American Journal of Obstetrics & Gynecology
Volume 202, Issue 1 , Pages 51.e1-51.e10, January 2010

Association between prepregnancy body mass index and congenital heart defects

Presented at the 13th Annual Maternal and Child Health Epidemiology Conference, Atlanta, GA, Dec. 10-12, 2007.

  • Suzanne M. Gilboa, PhD

      Affiliations

    • National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA
    • ,
  • Adolfo Correa, MD, PhD

      Affiliations

    • National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA
    • ,
  • Lorenzo D. Botto, MD

      Affiliations

    • Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT
    • ,
  • Sonja A. Rasmussen, MD, MS

      Affiliations

    • National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA
    • ,
  • D. Kim Waller, PhD

      Affiliations

    • School of Public Health, University of Texas Health Sciences Center at Houston, Houston, TX
    • ,
  • Charlotte A. Hobbs, MD, PhD

      Affiliations

    • Department of Pediatrics, Birth Defects Research Section, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute, Little Rock, AR
    • ,
  • Mario A. Cleves, PhD

      Affiliations

    • Department of Pediatrics, Birth Defects Research Section, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute, Little Rock, AR
    • ,
  • Tiffany J. Riehle-Colarusso, MD, MSE

      Affiliations

    • National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA
    • ,
  • National Birth Defects Prevention Study

Received 21 January 2009; received in revised form 9 July 2009; accepted 6 August 2009. published online 05 October 2009.

Article Outline

Objective

The purpose of this study was to examine associations between prepregnancy body mass index (BMI) and congenital heart defects (CHDs).

Study Design

These analyses included case infants with CHDs (n = 6440) and liveborn control infants without birth defects (n = 5673) enrolled in the National Birth Defects Prevention Study (1997-2004).

Results

Adjusted odds ratios for all CHDs combined were 1.16 (95% confidence interval [CI], 1.05–1.29), 1.15 (95% CI, 1.00–1.32), and 1.31 (95% CI, 1.11–1.56) for overweight status, moderate obesity, and severe obesity, respectively. Phenotypes associated with elevated BMI (≥25.0 kg/m2) were conotruncal defects (tetralogy of Fallot), total anomalous pulmonary venous return, hypoplastic left heart syndrome, right ventricular outflow tract (RVOT) defects (pulmonary valve stenosis), and septal defects (secundum atrial septal defect).

Conclusion

These results corroborated those of previous studies and suggested new associations between obesity and conotruncal defects and RVOT defects.

Key words: body mass index, congenital heart defects, gestational diabetes, obesity

 

Congenital heart defects (CHDs) are among the most common types of birth defects1 and are a leading cause of birth defects-associated morbidity, mortality, and medical expenditures.2, 3, 4 Pregestational diabetes mellitus (PGDM) is a recognized risk factor for CHDs.5, 6 Given this relationship, other conditions that are associated with alterations in glycemic control, such as prepregnancy overweight status and obesity, have been considered potential risk factors for CHDs.7, 8, 9, 10, 11, 12, 13, 14

The prevalence of prepregnancy obesity has risen substantially in the last 15 years: 1 recent study that included data from 9 states suggested the prevalence of prepregnancy obesity increased from 13% to 22% (nearly a 70% increase) from 1993 to 2003.15 Women who are obese are at increased risk for gestational diabetes mellitus (GDM) and hypertension, and pregnancies among women who are obese are at increased risk for several adverse outcomes, including fetal death, macrosomia, and large for gestational age.16, 17, 18, 19, 20, 21

Several studies also have suggested that increased body mass index (BMI) is associated with delivering an infant with a birth defect.7, 8, 9, 10, 11, 12, 13, 14, 22, 23, 24, 25 A metaanalysis focusing on neural tube defects (NTDs) estimated overall odds ratios (ORs) for an NTD-affected pregnancy of 1.22 (95% confidence interval [CI], 0.99–1.49) for mothers who are overweight, 1.70 (95% CI, 1.34–2.15), for mothers who are moderately obese, and 3.11 (95% CI, 1.75–5.46) for mothers who are severely obese, compared with mothers of normal weight.26

With respect to CHDs, the literature has been less consistent.7, 8, 9, 10, 11, 12, 13, 14 Most studies have shown weak associations between overweight status, obesity, or both and all CHDs combined,7, 8, 11, 12, 13 with a few studies suggesting associations with specific phenotypes, such as ventricular septal defects,7, 12 atrial septal defects,7, 12 and left ventricular outflow tract (LVOT) defects.12 Two California analyses found no association with the conotruncal defects of tetralogy of Fallot or transposition of the great arteries9, 10; other studies have noted elevated, but not statistically significant, associations with conotruncal defects.11, 12

Given the increased prevalence of prepregnancy obesity, the increased risk of alterations in glucose metabolism among women who are overweight or obese, and the association of maternal PGDM with CHDs, it is valuable to clarify the association between prepregnancy BMI and CHDs. We used data from the National Birth Defects Prevention Study (NBDPS) to assess whether prepregnancy weight status (underweight, overweight, moderately obese, or severely obese) was associated with CHD phenotypes.

