Folic acid antagonist use before and during pregnancy and risk for selected birth defects.

BACKGROUND: Maternal folic acid (FA) intake before and during early pregnancy reduces the risk for neural tube defects (NTDs); evidence suggests it may also reduce the risk for oral clefts, urinary defects, and cardiac defects. We sought to re-examine the use of drugs, which affect folate metabolism, dihydrofolate reductase inhibiting (DHFRI) medications, and anti-epileptic drugs (AEDs), in data collected in the post-FA fortification era (1998+) in the Slone Birth Defects Study. METHODS: We assessed maternal DHFRI and AED use and risk for NTDs, oral clefts, and urinary and cardiac defects. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. We assessed daily average FA intake of ≥400 mcg as a potential effect modifier. RESULTS: We analyzed data from 10,209 control and 9,625 case mothers. Among controls, the prevalence of exposure to DHFRI medications was 0.3% and to AEDs was 0.5%. Maternal use of AEDs was associated with increased risks for NTDs (OR: 3.4; 95% CI: 1.5, 7.5), oral clefts (OR: 2.3; 95% CI: 1.3, 4.0), urinary defects (OR: 1.6; 95% CI: 1.0, 2.7), and cardiac defects (OR: 1.6; 95% CI: 1.1, 2.3); similar or further increased risks were found among those with FA intake ≥400 mcg per day. DHFRI use was rare and relative risk estimates were imprecise and consistent with the null. CONCLUSIONS: Similar to our previous analyses, we observed associations between AED use and these defects. For DHFRI exposure, we found no evidence for increased risk of these defects. Though statistical power to examine FA effect modification was low, we found no evidence of further protection among those with FA intake ≥400 mcg, with some associations somewhat stronger in this group.

Maternal Use of Specific Antidepressant Medications During Early Pregnancy and the Risk of Selected Birth Defects.

Importance: Antidepressants are commonly used during pregnancy, but limited information is available about individual antidepressants and specific birth defect risks. Objective: To examine associations between individual antidepressants and specific birth defects with and without attempts to partially account for potential confounding by underlying conditions. Design, Setting, and Participants: The population-based, multicenter case-control National Birth Defects Prevention Study (October 1997-December 2011) included cases with selected birth defects who were identified from surveillance systems; controls were randomly sampled live-born infants without major birth defects. Mothers of cases and controls participated in an interview after the expected delivery date. The data were analyzed after the completion of the National Birth Defects Prevent Study's data collection. Exposures: Self-reported antidepressant exposure was coded to indicate monotherapy exposure to antidepressants. Main Outcomes and Measures: We used multivariable logistic regression to calculate adjusted odds ratios (aORs) and 95% confidence intervals for associations between maternal antidepressant use and birth defects. We compared early pregnancy antidepressant-exposed women with those without antidepressant exposure and, to partially account for confounding by underlying maternal conditions, those exposed to antidepressants outside of the birth defect development critical period. Results: This study included 30 630 case mothers of infants with birth defects and 11 478 control mothers (aged 12-53 years). Early pregnancy antidepressant use was reported by 1562 case mothers (5.1%) and 467 control mothers (4.1%), for whom elevated aORs were observed for individual selective serotonin reuptake inhibitors (SSRIs) and selected congenital heart defects (CHD) (eg, fluoxetine and anomalous pulmonary venous return: aOR, 2.56; 95% CI, 1.10-5.93; this association was attenuated after partially accounting for underlying conditions: aOR, 1.89; 95% CI, 0.56-6.42). This pattern was observed for many SSRI-CHD combinations. Associations between SSRIs and non-CHD birth defects often persisted or strengthened after partially accounting for underlying conditions (eg, citalopram and diaphragmatic hernia: aOR, 5.11; 95% CI, 1.29-20.24). Venlafaxine had elevated associations with multiple defects that persisted after partially accounting for underlying conditions (eg, anencephaly and craniorachischisis: aOR, 9.14; 95% CI, 1.91-43.83). Conclusions and Relevance: We found some associations between maternal antidepressant use and specific birth defects. Venlafaxine was associated with the highest number of defects, which needs confirmation given the limited literature on venlafaxine use during pregnancy and risk for birth defects. Our results suggest confounding by underlying conditions should be considered when assessing risk. Fully informed treatment decision-making requires balancing the risks and benefits of proposed interventions against those of untreated depression or anxiety.

