Investigating the association between vitamin D dietary intake during pregnancy and incidence of clubfoot in neonates.

AIMS: Talipes equinovarus (clubfoot) is a congenital lower foot deformity that results from a neuromuscular deficiency, but the precise etiology remains elusive. Vitamin D is important for fetal neuromuscular development. In this study, we investigated the association between dietary vitamin D intake during pregnancy and incidence of clubfoot in neonates, since such a question has thus far been overlooked. METHODS: We conducted a secondary analysis of data collected in the United States, between 2007 and 2011 for a case-control study of children born with clubfoot. Participating mothers were interviewed by telephone about dietary and other health and life-style indicators. Exposure to vitamin D was recorded as the average daily intake of dietary vitamin D over a period of 6 months before pregnancy began. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. RESULTS: The dataset included 2667 study participants, of which 663 were cases. Logistic regression showed no significant association between dietary vitamin D or log10 (Vitamin D) intake during pregnancy and incidence of clubfoot in neonates (OR = 1.00, CI = 1.00-1.00, OR = 1.51, CI = 0.83-2.82, respectively). No interaction in the regression model was found between vitamin D and other predictor variables. Results were not confounded by supplement intake of vitamin D during pregnancy. CONCLUSIONS: Results show no evidence of an association between dietary vitamin D intake and incidence of clubfoot in neonates. The lack of association is not confounded by consumption of vitamin D supplements during pregnancy.

Periconceptional intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further reduce the risk of neural tube defects in offspring: a United States population-based case-control study of women meeting the folic acid recommendations.

BACKGROUND: Neural tube defects (NTDs) still occur among some women who consume 400 µg of folic acid for prevention. It has been hypothesized that intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further protect against NTDs. OBJECTIVES: To investigate whether intakes of vitamin B6, vitamin B12, choline, betaine, methionine, thiamine, riboflavin, and zinc, individually or in combination, were associated with NTD risk reduction in offspring of women meeting the folic acid recommendations. METHODS: Data were from the National Birth Defects Prevention Study (United States population-based, case-control). We restricted deliveries between 1999 and 2011 with daily periconceptional folic acid supplementation or estimated dietary folate equivalents ≥400 µg. NTD cases were live births, stillbirths, or terminations affected by spina bifida, anencephaly, or encephalocele (n = 1227). Controls were live births without a major birth defect (n = 7095). We categorized intake of each micronutrient as higher or lower based on a combination of diet (estimated from a food frequency questionnaire) and periconceptional vitamin supplementation. We estimated NTD associations for higher compared with lower intake of each micronutrient, individually and in combination, expressed as odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age, race/ethnicity, education, and study center. RESULTS: NTD associations with each micronutrient were weak to modest. Greater NTD reductions were observed with concurrent higher-amount intakes of multiple micronutrients. For instance, NTD odds were ∼50% lower among participants with ≥4 micronutrients with higher-amount intakes than among participants with ≤1 micronutrient with higher-amount intake (adjusted OR: 0.53; 95% CI: 0.33, 0.86). The strongest reduction occurred with concurrent higher-amount intakes of vitamin B6, vitamin B12, choline, betaine, and methionine (adjusted OR: 0.26; 95% CI: 0.09, 0.77) compared with ≤1 micronutrient with higher-amount intake. CONCLUSIONS: Our findings support that NTD prevention, in the context of folic acid fortification, could be augmented with intakes of methyl donors and other micronutrients involved in folate metabolism.

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

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

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.

Sociodemographic, health behavioral, and clinical risk factors for anotia/microtia in a population-based case-control study.

