Risk of major congenital malformations in relation to maternal overweight and obesity severity: Cohort study of 1.2 million singletons

Abstract

Objective
To estimate the risks of major congenital malformations in the offspring of mothers who are underweight (body mass index (BMI) <18.5), overweight (BMI 25 to <30), or in obesity classes I (BMI 30 to <35), II (35 to <40), or III (≥40) compared with offspring of normal weight mothers (BMI 18.5 to <25) in early pregnancy.

Design
Population based cohort study.

Setting
Nationwide Swedish registries.

Participants
1 243 957 liveborn singleton infants from 2001 to 2014 in Sweden. Data on maternal and pregnancy characteristics were obtained by individual record linkages.

Exposure
Maternal BMI at the first prenatal visit.

Main outcome measures
Offspring with any major congenital malformation, and subgroups of organ specific malformations diagnosed during the first year of life. Risk ratios were estimated using generalised linear models adjusted for maternal factors, sex of offspring, and birth year.

Results
A total of 43 550 (3.5%) offspring had any major congenital malformation, and the most common subgroup was for congenital heart defects (n=20 074; 1.6%). Compared with offspring of normal weight mothers (risk of malformations 3.4%), the proportions and adjusted risk ratios of any major congenital malformation among the offspring of mothers with higher BMI were: overweight, 3.5% and 1.05 (95% confidence interval 1.02 to 1.07); obesity class I, 3.8% and 1.12 (1.08 to 1.15), obesity class II, 4.2% and 1.23 (1.17 to 1.30), and obesity class III, 4.7% and 1.37 (1.26 to 1.49). The risks of congenital heart defects, malformations of the nervous system, and limb defects also progressively increased with BMI from overweight to obesity class III. The largest organ specific relative risks related to maternal overweight and increasing obesity were observed for malformations of the nervous system. Malformations of the genital and digestive systems were also increased in offspring of obese mothers.

Conclusions
Risks of any major congenital malformation and several subgroups of organ specific malformations progressively increased with maternal overweight and increasing severity of obesity. For women who are planning pregnancy, efforts should be encouraged to reduce adiposity in those with a BMI above the normal range.

Full text

the bmj |
BMJ
2017;357:j2563 | doi: 10.1136/bmj.j2563
RESEARCH
1
open access
1Department of Medicine,
Solna, Clinical Epidemiology
Unit, Karolinska Institutet,
SE-171 76 Stockholm, Sweden
2Department of Diabetes and
Endocrinology, Sachsska
Children’s Hospital,
Södersjukhuset, Stockholm,
Sweden
3Department of Epidemiology,
School of Public Health and
Center for Human Growth and
Development, University of
Michigan, Ann Arbor, MI, USA
4Department of Epidemiology
Research, Statens Serum
Institut, Copenhagen, Denmark
5Division of Obstetrics and
Gynecology, Department of
Women’s and Children’s Health,
Karolinska Institutet, Stockholm,
Sweden
Correspondence to: M Per sson
Martina.Persson@ki.se
Additio nal material is published
online onl y. To view please visit
the journal online.
Cite this as: BMJ ;:j
http://dx.doi.org/10.1136/bmj.j2563
Accepted: 24 May 2017
Risk of major congenital malformations in relation to
maternaloverweight and obesity severity: cohort study
of1.2million singletons
Martina Persson,1,2 Sven Cnattingius,1 Eduardo Villamor,1,3 Jonas Söderling,1 Björn Pasternak,1,4
Olof Stephansson,1,5 Martin Neovius1
ABSTRACT
OBJECTIVE
To estimate the risks of major congenital
malformations in the ospring of mothers who are
underweight (body mass index (BMI) <18.5),
overweight (BMI 25 to <30), or in obesity classes I (BMI
30 to <35), II (35 to <40), or III (≥40) compared with
ospring of normal weight mothers (BMI 18.5 to <25) in
early pregnancy.
DESIGN
Population based cohort study.
SETTING
