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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 (1.2 were considered to represent potentially meaningful associations. RESULTS: ORs for 1.2 for 4/8 noncardiac and 3/6 cardiac malformations. Among participants with any FA supplement use, ORs comparing 1.2 for

BACKGROUND: Risk factors for birth defects are frequently investigated using data limited to liveborn infants. By conditioning on survival, results of such studies may be distorted by selection bias, also described as “live birth bias”. However, the implications of live birth bias on risk estimation remain poorly understood. OBJECTIVES: We sought to quantify live birth bias and to investigate the conditions under which it arose. METHODS: We used data on 3,994 birth defects cases and 11,829 controls enrolled in the National Birth Defects Prevention Study to compare odds ratio (OR) estimates of the relationship between three established risk factors (antiepileptic drug use, smoking, and multifetal pregnancy) and four birth defects (anencephaly, spina bifida, omphalocele, and cleft palate) when restricted to live births as compared to among live births, stillbirths, and elective terminations. Exposures and birth defects represented varying strengths of association with live birth; all controls were liveborn. We performed a quantitative bias analysis to evaluate the sensitivity of our results to excluding terminated and stillborn controls. RESULTS: Cases ranged from 33% live born (anencephaly) to 99% (cleft palate). Smoking and multifetal pregnancy were associated with live birth among anencephaly (crude OR [cOR] 0.61 and cOR 3.15, respectively) and omphalocele cases (cOR 2.22 and cOR 5.22, respectively). For analyses of the association between exposures and birth defects, restricting to live births produced negligible differences in estimates except for anencephaly and multifetal pregnancy, which was two-fold higher among live births (adjusted OR [aOR] 4.93) as among all pregnancy outcomes (aOR 2.44). Within tested scenarios, bias analyses suggested that results were not sensitive to the restriction to liveborn controls. CONCLUSIONS: Selection bias was generally limited except for high mortality defects in the context of exposures strongly associated with livebirth. Findings indicate that substantial live birth bias is unlikely to affect studies of risk factors for most birth defects.

Background The 2016 Zika public health response in the United States highlighted the need for birth defect surveillance (BDS) programs to collect population-based data on birth defects potentially related to Zika as rapidly as possible through enhanced case ascertainment and reporting. The National Birth Defects Prevention Network (NBDPN) assessed BDS program activities in the United States before and after the Zika response. Methods The NBDPN surveyed 54 BDS programs regarding activities before and after the Zika response, lessons learned, and programmatic needs. Follow-up emails were sent and phone calls were held for programs with incomplete or no response to the online survey. Survey data were cleaned and tallied, and responses to open-ended questions were placed into best-fit categories. Results A 100% response rate was achieved. Of the 54 programs surveyed, 42 reported participation in the Zika public health response that included BDS activities. Programs faced challenges in expanding their surveillance effort given the response requirements but reported mitigating factors such as establishing and enhancing partnerships and program experience with surveillance and clinical activities. Beyond funding, reported program needs included training, surveillance tools/resources, and availability of clinical experts. Conclusions Existing BDS programs with experience implementing active case-finding and case verification were able to adapt their surveillance efforts rapidly to collect and report data necessary for the Zika response. Program sustainability for BDS remains challenging; thus, continued support, training, and resource development are important to ensure that the infrastructure built during the Zika response is available for the next public health response.

To use data from two large studies of birth defects to describe time trends in ondansetron use for the treatment of first-trimester nausea and vomiting of pregnancy and to investigate associations, either previously reported or undescribed, between first-trimester ondansetron use and major birth defects.We used data from two case-control studies, the National Birth Defects Prevention Study (1997-2011) and the Slone Birth Defects Study (1997-2014). The prevalence of ondansetron use for the treatment of first-trimester nausea and vomiting of pregnancy among control patients was calculated in 2-year intervals. Using women with untreated first-trimester nausea and vomiting of pregnancy as the reference, we calculated adjusted odds ratios (ORs) and 95% CIs for associations between first-trimester ondansetron use for treatment of nausea and vomiting of pregnancy and specific birth defects. A secondary exposure group of other prescription antiemetics was used to address confounding by indication.In the National Birth Defects Prevention Study and Slone Birth Defects Study, respectively, 6,751 and 5,873 control mothers and 14,667 and 8,533 case mothers who reported first-trimester nausea and vomiting of pregnancy were included in the analysis. Among women in the control group, ondansetron exposure increased from less than 1% before 2000 to 13% in 2013-2014. Ondansetron use was not associated with an increased risk for most of the 51 defect groups analyzed. Modest increases in risk were observed for cleft palate (adjusted OR 1.6, 95% CI 1.1-2.3) in the National Birth Defects Prevention Study and renal agenesis-dysgenesis (adjusted OR 1.8, 95% CI 1.1-3.0) in the Birth Defects Study, although these findings may be the result of chance.Off-label use of ondansetron for the treatment of nausea and vomiting of pregnancy increased to 13% by the end of the study period. For the majority of specific birth defects investigated, there was no increased risk associated with first-trimester use of ondansetron for treatment of nausea and vomiting of pregnancy compared with no treatment, although modest associations with cleft palate and renal agenesis-dysgenesis warrant further study.

BACKGROUND: Maternal exposure to drinking water disinfection byproducts (DBP)s may contribute to orofacial cleft (OFC) development, but studies are sparse and beset with limitations. METHODS: Population-based, maternal interview reports of drinking water filtration and consumption for 680 OFC cases (535 isolated) and 1826 controls were linked with DBP concentration data using maternal residential addresses and public water system monitoring data. Maternal individual-level exposures to trihalomethanes (THM)s and haloacetic acids (HAA)s (μg/L of water consumed) were estimated from reported consumption at home, work, and school. Compared to no exposure, associations with multisource maternal exposure

BACKGROUND Zika virus has recently emerged as a novel cause of microcephaly. CDC has asked states to rapidly ascertain and report cases of Zika-linked birth defects, including microcephaly. Massachusetts added head circumference to its birth certificate (BC) in 2011. The accuracy of head circumference measurements from state vital records data has not been reported. METHODS We sought to assess the accuracy of Massachusetts BC head circumference measurements by comparing them to measurements for 2,217 infants born during 2012-2013 captured in the Massachusetts Birth Defects Monitoring Program (BDMP) data system. BDMP contains information abstracted directly from infant medical records and served as the true head circumference value (i.e., gold standard) for analysis. We calculated the proportion of head circumference measurements in agreement between the BC and BDMP data. We assigned growth chart head circumference percentile categories to each BC and BDMP measurement, and calculated the sensitivity and specificity of BC-based categories to predict BDMP-based categories. RESULTS No difference was found in head circumference measurements between the two sources in 77.9% (n = 1,727) of study infants. The sensitivity of BC-based head circumference percentile categories ranged from 85.6% (

