterm birth in

first, second, and third childbirths, using a large popula-

tion-based cohort study. Subgroup analyses of spontaneous

and medically indicated preterm births were also

conducted.

Methods

The study was based on data from the Swedish Medical Birth

Register (MBR), which includes more than 98% of all births

in Sweden, and is validated annually against the National Pop-

ulation Register, using the mother’s and infant’s unique per-

sonal identification numbers. 29,30

Starting at the first antenatal

visit, information is prospectively collected during pregnancy

and delivery, using standardised records. We included live sin-

gleton births to women aged 20 years or older, recorded in

the MBR from 1990 to 2011. Consequently, the majority of

women contributed information about all of their births,

whereas some only provided information about their last birth

at the beginning of the observation period (1990), and others

only provided information about their first birth at the end of

the observation period (2011).

From 1990 to 2011, the total number of births in Swe-

den was 2 267 989. We excluded births to women younger

than 20 years (2.0%), births to women of parity 4 or more

(6.5%), multiple births (2.9%), stillbirths (0.3%), and preg-

nancies with missing data on gestation (0.1%) and unique

maternal identification number (0.1%), leaving 2 009 068

pregnancies in the final sample. Analyses stratified by spon-

taneous and medically indicated births were limited to the

period 2000–2011, when information about onset of labour was most complete (99%), leaving 1 087 907 pregnancies

in the stratified analyses.

The outcome variables were very preterm birth

(22–31 weeks of gestation) and moderately preterm birth (32–36 weeks of gestation), compared with pregnancies at ≥32 and ≥37 weeks of gestation, respectively. Specifying a group of extremely preterm births (<28 weeks of gestation) was not possible because of the insufficient power for anal-

yses by both maternal age and parity. The best available

estimate of gestational age was determined by a hierarchical

method based on expected date of parturition according to

ultrasound and last menstrual period.9 In Sweden, all

women are offered ultrasound pregnancy dating at

17 weeks or earlier, and more than 95% of women accept

this offer.31 Medically indicated births were defined as

either starting with the induction of labour or a caesarean

section before the onset of labour.

The independent variable was maternal age when giving

birth to the first, second, and third infant. In each parity

group, the maternal age range of 25–29 years was used as the reference group, and compared with maternal ages of

20–24, 30–34, 35–39, and 40 years or older. The rationale for the choice of reference group was the assumption that

25–29 years was an age range when outcomes would be optimal,5,32 considering the U-shaped association between

maternal age and rates of preterm birth. The maternal age

range of 25–29 years was also the interval with the largest number of live singleton births during the 21-year study

period (Table 1).

The principal analyses were adjusted for possible con-

founding factors, including year of birth, education,33,34

country of birth,3,33 smoking,15,33 BMI,15,33 and, in parous

women, history of preterm birth (<37 weeks of gesta- tion).

35,36 Information about smoking (dichotomised as

daily smoking versus non-daily smoking), and maternal

height and weight were recorded at the first antenatal visit

(commonly at 8–12 weeks of gestation). BMI was calcu- lated (weight/height2) and categorised according to the

World Health Organization as: underweight (BMI

<18.5 kg/m2), normal weight (BMI = 18.5–24.9 kg/m2), overweight (BMI = 25.0–29.9 kg/m2), and obese (BMI ≥30.0 kg/m2). The Swedish Register of Total Population provided information about the mother’s country of birth

(dichotomised as Nordic country, i.e. Sweden, Norway,

Finland, Denmark, and Iceland, versus not Nordic coun-

try). Level of education (low, elementary school or less;

medium, high school; high, college or university) was

obtained by linking to the Swedish Education Register. His-

tory of preterm birth was based on information about ges-

tational age at previous delivery recorded in the data set.

Additional analyses also included potentially mediating

factors occurring in the pathway between the independent

(maternal age when having a first, second, and third child)

and dependent (preterm birth) variables, such as gesta-

tional diabetes, pre-eclampsia, and small for gestational age

1236 ª 2016 Royal College of Obstetricians and Gynaecologists

Waldenstr€om et al.

T a b le

1 . R is k o f ve ry

a n d m o d e ra te ly

p re te rm

liv e b ir th

(P T B ) b y m a te rn a l a g e in

fi rs t, se co n d , a n d th ir d p re g n a n ci e s

M a te rn a l a g e , Y e a rs

V e ry

P T B (2 2 – 3 1 w e e k s o f g e st a ti o n )

M o d e ra te ly

P T B (3 2 – 3 6 w e e k s o f g e st a ti o n )

n %

M o d e l 1 *

M o d e l 2 * *

M o d e l 3 * * *

n %

M o d e l 1 *

M o d e l 2 * *

M o d e l 3 * * *

a O R (9 5 %

C I)

a O R 9 5 %

C I

a O R 9 5 %

C I

a O R (9 5 %

C I)

a O R 9 5 %

C I

a O R 9 5 %

C I

F ir st

b ir th s

n = 9 0 3 4 9 7

n = 8 4 1 0 4 6

n = 8 3 8 6 0 8

n = 8 9 5 9 3 7

n = 8 3 4 6 3 5

n = 8 3 2 3 3 4

2 0 – 2 4

1 6 7 3

0 .7 2

0 .9 7 (0 .9 1 – 1 .0 3 )

0 .8 4 (0 .7 8 – 0 .9 0 )

0 .8 7 (0 .8 1 – 0 .9 3 )

1 1 8 6 8

5 .1 5

1 .0 0 (0 .9 8 – 1 .0 2 )

0 .9 5 (0 .9 2 – 0 .9 7 )

0 .9 6 (0 .9 3 – 0 .9 8 )

