Short interpregnancy intervals and risks for birth defects: support for the nutritional depletion hypothesis.

BACKGROUND: Research suggests short interpregnancy intervals increase risks for adverse perinatal outcomes, including some birth defects. A hypothesized cause is nutritional depletion, including folic acid (FA). OBJECTIVES: We evaluated associations between short interpregnancy intervals, alone and in combination with FA intake, and the occurrence of select malformations. METHODS: Data were from the National Birth Defects Prevention Study (US case-control, 1997-2011). Participants included multiparous women whose prior pregnancy resulted in live birth. Cases included 8 noncardiac and 6 cardiac defect groups (n = 3219); controls were nonmalformed live-borns (n = 2508). We categorized interpregnancy interval (<6, 6-11, 12-17, and 18-23 mo) and periconceptional FA intake [no FA supplement use and dietary folate equivalents (DFE) <400 µg/d, no FA supplement use and DFE ≥400 µg/d, or any FA supplement use]. We controlled for age, race/ethnicity, income, pregnancy intention, and study center. ORs <0.8 or >1.2 were considered to represent potentially meaningful associations. RESULTS: ORs for <6 compared with 18-23 mo were >1.2 for 4/8 noncardiac and 3/6 cardiac malformations. Among participants with any FA supplement use, ORs comparing <6 with 6-23 mo were <1.2 for most defects. Conversely, most ORs were >1.2 for <6 mo + no FA supplement use and DFE <400 µg/d compared with 6-23 mo + any FA supplement use. Magnitude and precision varied by defect. CONCLUSIONS: Short interpregnancy intervals were associated with a trend of higher risks for several defects, notably in the absence of FA supplement use. To our knowledge, our study is the first to provide preliminary empirical support that these etiologies may be related to shorter interpregnancy intervals and possible nutritional deficiencies. Because FA intake is highly correlated with other nutrients, and because our estimates were generally imprecise, more research with larger sample sizes is needed to better understand the role of FA compared with other nutrients in each defect-specific etiology.

Does Maternal Exposure to Secondhand Tobacco Smoke During Pregnancy Increase the Risk for Preterm or Small-for-Gestational Age Birth?

Introduction While associations between active smoking and various adverse birth outcomes (ABOs) have been reported in the literature, less is known about the impact of secondhand smoke (SHS) on many pregnancy outcomes. Methods We examined the relationship between maternal exposure to SHS during pregnancy and preterm (< 37 weeks gestation) and small-for-gestational age (SGA; assessed using sex-, race/ethnic-, and parity-specific growth curves) singleton births using non-smoking controls from the National Birth Defects Prevention Study (1997-2011). Multivariable logistic regression models for household, workplace/school, and combined SHS exposure-controlled for maternal education, race/ethnicity, pre-pregnancy body mass index, and high blood pressure-were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Interaction was assessed for maternal folic acid supplementation, alcohol use, age at delivery, and infant sex. Results Infants of 8855 mothers were examined in the preterm birth analysis with 666 (7.5%) categorized as preterm, 574 moderately preterm (32-36 weeks), and 92 very preterm (< 32 weeks). For the SGA analysis, infants of 8684 mothers were examined with 670 (7.7%) categorized as SGA. The aORs for mothers reporting both household and workplace/school SHS were elevated for preterm (aOR 1.99; 95% CI 1.13-3.50) and moderately preterm birth (32-36 weeks) (aOR 2.17; 95% CI 1.22-3.88). No results for the SGA analysis achieved significance, nor was evidence of interaction evident. Conclusion The findings suggest an association between SHS from multiple exposure sources and preterm birth, but no evidence for association with SGA births. Continued study of SHS and ABOs is needed to best inform public health prevention programs.

Associations between maternal periconceptional exposure to secondhand tobacco smoke and major birth defects.

