Maternal overweight and obesity and risk of congenital heart defects in offspring
Post on 12-Jan-2017
Maternal overweight and obesity and risk of congenital heartdefects in offspringThis article has been corrected since online publication and a corrigendum appears in this issue
J Brite1,2,3, SK Laughon1, J Troendle4 and J Mills1
OBJECTIVE: Obesity is a risk factor for congenital heart defects (CHDs), but whether risk is independent of abnormal glucosemetabolism remains unknown. Data on whether overweight status increases the risk are also conflicting.RESEARCH DESIGN AND METHODS:We included 121 815 deliveries from a cohort study, the Consortium on Safe Labor (CSL), afterexcluding women with pregestational diabetes as recorded in the electronic medical record. CHD was identified via medical recorddischarge summaries. Adjusted odds ratios (ORs) for any CHD were calculated for prepregnancy body mass index (BMI) categoriesof overweight (25o30 kgm 2), obese (30o40 kgm 2) and morbidly obese (X40 kgm 2) compared with normal weight (18.5o25 kgm 2) women, and for specific CHD with obese groups combined (X30 kgm 2). A subanalysis adjusting for oral glucosetolerance test (OGTT) results where available was performed as a proxy for potential abnormal glucose metabolism present at thetime of organogenesis.RESULTS: There were 1388 (1%) infants with CHD. Overweight (OR 1.15, 95% confidence interval (95% CI): 1.011.32), obese(OR 1.26, 95% CI: 1.091.44) and morbidly obese (OR 1.34, 95% CI: 1.021.76) women had greater OR of having a neonate withCHD than normal weight women (Po0.001 for trend). Obese women (BMIX30 kgm 2) had higher OR of having an infant withconotruncal defects (OR 1.33, 95% CI: 1.031.72), atrial septal defects (OR 1.22, 95% CI: 1.041.43) and ventricular septal defects(OR 1.38, 95% CI: 1.061.79). Being obese remained a significant predictor of CHD risk after adjusting for OGTT.CONCLUSION: Increasing maternal weight class was associated with an increased risk for CHD. In obese women, abnormal glucosemetabolism did not completely explain the increased risk for CHD; the possibility that other obesity-related factors are teratogenicrequires further investigation.
International Journal of Obesity (2014) 38, 878882; doi:10.1038/ijo.2013.244
Keywords: prepregnancy BMI; congenital heart defects
INTRODUCTIONThe majority of studies have found an association betweenmaternal obesity and congenital heart defects (CHDs).19 It is notclear whether the association between obesity and CHD can beexplained by maternal diabetes, a known teratogen, becauseprevious studies have not had detailed information on maternalglucose status. It is also not known whether mild elevations inmaternal glucose could be responsible for the excess CHD seen inoffspring of obese women. This hypothesis is reasonable giventhat other adverse birth outcomes such as macrosomia have alinear association with maternal blood glucose even below thelevel that meets the criteria for a diagnosis of gestationaldiabetes.10,11 Thus, data are needed to clarify whether obesity isin fact a risk factor for CHD independent of blood glucose level.The literature is also conflicting regarding whether overweight
status increases the CHD risk.2,3,5,6 Moreover, most studies havehad insufficient numbers of subjects to investigate therelationship between obesity or overweight and classes ofcardiac defects or individual defects.7
Using data from the Consortium on Safe Labor (CSL), a largeUS cohort study, we investigated the association between
prepregnancy body mass index (BMI) and odds ratio (OR) ofcongenital cardiac defects overall and for specific defects whereenough cases were available. In a subset of women with diabetes-screening data available, we also investigated the OR of CHD byweight status after adjusting for blood glucose levels.