2 5 – 2 9

2 6 4 9

0 .7 4

1 1

1 1 8 1 2 5

5 .1 4

1 1

1

3 0 – 3 4

2 1 3 7

0 .9 1

1 .2 4 (1 .1 7 – 1 .3 1 )

1 .2 8 (1 .2 0 – 1 .3 6 )

1 .1 9 (1 .1 2 – 1 .2 7 )

1 1 9 8 4

5 .1 6

1 .0 1 (0 .9 9 – 1 .0 3 )

1 .0 2 (1 .0 0 – 1 .0 5 )

1 .0 0 (0 .9 8 – 1 .0 2 )

3 5 – 3 9

9 2 5

1 .2 8

1 .7 4 (1 .6 2 – 1 .8 8 )

1 .7 0 (1 .5 6 – 1 .8 4 )

1 .4 2 (1 .3 1 – 1 .5 5 )

4 1 7 5

5 .8 6

1 .1 5 (1 .1 2 – 1 .2 0 )

1 .1 6 (1 .1 2 – 1 .2 0 )

1 .0 9 (1 .0 5 – 1 .1 3 )

≥ 4 0

2 2 1

1 .8 1

2 .4 9 (2 .1 7 – 2 .8 6 )

2 .3 7 (2 .0 4 – 2 .7 7 )

1 .7 3 (1 .4 7 – 2 .0 3 )

7 4 6

6 .1 9

1 .2 3 (1 .1 4 – 1 .3 2 )

1 .2 2 (1 .1 3 – 1 .3 2 )

1 .0 9 (1 .0 0 – 1 .1 8 )

S e co

n d b ir th s

n = 7 9 3 0 9 1

n = 6 5 5 0 0 8

n = 6 5 3 4 2 2

n = 7 8 9 2 3 5

n = 6 5 2 1 9 3

n = 6 5 0 6 8 0

2 0 – 2 4

5 3 0

0 .5 4

1 .3 3 (1 .2 0 – 1 .4 7 )

1 .1 2 (0 .9 9 – 1 .2 7 )

1 .1 3 (0 .9 9 – 1 .2 8 )

3 5 1 6

3 .5 9

1 .2 1 (1 .1 6 – 1 .2 5 )

1 .0 8 (1 .0 3 – 1 .1 3 )

1 .1 0 (1 .0 5 – 1 .1 5 )

2 5 – 2 9

1 1 2 2

0 .4 1

1 1

1 8 2 5 4

2 .9 9

R e fe re n ce

= 1

1 1

3 0 – 3 4

1 3 0 9

0 .4 6

1 .1 4 (1 .0 5 – 1 .2 3 )

1 .1 8 (1 .0 7 – 1 .2 9 )

1 .1 1 (1 .0 0 – 1 .2 2 )

9 0 3 4

3 .1 6

1 .0 7 (1 .0 3 – 1 .1 0 )

1 .1 4 (1 .1 0 – 1 .1 8 )

1 .1 1 (1 .0 7 – 1 .1 5 )

3 5 – 3 9

7 4 3

0 .6 6

1 .6 5 (1 .5 0 – 1 .8 2 )

1 .6 8 (1 .5 0 – 1 .8 8 )

1 .4 8 (1 .3 2 – 1 .6 6 )

4 3 9 0

3 .9 1

1 .3 4 (1 .2 9 – 1 .3 9 )

1 .4 1 (1 .3 5 – 1 .4 7 )

1 .3 3 (1 .2 7 – 1 .3 9 )

≥ 4 0

1 5 2

0 .8 7

2 .2 0 (1 .8 5 – 2 .6 1 )

1 .9 7 (1 .6 0 – 2 .4 3 )

1 .5 9 (1 .2 8 – 1 .9 8 )

8 4 9

4 .9 2

1 .7 0 (1 .5 8 – 1 .8 3 )

1 .7 4 (1 .6 0 – 1 .8 9 )

1 .5 7 (1 .4 4 – 1 .7 1 )

T h ir d b ir th s

n = 3 1 2 4 8 0

n = 2 4 8 9 2 8

n = 2 4 8 3 3 4

n = 3 1 0 6 7 6

n = 2 4 7 7 1 1

n = 2 4 7 1 6 0

2 0 – 2 4

1 1 4

0 .8 0

1 .6 4 (1 .3 3 – 2 .0 3 )

1 .3 4 (1 .0 3 – 1 .7 5 )

1 .3 6 (1 .0 3 – 1 .7 9 )

6 6 6

4 .7 1

1 .3 7 (1 .2 6 – 1 .4 9 )

1 .2 0 (1 .0 8 – 1 .3 4 )

1 .2 4 (1 .1 3 – 1 .3 8 )

2 5 – 2 9

3 8 4

0 .4 9

1 1

1 2 7 2 9

3 .4 8

1 1

1

3 0 – 3 4

6 4 1

0 .5 1

1 .0 5 (0 .9 3 – 1 .1 9 )

1 .2 0 (1 .0 3 – 1 .4 1 )

1 .0 9 (0 .9 3 – 1 .2 9 )

4 0 6 3

3 .2 6

0 .9 4 (0 .8 9 – 0 .9 9 )

1 .0 5 (0 .9 9 – 1 .1 1 )

1 .0 2 (0 .9 6 – 1 .0 8 )

3 5 – 3 9

5 0 3

0 .6 3

1 .3 1 (1 .1 4 – 1 .5 0 )

1 .5 9 (1 .3 4 – 1 .8 9 )

1 .3 6 (1 .1 4 – 1 .6 2 )

2 8 5 9

3 .6 3

1 .0 5 (1 .0 0 – 1 .1 1 )

1 .2 5 (1 .1 7 – 1 .3 3 )

1 .1 7 (1 .1 0 – 1 .2 5 )

≥ 4 0

1 6 2

1 .1 0

2 .3 0 (1 .8 9 – 2 .7 5 )

2 .4 0 (1 .8 9 – 3 .0 5 )

1 .7 9 (1 .3 9 – 2 .3 1 )

7 1 0

4 .8 7

1 .4 3 (1 .3 2 – 1 .5 6 )

1 .5 9 (1 .4 3 – 1 .7 6 )

1 .4 1 (1 .2 7 – 1 .5 6 )

* A d ju st e d fo r ye a r o f b ir th

(1 9 9 0 – 1 9 9 9 ve rs u s 2 0 0 0 – 2 0 1 1 ).