Periconceptional folic acid and risk for neural tube defects among higher risk pregnancies.

BACKGROUND: Women with a previous neural tube defect (NTD)-affected pregnancy are recommended to consume 4,000 µg daily folic acid (FA) for prevention (10 times the general-population recommendation). Protection from doses between 400 and 4,000 µg for this and other higher risk groups is unclear. METHODS: In the case-control Slone Birth Defects Study (1988-2015), we examined the associations between periconceptional FA doses and NTDs among four higher risk groups: NTD family history, periconceptional antiepileptic drug exposure (AED), pregestational diabetes, and prepregnancy obesity. Mothers completed standardized interviews about pregnancy events and exposures. FA categorizations were based on (a) supplements only and (b) supplements and diet ("total folate"). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) (adjusted for age and study center) using logistic regression. RESULTS: Cases and controls included: 45 and 119 with family history, 25 and 108 with AED exposure, 12 and 63 with pregestational diabetes, 111 and 1,243 with obesity. Daily FA supplementation was associated with lower NTD risk compared to no supplementation (adjusted ORs were 0.33 [95% CI 0.13, 0.76] for family history, 0.31 [0.09, 0.95] for AED exposure, 0.25 [0.04, 1.05] for pregestational diabetes, 0.65 [0.40, 1.04] for obesity). Though estimates were imprecise, as total folate increased stronger point estimates were observed, notably among family history. No mothers with a prior NTD-affected pregnancy supplemented with 4,000 µg. CONCLUSIONS: Our findings reinforce that all women of childbearing potential should consume at least 400 µg FA/day to protect against NTDs. Higher risk groups may benefit from higher doses.

One-Carbon Cofactor Intake and Risk of Neural Tube Defects Among Women Who Meet Folic Acid Recommendations: A Multicenter Case-Control Study.

We aimed to investigate associations between individual and concurrent (≥2) intakes of one-carbon cofactors vitamins B6 and B12, choline, betaine, and methionine and neural tube defect (NTD) outcomes among mothers meeting the folic acid recommendations. In the Slone Birth Defects Study (case-control design; North America, 1998-2015), mothers of 164 NTD cases and 2,831 nonmalformed controls completed food frequency questionnaires and structured interviews. Estimated intakes of one-carbon cofactors were dichotomized (high vs. low) for all except betaine (low or middle vs. high). We used logistic regression models to estimate odds ratios and 95% confidence intervals adjusted for center, age, and race. The analysis was restricted to mothers with estimated daily total folate intake of ≥400 µg during periconception. Fewer cases, compared with controls, had high intakes for each one-carbon cofactor except betaine, where the starkest contrast occurred in the middle group. Women with concurrent high intakes of B6, B12, choline, and methionine and moderate intake of betaine had approximately half the risk of an NTD-affected pregnancy (odds ratio = 0.49, 95% confidence interval: 0.23, 1.08). These findings suggest that, in the presence of folic acid, one-carbon cofactors-notably when consumed together-might reduce NTD risk. Additional research should inform any changes to clinical recommendations.

Risk factors for congenital microcephaly in the pre-Zika era.

BACKGROUND: The Zika epidemic has brought increased attention to congenital microcephaly as a birth outcome. However, little is known about risks for microcephaly unrelated to Zika. METHODS: Using data from the Slone Epidemiology Center Birth Defects Study from 1993 to 2015, we identified 57 cases of microcephaly alone ("isolated") and 109 cases of microcephaly that included other major birth defects ("non-isolated"), and considered a large number of potential risk factors including demographic characteristics, illnesses, and medications used during pregnancy. Where numbers permitted, we used logistic regression models to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: Substantial differences in risk factors were observed for isolated versus non-isolated microcephaly. For isolated microcephaly, risk estimates were elevated for mothers of non-Hispanic, non-White race/ethnicity, and underweight pre-pregnancy body mass index (BMI). The risk for exposure anytime in pregnancy to acetaminophen was null; in contrast, the aOR for NSAIDs was 2.4 (95% CI: 1.3-4.2). This association was weakened (but not eliminated) after excluding those exposed to opioids or illicit drugs, and risk was not present among those reporting less frequent exposures. For non-isolated microcephaly, elevated risk estimates were found for urinary tract infection. CONCLUSIONS: Risk factors differed for isolated and non-isolated microcephaly. While some findings support previously reported associations, (e.g., smoking, alcohol, underweight BMI), we also identified risk factors not previously described, notably NSAID use for isolated microcephaly and urinary tract infection for non-isolated microcephaly; however, these results should be viewed as hypothesis generating.

