Maternal prepregnancy body mass index and congenital heart defects: Preliminary results from the National

Birth Defects Prevention Study, 1997-2003

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/m2) IOM Cutpoints (kg/m2)

Underweight <18.5 <19.8

Normal 18.5 - 24.9 19.8 - 26.0

Overweight 25.0 - 29.9 >26.0 - 29.0

Obesity I 30.0 - 34.9 >29.0

II 35.0 - 39.9

Extreme obesity III >40

1998

Obesity Trends* Among U.S. AdultsBRFSS, 1990, 1998, 2006

(*BMI 30, or about 30 lbs. overweight for 5’4” person)

2006

1990

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Prevalence among women 20-39 years of age

(Ogden et al. 2006. JAMA)

Years Overweight or obesity

BMI > 25

Obesity

BMI > 30

Extreme obesity

BMI > 40

1999-2000 54.4 28.3 6.0

2001-2002 54.7 29.8 5.0

2003-2004 51.7 28.9 8.0

Obesity and Pregnancy Outcomes

Several adverse pregnancy outcomes associated with obesity Macrosomia (> 4000g or 4500g) Large for gestational age (> 90th %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 1997-2002 (Waller et al. 2007) Overweight: 1.13 (1.01-1.26) Obese: 1.40 (1.24-1.59)

Prospective cohort 1984-1987 (Moore et al. 2000) Obese: PR = 0.89 (0.35-2.2)

Obesity and CHD Specific CHD phenotypes associated with

body mass index Shaw et al., 2000

Two California case-control studies (1987-1989; 1989-1991) Watkins and Botto, 2001

Atlanta Birth Defects Case Control Study (1968-1980) Watkins et al., 2003

Atlanta Birth Defects Risk Factor Surveillance Study (1993-1997) Cedergren and Källén, 2003

Swedish medical registries (1992-2001)

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Watkins and Botto, 2001* Watkins et al., 2003† Cedergren and Källén, 2003‡

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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 1,1997 - 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. 2007. Seeking causes: Classifying and evaluating congenital heart defects in etiologic studies. Birth Defects Res Part A Clin Molec Teratol 79:714-727

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/m2)

Simple, isolated cases (n=3390)

Controls (n=4774)

N (%) N (%)

< 18.5 172 (5.1) 285 (6.0)

18.5 – 24.9 1794 (52.9) 2707 (56.7)

25.0 – 29.9 809 (23.9) 1056 (22.1)

> 30.0 615 (18.1) 726 (15.2)

28-29%

Results: Main EffectsSimple, Isolated Heart Defect No. Cases OR (95% CI) No. Cases OR (95% CI)

Any Heart Defect 809 1.20 (1.07,1.35) 615 1.22 (1.07,1.40)Conotruncal Defects 167 1.16 (0.95,1.43) 136 1.33 (1.06,1.67) Tetralogy of Fallot 86 1.15 (0.87,1.51) 75 1.36 (1.00,1.84) D-Transposition of the Great Arteries 54 1.00 (0.71,1.40) 41 1.16 (0.79,1.69)Atrioventricular Septal Defect 16 0.94 (0.50,1.75) 13 1.14 (0.59,2.19)Anomalous Pulmonary Venous Return 23 1.04 (0.62,1.75) 26 1.74 (1.05,2.88) Total Anomalous Pulmonary Venous Return 20 1.21 (0.69,2.14) 24 2.27 (1.32,3.91)Left Ventricular Outflow Tract Obstruction Defects 133 1.21 (0.96,1.52) 97 1.18 (0.90,1.53) Hypoplastic Left Heart Syndrome 58 1.48 (1.05,2.09) 44 1.38 (0.93,2.04) Coarctation of the Aorta 50 1.14 (0.79,1.64) 35 1.18 (0.78,1.79) Aortic Stenosis 23 0.91 (0.55,1.50) 16 0.82 (0.46,1.46)Right Ventricular Outflow Tract Obstruction Defects 145 1.34 (1.07,1.69) 107 1.35 (1.05,1.75) Pulmonary Atresia 22 1.49 (0.82,2.68) 9 0.99 (0.45,2.19) Pulmonary Valve Stenosis 107 1.41 (1.08,1.83) 85 1.46 (1.09,1.95)Septal Defects 325 1.19 (1.01,1.40) 236 1.11 (0.92,1.34) Ventricular Septal Defect Perimembranous 140 1.11 (0.88,1.39) 96 0.99 (0.76,1.29) Ventricular Septal Defect Muscular 37 1.83 (1.00,3.35) 17 1.15 (0.54,2.44) Atrial Septal Defects 147 1.25 (1.00,1.58) 115 1.21 (0.94,1.57) Atrial Septal Defect Secundum 117 1.28 (0.99,1.64) 93 1.20 (0.90,1.59) Atrial Septal Defect NOS 30 1.13 (0.70,1.83) 22 1.27 (0.75,2.14)Special Association: Coarctation of the Aorta + Ventricular Septal Defect* 17 0.74 (0.43,1.30) 14 0.81 (0.43,1.51)Special Association: Ventricular Septal Defect + Atrial Septal Defect* 62 1.24 (0.89,1.73) 50 1.37 (0.96,1.97)* Associated, Isolated Heart Defects

Overweight Obese

Results: GDM Stratification

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Results: Race/Ethnicity Stratification

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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/E Underweight Average weight

Overweight Obese Total

NHW 169 (5.7) 1769 (59.5) 616 (20.7) 419 (14.1) 2973

NHB 32 (5.5) 278 (47.9) 143 (24.7) 127 (21.9) 580

Hispanic 52 (5.5) 493 (52.0) 146 (25.9) 158 (16.7) 949

Other 31 (11.8) 161 (61.5) 49 (18.7) 21 (8.0) 262

4764

* n=10 controls with missing race data

Age x BMI (Among Controls)N (Row percents)

Maternal age

Underweight Average weight

Overweight Obese Total

< 20 65 (12.4) 324 (61.7) 89 (17.0) 47 (8.9) 525

20-24 90 (8.6) 538 (51.6) 247 (23.7) 168 (16.1) 1043

25-29 55 (4.4) 687 (55.5) 290 (23.4) 206 (16.6) 1238

30-34 56 (4.3) 747 (57.6) 288 (22.2) 206 (15.9) 1297

> 35 19 (2.8) 411 (61.3) 142 (21.2) 99 (14.8) 671

4774

Missing BMI Data

Race/Ethnicity

CHD Cases

(n=228*)

Controls

(n=205*)

Missing N (%)

NHW 26 (11.4) 18 (8.8)

NHB 13 (5.7) 2 (1.0)

Hispanic 182 (79.8) 170 (82.9)

Other 6 (2.6) 13 (6.3)

* Includes 1 CHD case and 2 controls missing race/ethnicity.