OBJECTIVE: Anotia and microtia are congenital malformations of the external ear with few known risk factors. We conducted a comprehensive assessment of a wide range of potential risk factors using data from the National Birth Defects Prevention Study (NBDPS), a population-based case-control study of non-chromosomal structural birth defects in the United States. METHODS: Mothers of 699 infants with anotia or microtia (cases) and 11,797 non-malformed infants (controls) delivered between 1997 and 2011 were interviewed to obtain information about sociodemographic, health behavioral, and clinical characteristics. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated with logistic regression. RESULTS: Infants with anotia/microtia were more likely to be male (aOR, 1.29; 95% CI, 1.10-1.50) and from a multifetal pregnancy (aOR, 1.68; 95% CI, 1.16-2.42). Cases were also more likely to have parents of Hispanic ethnicity (maternal aOR, 3.19; 95% CI, 2.61-3.91; paternal aOR, 2.11; 95% CI, 1.54-2.88), and parents born outside the United States (maternal aOR, 1.29; 95% CI, 1.06-1.57; paternal aOR, 1.92; 95% CI, 1.53-2.41). Maternal health conditions associated with increased odds of anotia/microtia included obesity (aOR, 1.31; 95% CI, 1.06-1.61) and pre-pregnancy diabetes (type I aOR, 9.89; 95% CI, 5.46-17.92; type II aOR, 4.70; 95% CI, 2.56-8.63). Reduced odds were observed for black mothers (aOR, 0.57; 95% CI, 0.38-0.85) and mothers reporting daily intake of folic acid-containing supplements (aOR, 0.59; 95% CI, 0.46-0.76). CONCLUSION: We identified several risk factors for anotia/microtia, some which have been previously reported (e.g., diabetes) and others which we investigate for perhaps the first time (e.g., binge drinking) that warrant further investigation. Our findings point to some potentially modifiable risk factors and provide further leads toward understanding the etiology of anotia/microtia.

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.

Prenatal Treatment and Outcomes of Women With Opioid Use Disorder.

OBJECTIVE: To describe the characteristics, treatment, and outcomes of pregnant women with opioid use disorder. METHODS: Women attending an obstetric and addiction recovery clinic in Boston from 2015 to 2016 were enrolled in a prospective cohort study and followed through delivery (N=113). Buprenorphine or methadone was initiated clinically. The Addiction Severity Index was administered at enrollment. Prenatal and delivery data were systematically abstracted from medical charts. RESULTS: Most women in the cohort were non-Hispanic white (80.5%) with a mean age of 28 years. Few women were married (8.9%). More than half of the cohort had been incarcerated, 29.2% had current legal involvement, and 15.0% generally had unstable housing. A majority (70.8%) were infected with hepatitis C and histories of sexual (56.6%) and physical (65.5%) abuse were prevalent. Regular substance used included heroin (92.0%), injection heroin (83.2%), other opioids (69.0%), marijuana (73.5%), alcohol (56.6%), and cocaine (62.8%). Fifty-nine women (52.2%) were treated initially with prenatal buprenorphine and 54 (47.8%) with methadone; 49.6% also were taking concomitant psychotropic medications. Employment (0.766±0.289) and psychologic (0.375±0.187) Addiction Severity Index scores were the highest, indicating the most severe problems in these areas. Opioid use relapse did not differ by treatment (44.7% overall). Thirteen (22.5%) of 59 women treated with buprenorphine transitioned to methadone mainly because of positive opioid screens. Overall, 23.0% (n=26) of the cohort discontinued clinical care. The number of pregnancy losses was small (three therapeutic abortions, four miscarriages, one stillbirth), with an overall live birth rate of 90.8% (95% CI 82.7-95.9). CONCLUSION: These data on the social circumstances, substance use, treatment, and treatment outcomes of pregnant women with opioid use disorder may help clinicians to understand and treat this clinically complex population.

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.

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.

Nitrosatable Drug Exposure during Pregnancy and Preterm and Small-for-Gestational-Age Births.

