Objective: To examine associations between maternal use of cough medications containing dextromethorphan (DM) without guaifenesin (glyceryl guaiacolate (GG)) (‘DM alone’), GG without DM (‘GG alone’) or DM +GG and major birth defects in offspring.
Design: Population-based case–control study.
Setting: The multisite, US National Birth Defects Prevention Study.
Participants: Mothers of 1644 children with neural tube defects (NTDs), 15 110 with non-NTDs, and 10 671 control children without a birth defect diagnosis.
Main outcome measures: ORs and 95% CIs.
Results: For NTD analysis, 1.7% of mothers of case children and 1.2% of mothers of control children reported using DM alone, 1.1% and 0.6% GG alone, and 0.4% and 0.2% DM +GG. Respective percentages for non-NTD analysis were 2.2% and 1.9% for DM alone, 1.7% and 1.6% for GG alone, and 0.5% and 0.4% for DM +GG. For all NTDs and subtypes, adjusted OR estimates for DM alone were near the null with 95% CIs that included 1.0. Estimates (95% CI) were 1.8 (1.0 to 3.3) for GG alone and 1.8 (0.6 to 4.8) for DM +GG with all NTDs and 2.2 (1.1 to 4.3) for GG alone with spina bifida. Of the 45 adjusted OR estimates for non-NTDs, 39 ranged from 0.5 to 1.6 with 95% CIs that included 1.0. Near twofold or higher estimates (95% CI) were observed for the remainder and included 1.9 (1.0 to 3.7) for hydrocephalus, 2.9 (1.3 to 6.5) for atrioventricular septal defect and 1.8 (1.1 to 3.0) for transverse limb deficiency with DM alone; 2.1 (1.1 to 4.0) for small intestinal atresia/stenosis and 2.1 (0.9 to 4.5) for omphalocele with GG alone; and 3.2 (1.5 to 6.9) for gastroschisis with DM +GG.
Conclusions: Maternal use of medications containing DM alone, GG alone or DM +GG showed positive associations with a small number of birth defects. These observations, which should be interpreted with caution due to small proportions of exposed mothers, may represent true signals or chance findings and warrant evaluation in future studies.

Background: Congenital heart defects (CHDs) are the leading cause of infant death from birth defects. Animal studies suggest in utero alcohol exposure is a teratogen for cardiogenesis; however, results from epidemiologic studies are mixed.
Methods: Data from the National Birth Defects Prevention Study were used to estimate associations between CHDs and case (n = 7076) and control (n = 7972) mother reports of periconceptional (1 month before pregnancy through the first trimester) alcohol consumption with expected delivery dates during 1997 to 2007. CHDs were examined by category (conotruncal, septal, left ventricular outflow tract obstruction, and right ventricular outflow tract obstruction, heterotaxy with CHD) and subtype (e.g., tetralogy of Fallot [TOF]). Alcohol measures examined were any consumption, maximum average drinks per month, binge drinking, and alcohol type. Adjusted odds ratios and 95% confidence intervals were estimated using unconditional logistic regression analysis.
Results: Increased risks, albeit marginally statistically significant, were observed for TOF and each maternal alcohol measure examined and for right ventricular outflow tract obstruction and heterotaxy with CHD and consumption of distilled spirits. Significantly reduced risks were observed for several CHD categories (septal defects, left ventricular outflow tract obstruction, and right ventricular outflow tract obstruction) and some corresponding subtypes with different alcohol measures. Significant risks were not observed for the other CHDs examined.
Conclusion: Analysis of this large, well-defined study sample did not show statistically significant increased risks between measures of maternal alcohol consumption and most CHDs examined. These findings may reflect, in part, limitations with retrospective exposure assessment or unmeasured confounders. Additional studies with continued improvement in measurement of alcohol consumption are recommended.

