Use of clomiphene citrate and birth defects, National Birth Defects Prevention Study, 1997-2005.

BACKGROUND: Clomiphene citrate (CC) is the first line drug for subfertility treatment. Studies assessing the association between CC and birth defects have been inconclusive. METHODS: We used data from the National Birth Defects Prevention Study, a population-based, multi-site case-control study of major birth defects. Women from 10 US regions with deliveries affected by at least one of >30 birth defects (cases) and mothers of live born infants without a major birth defect (controls) who delivered October 1997-December 2005 were interviewed. The exposure of interest was reported CC use in the period from 2 months before conception through the first month of pregnancy. Women who conceived using assisted reproductive technology were excluded. Thirty-six birth defect categories with at least three exposed cases were studied. Multiple logistic regression was used to control for potential confounders. RESULTS: CC use was reported by 1.4% of control mothers (94/6500). Among 36 case-groups assessed, increased adjusted odds ratios (aOR) were found [all: aOR, 95% confidence interval (CI)] for anencephaly (2.3, 1.1-4.7), Dandy-Walker malformation (4.4, 1.7-11.6), septal heart defects (1.6, 1.1-2.2), muscular ventricular septal defect (4.9, 1.4-16.8), coarctation of aorta (1.8, 1.1-3.0), esophageal atresia (2.3, 1.3-4.0), cloacal exstrophy (5.4, 1.6-19.3), craniosynostosis (1.9, 1.2-3.0) and omphalocele (2.2, 1.1-4.5). CONCLUSIONS: Several associations between CC use and birth defects were observed. However, because of the small number of cases, inconsistency of some findings with previous reports, and the fact that we cannot assess the CC effect separately from that of the subfertility, these associations should be interpreted cautiously.

Assisted reproductive technology and major structural birth defects in the United States.

BACKGROUND: With >1% of US births occurring following use of assisted reproductive technology (ART), it is critical to examine whether ART is associated with birth defects. METHODS: We analyzed data from the National Birth Defects Prevention Study, a population-based, multicenter, case-control study of birth defects. We included mothers of fetuses or live-born infants with a major birth defect (case infants) and mothers who had live-born infants who did not have a major birth defect (control infants), delivered during the period October 1997-December 2003. We compared mothers who reported ART use (IVF or ICSI) with those who had unassisted conceptions. Multiple logistic regression was used to adjust for the following confounders: maternal race/ethnicity, maternal age, smoking and parity; we stratified by plurality. RESULTS: ART was reported by 1.1% of all control mothers, and by 4.5% of control mothers 35 years or older. Among singleton births, ART was associated with septal heart defects (adjusted odds ratio [aOR] = 2.1, 95% confidence intervals [CI] 1.1-4.0), cleft lip with or without cleft palate (aOR = 2.4, 95% CI 1.2-5.1), esophageal atresia (aOR = 4.5, 95% CI 1.9-10.5) and anorectal atresia (aOR = 3.7, 95% CI 1.5-9.1). Among multiple births, ART was not significantly associated with any of the birth defects studied. CONCLUSIONS: These findings suggest that some birth defects occur more often among infants conceived with ART. Although the mechanism is not clear, couples considering ART should be informed of all potential risks and benefits.

Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects.

CONTEXT: Daily consumption of 400 microg of folic acid before conception and during early pregnancy dramatically reduces the occurrence of neural tube defects (NTDs). Before food fortification, however, only an estimated 29% of US reproductive-aged women were taking a supplement containing 400 microg of folic acid daily. The US Food and Drug Administration authorized addition of folic acid to enriched grain products in March 1996, with compliance mandatory by January 1998. OBJECTIVE: To evaluate the impact of food fortification with folic acid on NTD birth prevalence. DESIGN, SETTING, AND POPULATION: National study of birth certificate data for live births to women in 45 US states and Washington, DC, between January 1990 and December 1999. MAIN OUTCOME MEASURE: Birth certificate reports of spina bifida and anencephaly before fortification (October 1995 through December 1996) compared with after mandatory fortification (October 1998 through December 1999). RESULTS: The birth prevalence of NTDs reported on birth certificates decreased from 37.8 per 100 000 live births before fortification to 30.5 per 100 000 live births conceived after mandatory folic acid fortification, representing a 19% decline (prevalence ratio [PR], 0.81; 95% confidence interval [CI], 0.75-0.87). During the same period, NTD birth prevalence declined from 53.4 per 100 000 to 46.5 per 100 000 (PR, 0.87; 95% CI, 0.64-1.18) for women who received only third-trimester or no prenatal care. CONCLUSIONS: A 19% reduction in NTD birth prevalence occurred following folic acid fortification of the US food supply. However, factors other than fortification may have contributed to this decline.

Maternal smoking and birth defects: validity of birth certificate data for effect estimation.

OBJECTIVES: The authors sought to assess the validity of birth certificate data for estimating the association between maternal smoking and birth defects. The US standard birth certificate includes check boxes for maternal smoking and for 21 congenital anomalies. The sensitivity and specificity of birth certificate data have been studied, but previous studies have not addressed the validity of these data for estimating the association between birth defects and maternal smoking or other risk factors. METHODS: US public-use natality data (1997-1998) were used to calculate the prevalence ratio (adjusted for maternal age, race/ethnicity, and education) for the association between maternal smoking and 13 defects/defect categories. All analyses were restricted to 45 states, New York City, and the District of Columbia because they collect both maternal smoking and birth defect data. RESULTS: Maternal smoking was associated with an increased prevalence of hydrocephaly (adjusted prevalence ratio [PR] = 1.24; 95% confidence interval [CI] = 1.08, 1.43), microcephaly (PR 1.47; 95% CI 1.15, 1.88), omphalocele/gastroschisis (PR 1.37; 95% CI 1.22, 1.53), cleft lip/palate (PR 1.35; 95% CI 1.25, 1.45), clubfoot (PR 1.62; 95% CI 1.49, 1.75), and polydactyly/syndactyly/adactyly (PR 1.33; 95% CI 1.23, 1.43 ). Previous studies have indicated an association between maternal smoking and gastroschisis, oral clefts, and clubfoot with effect estimates of similar magnitude to this study. CONCLUSIONS: These findings suggest that birth certificate data may be useful for exploratory or corroborative studies estimating the association between birth defects and some risk factors recorded on birth certificates.

Family history, maternal smoking, and clubfoot: an indication of a gene-environment interaction.

Although epidemiologic studies of some birth defects have suggested a gene-smoking interaction, the possibility of this interaction in clubfoot has not been examined. The authors analyzed risk factors among 346 infants with isolated clubfoot and 3,029 infants without defects from the Atlanta Birth Defects Case-Control Study. All infants were born during 1968-1980, and mothers were interviewed in 1982-1983. The authors examined the family history-smoking interaction as an indication of a gene-environment interaction. They defined "smoking" as smoking any time during the first 3 months of pregnancy and "family history" as having a first-degree relative with clubfoot. Conditional logistic regression (matching variables: race, birth hospital, and birth period) was used to obtain effect estimates. The adjusted odds ratios were 1.34 (95% confidence interval (CI): 1.04, 1.72) for smoking only, 6.52 (95% CI: 2.95, 14.41) for family history only, and 20.30 (95% CI: 7.90, 52.17) for a joint exposure of smoking and family history. The effect estimate for the joint exposure was higher than would be expected under either an additive or a multiplicative model of interaction and showed a statistically significant departure from additivity. This study confirms the importance of familial factors and smoking in the etiology of clubfoot and identifies a potentially important interaction.