Nationwide Swedish registries.
PARTICIPANTS
1 243 957 liveborn singleton infants from 2001 to 2014
in Sweden. Data on maternal and pregnancy
characteristics were obtained by individual record
linkages.
EXPOSURE
Maternal BMI at the rst prenatal visit.
MAIN OUTCOME MEASURES
Ospring with any major congenital malformation, and
subgroups of organ specic malformations diagnosed
during the rst year of life. Risk ratios were estimated
using generalised linear models adjusted for maternal
factors, sex of ospring, and birth year.
RESULTS
A total of 43 550 (3.5%) ospring had any major
congenital malformation, and the most common
subgroup was for congenital heart defects
(n=20 074; 1.6%). Compared with ospring of
normal weight mothers (risk of malformations
3.4%), the proportions and adjusted risk ratios of
any major congenital malformation among the
ospring of mothers with higher BMI were:
overweight, 3.5% and 1.05 (95% condence interval
1.02 to 1.07); obesity class I, 3.8% and 1.12 (1.08 to
1.15), obesity class II, 4.2% and 1.23 (1.17 to 1.30),
and obesity class III, 4.7% and 1.37 (1.26 to 1.49).
The risks of congenital heart defects, malformations
of the nervous system, and limb defects also
progressively increased with BMI from overweight to
obesity class III. The largest organ specic relative
risks related to maternal overweight and increasing
obesity were observed for malformations of the
nervous system. Malformations of the genital and
digestive systems were also increased in ospring
of obese mothers.
CONCLUSIONS
Risks of any major congenital malformation and
several subgroups of organ specic malformations
progressively increased with maternal overweight and
increasing severity of obesity. For women who are
planning pregnancy, eorts should be encouraged to
reduce adiposity in those with a BMI above the normal
range.
Introduction
Obesity has reached epidemic proportions globally
and is now a major health concern in pregnancy, in
both high and low income countries.1 In particular
the prevalence of severe obesity, commonly defined
as obesity classes II and III (body mass index (BMI)
≥35) is rapidly increasing.2-4 In the US, approximately
half of the women are overweight or obese at the first
antenatal visit,5 and the high prevalence of obesity
class III (BMI ≥40; 10-12%) in women of reproductive
age is of concern.6 In Sweden, the prevalence of early
pregnancy obesity (BMI ≥30) increased from 6.0% to
12.9% from 1992 to 2014.7 Globally, it was recently
reported that the number of women aged 18 years
and older with a BMI ≥35 doubled from approxi-
mately 50 million to 100 million between 2000 and
2010.8
Obesity in pregnancy adversely influences both fetal
and neonatal outcomes,9-15 including increased risks of
major congenital malformations, which are a common
cause of stillbirth16 and a major cause of infant mortal-
ity and long term morbidity.14 17 A meta-analysis
reported that the ospring of obese mothers are at
increased risk of a wide range of congenital malforma-
tions, including neural tube defects, cardiovascular
anomalies, cleft lip and palate, anorectal atresia, and
limb reduction anomalies.18 However, associations
between increasing severity of obesity and risks of mal-
formations were not analysed and it is not clear if risks
are also increased in the ospring of overweight moth-
ers. Several of the included studies also used non-stan-
dard definitions of normal weight, overweight, and
obesity.19-24 Since the prevalence of severe obesity is
increasing among women of reproductive age, it is of
WHAT IS ALREADY KNOWN ON THIS TOPIC
Maternal obesity increases risks of congenital malformations
It is not known if risks are increased in ospring of overweight mothers and if risks
increase with increasing severity of obesity
WHAT THIS STUDY ADDS
Risks of major congenital malformations in ospring progressively increase with
maternal overweight and severity of obesity

