Sarah C. Tinker

Folic Acid Intake Among U.S. Women Aged 15–44 Years, National Health and Nutrition Examination Survey, 2003–2006

BACKGROUND In 1998, the IOM recommended all women capable of becoming pregnant consume 400 microg of folic acid daily to prevent neural tube defects (NTDs). PURPOSE This paper aims to describe how different sources of folic acid contribute to achieving the recommended usual daily intake. METHODS Data on 2617 nonpregnant U.S. women aged 15-44 years from the 2003-2004 and 2005-2006 National Health and Nutrition Examination Surveys were analyzed in 2009. The usual daily folic acid intake from diet and supplements accounting for measurement error; the proportion of women consuming the recommended usual intake; and the adjusted associations of recommended intake with multiple characteristics were estimated. RESULTS Overall, 24% of nonpregnant U.S. women of childbearing age consumed the recommended usual intake (95% CI=20%, 27%). Intake was highest among non-Hispanic white women (30%), followed by Mexican-American (17%) and non-Hispanic black women (9%). Among women who used supplements with folic acid, 72% (95% CI=65%, 79%) consumed the recommended usual intake. Use of supplements was the strongest determinant (unadjusted prevalence ratio [PR]: 10.2, 95% CI=7.1, 14.7) of recommended intake, mediating associations of other characteristics. Among the 68% of women who did not use supplements, consumption of cereals with folic acid and having diabetes were the strongest determinants of recommended usual intake (PRs=20.2 and 0.10, respectively). CONCLUSIONS Given that consumption of folic acid is an important public health goal to prevent NTDs, an evaluation of strategies, beyond recommendations that women consume supplements, is needed.

The national birth defects prevention study: A review of the methods

BACKGROUND The National Birth Defects Prevention Study (NBDPS) is a large population-based multicenter case-control study of major birth defects in the United States. METHODS Data collection took place from 1998 through 2013 on pregnancies ending between October 1997 and December 2011. Cases could be live born, stillborn, or induced terminations, and were identified from birth defects surveillance programs in Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah. Controls were live born infants without major birth defects identified from the same geographical regions and time periods as cases by means of either vital records or birth hospitals. Computer-assisted telephone interviews were completed with women between 6 weeks and 24 months after the estimated date of delivery. After completion of interviews, families received buccal cell collection kits for the mother, father, and infant (if living). RESULTS There were 47,832 eligible cases and 18,272 eligible controls. Among these, 32,187 (67%) and 11,814 (65%), respectively, provided interview information about their pregnancies. Buccal cell collection kits with a cytobrush for at least one family member were returned by 19,065 case and 6,211 control families (65% and 59% of those who were sent a kit). More than 500 projects have been proposed by the collaborators and over 200 manuscripts published using data from the NBDPS through December 2014. CONCLUSION The NBDPS has made substantial contributions to the field of birth defects epidemiology through its rigorous design, including case classification, detailed questionnaire and specimen collection, large study population, and collaborative activities across Centers.

Periconceptional Use of Opioids and the Risk of Neural Tube Defects

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

U.S. women of childbearing age who are at possible increased risk of a neural tube defect‐affected pregnancy due to suboptimal red blood cell folate concentrations, National Health and Nutrition Examination Survey 2007 to 2012

BACKGROUND Red blood cell (RBC) folate concentrations are a potential biomarker of folate-sensitive neural tube defect (NTD) risk in the population. The purpose of this analysis was to describe women in the U.S. population with RBC folate concentrations below those associated with optimal NTD prevention. METHODS We used data from the 2007 to 2012 National Health and Nutrition Examination Survey (NHANES) to assess the RBC folate status of U.S. women of childbearing age relative to risk categories for NTD risk based on RBC folate concentrations. We defined suboptimal RBC folate concentrations as those associated with a prevalence of ≥9 NTDs per 10,000 live births. RESULTS Among nonpregnant women age 12 to 49 years, 22.8% (95% Confidence Interval: 21.1, 24.6) had suboptimal RBC folate concentrations. Women had greater odds of having a suboptimal RBC folate concentration if they did not use dietary supplements containing folic acid; had mandatorily fortified enriched cereal grain products as their only source of folic acid; were non-Hispanic black or Hispanic; or were current smokers. CONCLUSION Based on RBC folate concentrations, we would predict that the majority of U.S. women of reproductive age are not at increased risk for folate sensitive NTDs in the presence of mandatory folic acid fortification. Prevention policies and programs can be aimed at population subgroups identified as having higher predicted risk for folate-sensitive NTDs based on RBC folate concentrations.

Does obesity modify the association of supplemental folic acid with folate status among nonpregnant women of childbearing age in the United States

BACKGROUND Obesity is associated with an increased risk of having a pregnancy affected by a neural tube defect (NTD). It is not clear whether the amount of folic acid required by obese women to protect against NTDs is the same as that for nonobese women. METHODS We analyzed data from the National Health and Nutrition Examination Survey, representative of the noninstitutionalized civilian U.S. population, to assess whether body mass index (BMI; normal weight, overweight, and obese categories) modified the association between supplemental folic acid intake and folate status. We estimated the geometric mean concentration among nonpregnant women of childbearing age (15-44 years) during the postfortification period of: serum folate (2003-2008); red blood cell (RBC) folate (2007-2008); and plasma total homocysteine (tHcy; 2003-2006), adjusted for age, race and ethnicity, and total dietary folate expressed as dietary folate equivalents for strata of supplement use and BMI. RESULTS BMI was inversely associated with serum folate among women who did not use supplements containing folic acid; no differences between women in different BMI categories were observed among supplement users. Regardless of supplement use, obese women had the highest RBC folate concentrations. There were no differences in tHcy by BMI, regardless of supplement use. CONCLUSIONS These results do not support a straightforward modification of the relationship between supplemental folic acid intake and folate status by BMI. In this population, BMI may affect the body distribution of folate, as reflected by lower serum and higher RBC folate levels in obese women who do not use supplements.