MATERIALS AND METHODSStudy design and methodsThe CSL was an observational study of medical records with prospectivelyentered data conducted by the Eunice Kennedy Shriver National Institute ofChild Health and Human Development at 12 clinical centers (19 hospitals).It was designed to study contemporary obstetric management as well asmaternal, obstetric and neonatal outcomes given the changing maternalsocio-demographics in regard to increased maternal age and BMI.12,13
Information on maternal demographic characteristics (including height,prepregnancy weight, race, educational attainment, insurance status andage); medical, reproductive and prenatal history (including pregestationaldiabetes status, parity, and smoking and alcohol use during pregnancy);pregnancy complications including development of gestational diabetesmellitus (GDM); and labor, delivery, postpartum and newborn outcomeswas abstracted from electronic medical records. Information from the
1Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA;2Epidemiology and Biostatistics, CUNY School of Public Health at Hunter College, New York, NY, USA; 3CUNY Institute for Demographic Research (CIDR), New York, NY, USA and4Office of Biostatistics Research, Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD, USA. Correspondence: Dr SK Laughon, EpidemiologyBranch, NICHD, National Institutes of Health, 6100 Executive Boulevard, Room 7B03, Rockville, MD 20852, USA.E-mail: firstname.lastname@example.orgReceived 31 July 2013; revised 6 November 2013; accepted 1 December 2013; accepted article preview online 23 December 2013; advance online publication, 21 January 2014
International Journal of Obesity (2014) 38, 878882& 2014 Macmillan Publishers Limited All rights reserved 0307-0565/14
neonatal intensive care units was linked to the newborn records. Maternaland newborn discharge summaries, in International Classification of Diseases-9(ICD-9) codes, were linked to each delivery. CHD status for each infant wasobtained via discharge record ICD-9 codes (Supplementary Appendix A).Infants with isolated and multiple defects were examined together.CHDs were categorized as previously described,14 and infants with morethan one cardiac defect were categorized in a hierarchical manner. Infantswho had more than one cardiac defect were analyzed in each group.CHD cases related to aneuploidy were excluded.The CSL study included 208 695 women with 228 562 deliveries at 23
weeks of gestation or later, occurring between 2002 and 2008. Womenwere excluded if they had multiple gestations (n 3234), were missingprepregnancy BMI information (n 76 952), or had pregestational diabetes(n 18 786). One site was excluded because it did not report pregesta-tional diabetes status (n 7877). Women with missing BMI data had ahigher percentage of neonates with CHD, compared to those with knownBMI (1.7 versus 1.1%, Po0.01 by Chi-squared test). The critical period formost heart defects is 1460 days after conception.2 Because gestationaldiabetes is usually not diagnosed until later in pregnancy around 2428weeks of gestation,15 we included women with gestational diabetes in themain analysis. However, since some women diagnosed as havinggestational diabetes may have had undiagnosed diabetes duringorganogenesis, we performed a sensitivity analysis excluding all womenwith pregnancies complicated by gestational diabetes.
Statistical analysisPotential confounders were identified by comparing the distribution ofbaseline characteristics among women with infants with and without anytype of CHD. For categorical factors, Chi-squared tests were used. Forcontinuous factors, t-tests were used. All factors with Pp0.05 were thenincluded in a multivariable model. We adjusted for site to account for thepotential differences in diagnoses by the different institutions. We adjustedfor race and age because the Baltimore Washington Infant Heart Studyreported race and age differences for some defects.16 The multivariablemodel related the OR of having an infant with a CHD to categories of BMI(underweight: BMIo18.5 kgm 2; normal weight: BMI 18.5o25 kgm 2;overweight: BMI 25o30 kgm 2; obese: BMI 30o40 kgm 2; morbidlyobese: BMIX40 kgm 2), while adjusting for each of the selectedconfounders, site, age, race, insurance and maternal smoking. Womenwith multiple deliveries were accounted for in the model through acommon random effect using PROC GENMOD of SAS (SAS Institute Inc.,Cary, NC, USA).17 All reported tests were two-sided with Pp0.05 taken asstatistically significant. SAS version 9.1 was used for the statistical analysis.Additional models combined all obese subjects into a single group:
BMIX30. Further models examined specific types of CHD where n450,decided a priori. For each model, a test for trend was obtained by replacingthe categorical BMI with a continuous BMI term.OGTT results were available at one site (n 5131). We performed a
subanalysis additionally adjusting for continuous OGTT results as a proxyfor potential abnormal glucose metabolism present at the time oforganogenesis.
RESULTSAfter the exclusions noted above, the study sample consisted of121 815 singleton births from 114 819 women. There were 1388cases of any type of CHD, 1.1% of the study population. Table 1presents maternal characteristics. Mean maternal BMI was higherfor women who had a neonate with any type of CHD comparedwith women whose neonates did not have CHD (26.3 versus25.5 kgm 2, respectively, Po0.001). Compared with women whodid not give birth to an infant with CHD, women who gave birth toinfants with CHD were more likely to be overweight (25.4%compared with 23.7%) or obese (BMIX30 kgm 2) (22.6 versus19.6%). Women whose infants had CHD were also less likely to beprivately insured, and more likely to smoke during pregnancy andbe diagnosed with GDM.Increasing prepregnancy BMI was associated with an increased