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2017;357:j2563 | the bmj
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interest to investigate whether risks of major congeni-
tal malformations increase with severity of obesity in
mothers.
In this study we included information on 1 243 957 live
singleton births in Sweden recorded in the medical
birth register between 2001 and 2014. We investigated
associations between maternal BMI in early pregnancy
and risks of any major congenital malformation as well
as risks of the most prevalent subgroups of organ spe-
cific malformations.
Methods
Setting
The study was performed in Sweden, where prenatal
and delivery care is publicly funded, and participa-
tion in the standardised prenatal care programme is
almost 100%. The Swedish medical birth register
includes information on close to 100% of all births in
Sweden since 1973. Using standardised prenatal,
obstetrical, and neonatal records, information is pro-
spectively collected during pregnancy, delivery, and
the neonatal period.25 Individual information on
maternal height and weight has been included
since1992.
Data sources
By using the unique personal identification number
assigned to each Swedish resident,26 we linked data
from the medical birth register to the national patient
register,27 cause of death register, education register,
and total population register.28 The national patient
register includes diagnoses and dates on visits for hos-
pital based inpatient and outpatient care. Diagnoses
are coded according to the Swedish version of the ICD-
10 (international classification of diseases, 10th revi-
sion). In Sweden, all pregnant women are oered an
ultrasound examination at around 18 weeks of gesta-
tion. Abortion after 18 until 22 completed weeks must
be approved by the National Board of Health and Wel-
fare. Severe birth defects as indication for late abor-
tion are generally approved. In 2015, the rate of
abortions in Sweden was 20.9/1000 women (aged
15-44 years; 93% of abortions were performed before
12 weeks of gestation and 83% before nine weeks of
gestation).
Study population
From 1 January 2001 to 31 December 2014, we retrieved
information on 1 480 892 deliveries recorded in the
Swedish medical birth register. We excluded 42 638
(2.9%) multiple births (since they dier from single
births for malformation outcomes29 ) and 4598 (0.3%)
stillbirths (where diagnosis and registration of malfor-
mations is poor or missing). Of the remaining 1 433 656
live singleton births, 19 863 (1.4%) were excluded owing
to lack of valid personal identification numbers (18 929
for the mother and 934 for the infant), as these births
could not be linked to other registries. Because we
assumed that adiposity is unlikely to cause malforma-
tions for which another cause is known, we also
excluded 7514 (0.5%) infants with chromosomal aber-
rations, genetic syndromes, malformation syndromes
with known causes, and viral infections having a
possible association with malformations (see
supplementary eMethods).30 Finally, seven infants did
not have data on sex and were therefore excluded.
After these exclusions, 1 406 272 singletons remained,
of whom 1 243 957 (88.5%) had complete data on all
covariates.
Women missing data on BMI were more likely to have
missing data on smoking status and family situation
(see supplementary eTable 1). Maternal age, level of
education, parity, and proportion of women of Nordic
origin were similar in women with missing BMI data
compared with normal weight women. However,
women missing BMI data were more likely to have high
education and to be primiparous compared with obese
women.
Patient involvement
No patients were involved in setting the research ques-
tion or the outcome measures, nor were they involved in
developing plans for design, or implementation of the
study. No patients were asked to advise on interpreta-
tion or writing up of results. There are no plans to dis-
seminate the results of the research to study participants
or the relevant patient community.
Main exposure
We calculated early maternal pregnancy BMI from
measured weight and self reported height at the first
prenatal visit, which takes place during the first tri-
mester (first 14 weeks of gestation) for 90% of all
women.12 We calculated the median height of each
mother using information from all available pregnan-
cies.31 Data on maternal height and/or weight were
missing in 9.6% of live singleton births (see supple-
mentary eTable 1). Based on BMI, we categorised the
women as underweight (BMI <18.5), of normal weight
(18.5 to <25), overweight (25 to <30), or in obesity class
I (30 to <35), obesity class II (35 to <40), or obesity
class III (≥40).32
Covariates
Data on parity, whether the mother cohabited with a
partner or not, and self reported smoking were regis-
tered at the first prenatal visit. Information on maternal
age was obtained at delivery, highest attained educa-
tion was retrieved from the education register, and
mother’s country of birth was retrieved from the total
population register.
Outcomes
The main outcome was presence of any major congen-
ital malformations in liveborn infants (from 22 com-
pleted gestational weeks), as recorded in either the
medical birth register, the national patient register
within one year of birth (including inpatient and hos-
pital based outpatient care), or the cause of death reg-
ister. Major congenital malformations were coded
according to the ICD-10 classification and were defined
according to the European Surveillance of Congenital