An application of data mining to identify potential risk factors for anophthalmia and microphthalmia.

BACKGROUND: We examined a large number of variables to generate new hypotheses regarding a wider range of risk factors for anophthalmia/microphthalmia using data mining. METHODS: Data were from the National Birth Defects Prevention Study, a multicentre, case-control study from 10 centres in the United States. There were 134 cases of "isolated" and 87 "nonisolated" (with other major birth defects) of anophthalmia/microphthalmia and 11 052 nonmalformed controls with delivery dates October 1997-December 2011. Using random forest, a data mining procedure, we compared the two case types with controls for 201 variables. Variables considered important ranked by random forest were included in a multivariable logistic regression model to estimate odds ratios and 95% confidence intervals. RESULTS: Predictors for isolated cases included paternal race/ethnicity, maternal intake of certain nutrients and foods, and childhood health problems in relatives. Using regression, inverse associations were observed with greater maternal education and with increasing intake of folate and potatoes. Odds were slightly higher with greater paternal education, for increased intake of carbohydrates and beans, and if relatives had a childhood health problem. For nonisolated cases, predictors included paternal race/ethnicity, maternal intake of certain nutrients, and smoking in the home the month before conception. Odds were higher for Hispanic fathers and smoking in the home and NSAID use the month before conception. CONCLUSIONS: Results appear to support previously hypothesised risk factors, socio-economic status, NSAID use, and inadequate folate intake, and potentially provide new areas such as passive smoking pre-pregnancy, and paternal education and ethnicity, to explore for further understanding of anophthalmia/microphthalmia.

Periconceptional maternal fever, folic acid intake, and the risk for neural tube defects.

PURPOSE: Previous studies have shown an association between maternal fever in early pregnancy and neural tube defects (NTDs) such as spina bifida. Periconceptional folic acid intake has been shown to reduce the risk of these outcomes. METHODS: Using data from the Slone Epidemiology Center Birth Defects Study (1998-2015), we examined the impact of folic acid on the relationship between maternal fever in the periconceptional period (28 days before and after the last menstrual period) and NTDs. Logistic regression models were used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Mothers of 375 cases and 8247 nonmalformed controls were included. We observed an elevated risk for NTDs for fever in the periconceptional period (OR: 2.4; 95% CI: 1.5-4.0). This association was weaker for mothers who reported consuming the recommended amount of folic acid (≥400 µg per day; OR: 1.8; 95% CI: 0.8-4.0) than mothers with low folic acid intake (<400 µg per day; OR: 4.2; 95% CI: 2.2-8.2). CONCLUSIONS: Our data support an association between maternal periconceptional fever and an increased risk for NTDs and also provide evidence that this association was attenuated for mothers who reported consuming folic acid at recommended levels in the periconceptional period.

Preconceptional Iron Intake and Gestational Diabetes Mellitus.

Our objective was to assess the impact of preconceptional heme and non-heme iron on gestational diabetes mellitius (GDM) in the Boston University Slone Epidemiology Birth Defects Study (BDS). This retrospective cohort analysis included 7229 participants enrolled in the BDS between 1998 and 2008 who gave birth to non-malformed infants and were free of pre-existing diabetes. All data were collected through structured interviews conducted within 6 months of delivery. Calorie-adjusted and multivariable odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression models. Preconceptional dietary heme iron was modestly associated with an elevated risk of GDM among those (multivariable OR comparing the fifth quintile to the first: 1.55; 95% CI 0.98, 2.46). Conversely, preconceptional dietary non-heme iron was associated with a decreased risk of GDM among those in the fifth quintile of intake compared to the first (multivariable OR: 0.48; 95% CI 0.28, 0.81). Women who consumed supplemental iron during preconception also had a decreased risk of GDM (multivariable OR: 0.78; 95% CI 0.60, 1.02). In conclusion, our data support a positive association between preconceptional heme iron intake and GDM and an inverse association between preconceptional non-heme iron intake from foods and preconceptional intake from supplements.

Association of Clomiphene and Assisted Reproductive Technologies With the Risk of Neural Tube Defects.

