ORIGINAL ARTICLE

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 (25–o30 kg m� 2), obese (30–o40 kg m� 2) and morbidly obese (X40 kg m� 2) compared with normal weight (18.5–o25 kg m� 2) women, and for specific CHD with obese groups combined (X30 kg m� 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 (OR¼ 1.15, 95% confidence interval (95% CI): 1.01–1.32), obese(OR¼ 1.26, 95% CI: 1.09–1.44) and morbidly obese (OR¼ 1.34, 95% CI: 1.02–1.76) women had greater OR of having a neonate withCHD than normal weight women (Po0.001 for trend). Obese women (BMIX30 kg m� 2) had higher OR of having an infant withconotruncal defects (OR¼ 1.33, 95% CI: 1.03–1.72), atrial septal defects (OR¼ 1.22, 95% CI: 1.04–1.43) and ventricular septal defects(OR¼ 1.38, 95% CI: 1.06–1.79). 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, 878–882; 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).1–9 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 overweightstatus 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: laughonsk@mail.nih.govReceived 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, 878–882& 2014 Macmillan Publishers Limited All rights reserved 0307-0565/14

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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 23weeks of gestation or later, occurring between 2002 and 2008. Womenwere excluded if they had multiple gestations (n¼ 3234), were missingprepregnancy BMI information (n¼ 76 952), or had pregestational diabetes(n¼ 18 786). One site was excluded because it did not report pregesta-tional diabetes status (n¼ 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 14–60 days after conception.2 Because gestationaldiabetes is usually not diagnosed until later in pregnancy around 24–28weeks 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 kg m� 2; normal weight: BMI 18.5–o25 kg m� 2;overweight: BMI 25–o30 kg m� 2; obese: BMI 30–o40 kg m� 2; morbidlyobese: BMIX40 kg m� 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 (n¼ 5131). We performed asubanalysis 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 kg m� 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 kg m� 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 increasedOR 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 kg m� 2). Womenwho were diagnosed with GDM had significantly higher OR(OR¼ 2.12, 95% confidence interval (95% CI): 1.73–2.59) 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 kg m� 2)in the fully adjusted model: OR¼ 1.18 (95% CI: 1.02–1.36) (data notshown). The association was in the same direction but wasno longer significant for overweight women: OR¼ 1.09 (95%CI: 0.95–1.25).

Regarding specific categories and types of CHD, the combinedobesity group (BMIX30 kg m� 2) had significantly increased OR forconotruncal defects (OR¼ 1.33, 95% CI: 1.03–1.72), ventricularseptal defects (OR¼ 1.38, 95% CI: 1.06–1.79) and atrial septaldefects (OR¼ 1.22, 95% CI: 1.04–1.43) (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 prepregnancyBMI 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

CHD(n¼ 1388)

No CHD(n¼ 120 427)

P-value

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, 18.5–o25 kgm� 2 651 (47.0) 62 162 (51.7)Overweight, 25–o30 kgm� 2 352 (25.4) 28 519 (23.7)Obese, 30–o40 kgm� 2 255 (18.4) 19 463 (16.2)Morbidly obese, 40þ kgm� 2 58 (4.2) 4087 (3.4)All obese, 30þ 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)2þ 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.

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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 OR¼ 1.06, 95% CI:1.02–1.10) (Table 4). Among all women at the site with OGTT results(n¼ 5131), obese women (BMIX30 kg m� 2) had an OR for givingbirth to an infant with any type of CHD of 1.96 (95% CI: 1.01–3.80)(P¼ 0.045) in the crude model and 2.38 (95% CI: 1.12–5.05)(P¼ 0.023) after adjusting for age and OGTT level. Moreover, thetest for trend between increasing BMI and OR for CHDs remainedsignificant (P¼ 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 tohave 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 glucoseconcentrations that do not meet the threshold for a diagnosis ofdiabetes.6,7 No study to date has been able to test this hypothesis.We used OGTT tests as a method of identifying possible glucose

Table 2. Odds ratios (ORs) and 95% confidence intervals (CIs) for congenital heart defects by categories of body mass index (BMI) among 121 815pregnancies in the Consortium on Safe Labor

Total (n) Cases (n) Crude Multivariablea

OR (95% CI) P-value OR (95% CI) P-value

P-value for trend testp0.001 P-value for trend testp0.001

Underweight, o18.5 kgm� 2 6268 72 1.11 (0.87–1.42) 0.405 1.08 (0.85–1.38) 0.529Normal weight, 18.5–o25 kgm� 2 62 813 651 1.00 (ref ) n/a 1.00 (ref ) n/aOverweight, 25–o30 kgm� 2 28 871 352 1.18 (1.03–1.34) 0.014 1.15 (1.01–1.32) 0.033Obese, 30–o40 kgm� 2 19 718 255 1.25 (1.08–1.45) 0.003 1.24 (1.07–1.44) 0.005Morbidly obese, 40þ kgm� 2 4145 58 1.36 (1.03–1.78) 0.028 1.34 (1.02–1.76) 0.036All obese, 30þ kgm� 2 23 863 313 1.27 (1.11, 1.45) 0.001 1.26 (1.09–1.44) 0.001

aAdjusted for site, age, race, insurance and maternal smoking.

