Dietary intake of choline and neural tube defects in Mexican Americans.

BACKGROUND: Low maternal intake of dietary choline and betaine (a choline derivative) has recently been investigated as a possible risk factor for neural tube defects (NTDs). METHODS: This case-control study examined the NTD risk associated with choline and betaine in 409 Mexican-American women who gave birth during 1995 to 2000 in the 14-county border region of Texas. RESULTS: Using data from the food frequency questionnaire and the lowest quartiles of intake as the reference categories, a protective association was suggested between higher intakes of choline and betaine and NTD risk although the 95% confidence intervals for all risk estimates included 1.0. For choline intake in the second, third, and fourth quartiles, adjusted odds ratios were 1.2, 0.80, and 0.89, respectively. Betaine appeared more protective with odds ratios of 0.62, 0.73, and 0.61, respectively, for the second, third, and fourth quartiles of intake. CONCLUSION: Study findings suggest that dietary betaine may help to prevent NTDs.

Epigenetic profiles in children with a neural tube defect; a case-control study in two populations.

Folate deficiency is implicated in the causation of neural tube defects (NTDs). The preventive effect of periconceptional folic acid supplement use is partially explained by the treatment of a deranged folate-dependent one carbon metabolism, which provides methyl groups for DNA-methylation as an epigenetic mechanism. Here, we hypothesize that variations in DNA-methylation of genes implicated in the development of NTDs and embryonic growth are part of the underlying mechanism. In 48 children with a neural tube defect and 62 controls from a Dutch case-control study and 34 children with a neural tube defect and 78 controls from a Texan case-control study, we measured the DNA-methylation levels of imprinted candidate genes (IGF2-DMR, H19, KCNQ1OT1) and non-imprinted genes (the LEKR/CCNL gene region associated with birth weight, and MTHFR and VANGL1 associated with NTD). We used the MassARRAY EpiTYPER assay from Sequenom for the assessment of DNA-methylation. Linear mixed model analysis was used to estimate associations between DNA-methylation levels of the genes and a neural tube defect. In the Dutch study group, but not in the Texan study group we found a significant association between the risk of having an NTD and DNA methylation levels of MTHFR (absolute decrease in methylation of -0.33% in cases, P-value = 0.001), and LEKR/CCNL (absolute increase in methylation: 1.36% in cases, P-value = 0.048), and a borderline significant association for VANGL (absolute increase in methylation: 0.17% in cases, P-value = 0.063). Only the association between MTHFR and NTD-risk remained significant after multiple testing correction. The associations in the Dutch study were not replicated in the Texan study. We conclude that the associations between NTDs and the methylation of the MTHFR gene, and maybe VANGL and LEKKR/CNNL, are in line with previous studies showing polymorphisms in the same genes in association with NTDs and embryonic development, respectively.

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.

Dieting to lose weight and occurrence of neural tube defects in offspring of Mexican-American women.

Lowered maternal weight gain and reduction in early pregnancy have been associated with risk of neural tube defects (NTDs) in offspring. We examined the association of self-reported maternal dieting behaviors on the occurrence of NTDs. We conducted a population based case-control study among Mexican-American women who were residents of the 14 Texas counties bordering Mexico. Case women had an NTD-affected pregnancy identified at birth or prenatally and had deliveries during the years 1995-2000. Control women were those who delivered live born infants without an apparent congenital malformation, randomly selected and frequency-matched to cases by year and facility. One hundred eighty-four case women and 225 control women were asked in person about the use of nutritional supplements, dieting to lose weight, and type of weight reduction supplements used during the 3 months before conception. Women who reported being on a diet to lose weight during the 3 months before conception had an NTD odds ratio (OR) of 1.9 (95% confidence interval (CI) = 1.1, 3.3) compared with those not reporting being on a diet. Neither consuming vitamin drinks (OR = 1.2) nor using diet pills (OR = 1.6) during the 3 months before conception had ORs that were different from the null, when compared to women not reporting those behaviors. The risk effect for dieting did not differ markedly among normal or underweight (OR = 2.0, 95% CI = 0.7, 5.6), overweight (OR = 1.9, 95% CI = 0.7, 5.0), or obese women (OR = 1.5, 95% CI = 0.6, 4.0). No effect was seen among dieting women who were consuming at least 1.0 mg/day of folate (OR = 1.1, CI = 0.3, 4.5). Maternal dieting prior to conception may increase the risk of NTDs in offspring.

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.

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.

