Karen Todoroff

Maternal illness, including fever, and medication use as risk factors for neural tube defects

We investigated if selected maternal illnesses or medications used during the periconceptional period increased risk of having neural tube defect (NTD)-affected pregnancies. We used a population-based case-control study of fetuses and liveborn infants with NTDs among 1989-1991 California births. In-person interviews were conducted with mothers of 538 (88% of eligible) NTD cases and 539 (88%) nonmalformed controls, usually within 5 months of delivery. A maternal fever or febrile illness episode in the first trimester was associated with an increased risk for having a NTD-affected pregnancy, odds ratio (OR) = 1.91 (95% confidence interval, 1.35-2.72) for fever and OR = 2.02 (1.20-3.43) for febrile illness. Risk estimates were not substantially altered after adjustment for maternal age, race/ethnicity, education, vitamin use, and body mass index. Other reported illnesses were generally not associated with risks of 1.5 or greater, or were too infrequent to adequately estimate risk. An OR of 1.5 or greater was observed for maternal use of guaifenesin, OR = 2.04 (0.79-5.28), and an OR of 0.5 or less was observed for maternal use of calcium-containing medicines, OR = 0.38 (0.14-1.03). Our findings are consistent with previous reports that suggested elevated NTD risks from maternal fever. We could not discriminate, however, whether the increased risks observed for maternal fever were indicative of a causal relation or due to reporting bias. Our findings suggest that many of the illnesses common to reproductive-aged women and the medications commonly used to treat them during pregnancy, except, perhaps, for those illnesses that are febrile-related, do not appear to substantially contribute to the occurrence of NTDs in the population.

Infant C677T mutation in MTHFR, maternal periconceptional vitamin use, and cleft lip

Studies have reported an association between homozygosity for a variant form of the methylenetetrahydrofolate reductase (MTHFR) gene and risk for neural tube defects. Because of MTHFRs involvement with folate metabolism and evidence that maternal use of a multivitamin with folic acid in early pregnancy reduces risk for cleft lip with or without cleft palate (CLP), we hypothesized that infants homozygous for the C677T genotype would be at increased risk for CLP because of lower MTHFR enzymatic activity. Data were derived from a large population-based, case-control study of fetuses and liveborn infants among a cohort of 1987 to 1989 California births. The analyses involved 310 infants with isolated CLP whose mothers completed a telephone interview and whose DNA was available from newborn screening blood specimens and involved 383 control infants without a congenital anomaly whose mothers completed a telephone interview and whose DNA was available. Cases and controls were genotyped TT if homozygous for the C677T allele, CT if heterozygous for the C677T allele, and CC if homozygous for the C677 (wild-type) allele. Odds ratios for CLP were 0.89 (0.55 to 1.4) and 0.78 (0.56 to 1.1) for infants with TT versus CC and infants with CT versus CC genotypes, respectively. Compared with the CC genotype, the odds ratios for CLP among infants with the TT genotype were 0.74 (0.39 to 1.4) for those infants whose mothers were users and 1.4 (0.54 to 3.6) for those infants whose mothers were not users of multivitamins containing folic acid periconceptionally. The two estimates were not statistically heterogeneous (P = 0.30). Our results did not indicate increased risks for CLP among infants homozygous for the C677T genotype, nor do they indicate an interaction between infant C677T genotype and maternal multivitamin use on the occurrence of CLP.

Periconceptional nutrient intake and risk for neural tube defect-affected pregnancies.

We investigated whether intakes of nutrients, including folate, by women in the periconceptional period were associated with risks of neural tube defect (NTD)-affected pregnancies. Data were part of a case-control study of fetuses and infants with NTDs among 1989-1991 California births. We conducted interviews with mothers of 409 NTD cases and 420 nonmal-formed controls. Nutrient intake for the 3 months before conception was derived from food frequency questionnaires and from questions to mothers about vitamin/mineral supplement use. We computed NTD risk for each nutrient controlling for the influence of all other studied nutrients and for maternal education, race/ethnicity, height, and prepregnancy weight. Most single nutrients reduced NTD risks when intakes were considered in quartiles and unadjusted for other nutrients. Some of the same nutrients, however, did not provide similar interpretations when we adjusted for other nutrients. Adjusted analyses revealed decreased NTD risks with increased intakes of methionine, lutein, magnesium, zinc, and thiamin for women who did not use vitamin supplements periconceptionally. We observed decreased NTD risks associated with increased intakes of linoleic acid, cysteine, calcium, and zinc for women who used supplements. We also observed increased NTD risks with increased intakes of oleic acid. For users as well as nonusers of vitamin supplements, we observed reduced risks with increased intakes of grains and dairy products. Chance was a likely alternative explanation for many of the observed risk patterns.