Background: Women of childbearing age report high rates of alcohol consumption, which may result in alcohol exposure during early pregnancy. Epidemiological research on congenital limb deficiencies (LDs) and periconceptional exposure to alcohol is inconclusive.
Methods: Data from the National Birth Defects Prevention Study (NBDPS) were examined for associations between LDs and patterns of maternal periconceptional (1 month before conception through the first trimester) alcohol consumption among LD case (n = 906) and unaffected control (n = 8352) pregnancies with expected delivery dates from 10/1997 through 12/2007. Adjusted odds ratios (aORs) and 95% confidence intervals were estimated from unconditional logistic regression analysis for all LDs combined, specific LD subtypes (preaxial/terminal transverse), and LD anatomic groups (upper/lower limbs); interactions with folic acid (FA) supplementation were tested.
Results: When compared with nondrinkers, inverse associations were found between all LDs combined, preaxial, and upper LDs and any reported periconceptional alcohol consumption (aORs ranged from 0.56-0.83), drinking without binging (aORs: 0.53-0.75), and binge drinking (≥4 drinks/occasion) (aORs: 0.64-0.94); however, none of the binge drinking aORs were statistically significant. Stratification by alcohol type showed inverse associations between all LDs combined, preaxial, transverse, and upper and lower LDs for drinking without binging of wine only (aORs: 0.39-0.67) and between all LDs combined and upper LDs for drinking without binging of combinations of alcohol (aORs: 0.63-0.87). FA did not modify observed associations.
Conclusion: Maternal periconceptional alcohol consumption did not emerge as a teratogen for selected LDs in the NBDPS. Future studies should evaluate additional rare LDs among more highly exposed populations.

Background: Adverse associations between maternal pesticide exposure and neural tube defects (NTDs) have been suggested but not consistently observed. This study used data from the multisite National Birth Defects Prevention Study to examine associations between maternal periconceptional (1 month preconception through 2 months postconception) occupational pesticide exposure and NTDs.
Methods: Mothers of 502 NTD cases and 2950 unaffected live-born control infants with estimated delivery dates from 1997 through 2002 were included. Duration, categorical intensity scores, and categorical frequency scores for pesticide classes (e.g., insecticides) were assigned using a modified, literature-based job-exposure matrix and maternal-reported occupational histories. Adjusted odds ratios (aORs) and 95% confidence intervals were estimated based on fitted multivariable logistic regression models that described associations between maternal periconceptional occupational pesticide exposure and NTDs. The aORs were estimated for pesticide exposure (any [yes/no] and cumulative exposure [intensity × frequency × duration] to any pesticide class, each pesticide class, or combination of pesticide classes) and all NTD cases combined and NTD subtypes.
Results: Positive, but marginally significant or nonsignificant, aORs were observed for exposure to insecticides + herbicides for all NTD cases combined and for spina bifida alone. Similarly, positive aORs were observed for any exposure and cumulative exposure to insecticides + herbicides + fungicides and anencephaly alone and encephalocele alone. All other aORs were near unity.
Conclusion: Pesticide exposure associations varied by NTD subtype and pesticide class. Several aORs were increased, but not significantly. Future work should continue to examine associations between pesticide classes and NTD subtypes using a detailed occupational pesticide exposure assessment and examine pesticide exposures outside the workplace.