BACKGROUND: While associations between secondhand smoke and a few birth defects (namely, oral clefts and neural tube defects) have been noted in the scientific literature, to our knowledge, there is no single or comprehensive source of population-based information on its associations with a range of birth defects among nonsmoking mothers. OBJECTIVE: We utilized data from the National Birth Defects Prevention Study, a large population-based multisite case-control study, to examine associations between maternal reports of periconceptional exposure to secondhand smoke in the household or workplace/school and major birth defects. STUDY DESIGN: The multisite National Birth Defects Prevention Study is the largest case-control study of birth defects to date in the United States. We selected cases from birth defect groups having >100 total cases, as well as all nonmalformed controls (10,200), from delivery years 1997 through 2009; 44 birth defects were examined. After excluding cases and controls from multiple births and whose mothers reported active smoking or pregestational diabetes, we analyzed data on periconceptional secondhand smoke exposure-encompassing the period 1 month prior to conception through the first trimester. For the birth defect craniosynostosis, we additionally examined the effect of exposure in the second and third trimesters as well due to the potential sensitivity to teratogens for this defect throughout pregnancy. Covariates included in all final models of birth defects with ≥5 exposed mothers were study site, previous live births, time between estimated date of delivery and interview date, maternal age at estimated date of delivery, race/ethnicity, education, body mass index, nativity, household income divided by number of people supported by this income, periconceptional alcohol consumption, and folic acid supplementation. For each birth defect examined, we used logistic regression analyses to estimate both crude and adjusted odds ratios and 95% confidence intervals for both isolated and total case groups for various sources of exposure (household only; workplace/school only; household and workplace/school; household or workplace/school). RESULTS: The prevalence of secondhand smoke exposure only across all sources ranged from 12.9-27.8% for cases and 14.5-15.8% for controls. The adjusted odds ratios for any vs no secondhand smoke exposure in the household or workplace/school and isolated birth defects were significantly elevated for neural tube defects (anencephaly: adjusted odds ratio, 1.66; 95% confidence interval, 1.22-2.25; and spina bifida: adjusted odds ratio, 1.49; 95% confidence interval, 1.20-1.86); orofacial clefts (cleft lip without cleft palate: adjusted odds ratio, 1.41; 95% confidence interval, 1.10-1.81; cleft lip with or without cleft palate: adjusted odds ratio, 1.24; 95% confidence interval, 1.05-1.46; cleft palate alone: adjusted odds ratio, 1.31; 95% confidence interval, 1.06-1.63); bilateral renal agenesis (adjusted odds ratio, 1.99; 95% confidence interval, 1.05-3.75); amniotic band syndrome-limb body wall complex (adjusted odds ratio, 1.66; 95% confidence interval, 1.10-2.51); and atrial septal defects, secundum (adjusted odds ratio, 1.37; 95% confidence interval, 1.09-1.72). There were no significant inverse associations observed. CONCLUSION: Additional studies replicating the findings are needed to better understand the moderate positive associations observed between periconceptional secondhand smoke and several birth defects in this analysis. Increased odds ratios resulting from chance (eg, multiple comparisons) or recall bias cannot be ruled out.

Maternal Pre-pregnancy Body Mass Index and Autism Spectrum Disorder among Offspring: A Population-Based Case-Control Study.

BACKGROUND: Previous studies have attributed high maternal weight gain during pregnancy and pre-pregnancy obesity to a higher risk for autism spectrum disorder (ASD). Maternal underweight was not previously explored with respect to ASD risk. METHODS: We evaluated the association between maternal pre-pregnancy body mass index (BMI) and ASD occurrence among singletons born into the General Practice Research Database from 1993 to 2008. Case subjects were children with a diagnosis of ASD from birth to 2010. Up to four control subjects were matched to each case subject on birth year, sex, and general practice. Restricted cubic splines were used to assess the non-linearity of the association between maternal BMI and ASD. All study subjects were classified as underweight, normal weight, overweight, or obese based on maternal pre-pregnancy BMI using the WHO Classification Standard. Conditional logistic regression was used to calculate unadjusted and multivariable adjusted odds ratios for the association between categorical BMI (reference=normal weight) and the occurrence of ASD. RESULTS: The association between maternal BMI and ASD occurrence was non-linear and J-shaped. The adjusted ORs for maternal underweight and obesity were 1.43 (95% CI 1.01, 2.04) and 1.54 (95% CI 1.26, 1.89) respectively. CONCLUSIONS: Results suggest that extremes in maternal BMI may be associated with modest increases in the risk for ASD among offspring.

Sex ratios among infants with birth defects, National Birth Defects Prevention Study, 1997-2009.

A small number of population-based studies have examined sex differences among infants with birth defects. This study presents estimates of sex ratio for both isolated cases and those with multiple congenital anomalies, as well as by race/ethnicity. Male-female sex ratios and their 95% confidence intervals were calculated for 25,952 clinically reviewed case infants included in the National Birth Defects Prevention Study (1997-2009), a large population-based case-control study of birth defects. The highest elevations in sex ratios (i.e., male preponderance) among isolated non-cardiac defects were for craniosynostosis (2.12), cleft lip with cleft palate (2.01), and cleft lip without cleft palate (1.78); the lowest sex ratios (female preponderance) were for choanal atresia (0.45), cloacal exstrophy (0.46), and holoprosencephaly (0.64). Among isolated cardiac defects, the highest sex ratios were for aortic stenosis (2.88), coarctation of the aorta (2.51), and d-transposition of the great arteries (2.34); the lowest were multiple ventricular septal defects (0.52), truncus arteriosus (0.63), and heterotaxia with congenital heart defect (0.64). Differences were observed by race/ethnicity for some but not for most types of birth defects. The sex differences we observed for specific defects, between those with isolated versus multiple defects, as well as by race/ethnicity, demonstrate patterns that may suggest etiology and improve classification.