* * A d ju st e d fo r ye a r o f b ir th , e d u ca ti o n (l o w , m e d iu m , h ig h ), co u n tr y o f b ir th

(N o rd ic

ve rs u s N o t N o rd ic ), sm

o k in g in

e a rl y p re g n a n cy , B M I, a n d , in

p a ro u s w o m e n , P T B in

th e p re vi o u s

p re g n a n cy .

* * * A s a b o ve

p lu s th e a g e -r e la te d fa ct o rs

o f h yp e rt e n si o n , d ia b e te s,

g e st a ti o n a l d ia b e te s,

p re -e cl a m p si a , a n d S G A .

1237ª 2016 Royal College of Obstetricians and Gynaecologists

Risk of preterm birth by maternal age and parity

Table 2. Variables analysed, and their relationship with rates of very preterm (22–31 weeks of gestation) and moderately preterm (32–36 weeks of gestation) live births (preterm birth)

Variables All pregnancies Very PTB Moderately PTB

n = 2 009 068 % n = 13 220* % n = 83 802** %

Materna age (years)

20–24 343 560 17.1 2306 0.7 15 991 4.7

25–29 710 196 35.3 4131 0.6 29 051 4.1

30–34 646 736 32.2 4082 0.6 25 049 3.9

35–39 264 222 13.2 2166 0.8 11 411 4.4

40 and older 44 354 2.2 535 1.2 2300 5.2

Parity

First birth 903 497 45.0 7560 0.8 46 734 5.2

Second birth 793 091 39.5 3856 0.5 26 043 3.3

Third birth 312 480 15.6 1804 0.6 11 025 3.5

Time

1990–1999 921 161 45.9 5961 0.7 38 688 4.2

2000–2011 1 087 907 54.1 7259 0.7 45 114 4.2

Education

Elementary school or less 219 117 11.2 1832 0.8 10 364 4.8

High school 962 883 49.1 6408 0.7 41 492 4.3

College or university 778 523 39.7 4555 0.6 29 711 3.8

Country of birth

Not Nordic 298 003 14.8 2364 0.8 12 543 4.2

Nordic 1 711 065 85.2 10 856 0.6 71 259 4.2

BMI (kg/m2)

Low: <18.5 41 383 2.7 279 0.7 2250 5.5

Normal weight: 18.5–24.9 993 000 64.3 5232 0.5 38 368 3.9

Overweight: 25–29.9 362 945 23.5 2264 0.6 14 722 4.1

Obese: ≥30 146 966 9.5 1349 0.9 7093 4.9

Smoking in early pregnancy

Yes 233 766 12.3 2029 0.9 11 611 5.0

No 1 669 868 87.7 9254 0.6 65 660 4.0

Pregestational hypertension

Yes 11 052 0.6 383 3.5 1085 10.2

No 1 998 016 99.4 12 837 0.6 82 717 4.2

Preeclampsia

Yes 56 943 2.8 2986 5.2 9922 18.4

No 1 952 125 97.2 10 234 0.5 73 880 3.8

Pregestational diabetes

Yes 12 180 0.6 231 1.9 1965 16.4

No 1 996 888 99.4 12 989 0.7 81 837 4.1

Gestational diabetes

Yes 16 993 0.8 148 0.9 1346 8.0

No 1 992 075 99.2 13 072 0.7 82 456 4.2

Intrauterine growth restriction (SGA)

Yes 46 988 2.3 3265 6.9 6689 15.3

No 1 956 773 97.7 9633 0.5 76 530 3.9

PTB in first pregnancy*** Second births: n = 793 091 n = 3856*** n = 26 043***

Yes 36 689 5.8 876 2.4 5195 14.5

No 590 702 94.2 1996 0.3 14 621 2.5

PTB in second pregnancy**** Third births: n = 312 480 n = 1804**** n = 11 025****

Yes 11 015 4.9 332 3.0 1645 15.4

No 213 615 95.1 888 0.4 6058 2.8

Denominators: *2 009 068; **1 995 848 (very PTB excluded); ***second births only—very PTB, 793 091; moderately PTB, 789 235 (very PTB excluded); ****third births only—very PTB, 312 480; moderately PTB, 310 676 (very PTB excluded).

1238 ª 2016 Royal College of Obstetricians and Gynaecologists

Waldenstr€om et al.

(SGA). Also, pregestational hypertension and diabetes were

included in these analyses, as these diseases are associated

with age.