Table 3. Odds ratios (ORs)a and 95% confidence intervals (CIs) for the effect of prepregnancy body mass index (BMI) on risk of types of congenitalheart defectsb

Conotruncal P-value fortrend test: 0.050

Ventricular septal P-value fortrend test: 0.029

Atrial septal P-value fortrend test: 0.021

ORa

(95% CI)Totalcases

P-value ORa

(95% CI)Totalcases

P-value ORa

(95% CI)Total N

casesP-value

P-value fortrend test: 0.050

P-value fortrend test: 0.029

P-value fortrend test: 0.021

Underweight (n¼ 6268), o18.5 kgm� 2 1.04 (0.66–1.67) 20 0.842 0.99 (0.60–1.64) 17 0.974 0.99 (0.74–1.32) 51 0.929Normal weight (n¼ 62 813), 18.5–o25 kgm2 1.00 (ref ) 187 n/a 1.00 (ref ) 169 n/a 1.00 (ref ) 505 n/aOverweight (n¼ 28 871), 25–o30 kgm� 2 1.18 (0.92–1.51) 101 0.186 1.15 (0.89–1.49) 89 0.286 1.12 (0.96–1.30) 267 0.145Obese (n¼ 19 718), 30–o40 kgm� 2 1.35 (1.03–1.77) 77 0.030 1.39 (1.05–1.83) 71 0.021 1.19 (1.01–1.42) 191 0.042Morbidly obese (n¼ 4145), 40þ kgm� 2 1.21 (0.70–2.10) 14 0.492 1.36 (0.79–2.34) 14 0.272 1.37 (1.00–1.86) 46 0.048All obese (n¼ 23 863), 30þ kgm� 2 1.33 (1.03–1.72) 91 0.031 1.38 (1.06–1.79) 85 0.016 1.22 (1.04–1.43) 237 0.014N 399 360 1060

aAdjusted for site, age, race, insurance and maternal smoking. bSample sizes (no50) too small for all other CHD types.

Table 4. Odds ratio of congenital heart disease by prepregnancy BMI category at site where OGTT results known (n¼ 5131)

BMIa Total (n) Cases (n) Crude Age adjusted Adjusted for age and OGTT

OR (95% CI) P-value OR (95% CI) P-value OR (95% CI) P-value

Normal weight, 18.5–24.9 2226 16 1.00 (ref) n/a 1.00 (ref) n/a 1.00 (ref ) n/aOverweight, 25–29.9 1272 10 1.10 (0.50–2.42) 0.8219 1.09 (0.49–2.42) 0.8261 0.83 (0.33–2.05) 0.686Obese, 30–39.9 1115 12 1.50 (0.71–3.19) 0.2884 1.50 (0.71–3.16) 0.2877 2.04 (0.90–4.62) 0.088Morbidly obese, 40þ 311 8 3.65 (1.55–8.58) 0.0030 3.63 (1.55–8.51) 0.0030 3.63 (1.33–9.91) 0.021All obese, 30þ 1426 20 1.96 (1.01–3.80) 0.0451 1.95 (1.02–3.76) 0.0445 2.38 (1.12–5.05) 0.023

Abbreviations: BMI, body mass index; CI, confidence interval; OGTT, oral glucose tolerance test; OR, odds ratio. aUnderweight category had an insufficientnumber of cases (n)¼ 1.

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abnormalities during organogenesis. Even after adjusting forglucose status, increasing BMI was associated with increasing riskof CHD, and obese women still had higher risk of CHD.

The fact that maternal obesity was associated with risk of CHDeven after taking abnormal glucose metabolism (albeit evaluatedlater in pregnancy) into account suggests that abnormalities inglucose metabolism do not fully explain the increased risk for CHDfound in obese women. Furthermore, obesity remained asignificant risk factor for CHD after we excluded all subjects withGDM (or undiagnosed pregestational diabetes), providing addi-tional support for the hypothesis that other factors contribute tothe increased risk for CHD in obese women. Obesity is associatedwith a wide range of metabolic abnormalities, but little is knownabout their potential teratogenicity. Our results raise importantquestions for future investigation. It has been hypothesizedmothers with high prepregnancy BMI may be at higher risk ofgiving birth to an infant with CHD because obese women may bemore likely to be dieting when they conceive;19 may have reducedfolate levels;20 or may have more-difficult-to-read ultrasoundscans, resulting in fewer terminations of pregnancy for fetalanomaly and therefore increased prevalence at birth.1,7

Most studies have found that obesity was a risk factor for CHD,with similar effect sizes to our study.2,4–7 The data are much lessconsistent, however, regarding the risk associated with beingoverweight. Two prior case–control studies2,3 and two studiesusing birth certificate data with inherent limitations5,6 did not findoverweight to be associated with CHD while other studiesdid,1,4,8,9 including a meta-analysis.7 Our study found thatoverweight status had a modest effect on CHD risk afteraccounting for other factors.

