Gene-Folic Acid Interactions and Risk of Conotruncal Heart Defects: Results from the National Birth Defects Prevention Study.

Conotruncal heart defects (CTDs) are heart malformations that affect the cardiac outflow tract and typically cause significant morbidity and mortality. Evidence from epidemiological studies suggests that maternal folate intake is associated with a reduced risk of heart defects, including CTD. However, it is unclear if folate-related gene variants and maternal folate intake have an interactive effect on the risk of CTDs. In this study, we performed targeted sequencing of folate-related genes on DNA from 436 case families with CTDs who are enrolled in the National Birth Defects Prevention Study and then tested for common and rare variants associated with CTD. We identified risk alleles in maternal MTHFS (ORmeta = 1.34; 95% CI 1.07 to 1.67), maternal NOS2 (ORmeta = 1.34; 95% CI 1.05 to 1.72), fetal MTHFS (ORmeta = 1.35; 95% CI 1.09 to 1.66), and fetal TCN2 (ORmeta = 1.38; 95% CI 1.12 to 1.70) that are associated with an increased risk of CTD among cases without folic acid supplementation. We detected putative de novo mutations in genes from the folate, homocysteine, and transsulfuration pathways and identified a significant association between rare variants in MGST1 and CTD risk. Results suggest that periconceptional folic acid supplementation is associated with decreased risk of CTD among individuals with susceptible genotypes.

Innovative approach to identify multigenomic and environmental interactions associated with birth defects in family-based hybrid designs.

Genes, including those with transgenerational effects, work in concert with behavioral, environmental, and social factors via complex biological networks to determine human health. Understanding complex relationships between causal factors underlying human health is an essential step towards deciphering biological mechanisms. We propose a new analytical framework to investigate the interactions between maternal and offspring genetic variants or their surrogate single nucleotide polymorphisms (SNPs) and environmental factors using family-based hybrid study design. The proposed approach can analyze diverse genetic and environmental factors and accommodate samples from a variety of family units, including case/control-parental triads, and case/control-parental dyads, while minimizing potential bias introduced by population admixture. Comprehensive simulations demonstrated that our innovative approach outperformed the log-linear approach, the best available method for case-control family data. The proposed approach had greater statistical power and was capable to unbiasedly estimate the maternal and child genetic effects and the effects of environmental factors, while controlling the Type I error rate against population stratification. Using our newly developed approach, we analyzed the associations between maternal and fetal SNPs and obstructive and conotruncal heart defects, with adjustment for demographic and lifestyle factors and dietary supplements. Fourteen and 11 fetal SNPs were associated with obstructive and conotruncal heart defects, respectively. Twenty-seven and 17 maternal SNPs were associated with obstructive and conotruncal heart defects, respectively. In addition, maternal body mass index was a significant risk factor for obstructive defects. The proposed approach is a powerful tool for interrogating the etiological mechanism underlying complex traits.

Obstructive heart defects associated with candidate genes, maternal obesity, and folic acid supplementation.

Right-sided and left-sided obstructive heart defects (OHDs) are subtypes of congenital heart defects, in which the heart valves, arteries, or veins are abnormally narrow or blocked. Previous studies have suggested that the development of OHDs involved a complex interplay between genetic variants and maternal factors. Using the data from 569 OHD case families and 1,644 control families enrolled in the National Birth Defects Prevention Study (NBDPS) between 1997 and 2008, we conducted an analysis to investigate the genetic effects of 877 single nucleotide polymorphisms (SNPs) in 60 candidate genes for association with the risk of OHDs, and their interactions with maternal use of folic acid supplements, and pre-pregnancy obesity. Applying log-linear models based on the hybrid design, we identified a SNP in methylenetetrahydrofolate reductase (MTHFR) gene (C677T polymorphism) with a main genetic effect on the occurrence of OHDs. In addition, multiple SNPs in betaine-homocysteine methyltransferase (BHMT and BHMT2) were also identified to be associated with the occurrence of OHDs through significant main infant genetic effects and interaction effects with maternal use of folic acid supplements. We also identified multiple SNPs in glutamate-cysteine ligase, catalytic subunit (GCLC) and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) that were associated with elevated risk of OHDs among obese women. Our findings suggested that the risk of OHDs was closely related to a combined effect of variations in genes in the folate, homocysteine, or glutathione/transsulfuration pathways, maternal use of folic acid supplements and pre-pregnancy obesity.