Background Malformations surveillance programs among newborn infants are used to determine the prevalence of congenital anomalies. A comparison in the same group of infants between the malformations detected at birth and those detected at 1 year of age will identify errors in the surveillance process and, also, the abnormalities more likely not to be detected at birth, but later in the first year of life. Methods The malformations identified at birth by Brigham and Women's Hospital (BWH) in the years 2000 and 2005 have been compared with the abnormalities detected in the same infants up to age 1 year by the Massachusetts Birth Defects Monitoring Program. Results The Massachusetts Birth Defects Monitoring Program identified 557 malformed infants in 2000 and 415 in 2005. Of these, 34 (3.5%) of the malformed infants were missed at birth by BWH Surveillance Program. An additional 22 (2.3%) malformed infants had delayed detection, as they were identified later in the first year. The reasons were the fact that: (1) the Surveillance staff reviewed the physicians' recorded findings only on the first day of life; (2) failure of the examining pediatrician to record the presence of a malformation in her/his notes. The most common abnormalities with delayed detection were mild heart defects, such as atrial septal defects. Conclusion These findings emphasize the importance in a newborn malformations surveillance program of continued follow up in the first days of life, especially in small, premature infants. Birth Defects Research, 2017. © 2017 Wiley Periodicals, Inc.

Background Assisted reproductive technology (ART) has been associated with birth defects, but the contributions of multiple births and underlying subfertility remain unclear. We evaluated the effects of subfertility and mediation by multiple births on associations between ART and nonchromosomal birth defects. Methods We identified a retrospective cohort of Massachusetts live births and stillbirths from 2004 to 2010 among ART-exposed, ART-unexposed subfertile, and fertile mothers using linked information from fertility clinics, vital records, hospital discharges, and birth defects surveillance. Log-binomial regression was used to estimate prevalence ratios and 95% confidence intervals (CIs). Mediation analyses were performed to deconstruct the ART-birth defects association into the direct effect of ART, the indirect effect of multiple births, and the effect of ART-multiples interaction. Results Of 17,829 ART-exposed births, 355 had a birth defect, compared with 162 of 9431 births to subfertile mothers and 6183 of 445,080 births to fertile mothers. The adjusted prevalence ratio was 1.5 (95% CI, 1.3–1.6) for ART and 1.3 (95% CI, 1.1–1.5) in subfertile compared with fertile deliveries. We observed elevated rates of several birth defects with ART, including tetralogy of Fallot and hypospadias. Subfertility and multiple births affect these associations, with multiple births explaining 36% of the relative effect of ART on nonchromosomal birth defects. Conclusion Although the risk of birth defects with ART is small, a substantial portion of the relative effect is mediated through multiple births, with subfertility contributing an important role. Future research is needed to determine the impact of newer techniques, such as single embryo transfer, on these risks. Birth Defects Research, 2017. © 2017 Wiley Periodicals, Inc.

Background Congenital microcephaly has been linked to maternal Zika virus infection. However, ascertaining infants diagnosed with microcephaly can be challenging. Methods Thirty birth defects surveillance programs provided data on infants diagnosed with microcephaly born 2009 to 2013. The pooled prevalence of microcephaly per 10,000 live births was estimated overall and by maternal/infant characteristics. Variation in prevalence was examined across case finding methods. Nine programs provided data on head circumference and conditions potentially contributing to microcephaly. Results The pooled prevalence of microcephaly was 8.7 per 10,000 live births. Median prevalence (per 10,000 live births) was similar among programs using active (6.7) and passive (6.6) methods; the interdecile range of prevalence estimates was wider among programs using passive methods for all race/ethnicity categories except Hispanic. Prevalence (per 10,000 live births) was lowest among non-Hispanic Whites (6.5) and highest among non-Hispanic Blacks and Hispanics (11.2 and 11.9, respectively); estimates followed a U-shaped distribution by maternal age with the highest prevalence among mothers

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.

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 (

Background Birth defects are the leading cause of infant death. While causes of most are unknown, those that might be due to medication use are among the most preventable. This study describes an approach to identifying those medications that most warrant attention by using a “screen” program that calculates odds ratios for pairs of exposures and specific birth defects. Methods We discuss the development of this tool and illustrate its application to two large risk factor studies, the Slone Epidemiology Center's Birth Defects Study and the Centers for Disease Control and Prevention's National Birth Defects Prevention Study, ideal settings for the systematic study of risks and relative safety of drugs in relation to birth defects while recognizing the inherent limitations of such an approach. Results Suggestions for establishing criteria for exposures and outcomes that balance the need for specific details with the practical considerations of sample size and volume of output are presented. Selection of appropriate exposure reference categories and control groups is also discussed, as well as the need to address potential confounding. An example that motivated a detailed investigation of possible associations between a medication (butalbital) and selected specific birth defects is provided. Conclusion While screening programs such as the one described can be a valuable tool for exploring potential associations in large data bases, they must be applied with caution. The issue of multiple testing and chance findings is a major concern. While statistics are a necessary component, human judgment must be an integral part of the process. Birth Defects Research (Part A), 2015. © 2015 Wiley Periodicals, Inc.

Background The Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS) is a population-based, multi-Center case-control study of modifiable risk factors for selected birth defects in the United States. BD-STEPS is the second major research effort of the Centers for Birth Defects Research and Prevention, which extends and expands the initial research effort, the National Birth Defects Prevention Study (NBDPS).

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. © 2015 Wiley Periodicals, Inc.

Assisted reproductive technology (ART) has been associated with birth defects, but the contributions of multiple births and underlying subfertility remain unclear. We evaluated the effects of subfertility and mediation by multiple births on associations between ART and nonchromosomal birth defects.We identified a retrospective cohort of Massachusetts live births and stillbirths from 2004 to 2010 among ART-exposed, ART-unexposed subfertile, and fertile mothers using linked information from fertility clinics, vital records, hospital discharges, and birth defects surveillance. Log-binomial regression was used to estimate prevalence ratios and 95% confidence intervals (CIs). Mediation analyses were performed to deconstruct the ART-birth defects association into the direct effect of ART, the indirect effect of multiple births, and the effect of ART-multiples interaction.Of 17,829 ART-exposed births, 355 had a birth defect, compared with 162 of 9431 births to subfertile mothers and 6183 of 445,080 births to fertile mothers. The adjusted prevalence ratio was 1.5 (95% CI, 1.3-1.6) for ART and 1.3 (95% CI, 1.1-1.5) in subfertile compared with fertile deliveries. We observed elevated rates of several birth defects with ART, including tetralogy of Fallot and hypospadias. Subfertility and multiple births affect these associations, with multiple births explaining 36% of the relative effect of ART on nonchromosomal birth defects.Although the risk of birth defects with ART is small, a substantial portion of the relative effect is mediated through multiple births, with subfertility contributing an important role. Future research is needed to determine the impact of newer techniques, such as single embryo transfer, on these risks. Birth Defects Research 109:1144-1153, 2017. © 2017 Wiley Periodicals, Inc.