Clomiphene and assisted reproductive technologies (ART) are methods used to help subfertile couples become pregnant. ART has been reported to be associated with neural tube defects (NTDs) in offspring. To evaluate these associations, we studied mothers of 219 cases and 4,262 controls from the Slone Epidemiology Center Birth Defects Study (1993-2012) who were interviewed within 6 months after delivery about pregnancy events, including use of fertility treatments. We considered exposures to clomiphene (without ART) and ART during the periconceptional period. Logistic regression models were used to calculate adjusted odds ratios and 95% confidence intervals, controlling for education and study center. We observed elevated adjusted odds ratios of 2.1 (95% confidence interval: 0.9, 4.8) and 2.0 (95% confidence interval: 1.1, 3.6) for clomiphene and ART exposure, respectively. We performed a mediation analysis to assess whether the observed elevated NTD risk was mediated through multiple births. For clomiphene exposure without ART use, the direct effect estimate of the adjusted odds ratio (aORDE) was 1.7 and the indirect effect estimate (aORIE) was 1.4. Conversely, for ART exposure, the aORDE was 0.9 and the aORIE was 2.5. Our findings suggest that relatively little of the clomiphene-NTD association is mediated through the pathway of multiple births, while the ART-NTD association was explained by the multiple-births pathway.

Impact of Periconceptional Use of Nitrosatable Drugs on the Risk of Neural Tube Defects.

Nitrosatable drugs (NSDs) can, in the presence of nitrosating agents and highly acidic conditions, form N-nitroso compounds that have been found to be teratogenic in animal models. Using data from the Slone Epidemiology Center Birth Defects Study collected from 1998 to 2012, we compared maternal periconceptional NSD use between 334 neural tube defect cases and 7,619 nonmalformed controls. We categorized NSDs according to their functional group (secondary amine, tertiary amine, and amide). With logistic regression models, we estimated adjusted odds ratios and 95% confidence intervals. Neural tube defect risk was associated with maternal periconceptional use of secondary (adjusted odds ratio (aOR) = 1.7, 95% confidence interval (CI): 1.1, 2.4) and tertiary (aOR = 1.7, 95% CI: 1.2, 2.5) amines; an association was observed for amides, but the 95% confidence interval included the null (aOR = 1.4, 95% CI: 0.7, 2.5). Within the secondary amine group, elevated adjusted odds ratios were observed for 3 drugs but were null for the remaining medications. Increases in risk were observed for both strata of folic acid intake (<400 µg/day, ≥400 µg/day), with a slightly higher risk in the ≥400-µg/day stratum. Our findings support previously reported positive associations between neural tube defects and periconceptional exposure to NSDs containing a secondary or tertiary amine or amide.

Maternal cigarette, alcohol, and coffee consumption in relation to risk of clubfoot.

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.

Use of selective serotonin-reuptake inhibitors during pregnancy and the risk of clubfoot.

BACKGROUND: Selective serotonin-reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants. Previous studies have suggested that SSRIs may increase the risk of birth defects, including clubfoot. Using data from a population-based case-control study, we evaluated whether SSRI use increased the risk of clubfoot. METHODS: Mothers were interviewed within 1 year after delivery about sociodemographic factors, pregnancy events, and exposures. They were specifically asked if they experienced depression or anxiety or if they took any of the following SSRIs: citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, or fluoxetine. We used logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We included a total of 622 clubfoot cases and 2002 nonmalformed controls born between 2006 and 2011 in Massachusetts, New York, and North Carolina. For the 2nd or 3rd lunar month of pregnancy (the relevant gestational period), SSRI use for a period of more than 30 days was higher in case mothers (5%) than control mothers (3%). After adjustment for maternal smoking and body mass index, the OR for any SSRI use and clubfoot was 1.8 (95% CI = 1.1-2.8). When individual SSRIs were examined, ORs were elevated for sertraline (1.6 [0.8-3.2]), paroxetine (9.2 [0.7-484.6]), and escitalopram (2.9 [1.1-7.2]). CONCLUSION: Our data suggest an increased risk of clubfoot occurrence in relation to SSRI use. Drug-specific risks varied widely, and some estimates were unstable.

First-trimester exposure to bupropion and risk of cardiac malformations.

