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

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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.

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Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants

Emily Sonestedt, Kim Overvad (2016)

Summary Background Underweight and severe and morbid obesity are associated with highly elevated risks of adverse health outcomes. We estimated trends in mean body-mass index (BMI), which characterises its population distribution, and in the prevalences of a complete set of BMI categories for adults in all countries. Methods We analysed, with use of a consistent protocol, population-based studies that had measured height and weight in adults aged 18 years and older. We applied a Bayesian hierarchical model to these data to estimate trends from 1975 to 2014 in mean BMI and in the prevalences of BMI categories (<18·5 kg/m2 [underweight], 18·5 kg/m2 to <20 kg/m2, 20 kg/m2 to <25 kg/m2, 25 kg/m2 to <30 kg/m2, 30 kg/m2 to <35 kg/m2, 35 kg/m2 to <40 kg/m2, ≥40 kg/m2 [morbid obesity]), by sex in 200 countries and territories, organised in 21 regions. We calculated the posterior probability of meeting the target of halting by 2025 the rise in obesity at its 2010 levels, if post-2000 trends continue. Findings We used 1698 population-based data sources, with more than 19·2 million adult participants (9·9 million men and 9·3 million women) in 186 of 200 countries for which estimates were made. Global age-standardised mean BMI increased from 21·7 kg/m2 (95% credible interval 21·3–22·1) in 1975 to 24·2 kg/m2 (24·0–24·4) in 2014 in men, and from 22·1 kg/m2 (21·7–22·5) in 1975 to 24·4 kg/m2 (24·2–24·6) in 2014 in women. Regional mean BMIs in 2014 for men ranged from 21·4 kg/m2 in central Africa and south Asia to 29·2 kg/m2 (28·6–29·8) in Polynesia and Micronesia; for women the range was from 21·8 kg/m2 (21·4–22·3) in south Asia to 32·2 kg/m2 (31·5–32·8) in Polynesia and Micronesia. Over these four decades, age-standardised global prevalence of underweight decreased from 13·8% (10·5–17·4) to 8·8% (7·4–10·3) in men and from 14·6% (11·6–17·9) to 9·7% (8·3–11·1) in women. South Asia had the highest prevalence of underweight in 2014, 23·4% (17·8–29·2) in men and 24·0% (18·9–29·3) in women. Age-standardised prevalence of obesity increased from 3·2% (2·4–4·1) in 1975 to 10·8% (9·7–12·0) in 2014 in men, and from 6·4% (5·1–7·8) to 14·9% (13·6–16·1) in women. 2·3% (2·0–2·7) of the world’s men and 5·0% (4·4–5·6) of women were severely obese (ie, have BMI ≥35 kg/m2). Globally, prevalence of morbid obesity was 0·64% (0·46–0·86) in men and 1·6% (1·3–1·9) in women. Interpretation If post-2000 trends continue, the probability of meeting the global obesity target is virtually zero. Rather, if these trends continue, by 2025, global obesity prevalence will reach 18% in men and surpass 21% in women; severe obesity will surpass 6% in men and 9% in women. Nonetheless, underweight remains prevalent in the world’s poorest regions, especially in south Asia. Funding Wellcome Trust, Grand Challenges Canada.

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Obstetric and Perinatal Outcomes in Type 1 Diabetic Pregnancies

Martina Persson, Mikael Norman, Ulf Hanson (2009)

OBJECTIVE To perform comparative analyses of obstetric and perinatal outcomes between type 1 diabetic pregnancies and the general obstetric population in Sweden between 1991 and 2003. RESEARCH DESIGN AND METHODS This was a population-based study. Data were obtained from the Medical Birth Registry, covering >98% of all pregnancies in Sweden. A total of 5,089 type 1 diabetic pregnancies and 1,260,207 control pregnancies were included. Odds ratios (ORs) were adjusted for group differences in maternal age, parity, BMI, chronic hypertensive disease, smoking habits, and ethnicity. RESULTS In type 1 diabetes, preeclampsia was significantly more frequent (OR 4.47 [3.77–5.31]) as was delivery by cesarean section (5.31 [4.97–5.69]) compared with results for the general population. Stillbirth (3.34 [2.46–4.55]), perinatal mortality (3.29 [2.50–4.33]), and major malformations (2.50 [2.13–2.94]) were more common in type 1 diabetic than in control pregnancies. The risk of very preterm birth (<32 gestational weeks) was also higher among type 1 diabetic women (3.08 [2.45–3.87]). The incidence of fetal macrosomia (birth weight ≥2 SD above the mean) was increased in the diabetic group (11.45 [10.61–12.36]). CONCLUSIONS Type 1 diabetes in pregnancy is still associated with considerably increased rates of adverse obstetric and perinatal outcomes. The eightfold increased risk for fetal macrosomia in type 1 diabetic pregnancies is unexpected and warrants further investigation.

