Maternal obesity, interpregnancy weight changes and congenital heart defects in the offspring: a nationwide cohort study

Background Maternal obesity has been positively associated with increased risk of congenital heart defects in the offspring. However, none of the large studies have included the considerable proportion of congenital heart defects that are identified due to improvements in prenatal diagnostics and terminated in pregnancy. The mechanism behind the association is poorly understood, and a relation to interpregnancy weight changes is to be investigated. Objectives To evaluate the association between maternal obesity and congenital heart defects in the offspring when including all pregnancies and to investigate if interpregnancy weight change between the first and second pregnancy influences risk of fetal congenital heart defects. Study Design A nationwide cohort study of all singleton pregnancies in Denmark from 2008 to 2018. All data on maternal and offspring characteristics were retrieved from the Danish Fetal Medicine Database. The database included data on postnatal diagnoses of congenital heart defects in live births and prenatal diagnoses of congenital heart defects from ultrasound examinations during pregnancy resulting in live birth, stillbirth, spontaneous abortion after gestational week 12 or termination of pregnancies after gestational week 12. As this cohort encompassed all pregnancies over a 10-year period, it was possible for women to experience multiple pregnancies. Congenital heart defects and severe congenital heart defects were grouped according to European Surveillance of Congenital Anomalies’ definitions. Children or fetuses with chromosomal aberrations were excluded. Relative risks were calculated using log-linear Poisson models for congenital heart defects overall, severe congenital heart defects and for five of the most prevalent subtypes of congenital heart defects. Results Of the 547 178 pregnancies included in the cohort, 5 498 had congenital heart defects (1.0%). Risk of congenital heart defects became gradually higher with higher maternal BMI; for BMI 30-34.9 kg/m2, adjusted relative risk = 1.23 (95% confidence interval 1.12-1.36), for BMI 35-39.9 kg/m2, adjusted relative risk = 1.26 (95% confidence interval 1.09-1.46) and for BMI ≥ 40 kg/m2, adjusted relative risk = 1.81 (95% confidence interval 1.50-2.15). Data was adjusted for maternal age, smoking status and year of estimated due date. The same pattern was seen for the subgroup of severe congenital heart defects. Among the atrioventricular septal defects (n = 245), a particularly strong association with maternal BMI ≥ 40 kg/m2 was seen, adjusted relative risk = 4.19 (95% confidence interval 2.13-7.42). 107 627 women were identified with their first and second pregnancies in the cohort. Interpregnancy BMI change was positively, albeit not statistically significant, associated with risk of congenital heart defects in the second pregnancy when adjusting for maternal age and BMI, with an adjusted relative risk = 1.27 (95% confidence interval 0.96-1.64) among persons with a BMI increase of ≥ 4 kg/m2. Conclusions When including both pre- and postnatally diagnosed congenital heart defects, this study showed a positive dose-response association between maternal BMI and risk of congenital heart defects in the offspring. However, only a non-significant trend was seen between interpregnancy BMI changes and risk of congenital heart defects in the second pregnancies. Condensation Tweetable statement: The risk of fetal congenital heart defect is associated with high maternal BMI, and it may also be affected by a substantial weight gain between pregnancies. AJOG at a Glance A. Why was this study conducted? B. What are the key findings? C. What does this study add to what is already known? ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by The Danish Children Heart Foundation (18-R109-A5193-26043), The A.P. Moller Foundation (19-L-0096), and Aase and Ejnar Danielsen's Foundation (19-10-0493). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Statens Serum Institut has approval from the Danish Data Protection Agency to conduct register-based studies, and the project has been approved (journal no. 19/03354 and 20/09279). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors * AVSD : atrioventricular septum defect CHDs : congenital heart defects CoA : coarctation of the aorta EUROCAT : European Surveillance of Congenital Anomalies TGA : transposition of the great arteries ToF : Tetralogy of Fallot UVH : univentricular heart