Choanal atresia causes serious posterior nasal obstruction. This defect is the leading cause of nasal surgery in newborns, although its etiology is largely unknown. Data from the National Birth Defects Prevention Study, a population-based case-control study, were used to examine associations between maternal self-reports of exposures and occurrence of choanal atresia in their offspring. Overall, 117 case and 8350 control mothers with deliveries from 1997 through 2007 provided telephone interview reports of pre-pregnancy (one year before conception) and periconceptional (one month before through three months after conception) exposures. The exposures analyzed were pre-pregnancy dietary intake, pre-pregnancy and periconceptional caffeine consumption, and periconceptional cigarette smoking, alcohol drinking, and medication use. Independent associations between each exposure and all choanal atresia cases combined (n = 117) and isolated choanal atresia cases (those without additional unrelated major defects; n = 61) were examined. Odds ratios (ORs), both unadjusted (uORs) and adjusted (aORs) for potential confounders, and 95% confidence intervals (CIs) were estimated using unconditional logistic regression analysis. For all choanal atresia cases combined, positive associations were observed with maternal pre-pregnancy intake in the highest quartile for vitamin B-12 (aOR = 1.9; CI = 1.1,3.1), zinc (aOR = 1.7; CI = 1.0,3.1), and niacin (aOR = 1.8; CI = 1.0,3.1), and intake in the lowest quartile for methionine (aOR = 1.6; CI = 1.0,2.6) and vitamin D (aOR = 1.6; CI = 1.0,2.4) compared to intake in the two intermediate quartiles combined. Further, a positive association was observed with periconceptional use of thyroid medications (uOR = 2.6; CI = 1.0,6.3) compared to no use of such medications. Among isolated choanal atresia cases, negative associations were observed for pantothenic acid (aOR = 0.4; CI = 0.2,0.9) and fat (aOR = 0.5; 95% CI = 0.2,1.0) intake in the lowest quartile compared to that in the intermediate quartiles, and positive associations were observed for periconceptional cigarette smoking (aOR = 2.3; CI = 1.1,4.7) compared to no smoking and pre-pregnancy daily coffee intake of 3 or more cups (aOR = 2.5; CI = 1.1,5.6) compared to intake of less than 1 cup per day. The positive association for periconceptional exposure to thyroid medications also persisted for isolated choanal atresia cases (uOR = 4.0; CI = 1.1,11.2). Because of the large number of associations tested, these findings may be due to chance. Alternatively, they may contribute new hypotheses regarding the etiology of choanal atresia; thus, requiring replication in additional studies.

Previous epidemiologic studies of maternal exposure to drinking water nitrate did not account for bottled water consumption. The objective of this National Birth Defects Prevention Study (NBDPS) (USA) analysis was to assess the impact of bottled water use on the relation between maternal exposure to drinking water nitrate and selected birth defects in infants born during 1997-2005. Prenatal residences of 1,410 mothers reporting exclusive bottled water use were geocoded and mapped; 326 bottled water samples were collected and analyzed using Environmental Protection Agency Method 300.0. Median bottled water nitrate concentrations were assigned by community; mothers’ overall intake of nitrate in mg/day from drinking water was calculated. Odds ratios for neural tube defects, limb deficiencies, oral cleft defects, and heart defects were estimated using mixed-effects models for logistic regression. Odds ratios (95% CIs) for the highest exposure group in offspring of mothers reporting exclusive use of bottled water were: neural tube defects [1.42 (0.51, 3.99)], limb deficiencies [1.86 (0.51, 6.80)], oral clefts [1.43 (0.61, 3.31)], and heart defects [2.13, (0.87, 5.17)]. Bottled water nitrate had no appreciable impact on risk for birth defects in the NBDPS.

Background: Neural tube defects (NTD)s, which occur when the neural tube fails to close during early gestation, are some of the most common birth defects worldwide. Alcohol is a known teratogen and has been shown to induce NTDs in animal studies, although most human studies have failed to corroborate these results. Using data from the National Birth Defects Prevention Study, associations between maternal reports of periconceptional (1 month prior through 2 months postconception) alcohol consumption and NTDs were examined.
Methods: NTD cases and unaffected live born control infants, delivered from 1997 through 2005, were included. Interview reports of alcohol consumption (quantity, frequency, variability, and type) were obtained from 1223 case mothers and 6807 control mothers. Adjusted odds ratios (aOR)s and 95% confidence intervals were estimated using multivariable logistic regression analysis.
Results: For all NTDs combined, most aORs for any alcohol consumption, one or more binge episodes, and different type(s) of alcohol consumed were near unity or modestly reduced (≥ 0.7 < aOR ≤ 1.1) and were not statistically significant. Findings were similar for individual NTD subtypes.
Conclusions: These findings suggest no elevated association between maternal periconceptional alcohol consumption and NTDs. Underreporting of alcohol consumption, due to negative social stigma associated with alcohol consumption during pregnancy, and limited reports for mothers with early pregnancy loss of a fetus with an NTD may have affected the estimated odds ratios. Future studies should aim to increase sample sizes for less prevalent subtypes, reduce exposure misclassification, and improve ascertainment of fetal deaths and elective terminations.