Sociodemographic and hispanic acculturation factors and isolated anotia/microtia.

BACKGROUND: It has been observed in several studies that infants with anotia/microtia are more common among Hispanics compared with other racial/ethnic groups. We examined the association between selected Hispanic ethnicity and acculturation factors and anotia/microtia in the National Birth Defects Prevention Study. METHODS: We examined data from mothers of 351 infants with isolated anotia/microtia and 8435 unaffected infants from the National Birth Defects Prevention Study with an expected delivery date from 1997 to 2007. Sociodemographic, maternal, and acculturation factors (e.g., age, maternal education, household income, body mass index, gestational diabetes, folic acid, smoking, alcohol intake, study center, parental birthplace, and years lived in the United States, maternal language) were assessed as overall risk factors and also as risk factors among subgroups of Hispanics (United States- and foreign-born) versus non-Hispanic whites. RESULTS: Compared with non-Hispanic whites, both United States- and foreign-born Hispanic mothers demonstrated substantially higher odds of delivering infants with anotia/microtia across nearly all strata of sociodemographic and other maternal factors (adjusted odds ratios range: 2.1-11.9). The odds of anotia/microtia was particularly elevated among Hispanic mothers who emigrated from Mexico after age five (adjusted odds ratios = 4.88; 95% confidence interval = 2.93-8.11) or who conducted the interview in Spanish (adjusted odds ratios = 4.97; 95% confidence interval = 3.00-8.24). CONCLUSION: We observed that certain sociodemographic and acculturation factors are associated with higher risks of anotia/microtia among offspring of Hispanic mothers.

Antiherpetic medication use and the risk of gastroschisis: findings from the National Birth Defects Prevention Study, 1997-2007.

BACKGROUND: Previous studies examining the teratogenic effects of antiherpetic medications have found no associations for birth defects overall but have not examined the risk of specific birth defects. METHODS: The National Birth Defects Prevention Study ascertains population-based cases with birth defects and live-born controls without birth defects in 10 states across the United States for the purpose of identifying potential teratogenic risk factors. Mothers of cases and controls are interviewed within 2 years of their estimated date of delivery about demographic, medical and behavioural factors before and during pregnancy. This analysis examined the possible association between use of antiherpetic medications (acyclovir, valacyclovir or famciclovir) during early pregnancy and gastroschisis, a birth defect of the abdominal wall. RESULTS: The mothers of 1.1% (n = 10) of 941 gastroschisis cases and 0.3% (n = 27) of 8339 controls reported antiherpetic medication use during the month before conception through the third month of pregnancy. The adjusted odds ratios for such use in relation to gastroschisis were 4.7 [95% confidence interval 1.7, 13.3] and 4.7 [95% CI 1.2, 19.0] among women with and without self-reported genital herpes, respectively, when compared with women without antiherpetic use or herpes. Among women reporting no antiherpetic medication use, the odds ratio for self-reported genital herpes in relation to gastroschisis was 3.0 [95% CI 1.6, 5.7]. CONCLUSIONS: Our study raises the possibility of an increased risk of gastroschisis because of either antiherpetic medication use during early pregnancy or the underlying genital herpes infection for which it was indicated.

Impact of time to maternal interview on interview responses in the National Birth Defects Prevention Study.

Prenatal exposures often are assessed using retrospective interviews. Time from exposure to interview may influence data accuracy. We investigated the association of time to interview (TTI) with aspects of interview responses in the National Birth Defects Prevention Study, a population-based case-control study of birth defects in 10 US states. Mothers completed a computer-assisted telephone interview 1.5-24 months after their estimated date of delivery. Proxy metrics for interview quality were whether certain exposures were reported, whether the start month of reported medication use or illness was reported, or whether responses were missing. Interaction by case status was assessed. Interviews were completed with 30,542 mothers (22,366 cases and 8,176 controls) who gave birth between 1997 and 2007. Mothers of cases were interviewed later than were mothers of controls (11.7 months vs. 9.5 months, respectively). In adjusted analyses, having a TTI that was greater than 6 months was associated with only a few aspects of interview responses (e.g., start month of pseudoephedrine use). Interaction by case-control status was observed for some exposures; mothers of controls had a greater reduction in interview quality with increased TTI in these instances (e.g., report of morning sickness, start month of acetaminophen use and ibuprofen use). The results suggest that TTI might impact interview responses; however, the impact may be minimal and specific to the type of exposure.