OR for having an infant with CHD: 1.18-fold for overweight,1.25-fold for obese and 1.36-fold for morbidly obese women(Po0.001 for trend) (Table 2). These results remained significantbut were slightly attenuated after adjusting for site, age, race,
insurance and maternal smoking. There was no association of CHDwith underweight.GDM complicated 2.2% of pregnancies of normal weight, 4.5%
of overweight and 8% of all obese women (X30 kgm 2). Womenwho were diagnosed with GDM had significantly higher OR(OR 2.12, 95% confidence interval (95% CI): 1.732.59) of havinga baby with any type of CHD. Because some women whodeveloped GDM also might have had undiagnosed pregestationaldiabetes, we performed sensitivity analyses excluding all womenwho developed GDM. When women who developed GDM wereexcluded from the analytic population, the association betweenmaternal BMI and infant CHD was attenuated but remainedsignificant for the combined obesity categories (BMIX30 kgm 2)in the fully adjusted model: OR 1.18 (95% CI: 1.021.36) (data notshown). The association was in the same direction but wasno longer significant for overweight women: OR 1.09 (95%CI: 0.951.25).Regarding specific categories and types of CHD, the combined
obesity group (BMIX30 kgm 2) had significantly increased OR forconotruncal defects (OR 1.33, 95% CI: 1.031.72), ventricularseptal defects (OR 1.38, 95% CI: 1.061.79) and atrial septaldefects (OR 1.22, 95% CI: 1.041.43) (Table 3). There was noassociation between underweight and overweight status for anyspecific type of CHD in either crude or adjusted models.To determine whether the association between prepregnancy
BMI and CHD persisted after adjusting for glucose concentrationlater in pregnancy, we performed a subanalysis restricted to thesite that reported the results of 1-h OGTT for 485% of women.This site had fewer women with missing BMI than the overallstudy population, and CHD incidence at this site was 0.92% (47
Table 1. Baseline characteristics of the Consortium on Safe Labor(CSL) study population women by congenital heart disease (CHD)status in offspringa
No CHD(n 120 427)
BMI (kgm 2) 26.30 (6.88) 25.53 (6.21) o0.001BMI categories, n (%) 0.007Underweight, o18.5 kgm 2 72 (5.2) 6196 (5.2)Normal weight, 18.5o25 kgm 2 651 (47.0) 62 162 (51.7)Overweight, 25o30 kgm 2 352 (25.4) 28 519 (23.7)Obese, 30o40 kgm 2 255 (18.4) 19 463 (16.2)Morbidly obese, 40 kgm 2 58 (4.2) 4087 (3.4)All obese, 30 kgm 2 313 (22.6) 23 550 (19.6)
Insurance, n (%) o0.001Private 713 (55.4) 67 973 (61.5)Public/self-pay 569 (44.2) 42 395 (38.4)Other 6 (0.47) 139 (0.13)
Race, n (%) o0.001White 635 (45.8) 62 083 (51.6)Black 330 (23.8) 24 158 (20.1)Hispanic 305 (22.0) 23 294 (19.3)Asian/Pacific Islander 34 (2.5) 3527 (3.0)Multi-racial/Other 42 (3.1) 2985 (2.6)
Maternal age (years) 27.43 (6.23) 27.11 (5.91) 0.048Parity, n (%) 0.8780 46 889 (38.9) 541 (39.0)1 35 721 (29.7) 404 (29.1)2 37 817 (31.4) 443 (31.9)
Smoking during pregnancy, n (%) 0.017No/unknown 1274 (91.8) 112 464 (93.4)Yes 114 (8.2) 7963 (6.6)
Alcohol during pregnancy, n (%) 0.199No/unknown 1356 (97.7) 118 212 (98.1)Yes 32 (2.3) 2215 (1.8)
History of depression, n (%) 0.541No/unknown 1330 (95.8) 114 982 (95.5)Yes 58 (4.2) 5445 (4.5)
Gestational diabetes, n (%) o0.001No/unknown 1282 (92.4) 115 899 (96.2)Yes 106 (7.6) 4528 (3.8)
aData presented are mean and standard deviation or N (%) when indicated.
Maternal BMI and congenital heart defects in offspringJ Brite et al
& 2014 Macmillan Publishers Limited International Journal of Obesity (2014) 878 882
defects), which was similar to the 1.15% rate of CHD at sites thatdid not report OGTT values. We found after we adjusted for OGTTas a linear predictor, there was 6% increased OR of CHD with a oneunit increase in maternal BMI (adjusted OR 1.06, 95% CI:1.021.10) (Table 4). Among all women at the site with OGTT results(n 5131), obese women (BMIX30kgm 2) had an OR for givingbirth to an infant with any type of CHD of 1.96 (95% CI: 1.013.80)(P 0.045) in the crude model and 2.38 (95% CI: 1.125.05)(P 0.023) after adjusting for age and OGTT level. Moreover, thetest for trend between increasing BMI and OR for CHDs remainedsignificant (P 0.015) after adjusting for OGTT levels.
DISCUSSIONIn this large US cohort study, obese and overweight women weremore likely than normal weight women to deliver an infant with
any CHD and among obese women, conotruncal, ventricularseptal or atrial septal defects in particular. Increasing maternal BMIhad a dose-response effect on CHD risk. Obesity remained asignificant risk factor for CHD after adjusting for glycemic status asmeasured by OGTT.Women with BMIs above the normal range are more likely to
have pre-gestational diabetes mellitus, and diabetes is anestablished teratogen.18 Therefore, diabetes mellitus has beenput forth as a possible explanation for the observed increasedCHD risk in obese mothers.19 However, several studies have foundthe association persisted even after diabetic women wereexcluded.2,4,6,8 One possible explanation might be obese andoverweight women are more likely to have higher glu...