Folic acid awareness and supplementation among Texas women of childbearing age.

OBJECTIVE: Neural tube defects (NTDs) affect about seven of every 10,000 deliveries in Texas. To reduce the risk for NTDs, women are encouraged to supplement with 400 mcg folic acid daily during their reproductive years. This study examines folic acid awareness, knowledge, and supplementation practices among women of childbearing age (WCBA), including residents of Texas-Mexico border as well as women of Hispanic origin/ethnicity, populations that have NTD rates up to three times higher than the national average. METHODS: We conducted a statewide multistage sample telephone survey among Texas women of childbearing age in 2001. In total 1,196 women age 18 to 44 were interviewed. RESULTS: About 78% of WCBA knew about folic acid, 28% knew that folic acid prevents birth defects, and 25% knew to take folic acid before pregnancy. The prevalence of daily folic acid supplementation among all women of childbearing age was 33%. Education was the strongest predictor of folic acid awareness followed by race/ethnicity and age. Significant predictors of daily folic acid supplementation were education and ethnicity. CONCLUSIONS: Our findings suggest the need for more emphases on strategies to improve the level of folic acid supplementation among low educated women, and race ethnic minority populations.

Iron status indicators in women with prior neural tube defect-affected pregnancies.

OBJECTIVES: Iron deficiency is the most common nutrient deficiency in pregnant women and has been linked to negative impacts on the fetus. We describe the association of various iron-deficiency indices with risk of neural tube defect (NTD) among a high-risk Mexican-American population. METHODS: The study included 158 case-women (NTD-affected pregnancies) and 189 control-women (normal births) who were residents of the 14 Texas-Mexico border counties and delivered or terminated pregnancies during 1995-2000. In-person interviews and laboratory assays provided data. RESULTS: Case-women had higher odds of having minimal or no iron stores (serum ferritin <30 microg/L) compared to control-women (OR = 1.8, 95% CI = 1.0-3.3). The risk effect was not explained by low folate or B12 or other risk factors. CONCLUSION: Low serum ferritin may reflect the additive effect of multiple long-term factors, many of them related to poverty such as poor quality diet, lack of supplementation, and frequent pregnancies. Interpartum care is indicated in this population.

Implementation and outcomes of recommended folic acid supplementation in Mexican-American women with prior neural tube defect-affected pregnancies.

BACKGROUND: Upon discovering an NTD incidence rate of 27/10,000 in a Texas border county, the Texas Department of Health initiated folic acid intervention for prevention of recurrent NTDs in this predominantly Mexican-American population. This paper describes compliance of this population with USPHS folic acid recommendations and the impact of supplementation on pregnancy outcomes. METHODS: Based upon information from active surveillance, field teams personally contacted women having NTD-affected pregnancies to enroll them in FA intervention. Enrollees were provided FA at home visits at 3-month intervals throughout the project. RESULTS: Of 405 women identified with NTD-affected pregnancies, 299 (73.8%) enrolled in the intervention. One hundred ninety-three pregnancies occurred among 138 women. FA supplementation of 0.4 mg/day or more occurred during the last month preconception in 161 (83.4%) of the 193 pregnancies. No NTDs were detected in the 130 livebirths to women who received supplementation nor were NTDs detected in the 23 supplemented women who experienced pregnancy loss. CONCLUSIONS: Supplementation was successful in preventing recurrent NTDs in Mexican-American women.

The effect of fever, febrile illnesses, and heat exposures on the risk of neural tube defects in a Texas-Mexico border population.

BACKGROUND: Hyperthermia produces neural tube defects (NTDs) in a variety of animal species. Elevated maternal body temperatures may also place the developing human embryo at risk. We examined the relation between maternal hyperthermia and the development of NTDs in a high-risk Mexican-American population. METHODS: Case-women were Mexican-American women with NTD-affected pregnancies who resided and delivered in any of the 14 Texas counties bordering Mexico, during 1995-2000. Control-women were randomly selected from study area residents delivering normal live births, frequency-matched to cases by hospital and year. Information on maternal fevers, febrile illnesses, exposures to heat generated from external sources, and hyperthermia-inducing activities was gathered through in-person interviews, conducted about six weeks postpartum. RESULTS: The risk effect (OR) associated with maternal fever in the first trimester, compared to no fever, was 2.9 (95% CI, 1.5-5.7). Women taking fever-reducing medications showed a lower risk effect (OR, 2.4; 95% CI, 1.0-5.6) than those who did not (OR, 3.8; 95% CI, 1.4-10.9). First-trimester maternal exposures to heat devices such as hot tubs, saunas, or electric blankets were associated with an OR of 3.6 (95% CI, 1.1-15.9). Small insignificant effects were observed for activities such as cooking in a hot kitchen (OR, 1.6; 95% CI, 1.0-2.6) and working or exercising in the sun (OR, 1.4; 95% CI, 0.9-2.2). CONCLUSIONS: Maternal hyperthermia increases the risk for NTD-affected offspring. Women intending to become pregnant should avoid intense heat exposures, carefully monitor and manage their febrile illnesses, and routinely consume folic acid supplements.