Malformations surveillance programs among newborn infants are used to determine the prevalence of congenital anomalies. A comparison in the same group of infants between the malformations detected at birth and those detected at 1 year of age will identify errors in the surveillance process and, also, the abnormalities more likely not to be detected at birth, but later in the first year of life.The malformations identified at birth by Brigham and Women's Hospital (BWH) in the years 2000 and 2005 have been compared with the abnormalities detected in the same infants up to age 1 year by the Massachusetts Birth Defects Monitoring Program.The Massachusetts Birth Defects Monitoring Program identified 557 malformed infants in 2000 and 415 in 2005. Of these, 34 (3.5%) of the malformed infants were missed at birth by BWH Surveillance Program. An additional 22 (2.3%) malformed infants had delayed detection, as they were identified later in the first year. The reasons were the fact that: (1) the Surveillance staff reviewed the physicians' recorded findings only on the first day of life; (2) failure of the examining pediatrician to record the presence of a malformation in her/his notes. The most common abnormalities with delayed detection were mild heart defects, such as atrial septal defects.These findings emphasize the importance in a newborn malformations surveillance program of continued follow up in the first days of life, especially in small, premature infants. Birth Defects Research 110:142-147, 2018. © 2017 Wiley Periodicals, Inc.

Purpose To compare the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and/or opioids to the use of acetaminophen without NSAIDs or opioids with respect to associations with birth defects. Methods We used data from the National Birth Defects Prevention Study (1997–2011). Exposure was self-reported maternal analgesic use from the month before through the third month of pregnancy (periconceptional). Adjusted odds ratios (aORs) were calculated to examine associations with 16 birth defects. Results Compared to acetaminophen, mothers reporting NSAIDs were significantly more likely to have offspring with gastroschisis, hypospadias, cleft palate, cleft lip with cleft palate, cleft lip without cleft palate, anencephaly, spina bifida, hypoplastic left heart syndrome, pulmonary valve stenosis, and tetralogy of Fallot (aOR range, 1.2–1.6). Opioids were associated with tetralogy of Fallot, perimembranous ventricular septal defect, and ventricular septal defect with atrial septal defect (aOR range, 1.8–2.3), whereas use of both opioids and NSAIDs was associated with gastroschisis, cleft palate, spina bifida, hypoplastic left heart syndrome, and pulmonary valve stenosis (aOR range, 2.0–2.9). Conclusions Compared to periconceptional use of acetaminophen, selected birth defects occurred more frequently among infants of women using NSAIDs and/or opioids. However, we could not definitely determine whether these risks relate to the drugs or to indications for treatment.

To evaluate pregnancy and birth outcomes by type of infertility treatment received.Assisted reproductive technology (ART) data on women who were both treated and gave birth in Massachusetts were linked to vital records and hospital data. Singleton and twin live births were categorized by ART treatment parameters. Risks for adverse outcomes (pregnancy-induced hypertension [PIH], gestational diabetes [GDM, primary cesarean [CS], prematurity [PTB], low birthweight [LBW], small for gestational age [SGA], large for gestational age [LGA], and birth defects [BD]) were modeled using logistic regression (adjusted odds ratios and 95% confidence intervals), adjusted for parental and treatment factors. GDM and PIH were additionally modeled as adverse outcomes.Among the 8,948 pregnancies, risks were significantly higher among twins (PIH 2.58, GDM 1.30, CS 5.83, PTB 11.84, LBW 10.68, SGA 2.17, BD 2.54), donor oocytes (PIH 1.87, CS 1.43, PTB 1.43), ICSI (SGA 1.20), and the presence of1 fetal heartbeat at 6 weeks' gestation (2 fetal heartbeats: PTB 1.49, LBW 1.57; 3 fetal heartbeats: PTB 2.07, LBW 2.30, SGA 2.04). Thawed embryos were associated with a higher risk for PIH (1.30) but lower risks for LBW (0.79) and SGA (0.38). GDM was associated with increased risks for CS (1.22), LGA (1.40), and BD (1.50); PIH was associated with risks for CS (1.86), PTB (2.70), and LBW (1.83).Plurality is the predominant ART treatment risk factor associated with substantial excess morbidity for both mother and infants.

Background Clubfoot is associated with maternal cigarette smoking in several studies, but it is not clear if this association is confined to women who smoke throughout the at-risk period. Maternal alcohol and coffee drinking have not been well studied in relation to clubfoot. Methods The present study used data from a population-based case–control study of clubfoot conducted in Massachusetts, New York, and North Carolina from 2007 to 2011. Mothers of 646 isolated clubfoot cases and 2037 controls were interviewed about pregnancy events and exposures, including the timing and frequency of cigarette smoking, alcohol intake, and coffee drinking. Results More mothers of cases than controls reported smoking during early pregnancy (28.9% vs. 19.1%). Of women who smoked when they became pregnant, those who quit in the month after a first missed period had a 40% increase in clubfoot risk and those who continued to smoke during the next 3 months had more than a doubling in risk, after controlling for demographic factors, parity, obesity, and specific medication exposures. Adjusted odds ratios for women who drank >3 servings of alcohol or coffee per day throughout early pregnancy were 2.38 and 1.77, respectively, but the numbers of exposed women were small and odds ratios were unstable. Conclusions Clubfoot risk appears to be increased for offspring of women who smoke cigarettes, particularly those who continue smoking after pregnancy is recognisable, regardless of amount. For alcohol and coffee drinkers, suggested increased risks were only observed in higher levels of intake.