BACKGROUND: Nitrosatable drugs react with nitrite in the stomach to form N-nitroso compounds, observed in animal models to result in adverse pregnancy outcomes, such as birth defects and reduced fetal weight. Previous studies examining prenatal exposure to medications classified as nitrosatable have reported an increased risk of preterm births (PTBs) and small-for-gestational-age (SGA) infants. METHODS: Using data from mothers (controls) of babies without major birth defects from the National Birth Defects Prevention Study, prenatal nitrosatable drug usage by trimester and month of gestation was examined in relation to PTBs and SGA infants. RESULTS: Positive associations were observed with nitrosatable drug use and PTBs, with the strongest relationship with second trimester exposure (adjusted hazard ratio [aHR] 1.37, [95% confidence interval (CI) 1.10, 1.70]). Of the nitrosatable functional groups, secondary amines were the most notable, with a higher association among women with second (aHR 1.37, [95% CI 1.05, 1.79]) and third (aHR 1.34, [95% CI 1.02, 1.76]) trimester exposure compared with women with no prenatal nitrosatable drug use. Among SGA infants, a borderline association was noted with amide exposure during the third trimester (adjusted odds ratio 1.43 [95% confidence interval [CI] 1.00, 2.05]). CONCLUSIONS: Prenatal exposure to nitrosatable drugs during the second and third trimester of pregnancy, particularly secondary amines, might increase the risk of PTBs. However, prenatal exposure to nitrosatable drugs was not associated with SGA infants, with the exception of amide drugs.

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.

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).

Prenatal exposure to nitrosatable drugs, vitamin C, and risk of selected birth defects.

UNLABELLED: Nitrosatable drugs, such as secondary or tertiary amines and amides react with nitrite in an acidic environment to form N-nitroso compounds, teratogens in animal models. Vitamin C is a known nitrosation inhibitor. METHODS: Using data from the National Birth Defects Prevention Study, we assessed nitrosatable drug exposure and vitamin C intake during the first trimester among 11,606 case-mothers of infants with oral clefts, limb deficiencies (LDs), or congenital heart defects and 6807 control-mothers of infants without major birth defects during 1997-2005. Daily intake of vitamin C was estimated from maternal interviews that elicited information about supplement use and dietary intake. RESULTS: With no reported use of nitrosatable drugs as the referent group, a lower odds ratio (OR) was observed for transverse LDs among births to mothers exposed to secondary amine drugs and daily vitamin C supplementation (adjusted odds ratio [aOR] 1.2, 95% confidence interval [CI] 0.83-1.8) compared with women taking these drugs and no supplementation (aOR 2.7, 95% CI 1.5-4.6). The OR for longitudinal LDs associated with secondary amine exposure was lower with daily dietary vitamin C intake ≥85 mg (aOR 1.2, 95% CI 0.68-2.0) compared with <85 mg (aOR 1.9, 95% CI 1.2-3.1). Daily vitamin C supplementation in combination with higher dietary vitamin C intake reduced associations between nitrosatable drug exposures and limb deficiencies and atrial septal defects not otherwise specified. CONCLUSION: Prenatal dietary and vitamin C supplement intake may diminish the association between nitrosatable drug exposure during pregnancy and selected birth defects.

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.

Maternal medication and herbal use and risk for hypospadias: data from the National Birth Defects Prevention Study, 1997-2007.

PURPOSE: To investigate associations between maternal use of common medications and herbals during early pregnancy and risk for hypospadias in male infants. METHODS: We used data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study. We analyzed data from 1537 infants with second-degree or third-degree isolated hypospadias and 4314 live-born male control infants without major birth defects, with estimated dates of delivery from 1997 to 2007. Exposure was reported use of prescription or over-the-counter medications or herbal products, from 1 month before to 4 months after conception. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, adjusting for maternal age, race/ethnicity, education, pre-pregnancy body mass index, previous live births, maternal subfertility, study site, and year. RESULTS: We assessed 64 medication and 24 herbal components. Maternal uses of most components were not associated with an increased risk of hypospadias. A new associations was observed for venlafaxine (aOR 2.4; 95%CI 1.0, 6.0) [Correction made here after initial online publication.]. The previously reported association for clomiphene citrate was confirmed (aOR 1.9; 95%CI 1.2, 3.0). Numbers were relatively small for exposure to other specific patterns of fertility agents, but elevated aORs were observed for the most common of them. CONCLUSIONS: Overall, findings were reassuring that hypospadias is not associated with most medication components examined in this analysis. New associations will need to be confirmed in other studies. Increased risks for hypospadias associated with various fertility agents raise the possibility of confounding by underlying subfertility.