Data on maternal diseases were retrieved from the MBR:

pregestational diabetes [insulin dependent or non-insulin

dependent; International Classification of Diseases, ninth

revision (ICD-9) codes 250 and 648A; ICD-10 codes E10– E14 and O240–O243], gestational diabetes (ICD-9 code 648W; ICD-10 code O244), pregestational hypertension

(self-reported by check box at first antenatal visit, or by

ICD-9 codes 401–405, 642C, and 642H, or by ICD-10 codes 110–115, O10, and O11) and pre-eclampsia (includ- ing eclampsia; ICD-9 codes 642E–642G; ICD-10 codes O14 and O15). The registry also provided information about

SGA infants, defined as a birthweight of more than two

standard deviations below the mean for gestational age,

according to a sex-specific Swedish reference curve for

normal fetal growth.37

Pregnancies of nulliparous women (first births) and

pregnancies of women classed as para 1 (second births)

and para 2 (second births) were analysed separately (like

three cross-sectional studies). Rates of preterm birth were

calculated for each age group. The associations between

maternal age and each outcome were investigated by logis-

tic regression analyses. First, we adjusted for year of birth

(model 1). In the principal analyses (model 2), we also

adjusted for mother’s education, country of birth, smoking

habits, BMI, and in parous women also for preterm birth

in the previous pregnancy. Finally, we also adjusted for

potentially mediating factors (model 3).

The levels of missing data were low for the total sam-

ple (maternal age, 0%; parity, 0%; education, 2.4%;

country of birth, 0%; smoking, 5.2%; maternal diagnoses,

0%; and SGA, 0.3%), except regarding BMI (23.1%) and

history of previous preterm birth (20.9% in second births

and 28.1% in third births). Missing data on BMI (mater-

nal weight and height) was substantially explained by the

time-point when this information was included in the

Medical Birth Register. Missing data on history of previ-

ous preterm first and second births, respectively, were

related to how the study sample was defined, with infor-

mation missing in parous women who had their previous

birth prior to the onset of data collection in 1990. We

estimated the missing values in these three variables to

be nearly at random, and thus meeting the criteria for

multiple imputation.38 Imputations were conducted in

SPSS 22 (IBM Corporation, Armonk, NY, USA), in three

separate data sets, including first, second, and third

births, respectively. The SPSS ‘Automatic’ imputation

method was used (type of imputation model: logistic

regression), and 25 imputations were performed. The

imputed variable in the data set of first births was BMI,

the imputed variables in the data set of second births

were BMI and history of preterm birth in the first birth,

and the imputed variables in the data set of third births

were BMI and history of preterm birth in the second

birth. The variables used in the imputation procedure

included the outcome variables (very preterm birth, mod-

erately preterm birth, spontaneous and indicated very

preterm birth and moderately PTM respectively), and all

the independent variables listed in Table 2 (except par-

ity). All findings presented in Figure 1 and Table 1 are

based on the pooled estimates. Findings based on com-

plete case analyses are briefly described. (Principal find-

ings based on both original and computed data are

presented in Table S1).

0

1

2

3

4

5

6

7

20–24 25–29 30–34 35–39 ≥40 20–24 25–29 30–34 35–39 ≥40

Pe rc

en t

Maternal age

1st births 2nd births 3rd births

Moderately PTBVery PTB

Figure 1. Rates of very and moderately preterm birth (PTB) by maternal age in first, second, and third births (values presented in Table 1). Total

samples: first births—very preterm, 903 497; moderately preterm, 895 937; second births—very preterm, 793 091; moderately preterm, 789 235;

third births—very preterm, 312 480; moderately preterm, 310 676.

1239ª 2016 Royal College of Obstetricians and Gynaecologists

Risk of preterm birth by maternal age and parity

Results

In pregnant women aged 20 years or older who had their

first, second, or third birth, the overall rates of live single-

ton preterm birth were stable during the entire 21 years of

observation: 0.7% delivered very preterm and 4.2% deliv-

ered moderately preterm.

Table 1 presents the variables analysed in the study, and

the rates of very and moderately preterm birth in relation to

these variables. Figure 1 illustrates that rates of very and

moderately preterm birth increased after 30–34 years, and were most prevalent in first births. In parous women, the dis-

tribution of moderately preterm birth was U-shaped, with

increased rates in both the youngest and older age groups.

The risk of very preterm birth, expressed as adjusted

odds ratio, increased from maternal age 30–34 years in approximately the same way in first, second, and third

births, and ranged from 1.18 to 1.28 at 30–34 years, from

1.59 to 1.70 at 35–39 years, and from 1.97 to 2.40 at ≥40 years (Table 2, model 2). Having a third child at a young age (20–24 years) was also associated with an increased risk compared with the reference group.

The risk of moderately preterm birth increased by mater-

nal age from age 35–39 years, and ranged from 1.16 to 1.41 at 35–39 years, and from 1.22 to 1.74 at ≥40 years (Table 2, model 2). The age-related risks of moderately

preterm birth were consistently lower than the correspond-

ing risks of very preterm birth. As with very preterm birth,

the youngest women expecting their third birth had a

slightly higher risk than the reference group.

By including age-related pregnancy complications,

pregestational hypertension, and diabetes, the age-related

risk of very preterm birth was reduced in all parity groups,

but remained statistically significant, except in the youngest

age groups and in women who had their second and third

0 0.5

1 1.5

2 2.5

3 3.5

4

A dj

us te

d O

R (9

5% C

I)

Maternal age

Very preterm 1st births

0 0.5

1 1.5

2 2.5

3 3.5

4

A dj

us te

d O

R (9

5% C

I)

Maternal age

Moderately preterm 1st births

0 0.5

1 1.5

2 2.5

3 3.5

4

A dj

us te

d O

R (9

5% C

I)

Maternal age

Spontaneous Indicated

Very preterm 2nd births

0 0.5

1 1.5

2 2.5

3 3.5

4

A dj

us te

d O

R (9

5% C

I)

Maternal age

Moderately preterm 2nd births

0 0.5

1 1.5

2 2.5

3 3.5

4

A dj

us te

d O

R (9

5% C

I)

Maternal age

Very preterm 3rd births

0 0.5

1 1.5

2 2.5

3 3.5

4

A dj

us te

d O

R (9

5% C

I)

Maternal age

Moderately preterm 3rd births

Spontaneous Indicated Spontaneous Indicated

Spontaneous Indicated

Spontaneous Indicated Spontaneous Indicated

Figure 2. Spontaneous and medically indicated births by maternal age in first, second, and third births, 2000–2011. Adjusted odds ratio (OR) with 95% confidence interval (95% CI). Reference 1: maternal age 25–29 years. Analyses adjusted for education, country of birth, smoking, BMI, and, in parous women, history of preterm birth in the previous pregnancy.