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Anomalies classification (EUROCAT; www.euro-
cat-network.eu; see supplementary eTables 2 and 3 for
ICD-10 codes).
We analysed the most common subgroups of major
congenital malformations with a prevalence of ≥0.1%
as additional outcomes. These included major con-
genital malformations of the heart, limbs, genital
organs, urinary system, digestive system, orofacial
clefts, eye, nervous system, and other malformations.
In keeping with the EUROCAT definition, patent duc-
tus arteriosus in preterm infants and persistent pul-
monary stenosis were not considered as major
congenital malformations. Other minor malforma-
tions were also excluded in accordance with the
EUROCAT classification.
Statistical analysis
Using generalised linear models with a robust sand-
wich estimator, we estimated risk ratios and 95%
confidence intervals for the outcomes in offspring of
underweight mothers (BMI <18.5), overweight moth-
ers (25 to <30), and mothers in obesity classes I (30
to <35), II (35 to <40), and III (≥40) compared with
the offspring of normal weight mothers (18.5 to <25).
To adjust for the possible dependence in outcome
introduced by repeated births in the same mother,
we constructed models with mother’s identification
number as a cluster. The outcome was assumed to
follow a Poisson distribution. We made adjustments
for maternal age, height, parity, early pregnancy
smoking status (0, 1-9, or ≥10 cigarettes daily), edu-
cational level, mother’s country of birth, family situ-
ation (living or not living with a partner), and sex of
offspring.
Subgroup analyses—sex specific subgroup analy-
ses were performed for any congenital malforma-
tions as well as for subgroups of major congenital
malformations.
Sensitivity analyses—diabetes is a known teratogen33-35
and may also be in the causal pathway between obesity
and major congenital malformations. In sensitivity
analyses, we excluded women with pregestational dia-
betes to investigate whether the associations between
BMI and major congenital malformations were aected.
Although gestational diabetes generally develops after
the developmentally critical period for malformations,
we also performed an analysis where we excluded both
women with pregestational diabetes and women with
gestational diabetes.
An additional analysis was performed for the
association between BMI and the outcome of any
chromosomal aberration, genetic syndrome, malfor-
mation syndrome with known causes, and viral
infection having a possible association with malfor-
mations (infants with these conditions were excluded
from the study population of the main analyses;
n=7514, of whom 6495 had complete data on all
variables).
Data were analysed using SAS (version 9.4). We con-
sidered two sided P values <0.05 to be statistically sig-
nificant. No adjustment was made for multiple
comparisons.
Results
Major congenital malformations
During the study period a total of 1 243 957 liveborn sin-
gleton infants were included in the cohort, 43 550 (3.5%)
of whom had any major congenital malformation. Con-
genital heart defects were the most common malforma-
tion subtype (1.6%) followed by malformations of the
genital organs (0.5%), limbs (0.4%), urinary system
(0.3%), other (0.2%), eye (0.2%), digestive system
(0.2%), orofacial clefts (0.1%), and nervous system
(0.1%; fig 1).
BMI and major congenital malformations
The proportions of ospring with any major congenital
malformation were 3.4% for underweight mothers, 3.4%
for normal weight mothers, 3.5% for overweight moth-
ers, and 3.8% for mothers in obesity class I, 4.2% in obe-
sity class II, and 4.7% in obesity class III (table 1 ). In
unadjusted analyses, risk ratios of any malformation
were increased in ospring of overweight mothers, and
increased with severity of obesity. A weak U-shaped
relation was found between maternal age and risk of
any major congenital malformation. Risks of any major
congenital malformations were higher in boys than in
girls and in ospring of smokers, primiparous women,
mothers of low stature, and mothers who were
notcohabiting with their partner (table 1). Supplemen-
tary eTable 1 provides maternal characteristics by BMI
categories.
The adjusted risk ratios of any major congenital mal-
formation increased with maternal overweight and
severity of obesity (fig 2 ). Compared with ospring of
normal weight mothers, the adjusted risk ratios for any
major congenital malformation increased with mater-
nal BMI: 1.05 (95% confidence interval 1.02 to 1.07) in
overweight mothers, 1.12 (1.08 to 1.15) in mothers in obe-
sity class I, 1.23 (1.17 to 1.30) in mothers in obesity class
II, and 1.37 (1.26 to 1.49) in mothers in obesity class III
(fig 2).
The overall risk of any major congenital malforma-
tion was higher in boys (4.1%) than in girls (2.8%). In
Percentage
Nervous system
(n=1272)
Eye (n=2407)
Ear, face, and
neck (n=496)
Congenital heart
defects (n=20 074)
Respiratory
system (n=379)
Orofacial cles
(n=1860)
Digestive system
(n=1933)
Abdominal wall
defects (n=233)
Urinary system
(n=4211)
Genital organs
(n=5921)
Limb (n=4478)
Other (n=2672)
0
0.4
0.8
1.2
1.6
2.0
Fig  | Prevalence of major congenital malformations in Swedish live singleton births
between  and  (n=  )