Background: Epidemiologic literature suggests that exposure to air pollutants is associated with fetal development. Objectives: We investigated maternal exposures to air pollutants during weeks 2–8 of pregnancy and their associations with congenital heart defects. Methods: Mothers from the National Birth Defects Prevention Study, a nine-state case–control study, were assigned 1-week and 7-week averages of daily maximum concentrations of carbon monoxide, nitrogen dioxide, ozone, and sulfur dioxide and 24-hr measurements of fine and coarse particulate matter using the closest air monitor within 50 km to their residence during early pregnancy. Depending on the pollutant, a maximum of 4,632 live-birth controls and 3,328 live-birth, fetal-death, or electively terminated cases had exposure data. Hierarchical regression models, adjusted for maternal demographics and tobacco and alcohol use, were constructed. Principal component analysis was used to assess these relationships in a multipollutant context. Results: Positive associations were observed between exposure to nitrogen dioxide and coarctation of the aorta and pulmonary valve stenosis. Exposure to fine particulate matter was positively associated with hypoplastic left heart syndrome but inversely associated with atrial septal defects. Examining individual exposure-weeks suggested associations between pollutants and defects that were not observed using the 7-week average. Associations between left ventricular outflow tract obstructions and nitrogen dioxide and between hypoplastic left heart syndrome and particulate matter were supported by findings from the multipollutant analyses, although estimates were attenuated at the highest exposure levels. Conclusions: Using daily maximum pollutant levels and exploring individual exposure-weeks revealed some positive associations between certain pollutants and defects and suggested potential windows of susceptibility during pregnancy. Citation: Stingone JA, Luben TJ, Daniels JL, Fuentes M, Richardson DB, Aylsworth AS, Herring AH, Anderka M, Botto L, Correa A, Gilboa SM, Langlois PH, Mosley B, Shaw GM, Siffel C, Olshan AF, National Birth Defects Prevention Study. 2014. Maternal exposure to criteria air pollutants and congenital heart defects in offspring: results from the National Birth Defects Prevention Study. Environ Health Perspect 122:863–872; http://dx.doi.org/10.1289/ehp.1307289

OBJECTIVE: We aimed to examine trends in timing of diagnosis of critical congenital heart defects (CCHDs) and factors associated with delayed diagnosis (diagnosis after discharge home following delivery). METHODS: We examined a population-based retrospective cohort of CCHD cases among live births identified through the Massachusetts Birth Defects Monitoring Program. Congenital heart defects were considered critical if the infant received corrective surgery, interventional catheterization, palliative care, or died as a result of the defect within 12 months of birth. Timing of initial diagnosis was classified as prenatal, postnatal before discharge home, or delayed. Demographic, perinatal, and mortality information was obtained from the Registry of Vital Records and Statistics. Prevalence ratios (PRs) were used to examine associations with delayed diagnosis. RESULTS: Among 460 467 live births to Massachusetts residents between 2004 and 2009, we identified 916 CCHD cases, of which 126 (13.8%) had delayed diagnosis. Rates of prenatal CCHD diagnosis increased from 44.9% in 2004 to 63.8% in 2009, whereas rates of delayed diagnosis decreased from 17.1% to 10.6% over the same time period. Among cases with delayed diagnosis, the most common defects were coarctation, pulmonary valve stenosis, and tetralogy of Fallot. Delayed diagnosis was associated with delivery outside a tertiary hospital (adjusted PR: 3.6 [95% confidence interval: 2.5–5.2]) and isolated CCHD (adjusted PR: 1.7 [95% confidence interval: 1.1–2.7]). CONCLUSIONS: Despite increasing prenatal diagnosis of CCHDs, delayed diagnosis still occurs in over 10% of cases. Understanding factors associated with delayed diagnosis could help to improve prenatal and postnatal screening efforts, including pulse oximetry testing.

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. Birth Defects Research (Part A) 100:852–862, 2014. © 2014 Wiley Periodicals, Inc.

Clubfoot, a common major structural malformation, develops early in gestation. Epidemiologic studies have identified higher risks among boys, first-born children, and babies with a family history of clubfoot, but studies of risks associated with maternal exposures are lacking. We conducted the first large-scale, population-based, case-control study of clubfoot with detailed information on maternal medication use in pregnancy. Study subjects were ascertained from birth defect registries in Massachusetts, New York, and North Carolina during 2007-2011. Cases were 646 mothers of children with clubfoot without other major structural malformations (i.e., isolated clubfoot); controls were mothers of 2,037 children born without major malformations. Mothers were interviewed within 12 months of delivery about medication use, including product, timing, and frequency. Odds ratios were estimated for exposure to 27 medications in pregnancy months 2-4 after adjustment for study site, infant sex, first-born status, body mass index (weight (kg)/height (m)(2)), and smoking. Odds ratios were less than 1.20 for 14 of the medications; of the remainder, most odds ratios were only slightly elevated (range, 1.21-1.66), with wide confidence intervals. The use of antiviral drugs was more common in clubfoot cases than in controls (odds ratio = 4.22, 95% confidence interval: 1.52, 11.73). Most of these results are new findings and require confirmation in other studies.

Gastroschisis is a birth defect in which abdominal contents are located outside of the body wall and can lead to serious neonatal and long-term morbidity.1,2 The pathogenesis of gastroschisis is not known but the critical susceptibility window occurs during the first trimester.3 The increasing prevalence of gastroschisis within the United States (US) 4-7 suggests environmental factors may be important causes of this disease.3,8 However, the aetiology of gastroschisis remains elusive. Previous studies have found no evidence for an increased risk of birth defects overall due to antiherpetic medication use.9-13 However, in an exploratory analysis, one recent Danish study observed a strong but imprecise association between first trimester antiherpetic medication use and abdominal wall defects in the aggregate (prevalence odds ratio 3.58, 95% confidence interval [0.84, 15.27]).9 Antiherpetic medications are nucleoside analogues that disrupt DNA replication and pharmacokinetic studies have shown that acyclovir crosses the placenta,12,14,15 therefore it is possible that antiherpetic medications could affect embryogenesis, a process that involves rapid mitotic divisions and DNA replication. We examined the association between antiherpetic medication use and the risk of gastroschisis in the National Birth Defects Prevention Study (NBDPS), which includes the largest sample of gastroschisis cases with maternal exposure information in the US.

Prepregnancy diabetes and obesity have been identified as independent risk factors for several birth defects, providing support for a mechanism that involves hyperglycemia and hyperinsulinemia in the development of malformations. Data from the National Birth Defects Prevention Study from 1997 to 2007 were used to investigate the association between the maternal dietary glycemic index (DGI) and the risk of birth defects among nondiabetic women. DGI was categorized by using spline regression models and quartile distributions. Adjusted odds ratios and 95% confidence intervals were calculated. The joint effect of DGI and obesity was also examined. Among the 53 birth defects analyzed, high DGI, categorized by spline regression, was significantly associated with encephalocele (adjusted odds ratio (aOR) = 2.68), diaphragmatic hernia (aOR = 2.58), small intestinal atresia/stenosis (aOR = 2.97) including duodenal atresia/stenosis (aOR = 2.48), and atrial septal defect (aOR = 1.37). Using quartiles to categorize DGI, the authors identified associations with cleft lip with cleft palate (aOR = 1.23) and anorectal atresia/stenosis (aOR = 1.40). The joint effect of high DGI and obesity provided evidence of a synergistic effect on the risk of selected birth defects. High DGI is associated with an increased risk of a number of birth defects under study. Obesity coupled with high DGI appears to increase the risk further for some birth defects.

