Trends in first-trimester nausea and vomiting of pregnancy and use of select treatments: Findings from the National Birth Defects Prevention Study.

BACKGROUND: Although nausea and vomiting of pregnancy (NVP) is common, the secular and demographic trends of NVP and its treatments are not well-studied. OBJECTIVES: To describe the prevalence and patterns of first-trimester NVP and selected treatments among controls in the National Birth Defects Prevention Study (NBDPS). METHODS: National Birth Defects Prevention Study is a population-based case-control study of birth defects in the United States (1997-2011). We collected self-reported data about NVP and use of commonly reported pharmacological and herbal/natural treatments (ondansetron, promethazine, pyridoxine, metoclopramide, doxylamine succinate, ginger, phosphorated carbohydrate solution, and prochlorperazine) from mothers of non-malformed control infants. We estimated the prevalence of NVP and selected treatments and examined secular and demographic trends (education, race/ethnicity, and maternal age) for such use, adjusting for study centre. RESULTS: Among 10 540 mothers of controls, 7393 women (70.1%) reported first-trimester NVP, and 12.2% of those used one or more of the commonly reported treatments. Specific treatment use varied after adjustment for study centre (ondansetron: 3.4%; promethazine: 4.2%; pyridoxine: 3.2%; metoclopramide: 0.7%; doxylamine succinate: 1.7%; ginger: 1.0%; phosphorated carbohydrate solution: 0.4%; and prochlorperazine: 0.3%). Treatment use increased for each agent over the study period. Women with more years of education reported more NVP and treatment use. White (72%), Hispanic (71%), and other race (73%) women reported more NVP than Black women (67%); White women used selected NVP treatments most frequently, and Black women used them more than Hispanic women. Though women aged 25-34 years reported more NVP (72%) than younger (69%) or older (67%) women, the frequency of medication use was similar among women aged 25-34 and ≥35, and lower among women aged <25 years. CONCLUSIONS: National Birth Defects Prevention Study controls reported NVP at frequencies similar to those previously reported. Of note, we observed an increase in use of selected treatments over time, and variations in NVP and treatments by study site and demographic factors.

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.

Validity of maternal recall of gestational age and weight at birth: Comparison of structured interview and medical records.

PURPOSE: To assess agreement between maternal recall and medical records for gestational age (GA) at birth as derived from dating information and birthweight. METHODS: In the case-control Slone Birth Defects Study, within 6 months of delivery, trained nurses conducted standardized telephone interviews with mothers of infants with and without major structural malformations. In a subset of approximately 5000 case and control mothers from five US centers (2008-2012), a research nurse abstracted subjects' medical records. GA at delivery was calculated as date of delivery minus (estimated date of confinement [EDC] minus 280); if EDC was unknown, last menstrual period served as a proxy for start of pregnancy. Positive and negative predictive values (PPV and NPV, respectively) were calculated, using medical records as the standard, for categories of GA at delivery (ie, early preterm <238, late preterm <258, and term ≥259 d) and birthweight (low <2500, normal 2500 to 4500, and high >4500 g). RESULTS: The gestational age and birthweight validation samples comprised 3122 and 4760 women, respectively, with diverse characteristics. The PPV and NPV were high (>92% and >99%, respectively) for all categories of delivery GA and birthweight. CONCLUSIONS: Our findings suggest that mothers' recall may be a valid alternative to medical records to estimate delivery GA and birthweight. This study used standardized interviews conducted by trained research nurses, had a short recall period (<6 months post delivery), and for delivery GA, focused on date-derived GA. Further research is needed on the potential impact of study design, population characteristics, and comparison to other data sources.

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.

Tdap Vaccination Coverage During Pregnancy - Selected Sites, United States, 2006-2015.

Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine is recommended during the third trimester of each pregnancy to provide protection to newborns, who are at risk for pertussis-related morbidity and mortality (1). As part of its case-control surveillance study of medications and birth defects, the Birth Defects Study of the Slone Epidemiology Center at Boston University (the Birth Defects Study) has recorded data on vaccinations received during pregnancy since 2006. Among 5,606 mothers of infants without structural birth defects in this population (control group), <1% had received Tdap vaccine before 2009. By 2012, the percentage of mothers of infants in the control group (control infants) who had received Tdap increased to approximately 9%, and then in 2013 and continuing through 2015, increased markedly, to 28% and 54%, respectively. As the prevalence of maternal Tdap vaccination increased, so did the proportion of pregnant women who received Tdap in the third trimester, as recommended (94%-100% from 2010 to 2015). The vast majority of Tdap vaccinations (96%) were received in a traditional health care setting (e.g., the office of the woman's obstetrician or primary care physician or her prenatal clinic). Increasing vaccination coverage during pregnancy could help reduce the impact of pertussis on infant morbidity and mortality.

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.

Influenza Vaccination Coverage During Pregnancy - Selected Sites, United States, 2005-06 Through 2013-14 Influenza Vaccine Seasons.