One-carbon metabolite levels in mid-pregnancy and risks of conotruncal heart defects.

BACKGROUND: Evidence exists for an association between use of vitamin supplements with folic acid in early pregnancy and reduced risk for offspring with conotruncal heart defects. A few observations have been made about nutrients related to one-carbon metabolism other than folate. Our prospective study attempted to extend information on nutrition and conotruncal heart defects by measuring analytes in mid-pregnancy sera. METHODS: This study included data from a repository of women's mid-pregnancy serum specimens based on screened pregnancies in California from 2002-2007. Each woman's specimen was linked with delivery information to determine whether her fetus had a conotruncal heart defect or another structural malformation, or was nonmalformed. We identified 140 conotruncal cases and randomly selected 280 specimens as nonmalformed controls. Specimens were tested for a variety of analytes, including homocysteine, methylmalonic acid, folate, vitamin B12 , pyridoxal phosphate, pyridoxal, pyridoxic acid, riboflavin, total choline, betaine, methionine, cysteine, cystathionine, arginine, asymmetric and symmetric dimethylarginine. RESULTS AND CONCLUSIONS: We did not observe statistical evidence for substantial differences between cases and controls for any of the measured analytes. Analyses specifically targeting B-vitamins also did not reveal differences between cases and controls.

Conotruncal heart defects and common variants in maternal and fetal genes in folate, homocysteine, and transsulfuration pathways.

BACKGROUND: We investigated the association between conotruncal heart defects (CTDs) and maternal and fetal single nucleotide polymorphisms (SNPs) in 60 genes in the folate, homocysteine, and transsulfuration pathways. We also investigated whether periconceptional maternal folic acid supplementation modified associations between CTDs and SNPs METHODS: Participants were enrolled in the National Birth Defects Prevention Study between 1997 and 2008. DNA samples from 616 case-parental triads affected by CTDs and 1645 control-parental triads were genotyped using an Illumina® Golden Gate custom SNP panel. A hybrid design analysis, optimizing data from case and control trios, was used to identify maternal and fetal SNPs associated with CTDs RESULTS: Among 921 SNPs, 17 maternal and 17 fetal SNPs had a Bayesian false-discovery probability of <0.8. Ten of the 17 maternal SNPs and 2 of the 17 fetal SNPs were found within the glutamate-cysteine ligase, catalytic subunit (GCLC) gene. Fetal SNPs with the lowest Bayesian false-discovery probability (rs2612101, rs2847607, rs2847326, rs2847324) were found within the thymidylate synthetase (TYMS) gene. Additional analyses indicated that the risk of CTDs associated with candidate SNPs was modified by periconceptional folic acid supplementation. Nineteen maternal and nine fetal SNPs had a Bayesian false-discovery probability <0.8 for gene-by-environment (G × E) interactions with maternal folic acid supplementation. CONCLUSION: These results support previous studies suggesting that maternal and fetal SNPs within folate, homocysteine, and transsulfuration pathways are associated with CTD risk. Maternal use of supplements containing folic acid may modify the impact of SNPs on the developing heart.

Maternal dietary patterns are associated with risk of neural tube and congenital heart defects.

Studying empirically derived dietary patterns is useful in understanding dietary practice. We classified women by their dietary patterns using latent class analysis of 66 foods and studied the association of these patterns with neural tube defects (NTDs) and congenital heart defects (CHDs) in the U.S. National Birth Defects Prevention Study (1997-2005). Logistic regression models used data from 1,047 with an NTD, 6,641 with a CHD, and 6,123 controls that were adjusted for maternal characteristics and tested the effect modification of multivitamin supplement use. Four latent dietary patterns were identified: prudent, Western, low-calorie Western, and Mexican. Among participants who did not use supplements, those in the Mexican, Western, and low-calorie Western classes were significantly more likely (odds ratios of 1.6, 1.5, and 1.4, respectively) to have offspring born with NTDs than were those in the prudent class after adjustment of for dietary folic acid intake. In contrast, among supplement users, there was no difference in the incidence of NTDs between classes. Associations between dietary class and CHD subgroups were not modified by supplement use except for tetralogy of Fallot; among supplement users, those in the Western class were twice as likely (95% confidence interval: 1.4, 2.8) as the prudent class to have offspring with tetralogy of Fallot. Women who adhered to a Western diet were 1.2 (95% confidence interval: 1.03, 1.35) times more likely to have an infant with septal heart defect than were women who adhered to a prudent diet. A prudent dietary pattern, even with folate fortification, may decrease the risk of NTDs and some heart defects.