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Materials and Methods 

National birth defects prevention study 

The NBDPS is an ongoing, population-based, case-control study comprising data collected by 10 birth defects surveillance systems throughout the United States (Arkansas, California, Georgia/Centers for Disease Control and Prevention [CDC], Iowa, Massachusetts, New Jersey [through 2002], New York, North Carolina [beginning 2003), Texas, and Utah [beginning 2003]).27 Cases in the study had 1 or more of more than 30 eligible birth defects and were liveborn, stillborn, or electively terminated. Control infants were not matched with case infants and were liveborn infants without birth defects who were randomly selected either from birth certificates or hospital birth records.

The NBDPS enrolls all eligible cases and approximately 300 controls per study center, per year. This sample size goal was based on the assumption of etiologic heterogeneity among birth defects and that it would always be more informative to analyze specific birth defect phenotypes compared with controls, rather than all birth defects in the aggregate.

Mothers were interviewed by telephone in either English or Spanish using a computer-based questionnaire 6 weeks to 24 months after the estimated date of delivery. Interviewers obtained information on maternal demographic characteristics and exposures (eg, nutritional, behavioral, occupational) and medication use both before and during pregnancy. The participation rate for mothers of control infants was 67% and for mothers of CHD cases, 69%. The NBDPS was approved by the institutional review boards of the CDC and the participating study centers.

Clinical review and classification of congenital heart defects 

All CHD cases were confirmed by echocardiography, cardiac catheterization, surgery, or autopsy.28, 29 The medical records of case infants were reviewed, and each case was classified by a team of pediatric cardiologists and clinical geneticists on 2 distinct axes. The first axis of classification focused on the heart itself. “Simple” cardiac defects were anatomically discrete or a well-recognized single entity (eg, hypoplastic left heart syndrome or tetralogy of Fallot). “Associations” were common, uncomplicated combinations of cardiac defects.28 CHDs that included 3 or more distinct defects were considered “complex.” The second axis of classification considered the case infant as a whole. Cases with no major extracardiac defects were considered “isolated”; those with major extracardiac defects were considered “multiple.”29 The systematic review of all cases by clinical geneticists resulted in the exclusion of those with recognized or strongly suspected single-gene conditions or chromosome abnormalities from the NBDPS.

Inclusion criteria 

Case and control infants delivered on or after Oct. 1, 1997, who had an estimated date of delivery on or before Dec. 31, 2004, were eligible for this study. Mothers with self-reported PGDM (type 1 or type 2) or missing prepregnancy BMI were excluded. We included simple CHDs and CHD associations (ie, CHD combinations: coarctation of the aorta with ventricular septal defect, ventricular septal defect with atrial septal defect, and pulmonary valve stenosis with atrial septal defect) if there were at least 50 infants with no extracardiac defects. Also included were case infants with complex CHDs of heterotaxia (n = 169) or single ventricle (n = 174).

Because of the high prevalence of muscular ventricular septal defects, these lesions were captured by the study centers in California, Georgia (CDC), Iowa, Massachusetts, New York, and Texas only through Oct. 1, 1998, and by the Arkansas and New Jersey study centers only through Jan. 1, 1999. Because North Carolina and Utah joined the study in 2003, these centers did not provide any case infants with muscular ventricular septal defects. In addition, California began ascertaining cases with pulmonary valve stenosis according to NBDPS criteria for births on or after Jan. 1, 2002; therefore, any case infants with pulmonary valve stenosis from that study center prior to this date were excluded from the analyses. Control infants were similarly restricted by ascertainment dates and study center.

Exposure and covariate definitions 

All variable information was self-reported during the maternal telephone interviews. Self-reported prepregnancy height and weight were converted to metric units, and maternal BMI was calculated as weight in kilograms divided by height in meters squared. Five weight status groups were then formed using BMI: underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), moderately obese (30.0-34.9 kg/m2), and severely obese (≥35.0 kg/m2). For some analyses, the categories of overweight and moderate and severe obesity were combined.