Background: Many epidemiological and public health surveys report increasing difficulty obtaining high participation rates. We conducted a pilot follow-up study to determine whether a mailed or telephone survey would better facilitate data collection in a subset of respondents to an earlier telephone survey conducted as part of the National Birth Defects Prevention Study.
Methods: We randomly assigned 392 eligible mothers to receive a self-administered, mailed questionnaire (MQ) or a computer-assisted telephone interview (CATI) using similar recruitment protocols. If mothers gave permission to contact the fathers, fathers were recruited to complete the same instrument (MQ or CATI) as mothers.
Results: Mothers contacted for the MQ, within all demographic strata examined, were more likely to participate than those contacted for the CATI (86.6% vs. 70.6%). The median response time for mothers completing the MQ was 17 days, compared to 29 days for mothers completing the CATI. Mothers completing the MQ also required fewer reminder calls or letters to finish participation versus those assigned to the CATI (median 3 versus 6), though they were less likely to give permission to contact the father (75.0% vs. 85.8%). Fathers contacted for the MQ, however, had higher participation compared to fathers contacted for the CATI (85.2% vs. 54.5%). Fathers recruited to the MQ also had a shorter response time (median 17 days) and required fewer reminder calls and letters (median 3 reminders) than those completing the CATI (medians 28 days and 6 reminders).
Conclusions: We concluded that offering a MQ substantially improved participation rates and reduced recruitment effort compared to a CATI in this study. While a CATI has the advantage of being able to clarify answers to complex questions or eligibility requirements, our experience suggests that a MQ might be a good survey option for some studies.

Background: Congenital limb deficiencies (LD)s are characterised by the failure or disruption in formation of limbs or digits. Epidemiological research on maternal exposure to cigarette smoke and LDs is inconclusive.
Methods: Data from the National Birth Defects Prevention Study were used to examine LDs and maternal exposure to active or passive cigarette smoke. Mothers of LD case (n = 906) and unaffected control (n = 8352) pregnancies from October 1997 through December 2007 reported on exposure type and quantity. Logistic regression was used to estimate adjusted odds ratio (OR) and 95% confidence interval [95% CI]; interactions with folic acid (FA) intake were tested.
Results: For any LD, ORs were elevated for active (1.24 [95% CI 1.01, 1.53]), passive (home) (1.28 [95% CI 1.03, 1.59]), and ‘active and passive’ (1.34 [95% CI 1.05, 1.70]) exposures. The ORs for longitudinal LDs were elevated for passive (home) (1.62 [95% CI 1.14, 2.31]) and ‘active and passive’ (1.62 [95% CI 1.09, 2.41]) exposures. The OR for pre-axial LDs were elevated for any (1.39 [95% CI 1.01, 1.90]), active (1.53 [95% CI 1.03, 2.29]), passive (home) (1.82 [95% CI 1.23, 2.69]), and ‘active and passive’ (1.87 [95% CI 1.20, 2.92]) exposures. For lower limbs, ORs were elevated for passive (home) (1.44 [95% CI 1.01, 2.04]) and smoking 15 or more cigarettes/day (2.25 [95% CI 1.27, 3.97]). Interactions showed that ORs for any passive smoke exposure were 0.43 and 0.59 higher in the absence of FA intake for any and terminal transverse LDs.
Conclusions: Maternal active smoking and exposure to passive cigarette smoke emerged as a potential teratogen that affects limb and digit formation. FA was not found to mitigate the impact.