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analyses stratified by sex of offspring, the risk of any
malformation in boys of underweight mothers was
4.0%, normal weight mothers was 4.0%, and over-
weight mothers was 4.3% and in offspring of mothers
in obesity classes I, II, and III was 4.5%, 4.9%, and
5.3%, respectively (fig 2 ). The corresponding risks in
girls were 2.8%, 2.8%, 2.8%, 3.0%, 3.4%, and 4.0%.
The risk ratios of any malformation increased with
maternal severity of obesity in both boys and girls
(fig 2).
BMI and specic types of major congenital
malformations
The adjusted risk ratios of malformations of the ner-
vous system, heart, digestive system, genital organs,
limbs, and other malformations all increased with
increasing maternal BMI (P for trend ≤0.03 in all anal-
yses; figs 3 and 4).
The adjusted risk ratios for congenital heart
defects by maternal BMI were 1.05 (95% confidence
interval 1.01 to 1.08) for overweight mothers, 1.15
(1.09 to 1.20) for mothers in obesity class I, 1.26 (1.16
to 1.37) for mothers in obesity class II, and 1.44 (1.27
to 1.63) for mothers in obesity class III. The largest
organ specific increases in risk ratios related to over-
weight and severity of obesity were observed for mal-
formations of the nervous system. Compared with
offspring of normal weight mothers, the adjusted
risk ratios for malformations in the nervous system
were 1.15 (95% confidence interval 1.00 to 1.31) for
overweight mothers, 1.44 (1.20 to 1.73) for mothers in
obesity class I, 1.65 (1.23 to 2.21) for mothers in obe-
sity class II, and 1.88 (1.20 to 2.94) for mothers in
obesity class III (fig 3).
When comparing subgroups of malformations in
boys and girls, the largest sex dierence (with higher
proportions for boys) was noted for genital malforma-
tions (boys 0.9% and girls 0.04%) and malformations in
the urinary system (boys 0.5% and girls 0.2%; see sup-
plementary eFigure 1). In the sex stratified analyses of
malformation subtypes, comparisons were hampered
by reduced statistical power in the dierent BMI catego-
ries, especially in girls. The risks of congenital heart
defects increased with maternal overweight and
severity of obesity for boys, whereas only female o-
spring of mothers in obesity classes I to III were at
increased risks. Maternal BMI was associated with sta-
tistically significant increased risks of malformations in
the digestive system in boys but not in girls (see supple-
mentary eFigure 2).
Overall, 0.5% of infants who had diagnoses associ-
ated with increased risk of malformations were
excluded from the main analyses, with a range from
0.5% in the ospring of normal weight mothers to 0.8%
in the ospring of mothers in obesity class III. Risks of
these malformations also generally increased with
maternal overweight and severity of obesity (see sup-
plementary eTable 4).
Sensitivity analysis: exclusion of women with diabe-
tes—after exclusion of women with pregestational and
gestational diabetes, the associations between BMI and
overall major congenital malformations were materially
unchanged (see supplementary eTable 5).
Discussion
This large population based study found that overall
risks of major congenital malformations and risks of
several organ specific groups of malformations progres-
sively increase with maternal overweight and severity
of obesity. By finding a dose-response relation through-
out the spectrum of an above normal body mass index
(BMI) and associations between maternal overweight
and a range of malformation subgroups, this study sub-
stantially expands on previous data, which largely rest
on a meta-analysis of pooled studies with varying
definitions of obesity and no information on severity of
obesity.18
Table  | Maternal and birth characteristics and major congenital malformations in live
singleton births in Sweden
Characteristics Total No No (%)
Unadjusted risk
ratio (% CI) P value
Tota l 1 243 957 43 550 ( 3.5) -
Body mass index ( kg/m2):
<18.5 2 9 864 1020 (3.4) 1.00 (0.94 to 1.07)
<.001
18.5 to <25 756 432 25 713 ( 3.4) 1.00 (ref )
25 to <30 311 339 11 050 (3.5) 1.04 (1.02 to 1.07 )
30 to <35 103 0 85 3903 (3.8) 1.11 (1.0 8 to 1.15)
35 to <40 31 883 1335 (4. 2) 1. 23 (1.17 to 1.30)
≥40 11 35 4 529 (4.7 ) 1.3 7 (1.26 t o 1.49)
Maternal age (years):
13-24 178 3 88 6308 (3.5) 1.02 (0.99 to 1.05)
<.001
25 -29 374 411 12 861 (3.4) 1.00 (0.97 to 1.02)
30-34 433 659 14 964 (3. 5) 1.00 (re f )
≥35 257 499 9417 (3.7) 1.0 6 (1.03 t o 1.09)
Sex of o spring:
Girl 604 4 63 17 107 (2.8) 1.00 (ref ) <.001
Boy 639 494 26 443 (4.1) 1.46 (1. 43 t o 1.49)
Maternal height (cm):
130 -15 4 41 19 6 1556 ( 3.8) 1.10 (1.04 to 1.16)
0.006
155-159 126 17 5 4544 (3.6) 1.0 5 (1.01to 1.0 8)
160 -16 4 318 994 11 181 (3.5) 1.02 (0.99 to 1.05)
165-169 3 62 19 5 12 457 (3.4) 1.0 0 (ref )
170-174 27 2 951 9523 (3.5) 1.01 (0.99 to 1.04)
175 -200 122 4 4 6 4289 (3.5) 1.02 (0.98 to 1.05)
Smoking s tatus:
Non-smoker 1 152 475 40 144 ( 3.5) 1.00 (ref )
<.001 1-9 cigarettes/day 69 323 2531 (3.7) 1. 05 (1.01 to 1.09)
≥10 cigarettes/day 2 2 15 9 875 (3.9) 1.13 (1.0 6 to 1.2 1)
Educational level (years):
<10 108 174 4099 (3.8) 1. 00 (re f)
<.001 10-12 47 8 796 16 854 (3.5) 0.93 (0.90 to 0.96)
>12 656 987 2 2 597 ( 3.4) 0.91 (0.88 to 0.94)
Parity:
Primiparous 553 231 20 076 (3.6) 1.07 (1.05 to 1.09) <.001
Multiparous 690 726 23 474 (3.4) 1.0 0 (ref )
Maternal countr y of birth:
Nordic* 985 20 0 3 4 552 ( 3.5) 1.0 0 (ref ) 0.47
Non-Nordic 258 757 8998 (3.5) 0.99 (0.97 to 1.01)
Living with par tner:
Yes 1 17 2 665 40 812 (3. 5) 1.00 (re f) <.0 01
No 71 292 2738 (3.8) 1.10 (1.06 t o 1.15)
Supplem entary eTable 1 prov ides data for bir ths to mother s with missing dat a on body mass in dex.
*Swede n, Norway, D enmark, Finl and, and Iceland .