Eight covariates were considered in the study based on the literature and exploratory data analyses of the associations between the covariates and BMI and CHDs: maternal age (<20, 20-24, 25-29, 30-34, and ≥35 years old), maternal race or ethnicity (non-Hispanic white, non-Hispanic black or African American, Hispanic, and other race or ethnicity), maternal education (less than high school, completion of high school, and more than high school), parity (first live birth and >1 previous live birth), hypertension during the index pregnancy, and study center. Maternal smoking and folic acid supplement intake, 2 potentially time-varying covariates, were categorized on the basis of use during the month before pregnancy or the first month of pregnancy. GDM was explored as a potential effect measure modifier but not as a confounder.

Statistical analysis 

Frequency distributions and ORs were calculated to determine the associations between BMI and CHDs and between BMI and covariates of interest among control infants. We conducted conditional logistic regression using the 8 covariates described previously, grouping on study center. For the analyses of main effects, we restricted our case groups to simple and associated (combinations of) CHDs with no extracardiac defects. The presence of effect measure modification on both the additive and multiplicative scales was assessed separately for GDM, maternal race or ethnicity, and periconceptional folic acid supplement intake.

To determine whether the interactions led to greater than multiplicative effects, we calculated a P value for the likelihood ratio test comparing saturated multiple logistic regression models (main effects plus interaction terms) with reduced models (main effects only). Because raising the type 1 error rate for this test recently has been shown to be inappropriate in most settings,30 we used a P value cut point of .05 to determine whether multiplicative interactions were present.

Then to assess whether the interaction was a departure from additivity of effects, we calculated the relative excess risk caused by interaction (RERI)31 based on a model with disjoint exposure categories (eg, normal BMI and no GDM, normal BMI and GDM, overweight and no GDM, overweight and GDM, obese and no GDM, and obese and GDM). Statistically significant RERI estimates greater than 0 suggest greater than additive effects or evidence of a synergistic interaction. For these effect modification analyses, we collapsed the categories of moderate and severe obesity into a single group and did not limit our analyses to simple or associated CHDs without extracardiac defects but rather included multiple and complex CHDs to increase the available sample size.

We conducted 2 additional analyses to assess the sensitivity of our results to the effects of 2 strong but relatively uncommon risk factors for CHDs: multiple gestations and a first-degree family history of CHDs. All analyses were conducted in SAS version 9.1 (SAS Institute, Cary, NC).

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Results 

There were 6972 case infants with CHDs and 5958 control infants without birth defects initially considered in these analyses. Excluded from the analyses were 230 case and 32 control infants whose mothers had self-reported PGDM and 302 additional case and 253 additional control infants whose mothers were missing a value for BMI. This resulted in a total 6440 case and 5673 control infants available for analyses. The control group was the same for all analyses; the analyses of simple and associated CHDs without any extracardiac defects included a smaller grouping of case infants with CHDs (n = 4207).

Mothers of case infants were more likely than mothers of control infants to be overweight (23.7% vs 22.2%), moderately obese (11.4% vs 10.1%), or severely obese (7.4% vs 5.7%) (Table 1). Overall, mothers of case and control infants were similar with respect to age, race or ethnicity, education, parity, and folic acid supplement use. Mothers of case infants reported significantly more periconceptional smoking, gestational diabetes, and hypertension during pregnancy. A first-degree family history of CHDs and multiple gestations were both strongly associated with CHD case status. The distribution of CHD case infants and control infants differed significantly by study center.