1240 ª 2016 Royal College of Obstetricians and Gynaecologists

Waldenstr€om et al.

birth at 30–34 years. A similar pattern was found in mod- erately preterm births (Table 2, model 3).

Figure 2 illustrates the adjusted odds ratios of sponta-

neous and medically indicated preterm birth by parity and

maternal age, based on data from the second half of the

observation period. The risk of both spontaneous and med-

ically indicated very preterm births increased from mater-

nal age 30–34 years or 35–39 years. Also, the risk of medically indicated moderately preterm birth increased by

maternal age, whereas the associations with spontaneous

moderately preterm birth were weak, and were non-existent

in first births. Similarly to the previous analyses (Table 2),

women who had a third birth a young age (20–24 years) deviated from this pattern by being at higher risk than the

reference group. When including the potentially mediating

factors (the same factors listed in Table 2, model 3), the

age-related adjusted odds ratios for spontaneous preterm

birth remained essentially unchanged, whereas risks of

medically indicated preterm birth were substantially

reduced (data not shown). Still, women aged 35 years and

older were at increased risk of very preterm indicated first

births, and moderately preterm indicated first and second

births.

In first births, the presented findings based on imputed

data (BMI) were nearly identical as those based on com-

plete case analyses. In second and third births, the odds

ratios based on imputed data (BMI and history of preterm

birth) were marginally higher (Table S1 presents models 2

and 3 with both original and imputed results).

Discussion

Main findings We found that the risk of very preterm birth increased with

maternal age, irrespective of parity. In moderately preterm

births, the age-related associations were weaker, but still

obvious from age 35–39 years and older. Advancing mater- nal age increased the risks of both spontaneous and medi-

cally indicated preterm birth; the exception was

spontaneous moderately preterm birth in a woman’s first

delivery.

Strengths and limitations The strengths of this study include the high quality of data

in the Swedish Medical Birth Register, with few missing

cases (<2%), and the possibility to take important con- founding factors into account. Including the history of pre-

term birth in the analyses of second and third births was

particularly important considering that heredity is a strong

predictor of preterm birth.39 Still, residual confounding

may be a problem: in the case of cervical surgery or previ-

ous termination of pregnancy, for example. Another limita-

tion was the high proportions of missing values for BMI

and history of preterm birth, which justified multiple

imputation; however, the findings presented in this analysis

were basically the same as those obtained by complete case

analysis, and none of the conclusions were altered.

Interpretation The stronger association between advanced maternal age

and risk of very preterm birth, compared with moderately

preterm birth, is supported by other studies. 7,40,41

Our

results support the suggestion that advanced maternal age

is a risk factor for preterm birth over the full gestational

age range, but with more pronounced effects at the lower

end.7 This interpretation is also supported by findings that

the rate of miscarriage increases with advancing maternal

age.42 The physiological pathways may differ between very

and moderately preterm birth, however, with greater simi-

larities between miscarriage and very preterm birth than

between miscarriage and moderately preterm birth.

Intrauterine infection is the only pathological process for

which a causal link with preterm birth has been estab-

lished.1,43 We had no information on rates of chorioam-

nionitis, but pregnancy at age ≥35 years has been associated with a decreased risk for chorioamnionitis than

pregnancy at age 25–29 years.44 If anything, this could only have introduced conservative bias into our estimates of

age-related effects.

Advanced maternal age may contribute to the placental

and myometrial vascular lesions associated with preterm

birth.45,46 In indicated births, associations with advanced

maternal age were largely mediated by pre-eclampsia and

SGA (which both increased with maternal age within each

parity group), and these conditions are associated with vas-

cular disorders and decreased utero-placental blood flow. 47

Hormonal disorders, such as progesterone deficiency, is

another potential pathway. Progesterone is important for

pregnancy maintenance,48 and levels decline with maternal

age. Women diagnosed with luteal-phase deficiency, char-

acterised by progesterone deficiency, had lower rates of pre-

term birth if they were treated with progesterone than a

group without such treatment. 49

Our finding that advanced

maternal age carries a higher risk for very preterm birth

lends support to the hormone-deficiency hypothesis.

Emotional stress could also be at play in the causal path-

way. We found higher rates of potential stressors in the

very preterm group, such as migrant background, smoking,

overweight, and history of preterm birth. Stress may also

have contributed to the higher risk of preterm birth

observed in women who had their third birth at a young

age (20–24 years). Compared with the reference group (25–29 years), these women were more exposed to factors related to social vulnerability, including low level of educa-

tion, non-Nordic country of birth, and smoking. Although

these factors were adjusted for in the statistical analyses,

1241ª 2016 Royal College of Obstetricians and Gynaecologists

Risk of preterm birth by maternal age and parity

young mothers may also have been more exposed to

unmeasured factors related to psychosocial vulnerability,

and life stress and anxiety have been associated with short-

ened gestation.50

The independent effect of parity on pregnancy outcomes

is less explored. There is some evidence suggesting that the

haemodynamic adaptation occuring during the first preg-

nancy may permanently modify the uterine arteries, con-

tributing to decreased vascular resistance and facilitated

uteroplacental blood flow in the next pregnancy.51,52 This

may explain the higher birthweights with increasing parity,

particularly of the second born,53 and the lack of association

between advanced maternal age and stillbirth in second preg-

nancies.54 Such an explanation could be relevant for the

lower rates of preterm second and third births, as the SGA

rate (mediating factor) was higher in first births (3.3%),

compared with second and third births (1.5 and 1.6%,

respectively). Nevertheless, this interpretation does not shed

light on our principal finding that parity did not modify the

effect of advanced maternal age on risk of preterm birth.