Preconception folic acid supplementation and risk for chromosome 21 nondisjunction: a report from the National Down Syndrome Project.

Both a lack of maternal folic acid supplementation and the presence of genetic variants that reduce enzyme activity in folate pathway genes have been linked to meiotic nondisjunction of chromosome 21; however, the findings in this area of research have been inconsistent. To better understand these inconsistencies, we asked whether maternal use of a folic acid-containing supplement before conception reduces risk for chromosome 21 nondisjunction. Using questionnaire data from the National Down Syndrome Project, a population-based case-control study, we compared the use of folic acid-containing supplements among mothers of infants with full trisomy 21 due to maternal nondisjunction (n = 702) and mothers of infants born with no major birth defects (n = 983). Using logistic regression, adjusting for maternal age, race/ethnicity, and infant age at maternal interview, we found no evidence of an association between lack of folic acid supplementation and maternal nondisjunction among all case mothers (OR = 1.16; 95% CI: 0.90-1.48). In analyses stratified by meiotic stage and maternal age (<35 or ≥35 years), we found an association among older mothers experiencing meiosis II nondisjunction errors (OR = 2.00; 95% CI: 1.08-3.71). These data suggest that lack of folic acid supplementation may be associated specifically with MII errors in the aging oocyte. If confirmed, these results could account for inconsistencies among previous studies, as each study sample may vary by maternal age structure and proportion of meiotic errors.

Neural tube defects and maternal intake of micronutrients related to one-carbon metabolism or antioxidant activity.

BACKGROUND: Maternal nutritional status has been evaluated to clarify its role in development of neural tube defects (NTDs). Maternal folate intake during pregnancy has been closely evaluated for its association with NTDs. The study objective was to examine associations between NTDs and other dietary periconceptional micronutrient intake, particularly nutrients involved in one-carbon metabolism or antioxidant activity. METHODS: Using data from the National Birth Defects Prevention Study, 1997-2005, logistic regression models were used to estimate the relative risk of NTDs based on maternal micronutrient intake. RESULTS: Results were stratified according to folic acid supplement use, race/ethnicity, and maternal body mass index. Analyses included 954 cases (300 with anencephaly, 654 with spina bifida) and 6268 controls. Higher intakes of folate, thiamin, betaine, iron, and vitamin A were associated with decreased risk of anencephaly among some ethnic and clinical groups. In some groups, higher intakes of thiamin, riboflavin, vitamin B(6) , vitamin C, vitamin E, niacin, and retinol were associated with decreased risk of spina bifida. CONCLUSION: In addition to folic acid, other micronutrients, including thiamin, betaine, riboflavin, vitamin B(6) , vitamin C, vitamin E, niacin, iron, retinol, and vitamin A, may decrease the risk of NTD occurrence. Birth Defects Research (Part A) 2012. © 2012 Wiley Periodicals, Inc.

Lack of periconceptional vitamins or supplements that contain folic acid and diabetes mellitus-associated birth defects.

OBJECTIVE: The purpose of this study was to examine the risk of birth defects in relation to diabetes mellitus and the lack of use of periconceptional vitamins or supplements that contain folic acid. STUDY DESIGN: The National Birth Defects Prevention Study (1997-2004) is a multicenter, population-based case-control study of birth defects (14,721 cases and 5437 control infants). Cases were categorized into 18 types of heart defects and 26 noncardiac birth defects. We estimated odds ratios for independent and joint effects of preexisting diabetes mellitus and a lack of periconceptional use of vitamins or supplements that contain folic acid. RESULTS: The pattern of odds ratios suggested an increased risk of defects that are associated with diabetes mellitus in the absence vs the presence of the periconceptional use of vitamins or supplements that contain folic acid. CONCLUSION: The lack of periconceptional use of vitamins or supplements that contain folic acid may be associated with an excess risk for birth defects due to diabetes mellitus.

Lack of maternal folic acid supplementation is associated with heart defects in Down syndrome: a report from the National Down Syndrome Project.