Objective To determine whether psychosocial functioning in children with orofacial clefts and their parents differs from that in unaffected controls. Design The study used a nonrandomized, case-control design. Participants Outcomes were evaluated in 93 cases with orofacial clefts and 124 controls, aged 5 to 9 years, who were part of the Massachusetts Center for Birth Defects Research and Prevention registry. Main Outcome Measures Measures included the Child Behavior Checklist, the PedsQL 4.0, the Social Competence Scale, and the Parenting Stress Inventory. Results Group differences were negligible for all measures, and findings changed little with the application of inverse probability weighting to adjust for response bias. Stratified analyses revealed differences according to both sex and age, with worse outcomes observed in male cases and cases aged 7 to 9 years. Conclusions In contrast to previous studies, we found minimal differences in psychosocial functioning among children with orofacial clefts and their parents compared with unaffected controls. This may reflect ascertainment factors, and psychosocial differences may be less apparent in population-based versus clinic-based samples. Alternatively, social-emotional deficits may become apparent in older school-aged children, making the preschool and early elementary school years an optimal time for preventive interventions.

To evaluate the representativeness of controls in an ongoing, population-based, case-control study of birth defects in 10 centers across the United States, researchers compared 1997-2003 birth certificate data linked to selected controls (n = 6,681) and control participants (n = 4,395) with those from their base populations (n = 2,468,697). Researchers analyzed differences in population characteristics (e.g., percentage of births at > or =2,500 g) for each group. Compared with their base populations, control participants did not differ in distributions of maternal or paternal age, previous livebirths, maternal smoking, or diabetes, but they did differ in other maternal (i.e., race/ethnicity, education, entry into prenatal care) and infant (i.e., birth weight, gestational age, and plurality) characteristics. Differences in distributions of maternal, but not infant, characteristics were associated with participation by selected controls. Absolute differences in infant characteristics for the base population versus control participants were < or =1.3 percentage points. Differences in infant characteristics were greater at centers that selected controls from hospitals compared with centers that selected controls from electronic birth certificates. These findings suggest that control participants in the National Birth Defects Prevention Study generally are representative of their base populations. Hospital-based control selection may slightly underascertain infants affected by certain adverse birth outcomes.

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

Background Population-based birth defects surveillance is a core public health activity in the United States (U.S.); however, the lack of national data quality standards has limited the use of birth defects surveillance data across state programs. Development of national standards will facilitate data aggregation and utilization across birth defects surveillance programs in the U.S. Methods Based on national standards for other U.S. public health surveillance programs, existing National Birth Defects Prevention Network (NBDPN) guidelines for conducting birth defects surveillance, and information from birth defects surveillance programs regarding their current data quality practices, we developed 11 data quality measures that focused on data completeness (n = 5 measures), timeliness (n = 2), and accuracy (n = 4). For each measure, we established tri-level performance criteria (1 = rudimentary, 2 = essential, 3 = optimal). In January 2014, we sent birth defects surveillance programs in each state, District of Columbia, Puerto Rico, Centers for Disease Control and Prevention (CDC), and the U.S. Department of Defense Birth and Infant Health Registry an invitation to complete a self-administered NBDPN Standards Data Quality Assessment Tool. The completed forms were electronically submitted to the CDC for analyses. Results Of 47 eligible population-based surveillance programs, 45 submitted a completed assessment tool. Two of the 45 programs did not meet minimum inclusion criteria and were excluded; thus, the final analysis included information from 43 programs. Average scores for four of the five completeness performance measures were above level 2. Conversely, the average scores for both timeliness measures and three of the four accuracy measures were below level 2. Surveillance programs using an active case-finding approach scored higher than programs using passive case-finding approaches for the completeness and accuracy measures, whereas their average scores were lower for timeliness measures. Conclusions This initial, nation-wide assessment of data quality across U.S. population-based birth defects surveillance programs highlights areas for improvement. Using this information to identify strengths and weaknesses, the birth defects surveillance community, working through the NBDPN, can enhance and implement a consistent set of standards that can promote uniformity and enable surveillance programs to work towards improving the potential of these programs. Electronic supplementary material The online version of this article (doi:10.1186/s12889-015-2223-2) contains supplementary material, which is available to authorized users.

Birth defects are the leading cause of infant death. While causes of most are unknown, those that might be due to medication use are among the most preventable. This study describes an approach to identifying those medications that most warrant attention by using a "screen" program that calculates odds ratios for pairs of exposures and specific birth defects.We discuss the development of this tool and illustrate its application to two large risk factor studies, the Slone Epidemiology Center's Birth Defects Study and the Centers for Disease Control and Prevention's National Birth Defects Prevention Study, ideal settings for the systematic study of risks and relative safety of drugs in relation to birth defects while recognizing the inherent limitations of such an approach.Suggestions for establishing criteria for exposures and outcomes that balance the need for specific details with the practical considerations of sample size and volume of output are presented. Selection of appropriate exposure reference categories and control groups is also discussed, as well as the need to address potential confounding. An example that motivated a detailed investigation of possible associations between a medication (butalbital) and selected specific birth defects is provided.While screening programs such as the one described can be a valuable tool for exploring potential associations in large data bases, they must be applied with caution. The issue of multiple testing and chance findings is a major concern. While statistics are a necessary component, human judgment must be an integral part of the process.

Background Twinning has been associated with many types of birth defects, although previous studies have had inconsistent findings. Many studies lack information about potential confounders, particularly use of fertility treatment. Our objective was to assess the association between twinning and birth defects in the National Birth Defects Prevention Study (NBDPS). Methods We used data from the NBDPS, a population-based, case–control study of major birth defects in the USA, to evaluate associations between twinning and birth defects. The study population included mothers of twin and singleton controls (live-born infants without major birth defects), and cases (fetuses or infants with a major birth defect) born October 1997–December 2007. Adjusted ORs and 95% CIs were estimated using multivariable logistic regression stratified by use of fertility treatment. Twin sex-pairing data and a simulation approach were used to estimate the zygosity of twins. Results In the unassisted conception stratum, we observed significant positive associations between twinning and 29 of 45 defect groups. The largest effect estimates were observed for multiple ventricular septal defects and cloacal exstrophy. Among mothers reporting any use of fertility treatments, we observed a significant association with twinning for 5 of 25 defect groups, with the largest effect estimates for hypoplastic left heart syndrome and omphalocele. OR estimates in the estimated monozygotic stratum were generally further from the null than in the dizygotic stratum. Conclusions Compared with singletons, a wide range of birth defects are significantly more common among twins. Birth defect risk in twins may be differential by use of fertility treatment.