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Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.

Anne Sabers, , Erminio Bonizzoni … (2011)

Prenatal exposure to antiepileptic drugs is associated with a greater risk of major congenital malformations, but there is inadequate information on the comparative teratogenicity of individual antiepileptic drugs and the association with dose. We aimed to establish the risks of major congenital malformations after monotherapy exposure to four major antiepileptic drugs at different doses. The EURAP epilepsy and pregnancy registry is an observational cohort study representing a collaboration of physicians from 42 countries. We prospectively monitored pregnancies exposed to monotherapy with different doses of four common drugs: carbamazepine, lamotrigine, valproic acid, or phenobarbital. Our primary endpoint was the rate of major congenital malformations detected up to 12 months after birth. We assessed pregnancy outcomes according to dose at the time of conception irrespective of subsequent dose changes. After excluding pregnancies that ended in spontaneous abortions or chromosomal or genetic abnormalities, those in which the women had treatment changes in the first trimester, and those involving other diseases or treatments that could affect fetal outcome, we assessed rates of major congenital malformations in 1402 pregnancies exposed to carbamazepine, 1280 on lamotrigine, 1010 on valproic acid, and 217 on phenobarbital. An increase in malformation rates with increasing dose at the time of conception was recorded for all drugs. Multivariable analysis including ten covariates in addition to treatment with antiepileptic drugs showed that the risk of malformations was greater with a parental history of major congenital malformations (odds ratio 4·4, 95% CI 2·06-9·23). We noted the lowest rates of malformation with less than 300 mg per day lamotrigine (2·0% [17 events], 95% CI 1·19-3·24) and less than 400 mg per day carbamazepine (3·4% [5 events], 95% CI 1·11-7·71). Compared with lamotrigine monotherapy at doses less than 300 mg per day, risks of malformation were significantly higher with valproic acid and phenobarbital at all investigated doses, and with carbamazepine at doses greater than 400 mg per day. The risk of major congenital malformations is influenced not only by type of antiepileptic drug, but also by dose and other variables, which should be taken into account in the management of epilepsy in women of childbearing potential. Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, Netherlands Epilepsy Foundation, Stockholm County Council, and ALF. Copyright © 2011 Elsevier Ltd. All rights reserved.

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Author and article information

Contributors

Martina Persson: Role: consultant

Sven Cnattingius: Role: professor

Eduardo Villamor: Role: professor

Jonas Söderling: Role: statistician

Björn Pasternak: Role: senior researcher

Olof Stephansson: Role: consultant

Martin Neovius: Role: professor

Journal

Journal ID (nlm-ta): BMJ

Journal ID (iso-abbrev): BMJ

Journal ID (publisher-id): bmj

Title: The BMJ

Publisher: BMJ Publishing Group Ltd.

ISSN (Print): 0959-8138

ISSN (Electronic): 1756-1833

Publication date Collection: 2017

Publication date (Electronic): 15 June 2017

Volume: 357

Electronic Location Identifier: j2563

Affiliations

[1 ]Department of Medicine, Solna, Clinical Epidemiology Unit, Karolinska Institutet, SE-171 76 Stockholm, Sweden

[2 ]Department of Diabetes and Endocrinology, Sachsska Children’s Hospital, Södersjukhuset, Stockholm, Sweden

[3 ]Department of Epidemiology, School of Public Health and Center for Human Growth and Development, University of Michigan, Ann Arbor, MI, USA

[4 ]Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark

[5 ]Division of Obstetrics and Gynecology, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

Author notes

Correspondence to: M Persson Martina.Persson@ 123456ki.se

Article

Publisher ID: marp037094

DOI: 10.1136/bmj.j2563

PMC ID: 5470075

PubMed ID: 28615173

SO-VID: 4892ebef-774b-4869-91fc-97cea93bf4e6

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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 different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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

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Most cited references 40

Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants

Obstetric and Perinatal Outcomes in Type 1 Diabetic Pregnancies

Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.

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