TABLE 1. Characteristics of case infants with congenital heart defects and control infants, National Birth Defects Prevention Study, 1997-2004
CharacteristicInfants with congenital heart defects (n = 6440)Control infants (n = 5673)OR (95% CI)
n%n%
Weight status (BMI, kg/m2)
Underweight (<18.5)3715.83245.71.10(0.94–1.29)
Normal weight (18.5 to <25.0)333351.8319756.4Reference
Overweight (25.0 to <30.0)152723.7125922.21.16(1.06–1.27)
Moderately obese (30.0 to <35.0)73311.457210.11.23(1.09–1.39)
Severely obese (≥35.0)4767.43215.71.42(1.23–1.65)
Maternal age, y
<206019.361610.90.85(0.75–0.97)
20–24145122.5126522.31.00(0.91–1.11)
25–29170226.4148926.2Reference
30–34167025.9150026.40.97(0.88–1.08)
≥35101615.880314.21.11(0.99–1.24)
Maternal race or ethnicity
Non-Hispanic white397461.7350061.7Reference
Non-Hispanic black or African American76911.967011.81.01(0.90–1.13)
Hispanic125819.5112519.80.99(0.90–1.08)
Other4286.63596.31.05(0.91–1.22)
Missing110.2190.3
Maternal education
Less than high school98015.283114.6Reference
Completion of high school168626.2141124.91.01(0.90–1.14)
More than high school370457.5336459.30.93(0.84–1.04)
Missing701.1671.2
Parity
First birth264941.1228340.21.04(0.97–1.12)
Second or subsequent birth378758.8338859.7Reference
Missing40.120.0
Any periconceptional folic acid supplement usea
Yes337852.5301553.10.97(0.91–1.05)
No291645.3253444.7Reference
Missing1462.31242.2
Any periconceptional smokinga
Yes136621.2108819.21.13(1.04–1.24)
No502078.0453379.9Reference
Missing540.8520.9
Gestational diabetes
Yes3555.52243.91.43(1.21–1.70)
No588191.3532093.8Reference
Missing2043.21292.3
Hypertension
Yes70911.05269.31.21(1.07–1.36)
No572488.9513990.6Reference
Missing70.180.1
First-degree family history of CHD
Yes2233.5701.22.87(2.19–3.77)
No621796.5560398.8Reference
Multiple gestation
Yes4567.11672.92.51(2.10–3.01)
No598492.9550697.1Reference
Study center
Arkansas100315.669512.3Reference
California66010.272512.80.63(0.55–0.73)
Iowa6259.765411.50.66(0.57–0.77)
Massachusetts95714.973613.00.91(0.79–1.03)
New Jersey5138.05609.90.64(0.54–0.74)
New York4817.55149.10.65(0.55–0.76)
Texas91414.265311.50.97(0.84–1.12)
CDC/Atlanta, GA79112.359510.50.92(0.80–1.06)
North Carolina1792.82804.90.44(0.36–0.55)
Utah3174.92614.60.84(0.70–1.02)

BMI, body mass index; CDC, Centers for Disease Control; CHD, congenital heart defect; CI, confidence interval; OR, odds ratio.

Gilboa. Association between prepregnancy BMI and CHD. Am J Obstet Gynecol 2010.

aPericonceptional defined as 1 month before pregnancy through the first month of pregnancy.

Overall results 

Above-normal BMI (≥25.0 kg/m2) was associated with increased risk for several isolated CHDs: all CHDs combined (OR, 1.18; 95% CI, 1.08–1.29), conotruncal defects, tetralogy of Fallot, total anomalous pulmonary venous return, hypoplastic left heart syndrome, right ventricular outflow tract (RVOT) defects (particularly pulmonary valve stenosis, comprising 74% of RVOT defects), Ebstein's anomaly, septal defects, and secundum atrial septal defect (Table 2).

