Impact of Folic Acid Fortification of the U.S. Food Supply on the Occurrence of Neural Tube Defects

Daily consumption of 400 microg of folic acid before conception and during early pregnancy dramatically reduces the occurrence of neural tube defects (NTDs). Before food fortification, however, only an estimated 29% of US reproductive-aged women were taking a supplement containing 400 microg of folic acid daily. The US Food and Drug Administration authorized addition of folic acid to enriched grain products in March 1996, with compliance mandatory by January 1998. To evaluate the impact of food fortification with folic acid on NTD birth prevalence. National study of birth certificate data for live births to women in 45 US states and Washington, DC, between January 1990 and December 1999. Birth certificate reports of spina bifida and anencephaly before fortification (October 1995 through December 1996) compared with after mandatory fortification (October 1998 through December 1999). The birth prevalence of NTDs reported on birth certificates decreased from 37.8 per 100 000 live births before fortification to 30.5 per 100 000 live births conceived after mandatory folic acid fortification, representing a 19% decline (prevalence ratio [PR], 0.81; 95% confidence interval [CI], 0.75-0.87). During the same period, NTD birth prevalence declined from 53.4 per 100 000 to 46.5 per 100 000 (PR, 0.87; 95% CI, 0.64-1.18) for women who received only third-trimester or no prenatal care. A 19% reduction in NTD birth prevalence occurred following folic acid fortification of the US food supply. However, factors other than fortification may have contributed to this decline.

Impact of Folic Acid Fortification of the U.S. Food Supply on the Occurrence of Neural Tube Defects

Folic acid fortification in the United States became mandatory January 1, 1998, to reduce the occurrence of neural tube defects (NTDs). We evaluated the impact of folic acid fortification on orofacial clefts using United States birth certificate data for 45 states and the District of Columbia. Prevalence ratios (PRs) were calculated comparing orofacial cleft prevalence among births prefortification (1/1990-12/1996) and postfortification (10/1998-12/2002), based on fortification status at conception. The JoinPoint Regression Program and exponentially weighted moving average charts (EWMA) were used to assess the timing of any statistically significant changes in prevalence. Data were stratified by maternal race/ethnicity, age, smoking, and timing of prenatal care. Orofacial clefts declined following folic acid fortification (PR=0.94; 95% CI: 0.92-0.96). The EWMA chart flagged a significant decrease in the fourth quarter of 1998. The JoinPoint graph had one change in slope, with a significant quarterly percent change (-0.34) between 1996 and 2002. The decline in orofacial clefts occurred in non-Hispanic Whites but not other racial/ethnic groups, nonsmokers but not women who reported smoking during pregnancy, and women who received prenatal care in the first trimester but not women who began receiving care later in pregnancy. Folic acid fortification in the United States was associated with a small decrease in orofacial cleft prevalence, with the timing of the decline consistent with the introduction of fortification. The decline is much smaller than that observed for NTDs, but nonetheless suggests an additional benefit of this public health intervention.

Preconceptional intake of folate and vitamin B12 in the prevention of neural tube defects and Down syndrome

DNA methylation is an epigenetic mechanism that regulates gene expression and can be modified by one-carbon nutrients. The objective of this study was to investigate the impact of folic acid (FA) fortification of the US food supply on leukocyte global DNA methylation and the relationship between DNA methylation, red blood cell (RBC) folate, and other one-carbon biomarkers among postmenopausal women enrolled in the Women's Health Initiative Observational Study. We selected 408 women from the highest and lowest tertiles of RBC folate distribution matching on age and timing of the baseline blood draw, which spanned the pre- (1994–1995), peri- (1996–1997), or post-fortification (1998) periods. Global DNA methylation was assessed by liquid chromatography-tandem mass spectrometry and expressed as a percentage of total cytosine. We observed an interaction (P = 0.02) between fortification period and RBC folate in relation to DNA methylation. Women with higher (vs. lower) RBC folate had higher mean DNA methylation (5.12 vs. 4.99%; P = 0.05) in the pre-fortification period, but lower (4.95 vs. 5.16%; P = 0.03) DNA methylation in the post-fortification period. We also observed significant correlations between one-carbon biomarkers and DNA methylation in the pre-fortification period, but not in the peri- or post-fortification period. The correlation between plasma homocysteine and DNA methylation was reversed from an inverse relationship during the pre-fortification period to a positive relationship during the post-fortification period. Our data suggest that (1) during FA fortification, higher RBC folate status is associated with a reduction in leukocyte global DNA methylation among postmenopausal women and; (2) the relationship between one-carbon biomarkers and global DNA methylation is dependent on folate availability.