BACKGROUND: Maternal folic acid supplementation has been associated with a reduced risk for neural tube defects and may be associated with a reduced risk for congenital heart defects and other birth defects. Individuals with Down syndrome are at high risk for congenital heart defects and have been shown to have abnormal folate metabolism. METHODS: As part of the population-based case-control National Down Syndrome Project, 1011 mothers of infants with Down syndrome reported their use of supplements containing folic acid. These data were used to determine whether a lack of periconceptional maternal folic acid supplementation is associated with congenital heart defects in Down syndrome. We used logistic regression to test the relationship between maternal folic acid supplementation and the frequency of specific heart defects correcting for maternal race or ethnicity, proband sex, maternal use of alcohol and cigarettes, and maternal age at conception. RESULTS: Lack of maternal folic acid supplementation was more frequent among infants with Down syndrome and atrioventricular septal defects (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.08-2.63; p = 0.011) or atrial septal defects (OR, 1.69; 95% CI, 1.11-2.58; p = 0.007) than among infants with Down syndrome and no heart defect. Preliminary evidence suggests that the patterns of association differ by race or ethnicity and sex of the proband. There was no statistically significant association with ventricular septal defects (OR, 1.26; 95% CI, 0.85-1.87; p = 0.124). CONCLUSIONS: Our results suggest that lack of maternal folic acid supplementation is associated with septal defects in infants with Down syndrome. Birth Defects Research (Part A), 2011. © 2011 Wiley-Liss, Inc.

Association between selected folate pathway polymorphisms and nonsyndromic limb reduction defects: a case-parental analysis.

Inadequate folate status resulting from either genetic variation or nutritional deficiencies has been associated with an increased risk of congenital malformations including orofacial clefting, limb, cardiac and neural tube defects. Few epidemiological studies have examined the association between limb reduction defects (LRDs) and folate-related genetic polymorphisms other than MTHFR 677C→T. We conducted a case-parental analysis of 148 families who participated in the National Birth Defects Prevention Study to examine the association between nonsyndromic transverse and longitudinal LRDs with five single nucleotide polymorphisms (SNPs) in genes encoding enzymes in folate and methionine pathways. Log-linear Poisson regression, adapted for analysis of case-parental data assuming an additive genetic model, was used to estimate genetic relative risks and 95% confidence intervals for the association between LRDs and each SNP. Among women who did not take multivitamin supplements, the MTHFR 677T variant acts via the offspring's genome to increase the risk of LRDs. No association between LRDs and any fetal SNP was found among women who used multivitamin supplements. These results suggest the possibility that initiating folic acid supplementation prior to pregnancy may reduce the risk of having a LRD-affected pregnancy, especially in women whose offspring inherit one or two copies of the MTHFR 677T variant.

Trends in hospitalizations for neonatal jaundice and kernicterus in the United States, 1988-2005.

CONTEXT AND OBJECTIVE: Recent reports have raised global concerns about a reemergence of kernicterus. Accurate information on the incidence of kernicterus is unavailable because of the rarity of the condition and the lack of a systematic surveillance strategy. We used nationally representative hospital discharge data to evaluate trends in the diagnosis and management of neonatal jaundice and the incidence of kernicterus in relation to the American Academy of Pediatrics hyperbilirubinemia clinical practice guideline. PATIENTS AND METHODS: The data came from the Healthcare Cost and Utilization Project family of databases. The Nationwide Inpatient Sample and the Kids' Inpatient Database were combined to generate trend data for the years 1988-2005. All neonatal discharges with primary or secondary International Classification of Diseases, Ninth Revision, Clinical Modification diagnoses codes for jaundice or kernicterus occurring within the first 30 days of life were selected with population incidence rates calculated from estimates of term and preterm newborn hospitalizations derived from the Healthcare Cost and Utilization Project data. To increase the reliability of identified kernicterus hospitalizations, newborns with a diagnosis of kernicterus and a procedure code for phototherapy or exchange transfusion were included as cases. RESULTS: Hospital diagnosis codes for kernicterus likely included a substantial number of rule-out cases, because approximately 70% did not include a procedure code for phototherapy or exchange transfusion. Including only cases with a procedure code for phototherapy or exchange transfusion resulted in 2.7 per 100000 diagnosed with kernicterus over the entire study period. A diagnosis code for jaundice was recorded for 15.6% of newborns. The diagnosis of jaundice and kernicterus differed according to race and gender. Rates also were elevated in preterm relative to term infants for both jaundice and kernicterus. Trends in diagnosis for newborn jaundice were u-shaped, with rates falling in the years before the initial American Academy of Pediatrics guideline (1988-1993) and increasing in the years after publication of the guideline (1997-2005). In contrast, the number of newborn hospitalizations with a diagnosis of kernicterus generally declined throughout the study period. Most of the decline in hospitalizations for term infants with a diagnosis of kernicterus occurred before and immediately after publication of the 1994 guideline, going from 5.1 per 100000 in 1988 to 1.5 per 100000 in the years from 1994 to 1996 and has since remained constant. CONCLUSIONS: Nationally representative hospital data indicate a declining incidence of hospitalizations with a diagnosis of kernicterus in newborn infants over the period 1988-2005. The decline occurred before and immediately after publication of the 1994 American Academy of Pediatrics guideline on hyperbilirubinemia. Epidemiologic findings were mostly consistent with other studies. Healthcare Cost and Utilization Project data provide an important system for monitoring hospitalizations of uncommon newborn conditions such as kernicterus.