TABLE 2. Associationsa between prepregnancy body mass indexb and simple, isolated congenital heart defects, National Birth Defects Prevention Study, 1997-2004
Heart defectTotalUnderweightOverweightModerately obeseSeverely obeseOverweight plus obese
BMI <18.5BMI ≤25.0 to <30.0BMI ≤30.0 to <35.0BMI ≥35.0BMI ≥25.0
nnOR(95% CI)nOR(95% CI)nOR(95% CI)nOR(95% CI)nOR(95% CI)
Controls5673324 1259 572 321 2152
Any heart defect42072160.96(0.80–1.16)9981.16(1.05–1.29)4671.15(1.00–1.32)3141.31(1.11–1.56)17791.18(1.08–1.29)
Heterotaxiac169121.17(0.61–2.24)330.90(0.60–1.36)241.38(0.86–2.24)90.90(0.43–1.90)661.03(0.74–1.45)
Single ventriclec17480.81(0.39–1.70)370.98(0.66–1.45)170.96(0.55–1.65)101.08(0.55–2.11)641.00(0.71–1.39)
Conotruncal defects894471.04(0.75–1.44)2021.09(0.91–1.31)1001.20(0.95–1.53)661.36(1.01–1.83)3681.16(1.00–1.36)
Tetralogy of Fallot447180.86(0.52–1.42)1061.17(0.91–1.49)491.18(0.85–1.65)421.68(1.16–2.43)1971.24(1.01–1.53)
Dextrotransposition of the great arteries314170.98(0.58–1.65)640.92(0.68–1.25)361.20(0.82–1.76)130.82(0.46–1.47)1130.99(0.77–1.27)
Atrioventricular septal defect8130.59(0.18–1.93)180.96(0.55–1.69)50.58(0.23–1.49)71.42(0.62–3.23)300.94(0.58–1.52)
Anomalous pulmonary venous return14270.95(0.43–2.11)291.08(0.69–1.68)191.54(0.91–2.61)111.51(0.76–2.99)591.26(0.88–1.82)
Total anomalous pulmonary venous return11971.21(0.54–2.71)251.23(0.76–2.00)181.99(1.14–3.47)101.90(0.92–3.93)531.53(1.03–2.28)
Left ventricular outflow tract defects687310.92(0.62–1.37)1631.14(0.94–1.40)881.34(1.03–1.73)330.85(0.58–1.26)2841.15(0.97–1.37)
Hypoplastic left heart syndrome268100.81(0.42–1.57)661.27(0.94–1.73)381.51(1.03–2.22)181.21(0.72–2.06)1221.32(1.02–1.72)
Coarctation of the aorta25790.67(0.32–1.39)651.19(0.87–1.63)311.27(0.85–1.92)110.84(0.45–1.59)1071.16(0.89–1.52)
Aortic stenosis154111.45(0.75–2.77)300.87(0.56–1.34)171.06(0.62–1.82)40.34(0.11–1.10)510.84(0.58–1.21)
Right ventricular outflow tract defects669220.68(0.43–1.07)1751.35(1.11–1.65)741.20(0.91–1.58)611.61(1.17–2.20)3101.34(1.13–1.60)
Pulmonary atresia8330.76(0.23–2.49)241.65(0.98–2.77)101.56(0.77–3.19)41.15(0.40–3.28)381.55(0.98–2.47)
Pulmonary valve stenosis495140.60(0.34–1.05)1341.40(1.11–1.75)511.08(0.78–1.49)511.76(1.24–2.48)2361.36(1.12–1.66)
Ebstein's anomaly5631.05(0.31–3.58)151.66(0.86–3.21)81.90(0.83–4.34)52.33(0.86–6.28)281.78(1.02–3.13)
Septal defects17281051.03(0.80–1.31)4091.16(1.01–1.34)1811.02(0.84–1.24)1351.35(1.07–1.70)7251.15(1.02–1.30)
Ventricular septal defect, perimembranous734441.03(0.72–1.46)1751.13(0.93–1.37)640.85(0.64–1.13)561.23(0.89–1.71)2951.06(0.90–1.26)
Ventricular septal defect, muscular141111.76(0.78–3.97)371.32(0.82–2.13)130.99(0.50–1.99)40.95(0.31–2.93)541.21(0.79–1.85)
Atrial septal defect, secundum621340.93(0.62–1.37)1531.28(1.03–1.59)761.16(0.87–1.55)551.51(1.09–2.11)2841.29(1.07–1.55)
Atrial septal defect, not otherwise specified202151.27(0.71–2.27)431.02(0.70–1.51)251.26(0.78–2.03)171.63(0.93–2.86)851.17(0.86–1.61)
Coarctation of the aorta plus ventricular septal defectc11471.11(0.50–2.46)190.69(0.41–1.15)110.85(0.44–1.64)30.43(0.13–1.39)330.69(0.45–1.06)
Ventricular septal defect plus atrial septal defectc346211.07(0.65–1.79)801.09(0.82–1.45)431.31(0.91–1.87)211.11(0.69–1.80)1441.15(0.90–1.46)
Pulmonary valve stenosis plus atrial septal defectc8820.43(0.10–1.82)211.16(0.67–2.02)101.15(0.56–2.35)111.93(0.95–3.93)421.26(0.79–1.99)

BMI, body mass index; CI, confidence interval; OR, odds ratio.

Gilboa. Association between prepregnancy BMI and CHD. Am J Obstet Gynecol 2010.

aAdjusted for maternal age, race-ethnicity, education, hypertension, parity, smoking in the month prior to conception or the first month of pregnancy, and folic acid supplement use in the month prior to conception or the first month of pregnancy by conditional logistic regression grouping on study center;

bReference level for all analyses = BMI ≤18.5 to <25.0 kg/m2;

cCases of heterotaxia and single ventricle were all classified as complex. Coarctation of the aorta plus ventricular septal defect, ventricular septal defect plus atrial septal defect, and pulmonary valve stenosis plus atrial septal defect were all associated, isolated cases.

Associations with overweight and underweight status 

Maternal overweight status was associated with all CHDs combined (OR, 1.16; 95% CI, 1.05–1.29) as well as RVOT defects, pulmonary valve stenosis, septal defects, and secundum atrial septal defect (Table 2). Underweight status was associated with neither increased nor decreased risk for any isolated CHD.

Associations with moderate and severe obesity 

Adjusted ORs for all isolated CHDs combined were 1.15 (95% CI, 1.00–1.32) and 1.31 (95% CI, 1.11–1.56) for moderate and severe obesity, respectively (Table 2). Similar to the associations with overweight status, severe obesity was associated with RVOT defects, pulmonary valve stenosis, septal defects, and secundum atrial septal defect. Additionally, conotruncal defects and tetralogy of Fallot were associated with severe obesity.