The National Birth Defects Prevention Study (NBDPS) is a large population-based multicenter case-control study of major birth defects in the United States.Data collection took place from 1998 through 2013 on pregnancies ending between October 1997 and December 2011. Cases could be live born, stillborn, or induced terminations, and were identified from birth defects surveillance programs in Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah. Controls were live born infants without major birth defects identified from the same geographical regions and time periods as cases by means of either vital records or birth hospitals. Computer-assisted telephone interviews were completed with women between 6 weeks and 24 months after the estimated date of delivery. After completion of interviews, families received buccal cell collection kits for the mother, father, and infant (if living).There were 47,832 eligible cases and 18,272 eligible controls. Among these, 32,187 (67%) and 11,814 (65%), respectively, provided interview information about their pregnancies. Buccal cell collection kits with a cytobrush for at least one family member were returned by 19,065 case and 6,211 control families (65% and 59% of those who were sent a kit). More than 500 projects have been proposed by the collaborators and over 200 manuscripts published using data from the NBDPS through December 2014.The NBDPS has made substantial contributions to the field of birth defects epidemiology through its rigorous design, including case classification, detailed questionnaire and specimen collection, large study population, and collaborative activities across Centers.

The Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS) is a population-based, multi-Center case-control study of modifiable risk factors for selected birth defects in the United States. BD-STEPS is the second major research effort of the Centers for Birth Defects Research and Prevention, which extends and expands the initial research effort, the National Birth Defects Prevention Study (NBDPS).BD-STEPS focuses on 17 categories of structural birth defects selected based on severity, prevalence, consistent ascertainment, and previous findings that warrant additional research. Cases are identified through existing birth defects surveillance programs; controls are from vital records or birth hospital logs from the same catchment area. BD-STEPS uses a standardized computer-assisted telephone interview to collect information from case and control mothers on topics including demographics, health conditions, and medication use. Following the maternal interview, selected Centers request permission to sample residual newborn screening blood spots from state repositories for genetic analyses. New components planned for BD-STEPS include linkages with external datasets and use of online questionnaires to collect in-depth information on selected exposures.BD-STEPS extends NBDPS by continuing to collect data on many exposures that were assessed in NBDPS, allowing data from both studies to be combined and providing an unprecedented sample size to analyze rare exposures. BD-STEPS expands upon NBDPS by collecting more detailed information on existing exposures as well as new exposures.The goal of BD-STEPS is to provide women and healthcare providers with information they need to make decisions to promote the healthiest pregnancy possible.

Background The National Birth Defects Prevention Study (NBDPS) is a large population-based multicenter case–control study of major birth defects in the United States. Methods Data collection took place from 1998 through 2013 on pregnancies ending between October 1997 and December 2011. Cases could be live born, stillborn, or induced terminations, and were identified from birth defects surveillance programs in Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah. Controls were live born infants without major birth defects identified from the same geographical regions and time periods as cases by means of either vital records or birth hospitals. Computer-assisted telephone interviews were completed with women between 6 weeks and 24 months after the estimated date of delivery. After completion of interviews, families received buccal cell collection kits for the mother, father, and infant (if living). Results There were 47,832 eligible cases and 18,272 eligible controls. Among these, 32,187 (67%) and 11,814 (65%), respectively, provided interview information about their pregnancies. Buccal cell collection kits with a cytobrush for at least one family member were returned by 19,065 case and 6,211 control families (65% and 59% of those who were sent a kit). More than 500 projects have been proposed by the collaborators and over 200 manuscripts published using data from the NBDPS through December 2014. Conclusion The NBDPS has made substantial contributions to the field of birth defects epidemiology through its rigorous design, including case classification, detailed questionnaire and specimen collection, large study population, and collaborative activities across Centers. Birth Defects Research (Part A) 103:656–669, 2015. © 2015 Wiley Periodicals, Inc.

PurposePrevious research has suggested gastroschisis, a congenital malformation, may be linked to environmental or infectious factors and cases can occur in clusters. The objective of this study was to identify geographic areas of elevated gastroschisis risk.MethodsCases of gastroschisis were identified from birth defect registries in Massachusetts and Texas. Random samples of live births were selected as controls. Generalized additive models were used to create a continuous map surface of odds ratios (ORs) by smoothing over latitude and longitude. Maternal age, race/ethnicity, education, cigarette smoking, and insurance status (MA only) were assessed for confounding. We used permutation tests to identify statistically significant areas of increased risk.ResultsAn area of increased risk was identified in North Central Massachusetts but was not significant after adjustment (P value = .07; OR = 2.0). In Texas, two statistically significant areas of increased risk were identified after adjustment (P value = .02; OR = 1.3 and 1.2). Texas had sufficient data to assess the combination of space and time, which identified an increased risk in 2003 and 2004.ConclusionsThis study suggests there were areas of elevated gastroschisis risk in Massachusetts and Texas, which cannot be explained by the risk factors we assessed. Additional exploration of underlying artifactual, environmental, infectious, or behavioral factors may further our understanding of gastroschisis.

Little is known epidemiologically about laterality defects. Using data from the National Birth Defects Prevention Study (NBDPS), a large multi-site case-control study of birth defects, we analyzed prevalence and selected characteristics in children born with laterality defects born from 1998 to 2007. We identified 517 nonsyndromic cases (378 heterotaxy, 73.1%; 139 situs inversus totalis [SIT], 26.9%) resulting in an estimated birth prevalence of 1.1 per 10,000 live births (95% confidence interval 1.0–1.2). Prevalence did not differ significantly across sites, over time, or by inclusion of pregnancy termination. Laterality defects were more common among preterm cases compared to term cases, and in children born to mothers who were non-white or younger than 20 years compared to white mothers or those age 25–29 years. The distribution of associated cardiac and extra-cardiac defects, excluding the expected heterotaxy anomalies, varied by type of laterality defect. Cases with heterotaxy were significantly more likely than those with SIT to have double outlet right ventricle, atrioventricular canal defects, pulmonary stenosis, non-tetralogy of Fallot pulmonary atresia with ventricular septal defect, totally and partially anomalous pulmonary venous return; also more likely to have orofacial clefts, esophageal atresia, bowel atresias, and omphalocele, though not reaching statistical significance. Relatively more common among cases with SIT were Dandy- Walker malformation, anotia/microtia, and limb deficiency. The similarity in the demographic characteristics of heterotaxy and SIT supports the hypothesis that they are part of a continuum of abnormal left-right axis patterning. These findings on laterality defects may help guide clinical care, future research, and prevention strategies.