Maternal tea consumption during early pregnancy and the risk of spina bifida.

Studies have demonstrated that catechin, an antioxidant found in tea, can reduce the bioavailability of folate. Because periconceptional folic acid intake has been demonstrated to reduce the risk of spina bifida, tea consumption may put pregnant women at risk because of its possible antifolate properties. Using data collected in the Slone Epidemiology Center Birth Defects Study, we examined whether tea consumption during early pregnancy was associated with an increased risk of spina bifida. Mothers of 518 spina bifida cases and 6424 controls were interviewed within 6 months after delivery about pregnancy events and exposures. Data on tea intake were collected during three periods (1976-1988, 1998-2005 and 2009-2010). Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for study center. Intake of both periconceptional food folate and diet and supplemental folic acid were examined as a potential effect modifier. For 1976 to 1988, ORs were not elevated for daily tea intake. For 1998 and onward, ORs were also close to 1.0, but there was a modest increase for those who drank more than 3 cups/day (OR, 1.92; 95% CI, 0.84-4.38). Among women with total folic acid intake greater than 400 µg, consumption of 3 cups or more of tea per day was associated with an increased risk of spina bifida in 1976 to 1988 (OR, 2.04; 95% CI, 0.69-7.66) and in the later periods (OR, 3.13; 95% CI, 0.87-11.33). Our data do not support an overall association between tea consumption and spina bifida, but there is a suggestion of a possible interaction between higher levels of folic acid intake and tea consumption.

Nitrosatable drug exposure during early pregnancy and neural tube defects in offspring: National Birth Defects Prevention Study.

Nitrosatable drugs, such as secondary or tertiary amines and amides, form N-nitroso compounds in the presence of nitrite. Various N-nitroso compounds have been associated with neural tube defects in animal models. Using data from the National Birth Defects Prevention Study, the authors examined nitrosatable drug exposure 1 month before and 1 month after conception in 1,223 case mothers with neural tube defect-affected pregnancies and 6,807 control mothers who delivered babies without major congenital anomalies from 1997 to 2005. Nitrite intakes were estimated from mothers' responses to a food frequency questionnaire. After adjustment for maternal race/ethnicity, educational level, and folic acid supplementation, case women were more likely than were control women to have taken tertiary amines (odds ratio = 1.60, 95% confidence interval (CI): 1.31, 1.95). This association was strongest with anencephalic births (odds ratio = 1.96, 95% CI: 1.40, 2.73); odds ratios associated with tertiary amines from the lowest tertile of nitrite intake to the highest tertile were 1.16 (95% CI: 0.59, 2.29), 2.19 (95% CI: 1.25, 3.86), and 2.51 (95% CI: 1.45, 4.37), respectively. Odds ratios for anencephaly with nitrosatable drug exposure were reduced among women who also took daily vitamin supplements that contained vitamin C. Prenatal exposure to nitrosatable drugs may increase the risk of neural tube defects, especially in conjunction with a mother's higher dietary intake of nitrites, but vitamin C might modulate this association.

Folic acid intake and spina bifida in the era of dietary folic acid fortification.