Neural tube defects and maternal folate intake among pregnancies conceived after folic acid fortification in the United States.

Rates of neural tube defects have decreased since folic acid fortification of the food supply in the United States. The authors' objective was to evaluate the associations between neural tube defects and maternal folic acid intake among pregnancies conceived after fortification. This is a multicenter, case-control study that uses data from the National Birth Defects Prevention Study, 1998-2003. Logistic regression was used to compute crude and adjusted odds ratios between cases and controls assessing maternal periconceptional use of folic acid and intake of dietary folic acid. Among 180 anencephalic cases, 385 spina bifida cases, and 3, 963 controls, 21.1%, 25.2%, and 26.1%, respectively, reported periconceptional use of folic acid supplements. Periconceptional supplement use did not reduce the risk of having a pregnancy affected by a neural tube defect. Maternal intake of dietary folate was not significantly associated with neural tube defects. In this study conducted among pregnancies conceived after mandatory folic acid fortification, the authors found little evidence of an association between neural tube defects and maternal folic acid intake. A possible explanation is that folic acid fortification reduced the occurrence of folic acid-sensitive neural tube defects. Further investigation is warranted to possibly identify women who remain at increased risk of preventable neural tube defects.

Folic acid and the decline in neural tube defects in Arkansas.

Folic acid has been shown to reduce the risk of pregnancies affected by neural tube defects (NTDs) by as much as 70%. Cereal grains sold in the U.S. have been fortified with folic acid since 1998. The Arkansas Reproductive Health Monitoring System and the Arkansas Folic Acid Coalition have encouraged use of folic acid and monitored the impact of increased consumption of folic acid among Arkansans. NTDs in Arkansas have declined 40% since intervention programs were implemented. The greatest decline has been observed among white and Hispanic women. Efforts to encourage folic acid consumption should continue to target Arkansas women. NTDs include anencephaly and spina bifida. These birth defects result from incomplete closure of the fetal neural tube during the first month of pregnancy. Infants with anencephaly are born without all or most of their brain and die within a few days of life. Infants with spina bifida have varying degrees of impairment ranging from little noticeable disability to severe, lifelong disability. Folic acid, when taken in supplement form has been shown to reduce the risk of a pregnancy affected by a neural tube defect by as much as 70%. As a result of this finding, the U.S. Federal Drug Administration mandated that cereal grains sold in this country be fortified with at least 140 mcg of folic acid per 100 grams of grain by January 1, 1998. Prior to mandatory fortification, the March of Dimes and the U.S. Public Health Service released statements encouraging all women of reproductive age who are capable of becoming pregnant to take 400 mcg 'of synthetic folic acid daily. The Arkansas Reproductive Health Monitoring System (ARHMS) has monitored rates of NTDs in Arkansas since 1980. ARHMS is the lead agency of the Arkansas Folic Acid Coalition whose mission is to encourage folic acid use among all Arkansas women of reproductive age. In this report, we summarize efforts by ARHMS and the Arkansas Folic Acid Coalition to increase the awareness and use of folic acid in Arkansas, show how the rates of NTDs in the state have declined over the past 10 years, and estimate the direct health care and productivity cost savings to Arkansans over that time.