PURPOSE: Bupropion is a drug uniquely used both to treat depression and as an aid to smoking cessation. We investigated previously reported associations between first-trimester exposure to bupropion and cardiac defects. METHODS: Using data gathered since 2003 by the Slone Epidemiology Center's Case-control Birth Defects Study, we classified subjects with cardiac defects into subgroups. Exposure categories included first-trimester bupropion alone or in combination with other antidepressants, first-trimester antidepressants other than bupropion, and no exposure to any antidepressant at any time from 2 months prior to pregnancy through delivery. We calculated odds ratios and 95% confidence intervals, controlling for confounding using logistic regression. RESULTS: There were 8611 non-malformed infants and 7913 infants with cardiac defects. Eight cardiac subgroups had sufficient subjects (two or more exposed cases) for analysis. The adjusted odds ratio (aOR) for first-trimester bupropion use in relation to ventricular septal defect (VSD) was slightly elevated (1.6, 95% confidence interval 1.0-2.8); for exposure to bupropion alone, the aOR was 2.5 (95% confidence interval 1.3-5.0). Risks were not materially elevated for bupropion in relation to the other seven cardiac subgroups. CONCLUSIONS: We did not confirm previously reported associations for left-sided defects overall but had too few exposed cases to evaluate specific defects in this category. We did observe an elevated risk of VSD following first-trimester bupropion use, particularly when used without other antidepressants. This pattern for bupropion alone was observed in all our risk comparisons and was not explained by higher doses or gestational timing.

Medication use in pregnancy in relation to the risk of isolated clubfoot in offspring.

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.

Periconceptional use of opioids and the risk of neural tube defects.

OBJECTIVE: Opioid medications are among the most effective analgesics. However, the consequences of opioid exposure to the developing human offspring are not known. We assessed whether maternal opioid use in the periconceptional period was associated with the risk of neural tube defects in the offspring. METHODS: We used data from 1998 to 2010 from the Slone Epidemiology Center Birth Defects Study, an ongoing case-control study. Mothers were interviewed by telephone within 6 months of delivery about sociodemographic factors and exposures during pregnancy including detailed questions on type and timing of medication use. Mothers of 305 offsprings with neural tube defect were compared with mothers of 7,125 offsprings in the nonmalformed control group and 13,405 offsprings in the malformed control group. Periconceptional opioid use was defined as any reported use in the 2 months after the last menstrual period. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for study center. RESULTS: A higher percentage of mothers of offsprings with neural tube defects (3.9%) reported using an opioid medication than mothers of offsprings in the nonmalformed control group (1.6%) and offsprings in the malformed control group (2.0%) with adjusted ORs of 2.2 (95% CI 1.2 -4.2) and 1.9 (95% CI 1.0 -3.4), respectively. When offsprings were restricted to those with spina bifida, the adjusted ORs were 2.5 (95% CI 1.3-5.0) and 2.2 (95% CI 1.1-4.1), respectively. CONCLUSION: A 2.2-fold increase in risk would translate to a neural tube defect prevalence of 5.9 per 10,000 live births among women who use opioids. Overall, opioid use in the periconceptional period appeared to be associated with a modest increased risk of neural tube defects. LEVEL OF EVIDENCE: : II.

Risk of spina bifida and maternal cigarette, alcohol, and coffee use during the first month of pregnancy.

This study was conducted to assess the association between the risks of spina bifida (SB) in relation to cigarette, alcohol, and caffeine consumption by women during the first month of pregnancy. Between 1988-2012, this multi-center case-control study interviewed mothers of 776 SB cases and 8,756 controls about pregnancy events and exposures. We evaluated cigarette smoking, frequency of alcohol drinking, and caffeine intake during the first lunar month of pregnancy in relation to SB risk. Logistic regression models were used to calculate adjusted odds ratios and 95% confidence intervals. Levels of cigarette smoking (1-9 and ≥10/day), alcohol intake (average ≥4 drinks/day) and caffeine intake (<1, 1, and ≥2 cups/day) were not likely to be associated with increased risk of SB. Further, results were similar among women who ingested less than the recommended amount of folic acid (400 µg/day).

Vasoactive exposures during pregnancy and risk of microtia.

