Maternal prepregnancy body mass index and congenital heart defects: Preliminary results from the National Birth Defects Prevention Study, Adolfo Correa, Suzanne M. Gilboa, Lilah M. Besser, Lorenzo Botto, Sonja A. Rasmussen, D. Kim Waller, Charlotte A. Hobbs, Mario Cleves, Tiffany Riehle-Colarusso Disclaimer: The findings and conclusions in this presentation have not been formally disseminated by CDC and should not be construed to represent any agency determination or policy. National Center on Birth Defects and Developmental Disabilities

Body Mass Index  Body mass index (BMI) proxy for % body fat  Increasing prevalence of overweight and obesity Obesity Class NHLBI Cutpoints (kg/m 2 )IOM Cutpoints (kg/m 2 ) Underweight<18.5<19.8 Normal Overweight > ObesityI >29.0 II Extreme obesityIII>40

1998 Obesity Trends* Among U.S. Adults BRFSS, 1990, 1998, 2006 (*BMI  30, or about 30 lbs. overweight for 5’4” person) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Prevalence among women years of age (Ogden et al JAMA) YearsOverweight or obesity BMI > 25 Obesity BMI > 30 Extreme obesity BMI >

Obesity and Pregnancy Outcomes  Several adverse pregnancy outcomes associated with obesity  Macrosomia (> 4000g or 4500g)  Large for gestational age (> 90 th %ile)  Longer duration of labor  C-sections  Late fetal death

Obesity and Birth Defects  Obesity is a risk factor for structural birth defects, most consistently, for neural tube defects (NTDs)  Naeye, 1990  Waller et al., 1994  Shaw et al., 1996  Watkins et al., 1996  Werler et al., 1996  Källén, 1998 …  Waller et al., 2007

Obesity and CHD  Association with congenital heart defects (CHD) in the aggregate  NBDPS data (Waller et al. 2007)  Overweight: 1.13 ( )  Obese: 1.40 ( )  Prospective cohort (Moore et al. 2000)  Obese: PR = 0.89 ( )

Obesity and CHD  Specific CHD phenotypes associated with body mass index  Shaw et al., 2000  Two California case-control studies ( ; )  Watkins and Botto, 2001  Atlanta Birth Defects Case Control Study ( )  Watkins et al., 2003  Atlanta Birth Defects Risk Factor Surveillance Study ( )  Cedergren and Källén, 2003  Swedish medical registries ( )

Research Objectives  To investigate the relation between prepregnancy body mass index and the occurrence of congenital heart defects among women without pregestational diabetes.  To investigate possible effect measure modification by gestational diabetes, folic acid supplement intake, and race/ethnicity.

National Birth Defects Prevention Study  Population-based case-control design  AR, CA, GA (CDC), IA, MA, NC, NJ, NY, TX, UT  October 1, December 31, 2003  Cases: live births, stillbirths, or terminations  Controls: live births from vital records or hospital data  Computer-assisted telephone interview  Participation: CHD cases (72%); Controls (69%)

CHD Classification: Two Axes*  Axis 1: Heart complexity (Heart)  Simple: One primary cardiac lesion  Association: At least two distinct cardiac lesions  Complex  Axis 2: Extra-cardiac malformations (Baby)  Isolated: No major extra-cardiac defects  Multiple: Presence of major extra-cardiac defects  Syndrome  Complex * Botto LD, et al Seeking causes: Classifying and evaluating congenital heart defects in etiologic studies. Birth Defects Res Part A Clin Molec Teratol 79:

Congenital Heart Defects (Simple, isolated)  Any heart defect (n=3390)  Conotruncal defects (n=745)  Tetralogy of Fallot (n=377)  d-transposition of the great arteries (n=266)  Atrioventricular septal defect (n=74)  Anomalous pulmonary venous return (n=120)  Total anomalous pulmonary venous return (n=100)  Left ventricular outflow tract obstruction defects (n=552)  Hypoplastic left heart syndrome (n=221)  Coarctation of the aorta (COA) (n=207)  Aortic stenosis (n=116)  Right ventricular outflow tract obstruction defects (n=551)  Pulmonary valve stenosis (n=400)  Pulmonary atresia (n=74)  Septal defects (n=1348)  Ventricular septal defect (VSD) perimembranous (n=592)  VSD muscular (n=138)  Atrial septal defects (n=589)  Atrial septal defect secundum (n=464)  Atrial septal defect NOS (n=125)  COA + VSD (n=101)  ASD + VSD (n=263)

Exclusions  Exclusion of cases with “complex” heart or baby classification  N = 358 cases  Exclusion of mothers with “pregestational” diabetes  Type 1 or 2 diabetes diagnosed any time: before, during, or after index pregnancy, or at unknown date  N =185 cases; N = 26 controls  Exclusion of those with missing BMI  N = 230 cases; N = 208 controls

Exposure and Covariates  Self-reported height and weight converted to body mass index and categorized (NHLBI)  Potential confounders  Maternal age, race/ethnicity, education, parity, smoking (B1-P1)*, supplemental folic acid intake (B1-P1), hypertension during pregnancy, household income  Study center – conditional logistic regression * B1-P1 refers to the month before conception through the end of first month of pregnancy

Analysis  Analysis restricted to CHD outcomes with at least 50 isolated cases  Simple and multiple logistic regression  Assessment of effect measure modification using interaction terms and stratified models  Presentation of results for simple, isolated CHD

Results: BMI Distribution BMI category (kg/m 2 ) Simple, isolated cases (n=3390) Controls (n=4774) N (%) < (5.1)285 (6.0) 18.5 – (52.9)2707 (56.7) 25.0 – (23.9)1056 (22.1) > (18.1)726 (15.2) 28-29%

Results: Main Effects

Results: GDM Stratification

Results: Race/Ethnicity Stratification

Study Limitations Self-reported BMI –Potential misclassification of exposure due to underestimation of weight and overestimation of height Missing data –BMI data is missing more frequently among Hispanic mothers (due to missing height) Incomplete case ascertainment among elective terminations –Quality of ultrasound visualization is poorer among obese mothers

Conclusions Overweight status and obesity are associated with increased risk for selected CHD Underweight status appears to be unassociated with CHD Gestational diabetes during index pregnancy may modify the effect of overweight and obesity –May reflect role of undiagnosed type 2 diabetes Some evidence of effect measure modification of both overweight status and obesity by Hispanic ethnicity

Supplemental Slides

Race/Ethnicity x BMI (Among Controls)* N (Row percents) R/EUnderweightAverage weight OverweightObeseTotal NHW169 (5.7)1769 (59.5)616 (20.7)419 (14.1)2973 NHB32 (5.5)278 (47.9)143 (24.7)127 (21.9)580 Hispanic52 (5.5)493 (52.0)146 (25.9)158 (16.7)949 Other31 (11.8)161 (61.5)49 (18.7)21 (8.0) * n=10 controls with missing race data

Age x BMI (Among Controls) N (Row percents) Maternal age UnderweightAverage weight OverweightObeseTotal < 2065 (12.4)324 (61.7)89 (17.0)47 (8.9) (8.6)538 (51.6)247 (23.7)168 (16.1) (4.4)687 (55.5)290 (23.4)206 (16.6) (4.3)747 (57.6)288 (22.2)206 (15.9)1297 > 3519 (2.8)411 (61.3)142 (21.2)99 (14.8)

Missing BMI Data Race/Ethnicity CHD Cases (n=228*) Controls (n=205*) Missing N (%) NHW26 (11.4)18 (8.8) NHB13 (5.7)2 (1.0) Hispanic182 (79.8)170 (82.9) Other6 (2.6)13 (6.3) * Includes 1 CHD case and 2 controls missing race/ethnicity.