Energy and Nutrient Intakes and Health Practices of Latinas and White Non-Latinas in the 3 Months Before Pregnancy

OBJECTIVE To describe the health practices and energy and nutrient intakes from diet and supplements of foreign- and US-born Latinas and white non-Latinas in the 3 months before pregnancy. DESIGN A descriptive study in which data were obtained retrospectively from 2 questionnaires: an interviewer-administered questionnaire on the subjects medical, reproductive, family, occupational, and lifestyle history and a subject-administered (and interviewer-assisted) 100-item food frequency questionnaire. SUBJECTS/SETTING A population-based sample of California women (n = 462) who gave birth between 1989 and 1991 to single, live-born infants. One third of women were Latinas, of whom 58.1% were foreign born. STATISTICAL ANALYSES Means, standard deviations, and percentiles were computed for energy and nutrient intakes of the total population and for white non-Latinas; US-born Latinas; and foreign-born Latinas. One-way analysis of variance was used to compare group means. RESULTS Mean and median energy intake in all ethnic groups exceeded 2,000 kcal/day, although less than half of the population consumed 5 servings of fruit and vegetables per day. For iron, half of the women were below the Recommended Dietary Allowance. In contrast to the dietary intake of white non-Latinas and US-born Latinas, foreign-born Latinas had the lowest contribution of fat to total energy intake and the highest dietary intake of carbohydrate, cholesterol, fiber, grain products, protein foods, folate, vitamin C, iron, and zinc. CONCLUSIONS A womans ethnicity, as well as whether her place of birth was within or outside of the United States, may be predictors of her dietary and health practices before pregnancy. Vitamin, mineral, and food supplementation and consumption of cold breakfast cereal may be avenues for improving perinatal micronutrient intake.

Periconceptional intake of vitamin supplements and risk of multiple congenital anomalies

Numerous studies have reported reduced risks for a variety of single congenital anomaly phenotypes associated with maternal periconceptional use of vitamin supplements containing folic acid. Here we investigated whether periconceptional use of vitamin supplements containing folic acid by women altered their risk for delivering infants with multiple congenital anomalies (MCAs). Data were derived from a case-control study representing deliveries (fetal deaths and infants) from 2 California counties between January 1993 and July 1996. MCAs were defined as 2 or more congenital anomalies affecting more than one organ system or a major anomaly in combination with 2 minor anomalies. Controls were randomly selected from nonmalformed live-born infants. Telephone interviews were conducted with 112 (73.7% of eligible) case and 195 (78.0% of eligible) control mothers. Compared to women who did not use multivitamin supplements containing folic acid in the period 3 months before through 3 months after conception, women who used in this time period were observed to have an elevated risk to deliver fetuses or infants with MCAs, odds ratio = 2.6 (95% confidence interval 1.1-6.2). This elevated risk was not substantially altered (adjusted odds ratio = 2.9 [0.8-10.3]) by adjusting for maternal race/ethnicity, education, gravidity, body mass index, alcohol consumption, and cigarette smoking. No particular organ system seemed to be uniquely represented among the MCA fetuses and infants whose mothers used vitamin supplements. The observed elevated risk associated with maternal vitamin use is considered to be preliminary and needs to be replicated in other populations.

Maternal periconceptional use of electric bed-heating devices and risk for neural tube defects and orofacial clefts.