We also examined the relationship between specific types ofCHD and prepregnancy BMI and found that obese women were atan increased risk of having a neonate with conotruncal, ventricularseptal and atrial septal defects. Our findings are consistent withprior studies that found an association between obesity or morbidobesity and atrial and ventricular septal defects.2,4,6,7,19 Althoughour numbers of specific defects were small, our finding thatoverweight women were not at risk for giving birth to an infantwith atrial or ventricular septal defects is similar to priorreports.4,6,7 Results have been more mixed for conotruncaldefects. One study found an increased risk in obese mothers forconotruncal defects in general.4 In contrast, several studies havefound no association between prepregnancy BMI for obese oroverweight mothers and conotruncal defects in general5,21,22 ortetralogy of Fallot specifically.2,7,21,22

Some limitations of our study should be noted. BMI data werenot available on all women. However, CHD prevalence wassomewhat higher in women with missing BMI data (1.68%) thanthose in the analytic population (1.15%). We did not have data onpotential teratogens such as drugs, although they account for asmall percentage of CHD. Cases not identified in the nursery orcases terminated prenatally were not available for study. Manycases of CHD, particularly atrial septal defects, ventricular septaldefects and coarctation of aorta, may not be diagnosed beforedischarge after birth, and we did not have full clinical data oninfants outside of ICD-9 discharge codes. Finally, we were unableto account for any misclassification of ICD-9 coding, despitethe fact classification for congenital heart disease has beenshown to be inaccurate for certain types of defects, particularlytetralogy of Fallot, where the sensitivity was 83% based onICD-9 reports.23

A major strength of our study was the ability to examine therole of potentially impaired glucose tolerance. Our study also hada large sample size, comprehensive maternal and infant demo-graphic and delivery characteristics, and reliable, uniform datacollection from medical charts. Because data were gatheredprospectively from the medical records, several types of measure-ment error and bias, particularly recall bias, were greatly minimized.

Our findings have important public health implicationsconsidering that approximately two thirds of American women20–39 are overweight or obese according to the 2009-2010(NHANES) National Health and Nutrition Examination Surveyand are at greater risk of giving birth to a child with CHD.24

A simulation conducted by Honein et al. demonstrated thatprepregnancy obesity may contribute to 2850 (95% CI: 1035–5065) CHD cases each year in the US. Worldwide, the burden ofoverweight and obesity is increasing, particularly in Latin Americaand the Caribbean, where 23% of women 20–29 are overweightand 11% are obese.25

CONCLUSIONIn summary, women who were obese when they conceived wereat increased risk of having an infant with a CHD. Abnormalities inglucose metabolism likely did not completely explain theincreased risk in obese women. Other obesity-related factorsshould be investigated as potential teratogens. Women should becounseled before conception that obesity increases the risk forCHD and that weight reduction may decrease their risk.

CONFLICT OF INTERESTThe authors declare no conflict of interest.

ACKNOWLEDGEMENTSInstitutions involved in the Consortium include, in alphabetical order: BaystateMedical Center, Springfield, MA; Cedars-Sinai Medical Center Burnes Allen ResearchCenter, Los Angeles, CA; Christiana Care Health System, Newark, DE; GeorgetownUniversity Hospital, MedStar Health, Washington, DC; Indiana University ClarianHealth, Indianapolis, IN; Intermountain Healthcare and the University of Utah, SaltLake City, Utah; Maimonides Medical Center, Brooklyn, NY; MetroHealth MedicalCenter, Cleveland, OH; Summa Health System, Akron City Hospital, Akron, OH; TheEMMES Corporation, Rockville, MD (Data Coordinating Center); University of Illinois atChicago, Chicago, IL; University of Miami, Miami, FL; and University of Texas HealthScience Center at Houston, Houston, Texas. The named authors alone are responsiblefor the views expressed in this manuscript, which does not necessarily represent thedecisions or the stated policy of the NICHD. JB, SKL, JT and JM were supported by theIntramural Research Program of the Eunice Kennedy Shriver National Institute of ChildHealth & Human Development, National Institutes of Health. The data included in thispaper were obtained from the Consortium on Safe Labor, which was supported bythe Intramural Research Program of the Eunice Kennedy Shriver National Institute ofChild Health and Human Development, National Institutes of Health, throughContract No. HHSN267200603425C.

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Supplementary Information accompanies this paper on International Journal of Obesity website (http://www.nature.com/ijo)

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