Since 1997, the National Birth Defects Prevention Network (NBDPN), in collaboration with the Centers for Disease Control and Prevention (CDC), has published data on major birth defects affecting the central nervous, eye, ear, cardiovascular, orofacial, gastrointestinal, genitourinary, and musculoskeletal systems, as well as trisomies, amniotic bands, and fetal alcohol syndrome, from population-based birth defects surveillance programs in the United States. Annually, the NBDPN Data Committee issues a data request to population-based birth defects programs for data on 47 major birth defects; the specific defects with accompanying diagnostic codes are detailed in Appendix 1 on page 10. This year’s report containing data from 41 population-based birth defects surveillance programs for births occurring from January 1, 2005, through December 31, 2009, is available as a supplement on pages. The data are presented by racial/ethnic groups for all defects and additionally by maternal age for triso-mies 13, 18, and 21. To calculate prevalence, programs were also asked to provide the number of total live births and male live births for each calendar year submitted. The standard method for calculating birth defects prevalence is to divide the number of cases (birth defect for any pregnancy outcome) by total live births for the catchment area and then multiply by 10,000 to obtain the prevalence per 10,000 live births; Mason et al. (2005) provide further detail and rationale for this approach. This methodology is used for all defects except hypospadias, which is calculated using a denominator of total male live births. An attempt was made to standardize both the submitted data and presentation of state surveillance data, however, differences in the way programs collect and report birth defects data are listed in the footnotes of the accompanying tables and may be referenced in the program directories on pages S121-S169 (online). Some programs were able to only provide data for selected years, were unable to report counts and prevalence by race/ethnicity, or were unable to provide data for each specific defect requested due to differences in the coding systems (i.e., International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] vs CDC/British Pediat-ric Association [BPA]) Classification of Diseases used to classify birth defects. Critical Congenital Heart Defects Targeted for Pulse Oximetry Screening This year’s data report includes several enhancements to address the interest in pulse oximetry screening of new-borns for critical congenital heart defects (CCHDs). Congenital heart defects (CHDs) occur in an estimated 1 in 110 births in the United States (Reller et al., 2008) and approximately 25% of CHDs are considered CCHDs, defined as requiring surgery or catheter intervention within the first year of life (Mahle et al., 2009). Children with CCHDs are at risk for death or disability if the defect is not detected shortly after birth (Mahle et al., 2009). Thus, in 2011, the Secretary of Health and Human Services recommended that CCHDs be added to the U.S. Recommended Uniform Screening Panel for newborns (Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children, 2011). When implemented, newborns would undergo pulse oximetry screening for CCHDs after 24 hours of life, which detects low blood oxygen levels (hypoxemia). The Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (2011) named seven CCHDs as primary targets for screening: common truncus, d-transposition of the great arteries, tetralogy of Fallot, pulmonary valve atresia, tricuspid valve atresia, hypoplastic left heart syndrome, and total anomalous pulmonary venous return (Mahle et al., 2009; Kemper et al., 2011). Other CCHDs may also be detected using pulse oximetry screening, but because they may not consistently have hypoxemia at or soon after birth, their identification would be variable and incomplete. The following CCHDs are considered secondary targets of pulse oximetry screening: coarctation of the aorta, double outlet right ventricle, Ebstein anomaly, interrupted aortic arch, single ventricle, severe aortic stenosis and severe pulmonary stenosis (Mahle et al., 2009). The implementation of pulse oximetry screening for CCHDs is currently underway in a few states, with more considering legislation and implementation (Olney and Botto, 2012). Surveillance case definitions, including both ICD-9-CM and CDC/BPA diagnostic codes, for each of the seven primary CCHD targets of pulse oximetry screening are presented in Appendix 2. In using these case definitions, it is important to consider as a potential limitation the coding system’s ability to capture cases of CCHDs. Three of the seven conditions (‘pulmonary valve atresia and stenosis’, ‘tricuspid valve atresia and stenosis’, and ‘transposition of the great arteries’) include both broad codes to capture all possible cases that are generally collected for surveillance purpose and more refined codes that are targeted for newborn screening of CCHDs using pulse oximetry. For example, the surveillance category of ‘tricuspid valve atresia and stenosis’ encompasses both tricuspid valve atresia (one of the seven targeted CCHDs) as well as milder cases of tricuspid stenosis. Programs that are able to use more refined codes provided data separately for pulmonary valve atresia, tricuspid valve atresia, and d-transposition of the great arteries.

Clubfoot is a common structural malformation, occurring in approximately 1/1,000 live births. Previous studies of sociodemographic and pregnancy-related risk factors have been inconsistent, with the exception of the strong male preponderance and association with primiparity. Hypotheses for clubfoot pathogenesis include fetal constraint, Mendelian-inheritance, and vascular disruption, but its etiology remains elusive. We conducted a population-based case-control study of clubfoot in North Carolina, Massachusetts, and New York from 2007 to 2011. Mothers of 677 clubfoot cases and 2,037 non-malformed controls were interviewed within 1 year of delivery about socio-demographic and reproductive factors. Cases and controls were compared for child's sex, maternal age, education, cohabitation status, race/ethnicity, state, gravidity, parity, body mass index (BMI), and these pregnancy-related conditions: oligohydramnios, breech delivery, bicornuate uterus, plural birth, early amniocentesis (

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.

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.

Objective To assess the validity of outcome data reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) compared with data from vital records and the birth defects registry in Massachusetts. Design Longitudinal cohort. Setting Not applicable. Participant(s) A total of 342,035 live births and fetal deaths from Massachusetts mothers giving birth in the state from July 1, 2004, to December 31, 2008; 9,092 births and fetal deaths were from mothers who had conceived with the use of assisted reproductive technology (ART) and whose cycle data had been reported to the SART CORS. Intervention(s) Not applicable. Main Outcome Measure(s) Percentage agreement between maternal race and ethnicity, delivery outcome (live birth or fetal death), plurality (singleton, twin, or triplet+), delivery date, and singleton birth weight reported in the SART CORS versus vital records; sensitivity and specificity for birth defects among singletons as reported in the SART CORS versus the Massachusetts Birth Defects Monitoring Program (BDMP). Result(s) There was >95% agreement between the SART CORS and vital records for fields of maternal race/ethnicity, live birth/fetal death, and plurality; birth outcome date was within 1 day with 94.9% agreement and birth weight was within 100 g with 89.6% agreement. In contrast, sensitivity for report of any birth defect was 38.6%, with a range of 18.4%–50.0%, for specific birth defect categories. Conclusion(s) Although most SART CORS outcome fields are accurately reported, birth defect variables showed poor sensitivity compared with the gold standard data from the BDMP. We suggest that reporting of birth defects be discontinued.