Electric and magnetic fields are of concern as risk factors for adverse reproductive outcomes, including congenital anomalies. Among residential exposures to electric and magnetic fields, electric bed-heating devices such as electric blankets may be a substantial source of such exposures, and their use is fairly common. Two population-based case-control studies were analyzed to investigate whether the periconceptional use of electric blankets, bed warmers, or electrically heated waterbeds increased the risk of women to deliver infants or fetuses with neural tube defects (NTDs) or orofacial clefts. We obtained information on bed-heating devices from 538 NTD cases and their 539 controls in one study, and 265 NTD cases and 481 controls and 652 orofacial cleft cases and their 734 controls from another study. Our results revealed a few modestly elevated risks of certain anomaly phenotypes with maternal use of certain bed-heating devices, but risks tended to be imprecise. In general, women who reported more frequent use of a bed-heating device, or longer duration of use, did not appear to have a higher risk for delivering offspring with anomalies than were women who reported less frequent or shorter-duration use.

Microsatellites proximal to leptin and leptin receptor as risk factors for spina bifida

Several recent studies have observed an association between neural tube defect risk and prepregnant obesity. This association was generally stronger for spina bifida and was observed irrespective of additional maternal factors, including periconceptional intake of vitamin supplements. Other studies have identified mutations within the genes that code for leptin (LEP) and its receptor (LEPR), which have been linked to obesity in mice and humans. We investigated the potential association between nucleotide variation at the LEP and LEPR loci, and increased risk of spina bifida. We searched specifically for allelic association at a pair of highly polymorphic microsatellites closely linked to either the LEP or LEPR gene. Data were derived from a population-based case-control study that had previously identified an association between a womans prepregnant obesity and her risk of delivering an infant with spina bifida. A total of 56 spina bifida case infants and 126 nonmalformed control infants were genotyped for 10 microsatellite alleles closely linked to the LEP gene, and 49 cases and 125 controls were genotyped for 10 microsatellite alleles closely linked to the LEPR gene. In general, alleles were not observed to be exclusively associated with substantially greater spina bifida risk in the body mass index (BMI) category (obese) of >29 kg/m(2) compared with the BMI category (nonobese) of </=29 kg/m(2). Thus, these particular infant allelic variants did not appear to explain the previously reported elevated risk observed for women whose prepregnant BMI exceeded 29 kg/m(2). A modest elevated spina bifida risk, irrespective of maternal BMI, was observed for two LEP microsatellite alleles (257 and 271). These estimates, however, were imprecise. Compared with those infants who did not have either of these alleles and whose mothers prepregnant BMI was </=29 kg/m(2), we computed odds ratios for (1) having either the 257 or 271 allele and maternal BMI >29 kg/m; (2) having either allele and BMI </=29 kg/m(2); and (3) not having either allele but BMI >29 kg/m(2). The odds ratios (95% confidence interval) for these comparisons were: for allele 257, 4.5 (1.1-19.4), 1.9 (0.5-6.3), and 2.9 (1.3-6.4), respectively, and for allele 271, 6.7 (1.6-30.4), 2.7 (0.7-10.9), and 2.7 (1.2-5.9), respectively. Owing to the exploratory nature of this investigation, the significance of these latter results is unclear.

Maternal Exposure to Nitrate From Drinking Water and Diet and Risk for Neural Tube Defects

In this population-based case-control study conducted in California between June 1989 and May 1991, the authors investigated the association between maternal periconceptional exposure to nitrate from drinking water and diet and risk for neural tube defects. The mothers of 538 cases and 539 nonmalformed controls were interviewed regarding residential history, consumption of tap water at home, and dietary intake during the periconceptional period. Dietary nitrate exposure was not associated with increased risk for neural tube defects. Exposure to nitrate in drinking water at concentrations above the 45 mg/liter maximum contaminant level was associated with increased risk for anencephaly (odds ratio (OR) = 4.0, 95% confidence interval (CI): 1.0, 15.4), but not for spina bifida. Increased risks for anencephaly were observed at nitrate levels below the maximum contaminant level among groundwater drinkers only (OR = 2.1, 95% CI: 1.1,4.1 for 5-15 mg/liter; OR = 2.3, 95% CI: 1.1, 4.5 for 16-35 mg/liter; and OR = 6.9, 95% CI: 1.9, 24.9 for 36-67 mg/liter compared with <5 mg/liter). Adjustment for identified risk factors for anencephaly did not substantially alter these associations, nor did control for maternal dietary nitrate, total vitamin C intake, and quantity of tap water consumed. The lack of an observed elevation in risk for anencephaly in association with exposure to mixed water containing nitrate at levels comparable with the concentration in groundwater may indicate that something other than nitrate accounts for these findings.