Seasonal influenza vaccine is recommended for all pregnant women because of their increased risk for influenza-associated complications. In addition, receipt of influenza vaccine by women during pregnancy has been shown to protect their infants for several months after birth (1). As part of its case-control surveillance study of medications and birth defects, the Birth Defects Study of the Slone Epidemiology Center at Boston University has recorded data on vaccinations received during pregnancy since the 2005-06 influenza vaccination season. Among the 5,318 mothers of infants without major structural birth defects (control newborns) in this population, seasonal influenza vaccination coverage was approximately 20% in the seasons preceding the 2009-10 pandemic H1N1 (pH1N1) influenza season. During the 2009-10 influenza vaccination season, influenza vaccination coverage among pregnant women increased to 33%, and has increased modestly since then, to 41% during the 2013-14 season. Among pregnant women who received influenza vaccine during the 2013-14 season, 80% reported receiving their vaccine in a traditional health care setting, (e.g., the office of their obstetrician or primary care physician or their prenatal clinic) and 20% received it in a work/school, pharmacy/supermarket, or government setting. Incorporating routine administration of seasonal influenza vaccination into the management of pregnant women by their health care providers might increase coverage with this important public health intervention.

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.

CDC Grand Rounds: Understanding the Causes of Major Birth Defects - Steps to Prevention.

Major birth defects (birth defects) are defined as structural abnormalities, present at birth, with surgical, medical, or cosmetic importance. Each year in the United States, 3% of live births (approximately 120,000 infants) have an identifiable structural birth defect. Examples of birth defects include neural tube defects, such as spina bifida; orofacial clefts; abdominal wall defects, such as gastroschisis; and congenital heart defects, such as hypoplastic left heart syndrome. Collectively, congenital heart defects are the most common birth defects (27%), followed by musculoskeletal defects (18%), genitourinary defects (15%), orofacial defects (5%), and neural tube defects (2%).

Application of data screening to drug exposure in large risk factor studies of birth defects.

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.

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.

Maternal genitourinary infections and the risk of gastroschisis.

Genitourinary infections (GUIs) have been associated with increased risk of gastroschisis in 2 studies. Using data collected in the Slone Epidemiology Center Birth Defects Study, we examined the association between GUI and gastroschisis. From 1998 to 2010, mothers of 249 gastroschisis cases and 7,104 controls were interviewed within 6 months of delivery about pregnancy events, including vaginal infections, genital herpes, urinary tract infections (UTIs), and other sexually transmitted diseases (STDs). Women were considered exposed if they reported at least 1 instance of a GUI in the first trimester. Logistic regression models were used to calculate odds ratios and 95% confidence intervals. Women who reported having any GUI had an adjusted odds ratio of 1.8 (95% confidence interval (CI): 1.3, 2.4). The highest risk was seen among women who reported a UTI only (adjusted odds ratio = 2.3, 95% CI: 1.5, 3.5), while the odds ratio for an STD only was slightly elevated (adjusted odds ratio = 1.2, 95% CI: 1.0, 1.5). Among women under 25 years of age, the odds ratio for UTI only was 2.6 (95% CI: 1.7, 4.0), and among older women it was 1.8 (95% CI: 0.6, 5.9). When we considered the joint association of UTIs and young maternal age, a synergistic effect was observed. The results of this study add further evidence that UTIs may increase the risk of gastroschisis.

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.

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.

A description of spina bifida cases and co-occurring malformations, 1976-2011.

Mandatory folic acid fortification in the United States corresponded with a decline in the prevalence of spina bifida (SB). The aim of this study was to describe the epidemiologic characteristics of isolated versus non-isolated SB cases in both pre- and post-fortification periods. SB cases in the Slone Epidemiology Center Birth Defects Study from 1976 to 2011 without chromosomal anomalies and syndromes were included. A maternal interview, conducted within 6 months of delivery, collected information on demographics, reproductive history, diet, and supplement use. Daily folic acid intake in the periconceptional period was calculated using both dietary and supplement information and categorized as low intake (<400 µg/day) or high intake (≥400 µg/day). SB cases (n = 1170) were classified as isolated (80.4%) or non-isolated (19.1%). Non-isolated cases were further divided into subgroups based on accompanying major malformations (midline, renal, genital, heart, laterality). Compared to non-isolated cases, isolated cases were more likely to be white, non-Hispanic and have more than 12 years of education. Cases in the renal, genital, and heart subgroups had the lowest proportions of mothers with a high folic acid intake. The change from pre- to post-fortification was associated with a decrease in the proportion of isolated cases from 83% to 72%, though in both periods isolated cases were more likely to be female and their mothers were more likely to have high folic acid intake. These findings highlight the importance of separating isolated and non-isolated cases in etiologic research of SB.

Seasonal influenza vaccination during pregnancy and the risks of preterm delivery and small for gestational age birth.