Dietary nitrites and nitrates, nitrosatable drugs, and neural tube defects.

BACKGROUND: Amine-containing (nitrosatable) drugs can react with nitrite to form N-nitroso compounds, some of which are teratogenic. Data are lacking on whether dietary intake of nitrates and nitrites modifies the association between maternal nitrosatable drug exposure and neural tube defects (NTDs) in offspring. METHODS: We examined nitrosatable drug exposure and NTD-affected pregnancies in relation to dietary nitrite and total nitrite intake in a case-control study of Mexican American women. We interviewed 184 women with NTD-affected pregnancies and 225 women with normal live births, including questions on periconceptional drug exposures and dietary intake. For 110 study participants, nitrate was also measured in the usual source of drinking water. RESULTS: Women who reported taking drugs classified as nitrosatable were 2.7 times more likely to have an NTD-affected pregnancy than women without this exposure (95% confidence interval [CI] = 1.4-5.3). The effect of nitrosatable drugs was observed only in women with higher intakes of dietary nitrite and total nitrite (dietary nitrite + 5% dietary nitrate). Women within the highest tertile (greater than 10.5 mg/day) of total nitrite were 7.5 times more likely to have an NTD-affected pregnancy if they took nitrosatable drugs (95% CI = 1.8-45.4). The association between nitrosatable drug exposure and NTDs was also stronger in women whose water nitrate levels were higher. CONCLUSIONS: Findings suggest that effects of nitrosatable drug exposure on risk for neural tube defects in offspring could depend on the amounts of dietary nitrite and total nitrite intake.

Diarrhea: a new risk factor for neural tube defects?

BACKGROUND: Neural tube defects (NTDs) affect approximately 4000 US pregnancies annually. Folic acid supplementation taken before conception protects against the occurrence of NTDs. Adequate levels of vitamin B12 also appear to play a significant role. Gastrointestinal disturbances, such as those caused by diarrhea, might negatively affect the availability of these vitamins, thereby increasing the risk of these birth defects. METHODS: To determine whether periconceptional diarrhea increases the risk of NTD-affected pregnancies, a population-based case-control study was conducted in the 14 Texas-Mexico border counties. Information on diarrhea and other risk factors was ascertained by in-person interview. Study subjects were Mexican-American women who resided and delivered in any border county during 1995-2000. Case women, identified through active surveillance, had liveborn or stillborn infants or fetuses diagnosed with anencephalus, spina bifida, or encephalocele. Control women were randomly selected from women delivering normal live births in study area health facilities. RESULTS: One or more episodes of periconceptional diarrhea were associated with increased risk of NTD-affected pregnancies compared to no episodes of diarrhea (OR = 3.7, 95% CI = 1.8-7.6). This association was independent of fever, obesity, maternal age, maternal birthplace, income, prior unproductive pregnancy, and dietary plus multivitamin folate intake, known risk factors for NTDs. CONCLUSIONS: Confirmation of this new risk factor might have public health implications due to the feasibility of modifying exposure.

Maternal stress, social support, and risk of neural tube defects among Mexican Americans.

BACKGROUND: Studies suggest that maternal psychologic stress can increase the risk of congenital malformations, including neural tube defects (NTDs). We examined whether maternal stress and lack of social support contribute to NTD risk in a population living along the Texas-Mexico border. METHODS: Case mothers (N = 184) were Mexican-American women with NTD-affected pregnancies who delivered during 1995 to 2000 in one of the 14 Texas counties bordering on Mexico. Control mothers (N = 225) were randomly selected from Mexican-American women residing in the same area and delivering normal live births. We measured maternal stress by tallying the number of job changes, residential moves, and major injuries occurring during the year before conception. Social support was measured using social integration and perceived emotional support scales. RESULTS: Mothers who experienced one or more stressful life events during the year before conception had increased risks for NTDs (odds ratio [OR] = 2.9; 95% confidence interval [CI] = 1.8-4.7) compared with mothers experiencing no events. Mothers who scored low on emotional support had an elevated risk compared with those who scored high (OR = 4.6; CI = 2.2-9.7). Social support measures, such as network size and satisfaction, group interactions, and church attendance, were unrelated to NTD risk. The estimated effects were not modified or confounded by age, education, country of birth, income, obesity, vitamin supplements, dietary folate, cigarette smoking, or alcohol consumption. CONCLUSION: In this Mexican-American population, the occurrence of stressful life events was associated with NTD risk. These findings suggest that stress may exacerbate risk in populations with poor nutritional status and meager economic resources.