BACKGROUND: The US Food and Drug Administration mandated that enriched grain products be fortified with folic acid by 1998. We evaluated whether intake of folic acid from supplements and diet was associated with a reduction in spina bifida in the setting of folic acid fortification. METHODS: Data were collected as part of the Slone Birth Defects Study from 1998 to 2008. Mothers of infants with and without birth defects were interviewed within 6 months of delivery about pregnancy exposures, including details of diet and vitamin intake. Dietary natural folate and synthetic folic acid from fortification were combined into a single, weighted measure--dietary folate equivalent. Periconceptional folic acid supplementation and dietary folate consumption were compared between 205 mothers of spina bifida cases and 6357 mothers of nonmalformed controls. Relative risks of a spina bifida-affected birth were estimated with odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Spina bifida was not associated with regular folic acid supplementation (≥4 days per week) either around the time of conception (adjusted OR = 1.1 [95% CI = 0.74-1.7]) or initiated in early pregnancy (0.79 [0.54-1.2]). After adjustment for confounders, a 13% reduced odds of spina bifida was estimated for each 100-µg increase in daily dietary folate equivalent consumed. CONCLUSIONS: In the setting of folic acid fortification of grains, our data suggest that folic acid supplementation does not appear to offer further benefit for reducing risk of spina bifida. Rather, the folate-associated benefit on spina bifida risk was found with increasing amounts of dietary folic acid consumed, regardless of folic acid supplementation level.

Prevalence and patterns of nitrosatable drug use among U.S. women during early pregnancy.

BACKGROUND: Experimental evidence indicates that certain drugs, that are secondary or tertiary amines or amides, form N-nitroso compounds in the presence of nitrite in an acidic environment. Nitrosatable drugs have been associated with birth defects in a few epidemiologic studies. This study describes the prevalence and patterns of nitrosatable drug use among U.S. women during early pregnancy and examines maternal factors associated with such use. METHODS: Data were analyzed from the National Birth Defects Prevention Study and included 6807 mothers who gave birth to babies without major congenital malformations during 1997 to 2005. Information was collected by telephone interview about medication use, demographic factors, and maternal health. Drugs taken during the first trimester were classified according to nitrosatability, amine and amide functional groups, and primary indication of use. RESULTS: Approximately 24% of the women took one or more nitrosatable drugs during the first trimester, including 12.4%, 12.2%, and 7.6% who respectively took secondary amines, tertiary amines, or amides. Five of the ten most commonly taken drugs were available over the counter. Women who were non-Hispanic white (29.5%), with 1 year or more college education (27.3%) or 40 years or older (28.8%) had the highest prevalence of use. Supplemental vitamin C, an inhibitor of nitrosation, was not taken by 41.6% and 19.3% of nitrosatable drug users during the first and second months of pregnancy, respectively. CONCLUSIONS: In this U.S. population, ingestion of drugs classified as nitrosatable was common during the first trimester of pregnancy, especially among non-Hispanic white, more educated, and older mothers.

U.S. provider reported folic acid or multivitamin ordering for non-pregnant women of childbearing age: NAMCS and NHAMCS, 2005-2006.

Folic acid use started prior to pregnancy confers a decreased risk of neural tube defects, and yet 20-50% of pregnancies are unplanned. We sought to determine whether medical providers order folic acid (FA) or folic acid-containing multivitamins (MVI) for their non-pregnant female patients of childbearing age. This is a cross-sectional study using data from the CDC's National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS) (2005 and 2006). Among non-pregnant, female patients of childbearing age (15-44), the proportion of preventive visits during which a provider ordered FA/MVI supplements was determined and compared to pregnant patients. Next, the rates of FA/MVI orders were examined according to race/ethnicity, age, insurance status, region of the country, provider type, contraceptive care, income and education. Analyses were conducted using SAS-callable Sudaan to account for survey design and to obtain population estimates. There were 4,634 preventive visits for non-pregnant women of childbearing age, representing 32.1 million visits nationally. Of these visits, 7.2% included provider-ordered FA/MVI. Multivariable logistic regression analyses revealed that provider-ordered FA/MVI was most common for women ages 30-34, who receive Medicaid, and whose race/ethnicity was other than White, Black or Hispanic. Preventive care visits represent an important venue for counseling regarding the benefits of FA for women of childbearing age, but appear to be under-utilized in all women. Our findings suggest that annually there may be over 29 million missed opportunities to recommend folic acid to non-pregnant women seeking preventive care.