The importance of obesity and diabetes in the development of birth defects is a major concern. Prepregnancy obesity and diabetes are independent risk factors for congenital heart, neural tube, and gastrointestinal defects; hyperglycemia and hyperinsulinemia likely have a causal role in the process. This study was undertaken to investigate the association between dietary glycemic index (DGI) and various birth defect phenotypes among nondiabetic women and the impact of obesity on this association.
The National Birth Defects Prevention Study is an ongoing, multisite, case-control study that collects data on more than 30 structural birth defects. Cases among live births, fetal deaths, and electively terminated pregnancies were identified through surveillance systems in several states. Controls were nonmalformed, live-born infants randomly selected from birth certificates/hospital records. Maternal interviews were conducted within 2 years of the estimated date of delivery. Data on demographics, medication use, lifestyle behaviors, and health conditions were collected. One component of the interview was the shortened Willett food frequency questionnaire in which mothers recalled their average consumption of 58 different foods in the year before pregnancy. Data from this questionnaire were used to calculate DGI and dietary glycemic load. The analysis was restricted to determining the association between DGI and birth defects. The cutoff point was the DGI value that corresponded with a divergence of cases and controls at an odds ratio (OR) of 1.5. Dietary glycemic index was divided into quartiles based on the distribution among controls for each birth defect group. Case groups for which spline regression identified a divergence were assessed for interdependence between high DGI and obesity.
The analysis included 7505 controls and 18,964 cases among 53 case groups. Compared with mothers in the lowest DGI quartile, those in the highest quartile were more likely to be non-Hispanic black, younger than 25 years, have 12 years of education or less, and less likely to take folic acid. A prepregnancy body mass index of either less than 18.5 kg/m2 or 30 kg/m2 or greater was also associated with the highest DGI quartile. Encephalocele was the only CNS defect significantly associated with high DGI (adjusted OR [aOR] = 2.68). Spina bifida had an increased but not statistically significant aOR of 2.15. For gastrointestinal and genitourinary defects, the odds of esophageal atresia with or without tracheoesophageal fistula and anorectal atresia/stenosis, which was significant, were 32% and 40% higher in the highest quartile of DGI compared with the lowest quartile. Small intestinal atresia/stenosis and duodenal atresia/stenosis were significantly associated with high DGI. The odds of biliary atresia increased with each quartile of DGI resulting in an aOR of 1.69 in the highest quartile. Bladder exstrophy had an aOR of 4.10. Obesity with high DGI had a larger positive association with small intestinal atresia and duodenal atresia than high DGI without obesity. Most congenital heart defects were not significantly associated with quartiles of DGI. The odds of aortic stenosis and heterotaxia with a congenital heart defect increased with each quartile of DGI resulting in an aOR of 1.29 and 1.55 for those in the highest DGI quartile, respectively. Other birth defects significantly associated with high DGI were transverse limb deficiency, diaphragmatic hernia, and gastroschisis.
Among infants of nondiabetic women, high levels of DGI were associated with neural tube, gastrointestinal, and musculoskeletal defects, but not with various heart defects. These results offer evidence for the role of hyperglycemia in abnormal fetal development. Hyperinsulinemia with hyperglycemia might intensify the effect on the risk of birth defects compared with hyperglycemia alone. The findings highlight the interdependence of high DGI and obesity, which act synergistically. Future research using biologic samples could contribute to the understanding of the role of hyperglycemia and hyperinsulinemia in the development of birth defects.
Slone Epidemiology Center, Boston University (S.E.P., M.M.W., M.M.Y.), Boston MA; Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine (G.M.S.), Palo Alto, CA; and Massachusetts Department of Public Health (M.A.), Boston, MA