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

Objective To evaluate the hypothesis that children with craniosynostosis and their parents have differences in psychosocial outcomes, as compared with an unaffected control group. Design Two studies were conducted, both which followed children born with and without craniosynostosis. Study 1 ascertained affected children from clinics, and study 2 ascertained affected children from a population-based study of birth defects. Participants Study 1 included 22 children with single-suture craniosynostosis and 18 controls, ages 4 to 5 years. Study 2 included 24 children with nonsyndromic craniosynostosis and 124 unaffected controls, ages 5 to 9 years. Main Outcome Measures Outcome measures included the Child Behavior Checklist, Social Competence Scale, Pediatric Quality of Life Inventory, and Parenting Stress Index. Results We observed lower scores on measures of health-related quality of life in cases versus controls, with adjusted effect sizes ranging from −0.72 to −0.44 ( p < .05) on summary measures. Small but statistically nonsignificant increases in behavioral problems were observed in cases versus controls, with no apparent differences in social competence or parenting stress. Conclusions Results provide preliminary evidence suggesting that children with nonsyndromic craniosynostosis may have elevated risk for psychosocial difficulties, particularly health-related quality of life. Continued follow-up through preadolescence and adolescence is warranted.

We examined whether the use of nonsteroidal antiinflammatory drugs (NSAIDs) in early pregnancy was associated with a range of structural birth defects.Data were from the National Birth Defects Prevention Study, a multisite population-based, case-control study of risk factors for birth defects.Among women in the National Birth Defects Prevention Study, 22.6% reported the use of NSAIDs in the first trimester of pregnancy, most commonly ibuprofen, aspirin, and naproxen. Of the 29 defect groups that were examined, most were not associated with NSAID use. Small-to-moderate increased risks of some oral cleft groups, some neural tube defect groups, anophthalmia/microphthalmia, pulmonary valve stenosis, amniotic bands/limb body wall defects, and transverse limb deficiencies were associated with ibuprofen, aspirin, and naproxen exposure.The use of NSAIDs in early pregnancy does not appear to be a major risk factor for birth defects, although there were a few moderate associations between NSAIDs and specific birth defects.

BACKGROUND: Nausea and vomiting of pregnancy (NVP) occurs in up to 80% of pregnant women, but its association with birth outcomes is not clear. Several medications are used for the treatment of NVP; however, data are limited on their possible associations with birth defects. METHODS: Using data from the National Birth Defects Prevention Study (NBDPS)—a multi-site, population-based, case-control study—we examined whether NVP or its treatment was associated with the most common noncardiac defects in the NBDPS (nonsyndromic cleft lip with or without cleft palate [CL/P], cleft palate alone [CP], neural tube defects, and hypospadias) compared with randomly selected nonmalformed live births. RESULTS: Among the 4524 cases and 5859 controls included in this study, 67.1% reported first-trimester NVP, and 15.4% of them reported using at least one agent for NVP. Nausea and vomiting of pregnancy was not associated with CP or neural tube defects, but modest risk reductions were observed for CL/P (adjusted odds ratio [aOR] 5 0.87; 95% confidence interval [CI], 0.77–0.98) and hypospadias (aOR 5 0.84; 95% CI, 0.72–0.98). Regarding treatments for NVP in the first trimester, the following adjusted associations were observed with an increased risk: proton pump inhibitors and hypospadias (aOR 5 4.36; 95% CI, 1.21–15.81), steroids and hypospadias (aOR 5 2.87; 95% CI, 1.03–7.97), and ondansetron and CP (aOR 5 2.37; 95% CI, 1.18–4.76), whereas antacids were associated with a reduced risk for CL/P (aOR 5 0.58; 95% CI, 0.38–0.89). CONCLUSIONS: NVP was not observed to be associated with an increased risk of birth defects; however, possible risks related to three treatments (i.e., proton pump inhibitors, steroids and ondansetron), which could be chance findings, warrant further investigation. Birth Defects Research (Part A) 94:22–30, 2012. 2011 Wiley Periodicals, Inc.

Background: Evidence on the association between antibiotic use and combined oral contraceptive (COC) failure is controversial. We examined the effect of concomitant antibiotic treatment on the risk of breakthrough pregnancy among COC users.Study Designs: We performed a case-crossover study of 1330 COC failure cases among 17,721 women from the Slone Epidemiology Center Birth Defects Study (1997-2008) and among 25,941 women from the National Birth Defects Prevention Study (NBDPS, 1997-2005). Self-matched odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by comparing antibiotic use between the 4 weeks before conception ("case period") and the 4-8 weeks before conception ("control period") using conditional logistic regression. A case time-control analysis was conducted using nonusers of COCs with unplanned pregnancies as controls.Results: For the combined data, the self-matched OR was 1.08 (95% CI: 0.63-1.84) and the case time-control OR was 1.12 (0.63-1.98) for antibiotics overall. The results did not appreciably differ when adjusted for characteristics that might vary between the case and control period. However, among COC failure cases from the NBDPS, allowing a 1-month gap between the case and control period resulted in a self-matched OR of 1.45 (0.85-2.50) and a case time-control OR of 1.55 (0.86-2.79) for antibiotics overall.Conclusions: We did not find an association between concomitant antibiotic use and the risk of breakthrough pregnancy among COC users. However, due to limited power and potential carryover effects, findings from this study cannot rule out an elevated risk of COC failure among antibiotic users. (C) 2011 Elsevier Inc. All rights reserved.

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.

Objectives. To describe maternal exposure to tobacco in the three months before conception and throughout pregnancy, examine risk factors associated with tobacco exposure in pregnancy and smoking cessation, assess use of pharmacotherapy for smoking cessation and evaluate birth outcomes by smoking status. Design. A cohort of women from a multi-site United States study were asked retrospectively about their exposure to tobacco. Population. The study population was comprised of 4,667 mothers of non-malformed control infants who participated in the National Birth Defects Prevention Study from 1997 to 2003. Methods. Using computer-assisted telephone interview responses from this population-based sample, we assessed patterns of maternal smoking and exposure to environmental tobacco smoke (ETS) as well as use of pharmacotherapy for quitting smoking during pregnancy. Results. Overall, 961 (20.6%) mothers reported any smoking and 1,401 (30.0%) reported any exposure to ETS at home or work during the three months before conception through pregnancy. Of the 961 smokers, 512 (53.3%) reportedly quit smoking before or during pregnancy, including 379 (74% of quitters) in the first trimester, and 420 (43.7%) continued to smoke throughout the pregnancy. Only 2.1% of smokers reportedly used pharmacotherapy to quit smoking anytime from three months before conception through pregnancy. Low birthweight and preterm delivery rates were lowest among offspring of non-smokers and highest in offspring of those who continued to smoke throughout pregnancy. Conclusions. About one-half of mothers who reported preconceptional smoking quit before or during pregnancy. Use of pharmacotherapy to quit smoking during pregnancy was not common.