Maternal Exposure to Different Types of Hormonal Compounds from Oral Contraceptives in the First Trimester of Pregnancy and Its Association with Birth Defects

Oral contraceptives (OCs) are the most commonly used prescription medication by women of reproductive age. Prior studies on the association of OCs and birth defects lacked power or assessed all formulations for OCs in aggregate, and in the process overlooked the specific hormonal components contained in the OCs. We examined the association of specific types of hormonal compounds in OCs and 58 structural birth defects. We undertook an analysis of the complete database of the National Birth Defect Prevention Study (NBDPS), 1997-2011. NBDPS is a multi-center, nationwide case-control study conducted by the Centers for Disease Control and Prevention. After exclusions, we analyzed observations from 41,589 mothers in the NBDPS database. We classified OCs reported by the participants in the NBDPS into categories using a priori approaches: i) categorization by the type of progestin, ii) categorization by level of estrogen and iii) categorization by phasic or monophasic formulations. For each of the sub-groups of progestin, estrogen and phasic vs monophasic, we calculated adjusted odds ratios for associations between exposure to these types of OCs during the first trimester and 58 categories of birth defects. For use of any type of OC in the first trimester of pregnancy, we observed elevated adjusted odds ratios (ORs) for hypoplastic left heart syndrome (OR 1.59, [95% CI 1.08-2.35]), cleft palate (OR 1.38, [95% CI 1.05-1.81]), cleft lip with or without cleft palate (OR 1.40, [95% CI 1.14-1.71]) and gastroschisis (OR 1.39, [95% CI 1.08-1.79]). A fourth generation progestin, drospirenone was significantly associated with hydrocephaly (OR 3.63, [95% CI 1.05-12.55]); a third generation of progestin, norgestimate was significantly associated with double outlet right ventricular obstruction-other (OR 2.68, [95% CI 1.05-6.86]) and aortic stenosis (OR 2.10, [95% CI 1.14-3.89]). We observed a significant association of norethindrone containing OCs and cleft lip with or without cleft palate (OR 1.89 [95% CI 1.23-2.92]), desogestrel with cleft palate (OR 3.90, [95% CI 1.30-11.71]) and levonorgestrel with spina bifida (OR 1.95, [95% CI 1.12-3.39]). OCs containing high levels of estrogen and monophasic vs phasic pills were not associated with any birth defect. Our findings indicate a possible risk associated with exposure to any type of OCs during the first trimester and several major structural birth defects. These findings warrant caution in OC use and a need for further studies to look into the possible pathogenesis of specific birth defects and specific progestin compounds