Short interpregnancy interval and gastroschisis risk in the National Birth Defects Prevention Study.

BACKGROUND: The micronutrient depletion hypothesis proposes that consecutive pregnancies spaced too closely may leave insufficient time for maternal micronutrient replenishment. Short interpregnancy intervals (IPI) have been associated with an increased risk for several adverse pregnancy outcomes, but an association with gastroschisis risk has not been previously explored. METHODS: Within a population-based, case-control study, we evaluated the association between IPI length and gastroschisis risk using multivariable logistic regression models to estimate gastroschisis odds ratios for IPI <12 months and 12 to 17 months relative to those 18 to 23 months. We further evaluated the association between IPI and gastroschisis risk stratified by maternal age, periconceptional multivitamin use, preceding pregnancy outcome, study center region, and season of conception to explore whether observed associations were compatible with the hypothesis of maternal micronutrient depletion. RESULTS: For women with IPI <12 months, the adjusted odds ratio (aOR) was 1.7 (95% confidence interval [CI]: 1.1-2.5). The magnitude of the observed effect did not differ among strata of maternal age or periconceptional multivitamin use. However, the association was more pronounced after a miscarriage or termination (aOR: 2.5; 95% CI: 1.1-5.6) and among women who resided in northern study areas (aOR: 2.8; 95% CI: 1.3-5.9). The higher risk observed with short IPI among women in northern study areas was attenuated for spring/summer conceptions. CONCLUSION: Short IPI was associated with an increased risk for gastroschisis, particularly among women whose preceding pregnancy resulted in a miscarriage or termination and among those who resided in northern study areas with winter/fall conception.

Use of antiepileptic medications in pregnancy in relation to risks of birth defects.

PURPOSE: To evaluate use of specific antiepileptic drugs (AEDs) in pregnancy in relation to specific birth defects. METHODS: Using data from the National Birth Defects Prevention Study, we assessed use of AEDs and the risk of neural tube defects (NTDs), oral clefts (OCs), heart defects (HDs), hypospadias, and other major birth defects, taking specific agent, timing, and indication into consideration. RESULTS: Drug-specific increased risks were observed for valproic acid in relation to NTDs [adjusted odds ratio (aOR), 9.7;, 95% confidence interval (CI), 3.4-27.5], OCs (aOR, 4.4; 95% CI, 1.6-12.2), HDs (aOR, 2.0; 95% CI, 0.78-5.3), and hypospadias (aOR. 2.4; 95% CI, 0.62-9.0), and for carbamazapine in relation to NTDs (aOR, 5.0; 95% CI, 1.9-12.7). Epilepsy history without AED use did not seem to increase risk. CONCLUSIONS: Valproic acid, which current guidelines suggest should be avoided in pregnancy, was most notable in terms of strength and breadth of its associations. Carbamazapine was associated with NTDs, even after controlling for folic acid use. Sample sizes were still too small to adequately assess risks of less commonly used AEDs, but our findings support further study to identify lower risk options for pregnant women.

Reviewing the evidence for mycophenolate mofetil as a new teratogen: case report and review of the literature.

Mycophenolate mofetil (MMF) (CellCept) is an immunosuppressant drug that is teratogenic in rats and rabbits. Reports of malformations in 13 offspring of women exposed to MMF in pregnancy raise concern that MMF is also a human teratogen. We report an additional child with malformations following prenatal exposure to MMF and review the other 13 reports. We identified a Cambodian male born at 31 weeks' gestation to a mother who had been treated for lupus nephritis with MMF from before conception to 12 weeks' gestational age. He had bilateral moderate-to-severe microtia, external auditory canal atresia, bilateral conductive hearing loss, mild microcephaly, and apparently normal development. Among the 14 MMF-exposed offspring now reported, the underlying maternal conditions were kidney transplantation (7), lupus nephritis (4), liver transplantation (1), heart transplantation (1), and recurrent erythema multiforme (1). All were exposed in early pregnancy. The most distinctive malformation was moderate-to-severe microtia or anotia (12), with external auditory canal atresia in 9. Other common craniofacial malformations and minor anomalies included orofacial clefts (7), hypertelorism (3), coloboma (3), and micrognathia (3). Six had cardiovascular malformations, of which three were either conotruncal or aortic arch defects. MMF dose, reported in 12 patients, was <1 g/day in 4 and 1 g or more/day in 8; no correlation between dose and phenotype severity was apparent. While case reports have limited value in identifying human teratogens, the unusual distribution of malformations among the 14 reported exposed offspring identifies a phenotype suggesting that MMF is likely a human teratogen.