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Congenital heart defects were the most prevalent
subtype of organ specific malformation, and risks
increased with maternal overweight and increasing
obesity in a dose-response pattern. This is consistent
with findings from a meta-analysis focused on con-
genital heart defects, reporting increasing risks with
maternal overweight, and with women in obesity
class I (BMI 30 to <35) and obesity classes II and III
(BMI ≥35).36
The largest organ specific risk ratios related to
increasing maternal obesity were observed for malfor-
mations of the nervous system. Compared with o-
spring of normal weight mothers, ospring of mothers
in obesity class III had an almost doubled risk of major
congenital malformations of the nervous system. In line
with the present finding, a meta-analysis on maternal
BMI and risk of malformations reported a close to two-
fold increased risk of neural tube defects in ospring of
obese mothers.18 However, the obesity related risks of
malformations in the nervous system must be inter-
preted with caution as antenatal detection of these mal-
formations might be more dicult in obese women
compared with normal weight women.
Strengths and limitations of this study
Strengths of the present study include the population
based study design, with more than one million
singleton births. The large sample size enabled us to
investigate the eects of overweight and severity of
obesity on risks of major congenital malformations and
several specific malformation subgroups. Data on
exposures and outcomes were prospectively collected
within the universally accessible Swedish healthcare
system. Maternal BMI was calculated based on mea-
sured weight, which limits recall bias, but height was
self reported. We used standard BMI categories as
defined by WHO.32 Major congenital malformations
were classified according to the EUROCAT categorisa-
tion. Because we used data from several nationwide
registries, we had an opportunity to identify the major-
ity of infants with a diagnosis of a major congenital
malformation within the first year of life. Furthermore,
we were able to adjust risk estimates for important con-
founders.
Our study was restricted to live births. Malformations
are more common in pregnancies ending in miscarriage
or stillbirths, and some prenatally diagnosed malfor-
mations may also lead to induced abortions. In particu-
lar, most pregnancies complicated by neural tube
defects are terminated by induced abortion.7 The
Swedish national registries with patient level data do
not include individual data on malformations in preg-
nancies with miscarriages, stillbirths, and induced
abortions. However, aggregated data for Sweden
reported on the EUROCAT website for the period 2007-13
show that there were 551 cases of neural tube defects, of
which 396 (72%) were classified as termination of preg-
nancy for fetal anomaly.37
Antenatal detection of congenital malformations
may be more dicult in obese than in normal weight
women.38 If some malformations in ospring of obese
women (notably neural tube defects) were less likely
to be diagnosed prenatally and the women underwent
an induced abortion, we may have overestimated the
risks of malformations in ospring of obese mothers.
However, risks may be underestimated if obesity is
associated with malformations leading to sponta-
neous abortion. This hypothesis is supported by find-
ings from studies including information about
pregnancy terminations and reporting a doubled risk
of neural tube defects and a 50% increased risk of car-
diovascular anomalies in pregnancies with obesity.18
In this study we used BMI as a proxy for adiposity.
This is a reasonable assumption given the strong cor-
relation between BMI and fat mass in early preg-
nancy.39 We did not have information on the fat
distribution, which may be of interest to further
explore the association between overweight and
severity of obesity and risks of malformations. In
addition, we cannot rule out the possibility of resid-
ual confounding by unknown or unmeasured factors,
such as alcohol use. Power was limited for analyses of
less prevalent malformation subgroups by increasing
severity of maternal obesity.
Potential mechanisms
The pathophysiology of malformations is multifactorial,
with interactions between genetic and environmental
Overall
<18.5
18.5 to <25
25 to <30
30 to <35
35 to <40
≥40
Girls
<18.5
18.5 to <25
25 to <30
30 to <35
35 to <40
≥40
Boys
<18.5
18.5 to <25
25 to <30
30 to <35
35 to <40
≥40
1.01 (0.95 to 1.08)
1.00 (ref)
1.05 (1.02 to 1.07)
1.12 (1.08 to 1.15)
1.23 (1.17 to 1.30)
1.37 (1.26 to 1.49)
1.03 (0.93 to 1.13)
1.00 (ref)
1.01 (0.98 to 1.05)
1.08 (1.02 to 1.14)
1.21 (1.11 to 1.32)
1.44 (1.26 to 1.64)
1.00 (0.92 to 1.09)
1.00 (ref)
1.07 (1.04 to 1.10)
1.14 (1.09 to 1.19)
1.25 (1.16 to 1.34)
1.32 (1.18 to 1.48)
0.5 1.0 1.5 2.0
BMI (kg/m
2
) Adjusted risk ratio
(95% CI)
Adjusted risk ratio
(95% CI)
43 550 (3.5)
1020 (3.4)
25 713(3.4)
11 050 (3.5)
3903 (3.8)
1335 (4.2)
529 (4.7)
17 107 (2.8)
420 (2.8)
10 205 (2.8)
4237 (2.8)
1499 (3.0)
523 (3.4)
223 (4.0)
26 443 (4.1)
600 (4.0)
15 508 (4.0)
6813 (4.3)
2404 (4.5)
812 (4.9)
306 (5.3)
Events (%)
Fig  | Major congenital malformations in liveborn singletons by maternal body mass index
(BMI) in underweight (BMI <.; n= ), normal weight (BMI . to <; n= ),
and overweight (BMI  to <; n= ) women, and in women in obesity classes I (BMI
 to <; n= ), II (BMI  to <; n= ), and III (BMI ≥; n= ). Adjustment
was made for maternal age (-, -, -, ≥ years), height (-, -,
-, -, -, - cm), parity (primiparous, multiparous), early
pregnancy smoking status (non-smoker, -, ≥ cigarettes daily), educational level (<,
-, > years), maternal country of birth (Nordic (Sweden, Denmark, Finland, Iceland,
and Norway), non-Nordic), family situation (living with partner, not living with partner),
and sex of ospring