The division into spontaneous and medically indicated

births may be less pertinent for the understanding of how

advanced maternal age acts on the risk of delivering pre-

term; however, from a clinical point of view it is of interest

to show that advanced maternal age increased the risks of

both spontaneous and indicated very preterm births.

From a public health perspective, advanced maternal age

together with smoking and being overweight probably rep-

resent the most important modifiable risk factors for preg-

nancy complications such as very preterm birth.15,55

Parturients aged 35 years or older in the Nordic countries

increased from 5% in 1975 to around 20% in 2012, 56

and

a similar development has taken place in many other coun-

tries. This rapid change in the reproductive epidemiological

landscape has contributed to a significant number of very

preterm births. Despite a predicted overall increase in very

preterm births during the study period (women aged

≥35 years increased from 14% in 1990–1999 to 22% in 2000–2011, and women who were overweight increased from 29 to 36%, respectively), we found a stable rate of

preterm births over the study period. This indicates that

the adverse effects of advanced maternal age and over-

weight were outweighed by changes in other risk factors:

for instance, the reduction of smoking in early pregnancy

(from 16 to 6%), and possibly also the increase of women

with college or university education (from 34 to 53%).

Although preterm infant survival is high nowadays, and

has also increased for those born extremely preterm, 57

very

preterm infants is one of the most resource-demanding in-

hospital patient groups, and the final outcome is not

always full health.58,59 To challenge the continuing rapid

increase in maternal age, increased professional and

political knowledge as well as parental and public informa-

tion on the increased risk for preterm birth is warranted.

Conclusion

Our study suggests that advanced maternal age is an inde-

pendent risk factor for very preterm birth, irrespective of

parity. Although the absolute risk for very preterm birth

decreased in multiparas, possibly suggesting a benefit from

physiological adaptations during the first pregnancy, the age-

related increase in risk remained unchanged. The size of the

effect suggests that the risk of very preterm birth is of clinical

importance for pregnant women aged 35 years or older. In

moderately preterm births, advanced maternal age was only

associated with a modestly increased risk of medically indi-

cated preterm births. These findings help to move research

on age-related pathways for preterm birth forwards, and may

help in designing and testing effective interventions.

Disclosure of interests None declared. Completed disclosure of interests form

available to view online as supporting information.

Contribution to authorship UW (guarantor of the article) initiated the study, con-

ducted the analyses, and wrote the first draft of the paper.

SC contributed to the concept and design of the study,

interpretation of the data, and revision of the article

regarding important intellectual content. LV participated in

the analyses and interpretation of the data, and in the revi-

sion of the article. MN contributed to the concept and

design of the study, interpretation of the data, and revision

of the article regarding important intellectual content. All

four authors approved the final version of the article for

publication, and agreed to be accountable for all aspects of

the work in ensuring that questions related to accuracy or

integrity of any part of the work are appropriately investi-

gated and resolved.

Details of ethics approval The study was approved by the Regional Ethics Review Board

in Stockholm, 15 May 2013 (reg. no. 2013/731-31/1).

Funding No extra external funding was sought for this study. It was

conducted within the frame of our academic positions.

Acknowledgements The authors thank all of the women, midwives, and obste-

tricians who provided data for this study by completing the

antenatal, intrapartum, and postpartum records on which

the Swedish National Medical Birth Register is based.

1242 ª 2016 Royal College of Obstetricians and Gynaecologists

Waldenstr€om et al.

Supporting Information

Additional Supporting Information may be found in the

online version of this article:

Table S1. Risk of very and moderately preterm birth by

maternal age in first, second, and third births, presented

with original data (complete case analyses) and imputed

data &

References

1 Romero R, Espinoza J, Kusanovic JP, Gotsch F, Hassan S, Erez O, et al.

The preterm parturition syndrome. BJOG 2006;113 (Suppl 3):17–42. 2 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and

causes of preterm birth. Lancet 2008;371:75–84. 3 Schempf AH, Branum AM, Lukacs SL, Schoendorf KC. Maternal age

and parity-associated risks of preterm birth: differences by race/

ethnicity. Paediatr Perinatal Epidemiol 2007;21:34–43. 4 Schmidt L, Sobotka T, Bentzen JG, Nyboe Andersen A.

Demographic and medical consequences of the postponement of

parenthood. Hum Reprod Update 2012;18:29–43. 5 Auger N, Hansen AV, Mortensen L. Contribution of maternal age to

preterm birth rates in Denmark and Quebec, 1981–2008. Am J Public Health 2013;103:e33–8.

6 Auger N, Roncarolo F, Harper S. Increasing educational inequality in

preterm birth in Quebec, Canada, 1981–2006. J Epidemiol Community Health 2011;65:1091–6.

7 Ancel PY, Saurel-Cubizolles MJ, Di Renzo GC, Papiernik E, Breart G.

Very and moderate preterm births: are the risk factors different?