Total anomalous pulmonary venous return and LVOT defects (particularly hypoplastic left heart syndrome) were significantly associated with moderate obesity but not severe obesity. When moderate and severe obesity were combined into a single category to increase the sample size available (data not shown), all phenotypes, with the exception of all septal defects, that were associated with severe obesity remained associated with the combined category. In addition, hypoplastic left heart syndrome (OR, 1.47; 95% CI, 1.07–2.03) and total anomalous pulmonary venous return (OR, 1.96; 95% CI, 1.21–3.18) were also associated with this combined moderate and severe obesity category.

Sensitivity analyses conduced after the data were restricted to singleton deliveries (93% of case and 97% of control infants) or participants with no first-degree family history of a CHD (97% of case and 99% of control infants) did not yield meaningfully different results (data not shown).

Effect measure modification by gestational diabetes, race or ethnicity, and supplemental folic acid intake 

For several CHD groups and specific phenotypes, there appeared to be an association with overweight status (all CHDs combined, RVOT defects, pulmonary atresia, pulmonary valve stenosis, all septal defects combined, perimembranous ventricular septal defects, and secundum atrial septal defects) and obesity (all CHDs combined, total anomalous pulmonary venous return, RVOT defects, pulmonary valve stenosis, Ebstein's anomaly, and secundum atrial septal defects) that might be independent of the role of GDM (Table 3). However, there was no evidence of an interaction on the multiplicative scale between overweight status or obesity and GDM using a P value cut point of .05 (data not shown).

TABLE 3. Associationsa between prepregnancy body mass indexb and selected congenital heart defects in the presence and absence of gestational diabetes, National Birth Defects Prevention Study, 1997-2004
Heart defectNormal weightOverweightObese
BMI ≤18.5 to <25.0BMI ≤25.0 to <30.0BMI ≥30.0
GDM, OR (95% CI)No GDM, OR (95% CI)GDM, OR (95% CI)No GDM, OR (95% CI)GDM, OR (95% CI)
Any heart defect1.05(0.77–1.42)1.17(1.06–1.29)1.46(1.04–2.05)1.17(1.05–1.31)1.82(1.36–2.44)
Heterotaxiac0.74(0.18–3.13)0.89(0.58–1.36)1.25(0.29–5.34)1.15(0.73–1.83)1.39(0.42–4.60)
Single ventriclec0.77(0.19–3.21)0.91(0.60–1.38)1.66(0.50–5.52)0.95(0.59–1.54)0.94(0.22–3.94)
Conotruncal defects0.73(0.40–1.32)1.11(0.95–1.31)1.08(0.58–2.00)1.14(0.94–1.38)1.59(0.99–2.56)
Tetralogy of Fallot0.50(0.18–1.39)1.21(0.96–1.52)1.05(0.44–2.48)1.20(0.92–1.57)2.38(1.37–4.14)
Dextrotransposition of the great arteries1.21(0.55–2.67)0.99(0.75–1.30)1.14(0.40–3.20)1.03(0.75–1.42)0.46(0.11–1.91)
Atrioventricular septal defect0.49(0.07–3.56)0.92(0.60–1.43)NE0.84(0.49–1.42)1.04(0.25–4.37)
Anomalous pulmonary venous returnNE1.14(0.76–1.71)0.75(0.10–5.54)1.38(0.89–2.15)1.67(0.50–5.49)
Total anomalous pulmonary venous returnNE1.34(0.86–2.09)NE1.82(1.13–2.91)1.71(0.40–7.28)
Left ventricular outflow tract defects0.68(0.34–1.37)1.09(0.91–1.31)1.72(0.98–3.01)1.14(0.93–1.41)1.87(1.15–3.05)
Hypoplastic left heart syndrome0.58(0.14–2.40)1.31(0.96–1.79)2.48(1.03–5.97)1.31(0.92–1.87)2.81(1.40–5.64)
Coarctation of the aorta0.84(0.36–1.96)1.03(0.80–1.31)1.98(1.01–3.87)1.19(0.90–1.56)1.70(0.88–3.29)
Aortic stenosis0.31(0.04–2.28)1.06(0.73–1.53)0.45(0.06–3.36)1.10(0.73–1.68)1.53(0.54–4.39)
Right ventricular outflow tract defects1.65(1.00–2.74)1.44(1.20–1.72)2.06(1.17–3.63)1.44(1.17–1.76)1.82(1.09–3.03)
Pulmonary atresiaNE1.89(1.22–2.93)2.25(0.52–9.71)1.63(0.95–2.77)0.92(0.12–6.80)
Pulmonary valve stenosis2.18(1.29–3.70)1.53(1.25–1.87)1.88(0.98–3.63)1.35(1.07–1.71)2.21(1.30–3.76)
Ebstein's anomalyNE1.58(0.90–2.78)1.40(0.18–10.66)2.16(1.20–3.90)NE
Septal defects1.29(0.89–1.85)1.19(1.06–1.35)1.46(0.97–2.21)1.14(0.99–1.32)1.91(1.35–2.70)
Ventricular septal defect, perimembranous1.56(0.98–2.50)1.23(1.04–1.46)1.00(0.54–1.87)1.07(0.87–1.31)1.26(0.75–2.13)
Ventricular septal defect, muscular0.94(0.19–4.53)1.35(0.87–2.10)3.55(0.83–15.26)1.04(0.58–1.88)1.36(0.33–5.56)
Atrial septal defect, secundum1.28(0.78–2.10)1.25(1.05–1.48)1.33(0.74–2.39)1.27(1.05–1.54)2.74(1.82–4.14)
Atrial septal defect, not otherwise specified0.74(0.29–1.92)1.08(0.82–1.43)1.70(0.72–3.99)1.05(0.75–1.45)1.00(0.39–2.59)
Coarctation of the aorta plus ventricular septal defect1.56(0.48–5.10)0.69(0.42–1.15)1.27(0.30–5.45)0.85(0.49–1.47)0.49(0.07–3.58)
Ventricular septal defect plus atrial septal defect1.30(0.61–2.77)1.10(0.84–1.45)1.13(0.44–2.92)1.24(0.92–1.68)1.61(0.77–3.33)
Pulmonary valve stenosis plus atrial septal defect2.39(0.55–10.38)1.22(0.71–2.10)0.79(0.10–6.18)1.57(0.91–2.71)1.74(0.49–6.12)