doi: 10.1136/bmj.j2563 |
BMJ
2017;357:j2563 | the bmj
RESEARCH
6
factors. Other environmental factors associated with
increased risks of malformations include maternal
smoking, alcohol use, socioeconomic factors, antiepi-
leptic drugs, deficiency of folic acid and other vitamins,
and diabetes.40-43 In the present study, we excluded
malformations with a known cause other than maternal
overweight or obesity.
Diabetes and abnormal glucose tolerance are com-
mon complications of obesity.44 There is a statisti-
cally significant increase in risks of congenital
malformations in offspring of women with pregesta-
tional diabetes,45 and risks increase with degree of
maternal hyperglycaemia.46 Experimental studies
suggest that hyperglycaemia induces oxidative stress
and increased production of free radical species,
which may have a teratogenic effect.47 However, in a
recent meta-analysis of maternal BMI and risks of
malformations, inclusion of mothers with diabetes
had limited impact on the effect size.18 Furthermore,
risks of malformations are reported to remain
increased in obese women after excluding women
with diabetes,48 and when adjusting for abnormal
glucose tolerance in women with glucose values
below the threshold of diabetes.49 This is in line with
our findings of essentially unchanged risks of
malformations after exclusion of mothers with diabe-
tes. The possible teratogenic role of other metabolic
derangements associated with obesity, such as insu-
lin resistance, hyperlipidemia, and inflammation, is
unclear. The adipose tissue is an active metabolic
and endocrine organ,50 distributed subcutaneously
and in the visceral compartment. Visceral obesity in
pregnancy is associated with a state of inflammation,
vascular dysfunction, and abnormal placental
metabolism,51 which may adversely influence organ-
ogenesis and fetal development.
We found higher risks of several subtypes of mal-
formations in boys than in girls. In particular, risks of
genital malformations were markedly higher in boys.
One might speculate that this difference may be
partly attributed to the clinically more available eval-
uation of genital structures in boys compared with
girls. Data from experimental studies show higher
growth rate and substantially higher glucose con-
sumption in males at the embryonal stage, even
before sexual differentiation.52 53 Furthermore, male
preimplantation embryos are more vulnerable to heat
stress induced production of radical oxygen species
than female preimplantation embryos.54 One might
hypothesize that male embryos are more prone than
female embryos to respond with enhanced oxygen
radical production to different environmental
insults, which in turn could contribute to their
increased risk of malformations.
Folic acid supplementation has been associated
with decreased risks of neural tube defects and con-
genital heart malformations.55 56 In the present study
we did not have information on folic acid supplemen-
tation in early pregnancy. However, folic acid defi-
ciency is common in obesity,57 and according to a
recent national survey from the US, overweight and
obese women are less likely to take multivitamins
before pregnancy compared with normal weight
women.58 Thus it is possible that the increased risks
of neural tube defects and congenital heart defects in
offspring of obese mothers may be partly due to folic
acid deficiency.
Conclusion
We found that risks of major congenital malforma-
tions in offspring progressively increase with mater-
nal overweight and severity of obesity. This
underlines the importance of having a maternal BMI
in the normal range before pregnancy. Preventive
effects of weight reduction in early pregnancy cannot
be expected as organogenesis occurs within the first
eight weeks of gestation. Thus, efforts should be
made to encourage women of reproductive age to
adopt a healthy lifestyle and to obtain a normal body
weight before conception.
Nervous system
<18.5
18.5 to <25
25 to <30
30 to <35
35 to <40
≥40
Eye
<18.5
18.5 to <25
25 to <30
30 to <35
35 to <40
≥40
Congenital heart defects
<18.5
18.5 to <25
25 to <30
30 to <35
35 to <40
≥40
Orofacial cles
<18.5
18.5 to <25
25 to <30
30 to <35
35 to <40
≥40
1.28 (0.91 to 1.79)
1.00 (ref)
1.15 (1.00 to 1.31)
1.44 (1.20 to 1.73)
1.65 (1.23 to 2.21)
1.88 (1.20 to 2.94)
0.93 (0.71 to 1.23)
1.00 (ref)
1.00 (0.91 to 1.10)
1.00 (0.86 to 1.16)
1.02 (0.79 to 1.32)
1.03 (0.68 to 1.57)
0.99 (0.90 to 1.09)
1.00 (ref)
1.05 (1.01 to 1.08)
1.15 (1.09 to 1.20)
1.26 (1.16 to 1.37)
1.44 (1.27 to 1.63)
1.20 (0.90 to 1.60)
1.00 (ref)
1.09 (0.98 to 1.22)
1.11 (0.94 to 1.31)
1.52 (1.19 to 1.95)
1.44 (0.96 to 2.16)
0.5 1.0 1.5 2.0 2.5 3.0
BMI (kg/m
2
) Adjusted risk ratio
(95% CI)
Adjusted risk ratio
(95% CI)
1272 (0.10)
38 (0.13)
695 (0.09)
331 (0.11)
139 (0.13)
49 (0.15)
20 (0.18)
2407 (0.19)
54 (0.18)
1466 (0.19)
603 (0.19)
198 (0.19)
63 (0.20)
23 (0.20)
20 074 (1.61)
458 (1.53)
11 807 (1.56)
5082 (1.63)
1840 (1.78)
630 (1.98)
257 (2.26)
1860 (0.15)
49 (0.16)
1070 (0.14)
482 (0.15)
164 (0.16)
71 (0.22)
24 (0.21)
Events (%)
Fig  | Major congenital malformations in nervous system, eye, heart, and oral cles in
liveborn singletons by maternal body mass index (BMI) in underweight (BMI <.;
n= ), normal weight (BMI . to <; n= ), and overweight (BMI  to <;
n= ) women, and in women in obesity classes I (BMI  to <; n= ), II
(BMI  to <; n= ), and III (BMI ≥; n= ). Adjustment was made for
maternal age (-, -, -, ≥ years), height (-, -, -,
-, -, - cm), parity (primiparous, multiparous), early pregnancy
smoking status (non-smoker, -, ≥ cigarettes daily), educational level (<, -,
> years), maternal country of birth (Nordic (Sweden, Denmark, Finland, Iceland, and
Norway), non-Nordic), family situation (living with partner, not living with partner), and
sex of ospring