BJOG 1999;106:1162–70. 8 Lawlor DA, Mortensen L, Andersen AM. Mechanisms underlying the

associations of maternal age with adverse perinatal outcomes: a

sibling study of 264 695 Danish women and their firstborn

offspring. Int J Epidemiol 2011;40:1205–14. 9 Morken NH, Kallen K, Hagberg H, Jacobsson B. Preterm birth in

Sweden 1973–2001: rate, subgroups, and effect of changing patterns in multiple births, maternal age, and smoking. Acta Obstet

Gynecol Scand 2005;84:558–65. 10 Aldous MB, Edmonson MB. Maternal age at first childbirth and risk

of low birth weight and preterm delivery in Washington State.

JAMA 1993;270:2574–7. 11 Cnattingius S, Forman MR, Berendes HW, Isotalo L. Delayed

childbearing and risk of adverse perinatal outcome. A population-

based study. JAMA 1992;268:886–90. 12 Delbaere I, Verstraelen H, Goetgeluk S, Martens G, De Backer G,

Temmerman M. Pregnancy outcome in primiparae of advanced

maternal age. Eur J Obstet Gynecol Reprod Biol 2007;135:41–6. 13 Ludford I, Scheil W, Tucker G, Grivell R. Pregnancy outcomes for

nulliparous women of advanced maternal age in South Australia,

1998–2008. Aust N Z J Obstet Gynaecol 2012;52:235–41. 14 Nabukera S, Wingate MS, Alexander GR, Salihu HM. First-time births

among women 30 years and older in the United States: patterns

and risk of adverse outcomes. J Reprod Med 2006;51:676–82. 15 Waldenstrom U, Aasheim V, Nilsen AB, Rasmussen S, Pettersson HJ,

Schytt E. Adverse pregnancy outcomes related to advanced

maternal age compared with smoking and being overweight. Obstet

Gynecol 2014;123:104–12. 16 Cleary-Goldman J, Malone FD, Vidaver J, Ball RH, Nyberg DA,

Comstock CH, et al. Impact of maternal age on obstetric outcome.

Obstet Gynecol 2005;105:983–90.

17 Hoffman MC, Jeffers S, Carter J, Duthely L, Cotter A, Gonzalez-

Quintero VH. Pregnancy at or beyond age 40 years is associated

with an increased risk of fetal death and other adverse outcomes.

Am J Obstet Gynecol 2007;196:e11–3. 18 Jacobsson B, Ladfors L, Milsom I. Advanced maternal age and

adverse perinatal outcome. Obstet Gynecol 2004;104:727–33. 19 Jolly M, Sebire N, Harris J, Robinson S, Regan L. The risks associated

with pregnancy in women aged 35 years or older. Hum Reprod

2000;15:2433–7. 20 Joseph KS, Allen AC, Dodds L, Turner LA, Scott H, Liston R. The

perinatal effects of delayed childbearing. Obstet Gynecol

2005;105:1410–8. 21 Kenny LC, Lavender T, McNamee R, O’Neill SM, Mills T, Khashan

AS. Advanced maternal age and adverse pregnancy outcome:

evidence from a large contemporary cohort. PLoS One 2013;8:

e56583.

22 Khalil A, Syngelaki A, Maiz N, Zinevich Y, Nicolaides KH. Maternal

age and adverse pregnancy outcome: a cohort study. Ultrasound

Obstet Gynecol 2013;42:634–43. 23 Koo YJ, Ryu HM, Yang JH, Lim JH, Lee JE, Kim MY, et al. Pregnancy

outcomes according to increasing maternal age. Taiwan J Obstet

Gynecol 2012;51:60–5. 24 Chan BC, Lao TT. Effect of parity and advanced maternal age on

obstetric outcome. Int J Gynaecol Obstet 2008;102:237–41. 25 Luke B, Brown MB. Elevated risks of pregnancy complications and

adverse outcomes with increasing maternal age. Hum Reprod

2007;22:1264–72. 26 Forman MR, Meirik O, Berendes HW. Delayed childbearing in

Sweden. JAMA 1984;252:3135–9. 27 Cnattingius S, Berendes HW, Forman MR. Do delayed childbearers

face increased risks of adverse pregnancy outcomes after the first

birth? Obstet Gynecol 1993;81:512–6. 28 Kozuki N, Lee AC, Silveira MF, Victora CG, Adair L, Humphrey J,

et al. The associations of birth intervals with small-for-gestational-

age, preterm, and neonatal and infant mortality: a meta-analysis.

BMC Public Health 2013;13 (Suppl 3):S3.

29 K€all�en B, K€all�en K. The Swedish Medical Birth Registry: a summary

of content and quality. The Swedish Centre for Epidemiology. The

National Board of Health and Welfare, Stockholm, Sweden, 2014.

30 Cnattingius S, Ericson A, Gunnarskog J, Kallen B. A quality study of

a medical birth registry. Scand J Soc Med 1990;18:143–8. 31 Hogberg U, Larsson N. Early dating by ultrasound and perinatal

outcome. A cohort study. Acta Obstet Gynecol Scand 1997;76:907– 12.

32 Salihu HM, Wilson RE, Alio AP, Kirby RS. Advanced maternal age

and risk of antepartum and intrapartum stillbirth. J Obstet Gynaecol

Res 2008;34:843–50. 33 Nilsen AB, Waldenstrom U, Hjelmstedt A, Rasmussen S, Schytt E.

Characteristics of women who are pregnant with their first

baby at an advanced age. Acta Obstet Gynecol Scand 2012;91:353– 62.

34 Petersen CB, Mortensen LH, Morgen CS, Madsen M, Schnor O,

Arntzen A, et al. Socio-economic inequality in preterm birth: a

comparative study of the Nordic countries from 1981 to 2000.