Background: Animal studies demonstrate teratogenic effects of caffeine, whereas human studies are inconclusive.
Methods: Associations between maternal caffeine consumption and neural tube defects (NTDs) by type of NTD (anencephaly, spina bifida, or encephalocele) were examined using data from the National Birth Defects Prevention Study (NBDPS). Total average daily caffeine from coffee, tea, soda, and chocolate consumption during the year before pregnancy was estimated for 768 mothers of infants with NTDs and 4143 mothers of infants without birth defects who gave birth during 1997 through 2002. Periconceptional use of caffeine-containing medications was evaluated separately. Adjusted odds ratios (OR) and 95% confidence intervals (CI) associated with consumption of total caffeine and each caffeine source were estimated from logistic regression models.
Results: Positive associations were observed between spina bifida and total caffeine consumption (OR 1.4; 95% CI: 1.1-1.9) and each caffeine source except caffeinated tea, which showed a negative association with spina bifida (OR 0.7; 95% CI: 0.6-0.9). Associations with modestly increased risk of NTDs and encephalocele were also observed. The association between caffeine consumption and anencephaly differed by maternal race/ethnicity. No dose effects were found.
Conclusions: Additional studies should confirm whether women who consume caffeine are at increased risk for pregnancies complicated by NTDs.

Methods: This study used data from the National Birth Defects Prevention Study (NBDPS) to examine the association between maternal periconceptional exposure to cigarette smoking and alcohol and EA+/-TEF. Cases of EA+/-TEF and unaffected controls with an estimated date of delivery from October 1997 through December 2003 were identified, and telephone interview reports for smoking and alcohol exposure were obtained from birth mothers of 334 cases and 4,967 controls. Odds ratios (OR)s and 95% confidence intervals (CI)s, adjusted for several covariates, were calculated to assess associations.
Background: Esophageal atresia (EA) is a moderately frequent birth defect that often occurs with tracheo-esophageal fistula (TEF). Etiologic studies for EA+/-TEF have produced inconsistent results.
Results: ORs were near unity for all EA+/-TEF cases combined and any periconceptional exposure to cigarette smoking (OR = 1.1; CI = 0.8,1.6) or alcohol (OR = 1.2; CI = 0.8,1.8). For cigarette smoking, some elevated ORs were found but varied by type of smoking exposure. No consistent patterns were identified for number of cigarettes smoked per day. For alcohol, ORs were weak to moderately elevated with increasing number of drinks consumed and for binge drinkers compared to non-binge drinkers. ORs were further elevated among mothers who reported active+passive exposure to cigarette smoking and alcohol (OR = 2.5; CI = 1.1,5.6). For both exposures, ORs were higher for cases with additional major defects compared to isolated cases.
Conclusions: These results, based on one of the largest published samples of EA+/-TEF cases, suggest a role for these exposures in the etiology of EA+/-TEF, although further study is needed to replicate the observed associations.

Using data from the National Birth Defects Prevention Study, the authors investigated the association between maternal reports of periconceptional alcohol consumption and clefting. Cases with a cleft lip, cleft palate, or both and unaffected controls delivered from 1997 through 2002 were ascertained. Interview reports of alcohol consumption were obtained from 1,749 (75.1%) case and 4,094 (68.2%) control mothers. Adjusted odds ratios and 95% confidence intervals were calculated to assess associations. Compared with odds ratios for mothers with no reported consumption, those for mothers who consumed alcohol tended to be near to (cleft lip, cleft lip with cleft palate) or to exceed (cleft palate) unity. The odds ratios associated with binge drinking were elevated but did not demonstrate significantly increased risk for any phenotype; however, the odds ratios differed by the type of alcohol consumed, particularly for cleft palate (distilled spirits > wine > beer). These odds ratios were further increased among mothers with no reported folic acid intake. Although these findings suggest that the association between alcohol consumption and clefting might be most influenced by the type of beverage consumed and folic acid intake, they are preliminary and might reflect chance associations. Such findings need exploration in additional, large studies.