Hospitalizations of newborns with folate-sensitive birth defects before and after fortification of foods with folic acid.

CONTEXT: The prevalence of neural tube defects is reduced in populations of women who receive folic acid supplementation. Since 1998, grain products in the United States have been fortified with folic acid. Fortification may have additional benefits by reducing the national prevalence of newborn hospitalizations for other folate-sensitive birth defects. OBJECTIVE: Our purpose with this work was to compare rates of hospitalizations of newborns with folate-sensitive birth defects before and after implementation of fortification of grains. METHOD: National hospital discharge data from the Healthcare Cost and Utilization Project were used to compute rates of newborn hospitalizations for selected birth defects per 10,000 live births in the United States. Newborn hospitalization rates involving congenital anomalies recognizable at birth were analyzed for 5 years before fortification of grains and 5 years after fortification. Additional analyses compared changes in newborn hospitalization rates for birth defects by race/ethnicity, income, insurance status, and region of the country. RESULTS: Newborn hospitalization rates for spina bifida decreased 21% from 1993-1997 to 1998-2002. Newborn hospitalization rates also decreased for anencephaly (20%) and limb-reduction defects (4%). Decline in hospitalizations for spina bifida occurred more often among Hispanic newborns (33%) than among white (13%) or black (21%) newborns. Decline in limb-reduction defects was seen primarily among blacks (11%). Findings using hospitalization data were similar to recent reports using birth defect surveillance systems with the exception of findings for orofacial clefts and conotruncal heart defects. No reductions were noted in newborn hospitalizations for these anomalies. CONCLUSIONS: Results from this ecological study fail to demonstrate substantial declines in newborn hospitalizations beyond those anticipated from a reduction in neural tube defects. The society-wide impact of the fortification program on birth defects and other health conditions should continue to be monitored.

Awareness and use of folic acid among women in the lower Mississippi Delta.

CONTEXT: National and state efforts to increase folic acid awareness and use may not be reaching large segments of the population. PURPOSE: This study examines folic acid awareness and use among women of childbearing age in a representative, economically at-risk rural sample and identifies factors that influence awareness and use. METHODS: A cross-sectional random digit dialing telephone survey was completed with a representative sample of 646 women aged 14-45 years in 36 counties of the lower Mississippi Delta. Folic acid awareness and supplement use were estimated by percentages weighted to reflect the 36-county population. Pregnancy intentions and the ability to become pregnant were used to predict awareness and use among a subsample of sexually active women. FINDINGS: Compared to national samples, Delta women were less likely to have heard of folic acid (75% vs 64%) or to take a regular (5-7 days/wk) folic acid supplement (34% vs 22%). The proportion of women who took regular folic acid supplements was very low among some subgroups: African Americans (14%), those 14-19 years of age (12%), and those with low incomes (13%) and low educational levels (14%). Of the women who reported being sexually active, the ability to become pregnant more than doubled their likelihood of regular supplement use. CONCLUSIONS: The national folic acid campaign has not reached many women in the rural Mississippi Delta. A new mode of folic acid education is needed that is focused on low-income and young women and women not planning pregnancies. In the Delta and similar geographic regions, health care providers, black church leaders, and youth group leaders could be valuable advocates for folic acid.

Randomized trial of a physician-based intervention to increase the use of folic acid supplements among women.

OBJECTIVE: Fewer than one third of American women take folic acid daily, although many women report that they would take folic acid if their physicians advised them to do so. This study determined the impact of a physician intervention during routine gynecologic visits on folic acid supplementation. STUDY DESIGN: Patients were assigned randomly to receive brief folic acid counseling, a reminder phone call, and 30 folic acid tablets (n = 162 women; intervention group) or to receive counseling about other preventive health behaviors and a folic acid informational pamphlet (n = 160 women; control group). Self-reported folic acid use was compared at baseline and at 2 months. RESULTS: Of the 279 patients who completed the study, weekly folic acid intake increased in the intervention group by 68%, compared with 20% in the control group ( P =.008). No significant differences were found in daily intake. The women who were most influenced by the intervention were black and lower income and not planning pregnancies. CONCLUSION: With little effort expended to encourage folic acid use, gynecologists could potentially reduce the risk of folate-preventable birth defects among their patients by as much as 11%.

Birth defects in Arkansas: is folic acid fortification making a difference?