Paediatr Perinat Epidemiol 2009;23:66–75. 35 Cnattingius S, Granath F, Petersson G, Harlow BL. The influence of

gestational age and smoking habits on the risk of subsequent

preterm deliveries. N Engl J Med 1999;341:943–8. 36 Stephansson O, Dickman PW, Cnattingius S. The influence of

interpregnancy interval on the subsequent risk of stillbirth and early

neonatal death. Obstet Gynecol 2003;102:101–8.

1243ª 2016 Royal College of Obstetricians and Gynaecologists

Risk of preterm birth by maternal age and parity

37 Marsal K, Persson PH, Larsen T, Lilja H, Selbing A, Sultan B.

Intrauterine growth curves based on ultrasonically estimated foetal

weights. Acta Paediatr 1996;85:843–8. 38 Sterne JA, White IR, Carlin JB, Spratt M, Royston P, Kenward MG,

et al. Multiple imputation for missing data in epidemiological and

clinical research: potential and pitfalls. BMJ 2009;338:b2393.

39 Wilcox AJ, Skjaerven R, Lie RT. Familial patterns of preterm delivery:

maternal and fetal contributions. Am J Epidemiol 2008;167:474–9. 40 Auger N, Abrahamowicz M, Wynant W, Lo E. Gestational age-

dependent risk factors for preterm birth: associations with maternal

education and age early in gestation. Eur J Obstet Gynecol Reprod

Biol 2014;176:132–6. 41 Martius JA, Steck T, Oehler MK, Wulf KH. Risk factors associated

with preterm (<37 + 0 weeks) and early preterm birth (<32 + 0 weeks): univariate and multivariate analysis of 106 345 singleton births from the 1994 statewide perinatal survey of Bavaria.

Eur J Obstet Gynecol Reprod Biol 1998;80:183–9. 42 Stephenson MD. Frequency of factors associated with habitual

abortion in 197 couples. Fertil Steril 1996;66:24–9. 43 Romero R, Mazor M, Munoz H, Gomez R, Galasso M, Sherer DM.

The preterm labor syndrome. Ann N Y Acad Sci 1994;734:414–29. 44 Cavazos-Rehg PA, Krauss MJ, Spitznagel EL, Bommarito K, Madden

T, Olsen MA, et al. Maternal age and risk of labor and delivery

complications. Matern Child Health J 2015;19:1202–11. 45 Romero R, Sepulveda W, Baumann P, Yoon BH, Brandt F, Gomez R,

et al. The preterm labor syndrome: biochemical, cytologic,

immunologic, pathologic, microbiologic and clinical evidence that

preterm labor is a heterogeneous disease. Am J Obstet Gynecol

1993;168:288.

46 Naeye RL. Maternal age, obstetric complications, and the outcome

of pregnancy. Obstet Gynecol 1983;61:210–6. 47 Pluta R, Ulamek-Koziol M, Furmaga-Jablonska W, Czuczwar SJ.

Preeclampsia in the 21st century: unresolved questions concerning

etiology. Nutrition 2015;31:1179–81. 48 Mesiano S. Roles of estrogen and progesterone in human

parturition. Front Horm Res 2001;27:86–104.

49 Check JH, Lee G, Epstein R, Vetter B. Increased rate of preterm

deliveries in untreated women with luteal phase deficiencies.

Preliminary report. Gynecol Obstet Invest 1992;33:183–4. 50 Tegethoff M, Greene N, Olsen J, Meyer AH, Meinlschmidt G.

Maternal psychosocial adversity during pregnancy is associated with

length of gestation and offspring size at birth: evidence from a

population-based cohort study. Psychosom Med 2010;72:419–26. 51 Hafner E, Schuchter K, Metzenbauer M, Philipp K. Uterine artery

Doppler perfusion in the first and second pregnancies. Ultrasound

Obstet Gynecol 2000;16:625–9. 52 Prefumo F, Bhide A, Sairam S, Penna L, Hollis B, Thilaganathan B.

Effect of parity on second-trimester uterine artery Doppler flow

velocity and waveforms. Ultrasound Obstet Gynecol 2004;23:46–9. 53 Khong TY, Adema ED, Erwich JJ. On an anatomical basis for the

increase in birth weight in second and subsequent born children.

Placenta 2003;24:348–53. 54 Waldenstrom U, Cnattingius S, Norman M, Schytt E. Advanced

maternal age and stillbirth risk in nulliparous and parous women.

Obstet Gynecol 2015;126:355–62. 55 Cnattingius S, Lambe M. Trends in smoking and overweight during

pregnancy: prevalence, risks of pregnancy complications, and

adverse pregnancy outcomes. Semin Perinatol 2002;26:286–95. 56 [www.thl.fi/fi/web/thlfi-en/statistics/statistics-by-topic/sexual-and-

reproductive-health/parturients-deliveries-and-births/nordic-perinatal-

statistics]. Accessed 14 July 2016.

57 Fellman V, Hellstrom-Westas L, Norman M, Westgren M, Kallen K,

Lagercrantz H, et al. One-year survival of extremely preterm infants

after active perinatal care in Sweden. JAMA 2009;301:2225–33. 58 Serenius F, Kallen K, Blennow M, Ewald U, Fellman V, Holmstrom

G, et al. Neurodevelopmental outcome in extremely preterm infants

at 2.5 years after active perinatal care in Sweden. JAMA

2013;309:1810–20. 59 Costeloe KL, Hennessy EM, Haider S, Stacey F, Marlow N, Draper

ES. Short term outcomes after extreme preterm birth in England:

comparison of two birth cohorts in 1995 and 2006 (the EPICure

studies). BMJ 2012;345:e7976.

1244 ª 2016 Royal College of Obstetricians and Gynaecologists

Waldenstr€om et al.