BMI, body mass index; CI, confidence interval; GDM, gestational diabetes mellitus; NE, not estimated because of cell sizes of 0 or 1; OR, odds ratio.

Gilboa. Association between prepregnancy BMI and CHD. Am J Obstet Gynecol 2010.

aAdjusted for maternal age, race or ethnicity, education, hypertension, parity, smoking in the month prior to conception or the first month of pregnancy, and folic acid supplement use in the month prior to conception or the first month of pregnancy, by conditional logistic regression grouping on study center;

bReference level = BMI ≤18.5 to <25.0 kg/m2 and no GDM;

There was also no evidence of an interaction between overweight status and GDM on the additive scale; there were no statistically significantly elevated RERI estimates (>0). For 2 CHDs, tetralogy of Fallot (RERI, 1.69; 95% CI, 0.32–3.05) and LVOT defects (RERI, 1.06; 95% CI, 0.02–2.10), there was evidence of an additive interaction between obesity and GDM. All other RERI estimates were either less than 0 or had confidence intervals overlapping the null. There was no evidence of effect measure modification by periconceptional supplemental folic acid intake or race or ethnicity on either the additive or the multiplicative scales (data not shown).

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Comment 

Previous literature on the association between elevated BMI and CHDs has been largely inconsistent; the most frequently reported finding is a weak association between increased BMI and all CHDs combined. Our study corroborated this finding, detecting associations with overweight status, moderate obesity, and severe obesity. With respect to specific phenotypes, this study confirmed previously reported associations with septal defects.7, 12 The previous association with LVOT was with overweight status12; our study found an association with moderate obesity only.

We also reported new associations with conotruncal defects, total anomalous pulmonary venous return, and RVOT defects. Overweight status and obesity (moderate and severe obesity combined) were associated with 1 broad grouping (RVOT defects) and 2 specific phenotypes (pulmonary valve stenosis and secundum atrial septal defect).

One strength of our study is that it was the first to report phenotype-specific associations with both moderate and severe obesity. In addition, the NBDPS provided an opportunity to conduct the largest population-based analysis to date of the association between prepregnancy BMI and CHDs and to study specific CHD phenotypes never previously investigated. The classification of CHDs by pediatric cardiologists and clinical geneticists enabled the analysis of simple, isolated cases, the most clinically homogeneous of groupings.