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.

Epidemiology of Maternal Injuries During Pregnancy in a Population-Based Study, 1997–2005

BACKGROUND Maternal injuries during pregnancy are common and can cause adverse pregnancy outcomes. We sought to describe factors related to injury during pregnancy. METHODS We analyzed data from the National Birth Defects Prevention Study (NBDPS), a population-based, case-control study of birth defects in 10 U.S. states. We estimated the proportion of control mothers, a random sample of mothers delivering infants without major birth defects in the study regions, who reported an injury during pregnancy. We assessed associations with maternal and paternal characteristics using logistic regression to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI). RESULTS Between October 1997 and December 2005, 490 (7.4%) of 6609 mothers reported 527 injuries during pregnancy. Falls caused over half of reported injuries during pregnancy (51.6%), and 9.5% of reported injuries were intentionally inflicted. Mothers who reported an injury during pregnancy were more likely to be aged <18 years vs. 18-29 years (aOR 2.84, 95% CI 1.54-5.23) and less likely to be aged ≥30 years (aOR 0.67, 95% CI 0.51-0.89). They were more likely to use alcohol during pregnancy (aOR for nonbinge drinking 1.38, 95% CI 1.05-1.81), to smoke during pregnancy (aOR 1.37, 95% CI 1.02-1.85), to have epilepsy (aOR 3.31, 95% CI 1.48-7.38), and to be employed (aOR 1.44, 95% CI 1.08-1.93) than mothers who did not report an injury. CONCLUSIONS We identified several factors associated with maternal injury during pregnancy, an important step in identifying women who may be at higher risk and in designing interventions to prevent injuries during pregnancy.

Fortification of corn masa flour with folic acid in the United States: an overview of the evidence.

Corn masa flour, used to make products such as corn tortillas, is a staple food for Hispanic populations residing in the United States, particularly among Mexican Americans and Central Americans. Research has indicated that Hispanic women in the United States continue to be at a higher risk of having a neural tube defect–affected pregnancy than women of other races/ethnicities, even after the introduction of folic acid fortification of cereal grain products labeled as “enriched.” Corn masa flour has, therefore, been suggested as a potential food vehicle for folic acid in the United States. This paper explores the potential impact that folic acid fortification of corn masa flour could have on the Hispanic population in the United States.

Impact of Time to Maternal Interview on Interview Responses in the National Birth Defects Prevention Study

Prenatal exposures often are assessed using retrospective interviews. Time from exposure to interview may influence data accuracy. We investigated the association of time to interview (TTI) with aspects of interview responses in the National Birth Defects Prevention Study, a population-based case-control study of birth defects in 10 US states. Mothers completed a computer-assisted telephone interview 1.5-24 months after their estimated date of delivery. Proxy metrics for interview quality were whether certain exposures were reported, whether the start month of reported medication use or illness was reported, or whether responses were missing. Interaction by case status was assessed. Interviews were completed with 30,542 mothers (22,366 cases and 8,176 controls) who gave birth between 1997 and 2007. Mothers of cases were interviewed later than were mothers of controls (11.7 months vs. 9.5 months, respectively). In adjusted analyses, having a TTI that was greater than 6 months was associated with only a few aspects of interview responses (e.g., start month of pseudoephedrine use). Interaction by case-control status was observed for some exposures; mothers of controls had a greater reduction in interview quality with increased TTI in these instances (e.g., report of morning sickness, start month of acetaminophen use and ibuprofen use). The results suggest that TTI might impact interview responses; however, the impact may be minimal and specific to the type of exposure.

Maternal injuries during the periconceptional period and the risk of birth defects, National Birth Defects Prevention Study, 1997–2005

Maternal injuries during pregnancy are common (∼7% prevalence). However, few studies have examined the association between maternal injuries and birth defects. The National Birth Defects Prevention Study is a population-based case-control study of birth defects in 10 U.S. states. Cases were ascertained through surveillance; controls were randomly selected from infants delivered without major birth defects in the study regions. Mothers completed a telephone interview on exposures before and during pregnancy, including injuries. We assessed associations between periconceptional (month before until the end of the third month of pregnancy) maternal injuries and birth defects. We used logistic regression to estimate adjusted odds ratios (AORs) and 95% confidence intervals (CI). Periconceptional injuries were associated with interrupted aortic arch type B [AOR = 5.2, 95% CI 1.2, 23.2]; atrioventricular septal defect [AOR = 2.2, 95% CI 1.1, 4.4]; pulmonary atresia [AOR = 3.2, 95% CI 1.6, 6.4]; tricuspid atresia [AOR = 2.8, 95% CI 1.2, 6.7]; hypoplastic left heart syndrome [AOR = 2.0, 95% CI 1.1, 3.4]; anorectal atresia/stenosis [AOR = 1.7, 95% CI 1.0, 2.7]; longitudinal limb deficiency [AOR = 2.1, 95% CI 1.1, 3.9]; and gastroschisis [AOR = 1.8, 95% CI 1.2, 2.8]. Associations with longitudinal limb deficiency, gastroschisis and hypoplastic left heart syndrome were stronger for intentional injuries. Our results suggest maternal injury during the periconceptional period, particularly those inflicted intentionally, may be associated with select birth defects. This analysis was hypothesis-generating, with many associations tested. Further research is warranted.