the bmj |
BMJ
2017;357:j2563 | doi: 10.1136/bmj.j2563
RESEARCH
7
Contributors: MN and JS had full access to all of the data in the study
and take full responsibility for the integrity of the data and the
accuracy of the data analysis. SC, MN, BP, MP, OS, and EV conceived
and designed the study. All authors acquired, analysed, and
interpreted the data and critically revised the manuscript for important
intellectual content. SC, MN, and MP draed the manuscript. MN and
JS carried out the statistical analysis. SC, MN, and OS obtained funding
and provided administrative, technical, or material support. MN and JS
are the guarantors.
Funding: Research reported in this publication was supported by the
National Institute of Diabetes and Digestive and Kidney Diseases of
the National Institutes of Health under award number R01DK105948.
The content is solely the responsibility of the authors and does not
necessarily represent the ocial views of the National Institutes of
Health. The funders were not involved in the design and conduct of
the study; collection, management, analysis, or interpretation of the
data; and preparation, review, or approval of the manuscript. This
study was also funded by the Swedish Research Council for Health,
Working Life and Welfare (grant No 2014-0073) and an unrestricted
grant from Karolinska Institutet (distinguished professor award to SC).
MP was supported by Stockholm County Council (clinical post-doctoral
position). OS was supported by the Swedish Research Council (grant
No 2013-2429). BP was supported by the Danish Medical Research
Council. MN was supported by the Swedish Research Council (grant
No 2013-3770) and the National Institutes of Health (award No
R01DK105948).
Competing interests: All authors have completed the ICMJE uniform
disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no
support from any organisation for the submitted work; no nancial
relationships with any organizations that might have an interest in the
submitted work in the previous three years; no other relationships or
activities that could appear to have influenced the submitted work.
MN reports being a member of the scientic advisory board for Itrim
(<$5000 (£3876; €4430)/year).
Ethical approval: This study was approved by the regional research
ethics committee in Stockholm, Sweden (No 2012/1813-31/4).
Data sharing: No additional data available.
Transparency The lead author (MP) arms that the manuscript is an
honest, accurate, and transparent account of the study being reported;
that no important aspects of the study have been omitted; and that
any discrepancies from the study as planned (and, if relevant,
registered) have been explained.
This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this work
non-commercially, and license their derivative works on dierent
terms, provided the original work is properly cited and the use is
non-commercial. See: http://creativecommons.org/licenses/
by-nc/4.0/.
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Digestive system
<18.5
18.5 to <25
25 to <30
30 to <35
35 to <40
≥40
Urinary system
<18.5
18.5 to <25
25 to <30
30 to <35
35 to <40
≥40
Genital organs
<18.5
18.5 to <25
25 to <30
30 to <35
35 to <40
≥40
Limb
<18.5
18.5 to <25
25 to <30
30 to <35
35 to <40
≥40
Other
<18.5
18.5 to <25
25 to <30
30 to <35
35 to <40
≥40
0.98 (0.72 to 1.33)
1.00 (ref)
0.97 (0.87 to 1.09)
1.41 (1.21 to 1.63)
1.33(1.03 to 1.72)
1.54 (1.05 to 2.28)
1.18 (0.98 to 1.43)
1.00 (ref)
1.01 (0.94 to 1.09)
0.98 (0.88 to 1.10)
0.91 (0.74 to 1.11)
1.19 (0.88 to 1.60)
1.03 (0.87 to 1.22)
1.00 (ref)
1.04 (0.98 to 1.11)
1.12 (1.02 to 1.23)
1.27 (1.09 to 1.47)
1.43 (1.13 to 1.80)
1.02 (0.83 to 1.24)
1.00 (ref)
1.10 (1.03 to 1.18)
1.13 (1.02 to 1.25)
1.12 (0.93 to 1.34)
1.29 (0.98 to 1.70)
0.78 (0.59 to 1.04)
1.00 (ref)
0.96 (0.88 to 1.06)
1.00 (0.87 to 1.15)
1.55 (1.28 to 1.89)
1.39 (0.99 to 1.95)
0.5 1.0 1.5 2.0 2.5
BMI (kg/m
2
) Adjusted risk ratio
(95% CI)
Adjusted risk ratio
(95% CI)
1933 (0.16)
43 (0.14)
1134 (0.15)
452 (0.15)
215 (0.21)
63 (0.20)
26 (0.23)
4211 (0.34)
115 (0.39)
2544 (0.34)
1068 (0.34)
342 (0.33)
97 (0.30)
45 (0.40)
5921 (0.48)
145 (0.49)
3497 (0.46)
1496 (0.48)
529 (0.51)
182 (0.57)
72 (0.63)
4478 (0.36)
103 (0.34)
2616 (0.35)
1182 (0.38)
402 (0.39)
124 (0.39)
51 (0.45)
2672 (0.21)
49 (0.16)
1618 (0.21)
644 (0.21)
221 (0.21)
106 (0.33)
34 (0.30)
Events (%)
Fig  | Major congenital malformations in digestive, urinary, and genital systems; limbs;
and other malformations anliveborn singletons by maternal body mass index (BMI) in
underweight (BMI <.; n= ), normal weight (BMI . to <; n= ), and
overweight (BMI  to <; n= ) women, and in women in obesity classes I (BMI 
to <; n= ), II (BMI  to <; n= ), and III (BMI ≥; n= ). Adjustment
was made for maternal age (-, -, -, ≥ years), height (-, -,
-, -, -, - cm), parity (primiparous, multiparous), early
pregnancy smoking status (non-smoker, -, ≥ cigarettes daily), educational level (<,
-, > years), maternal country of birth (Nordic (Sweden, Denmark, Finland, Iceland,
and Norway), non-Nordic), family situation (living with partner, not living with partner),
and sex of ospring

RESEARCH
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Supplementary web appendix: eTables 1-5 and
eFigures 1 and 2