BACKGROUND: Influenza vaccination is routinely recommended for pregnant women, yet information on perinatal outcomes is sparse. METHODS: We investigated the associations between trivalent (seasonal) influenza vaccination during pregnancy and the risks of preterm delivery (PTD, live birth <37 weeks gestation) and small for gestational age birth (SGA, <10th percentile in weight for sex-specific gestational age) during the influenza seasons 2006-07 through 2009-10. The study population included 1619 mothers of live-born, non-malformed singleton infants interviewed as part of the Slone Epidemiology Center's Birth Defects Study. Associations between influenza vaccination and PTD and SGA were assessed using Cox and logistic regression models, respectively, with propensity scores used to adjust for confounding. Women vaccinated against pandemic H1N1 were excluded from the analysis. RESULTS: Influenza vaccination during pregnancy showed a near null association with PTD for influenza seasons 2006-07 through 2008-09 compared with unvaccinated women [adjusted hazard ratios (aHR) ranged from 0.79 [95% confidence interval (CI) 0.28, 2.21] in 2007-08 to 1.08 [95% CI: 0.40, 2.95] in 2008-09]. For 2009-10, the risk of PTD was higher in vaccinated women (aHR, 7.81 [95% CI: 2.66, 23.0]). Influenza vaccination was not associated with appreciable risks for SGA for all seasons with sufficient numbers of exposed SGA. CONCLUSION: Though limited by study size, these findings add support to previous observations of little or no increased risk of PTD or SGA associated with seasonal influenza vaccination for three of the four influenza seasons in our study. The increased risk of PTD observed for the 2009-10 influenza season warrants further investigation.

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.

Use of decongestants during pregnancy and the risk of birth defects.

Previous studies suggested that early pregnancy exposure to specific oral decongestants increases the risks of several birth defects. Using January 1993-January 2010 data from the Slone Epidemiology Center Birth Defects Study, we tested those hypotheses among 12,734 infants with malformations (cases) and 7,606 nonmalformed control infants in the United States and Canada. Adjusted odds ratios and 95% confidence intervals were estimated for specific birth defects, with controlling for potential confounders. Findings did not replicate several hypotheses but did support 3 previously reported associations: phenylephrine and endocardial cushion defect (odds ratio = 8.0; 95% confidence interval: 2.5, 25.3; 4 exposed cases), phenylpropanolamine and ear defects (odds ratio = 7.8; 95% confidence interval: 2.2, 27.2; 4 exposed cases), and phenylpropanolamine and pyloric stenosis (odds ratio = 3.2; 95% confidence interval: 1.1, 8.8; 6 exposed cases). Hypothesis-generating analyses involving multiple comparisons identified a small number of associations with oral and intranasal decongestants. Accumulating evidence supports associations between first-trimester use of specific oral and possibly intranasal decongestants and the risk of some infrequent specific birth defects.

Descriptive epidemiology of idiopathic clubfoot.

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 (<16 weeks), chorionic villous sampling (CVS), and plural gestation with fetal loss. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for state. Cases were more likely to be male (OR: 2.7; 2.2-3.3) and born to primiparous mothers (1.4; 1.2-1.7) and mothers with BMI ≥30 kg/m(2) (1.4; 1.1-1.8). These associations were greatest in isolated and bilateral cases. ORs for the pregnancy-related conditions ranged from 1.3 (breech delivery) to 5.6 (early amniocentesis). Positive associations with high BMI were confined to cases with a marker of fetal constraint (oligohydramnios, breech delivery, bicornuate uterus, plural birth), inheritance (family history in 1st degree relative), or vascular disruption (early amniocentesis, CVS, plural gestation with fetal loss). Pathogenetic factors associated with obesity may be in the causal pathway for clubfoot.

The impact of folic acid intake on the association among diabetes mellitus, obesity, and spina bifida.

OBJECTIVE: The purpose of this study was to investigate the relationship between spina bifida and 2 established risk factors (pregestational diabetes mellitus and obesity) in both the presence and absence of the recommended daily folic acid intake in the periconceptional period. STUDY DESIGN: Cases of spina bifida (n = 1154) and control subjects (n = 9439) from the Slone Epidemiology Center Birth Defects Study (1976-2011) were included. Information on preexisting diabetes mellitus (collected 1976-2011) and obesity (collected 1993-2011), defined as a body mass index of ≥30 kg/m(2), was collected through interviews that were conducted within 6 months of delivery. Periconceptional folic acid intake was calculated with both dietary and supplement information. Mothers were classified as consuming more or less than 400 µg/day of folic acid; food folate was included at a 30% discount for its lower bioavailability. Logistic regression models that were adjusted for maternal age, race, education, and study site were used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the joint effects of low folic acid intake coupled with diabetes mellitus or obesity. RESULTS: Case mothers were more likely to have diabetes mellitus or be obese (0.7% and 19.0%, respectively) than control mothers (0.4% and 10.8%, respectively). The joint effect of diabetes mellitus and lower folic acid intake on spina bifida was larger (aOR, 3.95; 95% CI, 1.56-10.00) than that of diabetes mellitus and higher folic acid intake (aOR, 1.31; 95% CI, 0.17-10.30). Folic acid intake made little difference on the association between obesity and spina bifida. CONCLUSION: Our findings suggest that folic acid further attenuates, although does not eliminate, the risk of spina bifida that is associated with diabetes mellitus than the risk with obesity.