BACKGROUND: Little is known about the etiology of nonsyndromic microtia. This study investigated the hypothesis that microtia is caused by vascular disruption. METHODS: The study analyzed data from the population-based National Birth Defects Prevention Study (NBDPS) for deliveries between 1997 and 2005. Four hundred eleven nonsyndromic cases of microtia, with or without additional defects, were compared to 6560 nonmalformed infants with respect to maternal exposures to vasoactive medications and smoking during the periconceptional period and conditions that have previously been associated with vascular events (multiple gestation, maternal history of type 1, type 2, or gestational diabetes, and hypertension). Odds ratios (ORs) were estimated with multivariable models, controlling for the effects of race/ethnicity, education, periconceptional folic acid use, and study center. RESULTS: Risk estimates for vasoactive medications and smoking were not meaningfully increased. Maternal type 1/2 diabetes was diagnosed before or during the index pregnancy in 4% and 1% of cases, respectively, compared to 1% and 0.05% of controls; the adjusted OR for these two groups combined was 7.2 (95% confidence interval [CI], 3.9-13.1). Gestational diabetes was observed for 9% of cases and 6% of controls; the OR was moderately elevated (OR, 1.4; 95% CI, 0.9-2.0). ORs were also increased for multiple gestations (OR, 2.5; 95% CI, 1.5-4.2) and pre-existing hypertension (OR, 1.6; 95% CI, 1.0-2.5). CONCLUSIONS: Because ORs were only elevated for diabetes and not for vasoactive exposures or other potential vascular events, findings suggest that some microtia occurrences may be part of the diabetic embryopathy rather than manifestations of vascular disruption. Birth Defects Research (Part A), 2013. © 2012 Wiley Periodicals, Inc.

Medications used to treat nausea and vomiting of pregnancy and the risk of selected 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] = 0.87; 95% confidence interval [CI], 0.77-0.98) and hypospadias (aOR = 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 = 4.36; 95% CI, 1.21-15.81), steroids and hypospadias (aOR = 2.87; 95% CI, 1.03-7.97), and ondansetron and CP (aOR = 2.37; 95% CI, 1.18-4.76), whereas antacids were associated with a reduced risk for CL/P (aOR = 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.

Case-control studies for identifying novel teratogens.

The case-control study design offers an operationally efficient approach to measuring an association between an exposure and an outcome, especially when the outcome is rare, as is true for specific birth defects. For example, instead of following 50,000 pregnant women to have sufficient statistical power to identify a doubling in risk of oral clefts associated with a common exposure (e.g., cigarette smoking), 75 cases and 3 controls per case could be studied with equal statistical power. Examples of case sources include hospital or clinical series, or birth defect registries. For validity, control subjects should represent the population base of the cases, which can be difficult to identify for non-population-based case groups. Case-control studies typically rely on retrospective exposure measurement, which presents a major challenge and sets up the possibility of recall bias. Approaches are discussed to keep sources of bias to a minimum, including recall, non-differential information, and selection biases. Case-control studies can play an important role in this process for both hypothesis-generation and hypothesis-testing of potential teratogens. Examples of case-control studies and their contributions to the field are presented. © 2011 Wiley-Liss, Inc.

Vitamin, fluoride, and iron use among US children younger than 12 years of age: results from the Slone Survey 1998-2007.

Pediatric vitamin and mineral supplements are thought to be used commonly in the United States, but details of their use are lacking. Using data from the Slone Survey (a cross-sectional national random-digit-dial medication use survey), this study sought to define the prevalence and patterns of use of supplemental vitamins, fluoride, and iron among US children younger than 12 years of age. Primary statistical analyses involved descriptive statistics and calculation of weighted prevalence of use estimates with 95% confidence intervals. Between February 1998 and April 2007, there were 2,857 children 0 to 11 years of age enrolled from the 48 contiguous United States with weighted prevalence of use of vitamins, iron, and fluoride as the primary outcome. The response rate to the survey was 61%. Overall, 23.1% of children had used a vitamin, fluoride, or iron supplement in the 7 days before the interview, with use being highest among 2- to 5-year-olds. Almost all vitamins and most fluoride and iron were taken in the form of multicomponent products. The most commonly taken specific vitamins were C, D, B-12, B-6, and B-2, each by >20% of children. Overall, 3.3% of study participants took supplemental fluoride and 9.7% took supplemental iron. In conclusion, this study found that almost one-quarter of US children younger than 12 years of age, and 30% of 2-year-olds, use supplemental vitamins, fluoride, and iron in a given week. These data should be combined with what is known about the need for pediatric supplementation with vitamins, fluoride, and iron to help clinicians and policy makers counsel parents about the optimal use of these products.