Homocysteine remethylation enzyme polymorphisms and increased risks for neural tube defects.

Folic acid supplementation can effectively reduce the risk of neural tube defects (NTDs); however, the mechanism underlying this beneficial effect remains unclear. Recent evidence suggests that certain folate pathway genes, as well as those related to homocysteine metabolism might be contributing to this effect. The purpose of this study is to investigate whether gene polymorphisms of methionine synthase (MTR) and methionine synthase reductase (MTRR) are involved in the risk for NTDs, specifically spina bifida. We detected MTR A2756G and MTRR A66G polymorphisms using PCR-RFLP analysis in a group of NTD infants, their mothers and normal controls. We found that infants with the MTRR mutant genotype had a 2.6-fold higher risk of NTDs when compared to the AA genotype (OR = 2.6, 95%CI = 1.3-5.3). Mothers with the MTRR mutant genotype also had a 1.9-fold higher risk of having an NTD baby compared to AA genotype (OR = 1.9, 95%CI = 1.1-3.1). Infants who carry mutant alleles for both MTRR and MTR had exceptionally elevated NTD risks, with odds ratios of 5.1 compared to infants with the wild type genotype at both loci (AA + AA) (OR = 5.1, 95%CI = 1.7-15.4). A comparable result was observed in the mothers of NTD cases (OR = 2.1, 95%CI = 1.0-4.7). Our results indicate that MTRR and MTR genes may interact to increase the infants' NTD risks. These results did not appear to be influenced by maternal periconceptional folic acid intake. However,the sample size of this study was limited, and a larger population study is needed to pursue these initial observations.

Maternal serum B12 levels and risk for neural tube defects in a Texas-Mexico border population.

PURPOSE: Neural tube defects (NTDs) are common birth defects that can be prevented with folate fortification and supplementation. Studies suggest that other nutrients may also be essential to neural tube closure and have a potential role in risk reduction, with vitamin B(12) mentioned most often. We determined the effect of maternal serum B(12) levels, measured postpartum, on the risk of NTDs among a high risk Mexican American population. METHODS: The case-control study included 157 Mexican American women with NTD-affected pregnancies and 186 Mexican American women with normal pregnancies, who were residents of Texas-Mexico border counties and delivered during 1995 to 2000. RESULTS: Compared with women in the highest vitamin B(12) quintile, women in the lowest quintile showed a strong risk effect (odds ratio (OR) = 3.0, confidence interval (CI): 1.4, 6.3); while those in the 2nd and 3rd quintiles showed moderate risk effects (OR = 1.6, CI = 0.7, 3.6 and OR = 1.7, CI = 0.8, 3.8, respectively). Adjusting for obesity, vitamin supplements, dietary folate, dietary B(12), red blood cell folate, and other covariates did not materially change these estimates. CONCLUSIONS: Insufficient levels of serum B(12), which are not normally indicative of a classical vitamin B(12) deficiency nor stem from an inadequate diet, may be an important etiologic factor for NTDs in this population.

Blood folate levels on the Texas-Mexico border.

The Texas-Mexico border population has a high prevalence of neural tube defects (NTDs). In 1998, in an effort to reduce the risk of NTD-affected pregnancies, the US Food and Drug Administration mandated folic acid fortification of enriched grain products. Since then, the median serum folate and red blood cell (RBC) folate levels of US women aged 15 through 44 years has risen. During 1995 through 2000, serum and RBC folate levels of 170 Mexican American women residing on the Texas-Mexico border who had delivered live, normal infants within the previous 3 months were tested. The median serum folate levels rose 46%, and RBC folate levels rose 44%. The increase suggests that food fortification may be affecting folate levels among populations with economic and cultural barriers to consuming fortified foods. However, more data are needed before we can assess the impact of food fortification on NTD rates on the border.