Several limitations should be noted. All data (with the exception of clinical data related to the birth defects) were self-reported, and height and weight used to calculate BMI were likely reported with error.32, 33 A recent study, however, found that among women of child-bearing age, self-reported height and weight measures correctly classified 84% of participants into appropriate BMI categories based on the true measured parameters.32 Literature suggests that errors in self-reporting are directly related to a person's overweight status; bias and unreliability in self-report increases with the magnitude of overweight.32, 33

Misclassification of BMI in our study was possible; most likely, we underestimated the proportion of overweight and obese mothers among both case and control infants. Misclassification of BMI might explain some unusual patterns in our results. For example, for some phenotypes, we observed elevated odds ratio estimates in the overweight and the severely obese groups but not in the moderately obese group (eg, RVOT defects, pulmonary valve stenosis, septal defects, and secundum atrial septal defect). For other phenotypes, the elevated estimates observed in the moderately obese group were seen in neither the overweight nor severely obese categories (eg, total anomalous pulmonary venous return, LVOT defects, and hypoplastic left heart syndrome). We do not have a biological hypothesis or mechanistic explanation for this unusual pattern; aside from chance resulting from random error, systematic error because of BMI misclassification may be responsible.

A related limitation, particular to the NBDPS, was the pattern of missing data for prepregnancy BMI. BMI was missing primarily when height was missing, which occurred disproportionately among Hispanic participants. Our analysis therefore could have been affected by a selection bias if these excluded women were unrepresentative of the included study population. Limiting our analysis to non-Hispanic women, however, did not markedly change our results (data not shown).

Another potential source of selection bias is the fact that the NBDPS does not have a 100% response rate. Approximately 30% of mothers of eligible cases and controls did not complete the computer-assisted telephone interview, either because they could not be found and contacted prior to 24 months after the estimated date of delivery or they refused participation. If participation in the study was related to prepregnancy BMI and that relationship between participation and BMI varied by case-control status, our results would be affected by selection bias. Given the data that were available to use however, we were unable to determine whether this happened.

Another concern is that study centers in Massachusetts and New Jersey did not ascertain case infants among pregnancy terminations, and New York began ascertaining pregnancy terminations only in the year 2000. In a study of BMI, this might be particularly important because visualization of the fetus on ultrasound is more difficult among obese women.34 This could be a source of bias, assuming prenatal detection of severe CHDs such as hypoplastic left heart syndrome results in the termination of some pregnancies.35 If obese women have lower rates of prenatal detection of severe CHDs, they might be overrepresented among case mothers because of this bias in ascertainment. We explored this hypothesis by excluding Massachusetts, New Jersey, and New York (31% of the study population) from the analyses; the results after excluding these centers were very similar to those reported in Table 2 (data not shown).

One previous study attempted to investigate associations with severe obesity as a risk category distinct from that of moderate obesity, but only among aggregations of CHDs.7 Our findings that some CHDs were associated with severe obesity but not moderate obesity, suggested that there might be heterogeneity of risk within the upper end of the BMI distribution, although limited sample size resulting in inadequate power was an alternative explanation.

The association between overweight status, obesity, and risk for GDM has been well documented.36, 37, 38 In addition, at least 2 studies have suggested the presence of an interaction between GDM and maternal BMI in relation to CHDs.39, 40 An explanation for this reported interaction, as well as the weak, but consistent, association between GDM and selected CHDs,5, 41, 42 might be the fact that these women had previously undiagnosed PGDM, a strong risk factor for CHDs.5, 6 Our results suggested the presence of a weak interaction (departure from additive effects) between GDM and obesity for 2 CHD phenotypes. Yet the NBDPS was not adequately powered to explore these interactions, and these results should be considered preliminary in light of their limited precision.

The mechanisms underlying the association between overweight status and obesity and CHDs are largely unknown. It is well established that pregestational diabetes is a risk factor for CHDs,5, 6 and both animal and human studies have shown that hyperglycemia during pregnancy plays an important role.43 Women who are overweight or obese, even those without overt diabetes, can still be affected by insulin resistance or abnormal glucose control,44 particularly those with central adiposity45 and decreased levels of physical activity.46

Given the increased prevalence of obesity and the public health importance of CHDs, further work is warranted to determine the extent to which other factors associated with overweight and obesity, such as the type of obesity,9, 45 patterns of dieting and weight change before and during pregnancy,9, 47, 48 physical inactivity,49 and inadequate levels of essential vitamins and nutrients,50, 51 play a role in the associations with CHDs.

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 This work was supported in part through cooperative agreements under Program Announcement #02081 from the Centers for Disease Control and Prevention to the centers participating in the National Birth Defects Prevention Study.

 Reprints not available from the authors.

 The views expressed herein are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

 Cite this article as: Gilboa SM, Correa A, Botto LD, et al. Association between prepregnancy body mass index and congenital heart defects. Am J Obstet Gynecol 2010;202:51.e1-10.

PII: S0002-9378(09)00903-X

doi:10.1016/j.ajog.2009.08.005

American Journal of Obstetrics & Gynecology
Volume 202, Issue 1 , Pages 51.e1-51.e10, January 2010

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