BACKGROUND: Since 1998, fortification of grain products with folic acid has been mandated in the United States, in an effort to reduce the prevalence of neural tube defects (NTDs). Published reports have shown a reduction in the prevalence of spina bifida since fortification was mandated, but no published studies have reported a reduction in birth defects, other than NTDs, that are postulated to be associated with folic acid deficiency. This study was performed to determine if fortification has reduced the prevalence of NTDs and other birth defects in Arkansas. METHODS: Using data from the Arkansas Reproductive Health Monitoring System, prevalences were computed for thirteen specific birth defects with prior evidence supporting a protective effect of folic acid or multivitamins. Prevalences were calculated using data for live births to Arkansas residents for 1993-2000. Exposure to folic acid fortification was classified by birth year as "pre-fortification" (1993-1995), "transition" (1996-1998) or "post-fortification" (1999-2000). Logistic regression analysis was used to compute crude and adjusted prevalence odds ratios comparing the identified time periods. RESULTS: Prevalences decreased between the pre- and post-fortification periods for spina bifida, orofacial clefts, limb reduction defects, omphalocele, and Down syndrome, but only the decrease in spina bifida was statistically significant (prevalence odds ratio 0.56; 95% confidence interval, 0.37, 0.83). CONCLUSION: In Arkansas, the prevalence of spina bifida has decreased since folic acid fortification of foods was implemented. Similar studies by other birth defects surveillance systems are needed to confirm a preventive effect of fortification for malformations other than spina bifida.

Folic acid use by women receiving routine gynecologic care.

OBJECTIVE: Many health professional groups recommend folic acid supplementation for all women able to become pregnant. In this study, we document folic acid supplement use among a sample of women receiving routine gynecologic care. METHODS: A short questionnaire was administered to 322 women aged 18-45 years who were seeking routine gynecologic care at participating clinics in Little Rock, Arkansas. Questions covered knowledge and use of folic acid supplements, pregnancy intention, and demographic and socioeconomic characteristics. Primary study outcomes were self-reported folic acid awareness, daily or weekly use of folic acid supplements, and intention to begin taking folic acid. Factors affecting study outcomes were examined individually by computing crude odd ratios and adjusted for other covariates using unconditional logistic regression. RESULTS: Although 61.8% of women reported awareness of the association between folic acid and birth defects prevention, only 27.1% of these women, and 22.7% of all study participants, reported daily use of a folic acid supplement. Substantially more women (39.8%) were taking a folic acid supplement at least once per week. Age, race, educational level, folic acid awareness, marital status, pregnancy intent, and other preventive health behaviors were the most important predictors of compliance. CONCLUSION: The results indicate a need for targeted interventions directed toward minority women, young women, and those of lower socioeconomic and educational status. The routine gynecologic visit is an ideal opportunity to counsel women of reproductive age to take folic acid daily. LEVEL OF EVIDENCE: III

Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States.

BACKGROUND: In 1992, the United States Public Health Service recommended that all women of childbearing age consume 400 microg of folic acid daily. The Food and Drug Administration authorized the addition of synthetic folic acid to grain products in March 1996 with mandatory compliance by January 1998. The impact of these public health policies on the prevalence of neural tube defects needs to be evaluated. We sought to determine the prevalences of spina bifida and anencephaly during the transition to mandatory folic acid fortification. METHODS: Twenty-four population-based surveillance systems were used to identify 5,630 cases of spina bifida and anencephaly from 1995-99. Cases were divided into three temporal categories depending on whether neural tube development occurred before folic acid fortification (January 1995 to December 1996), during optional fortification (January 1997 to September 1998), or during mandatory fortification (October 1998 to December 1999). Prevalences for each defect were calculated for each time period. Data were also stratified by programs that did and did not ascertain prenatally diagnosed cases. RESULTS: The prevalence of spina bifida decreased 31% (prevalence ratio [PR] = 0.69, 95% confidence interval [CI] = 0.63-0.74) from the pre- to the mandatory fortification period and the prevalence of anencephaly decreased 16% (PR = 0.84, 95% CI = 0.75-0.95). Stratification by prenatal ascertainment did not alter results for spina bifida but did impact anencephaly trends. CONCLUSIONS: The decline in the prevalence of spina bifida was temporally associated with folic acid fortification of US grain supplies. The temporal association between fortification and the prevalence of anencephaly is unclear.