Anencephaly is a lethal malformation characterized by the absence of the skull and both cerebral hemispheres caused by deficiency of closure of the neural tube at rostral level between 23 and 25 days of gestation (Bronberg et al. 2011). The occurrence of anencephaly and other neural tube defects (NTDs) such as meningocele and spina bifida are between 50 and 70 % preventable by periconceptional folic acid (FA) administration to reduce their prevalence across populations (Blencowe et al. 2010). The percentage decrease is dependent upon the background prevalence. The percentage of NTDs that are preventable by periconceptional folic acid intake is dependent on the prevalence of folate-sensitive NTDs in the population (Robbins et al. 2006; Bronberg et al. 2011). To prevent anemia due to iron deficiency and the occurrence of NTD, the Brazilian Ministry of Health approved the resolution RDC No. 344 on December 13, 2002, whereby the flour fortification of wheat and maize was regulated. This resolution determined that as of June 2004, wheat and corn flours be supplemented with at least 4.2 mg iron and 150 mcg of FA/100 g flour (ANVISA 2002). As in many South American countries, there are only two exceptions to penalized abortion in Brazil: in case of rape or to save the woman’s life. The Brazilian Criminal Code does not include fetal malformations as a cause of penalized abortion. This limitation was partially overcome in 2004, when the Brazilian Supreme Court of Justice authorized abortion in cases of anencephalic fetuses (Diniz 2007). Termination of pregnancy (TOP) with an anencephalic baby was made legal in 2012, without need of a special judicial authorization (Carvalho 2011). Until 2012, TOP had been legal in Brazil in cases of anencephaly only after special authorization from a judge. A survey performed with Brazilian obstetricians showed that 37 % of women with a pregnancy of anencephalic fetus had successfully obtained authorization for legal abortion (Diniz et al. 2009). About ten South American countries, in most of which abortion for congenital malformations is not authorized by law, primary prevention of anencephaly and other NTDs is managed through mandatory fortification of flour with FA (PAHO 2003). In some of these countries, fortification has proven to be an effective strategy for the primary prevention of anencephaly and NTDs. In particular, Argentina (Bronberg et al. 2011) and Chile (Cortes et al. 2012) have reduced the number of deaths by anencephaly by about 50 % in the post-fortification period compared to the pre-fortification stage. There are dissimilar records in Brazil in terms of fortification results according to NTDs, the type of data used (infant deaths or born alive), and level of spatial and temporal coverage these results are based on (Orioli et al. 2011; Pacheco et al. 2009; Fujimori et al. 2013; Schuler-Faccini et al. 2014). For its lethality, since 99 % of those born with anencephaly die within the first month of life and because the phenotype is well identified, even by non-specialists, anencephaly is a malformation whose epidemiological behavior can be analyzed with some confidence and provide an accurate and precise picture of the effect of flour fortification with FA and other preventive measures. Given the socioeconomic, geographical, ecological, and cultural diversity of Brazil, it is estimated that spatial and temporal variations of infant deaths from this NTD may be present. In this paper, the temporal variation and spatial distribution at different levels of the state organization in Brazil, infant and fetal deaths by anencephaly were analyzed in relation to the different phases that occurred in the process of fortification with FA.

The risk of recurrent neural-tube defects is decreased in women who take folic acid or multivitamins containing such during the periconceptional period. The extent to which folic acid supplementation can reduce the first occurrence of defects is not known. We conducted a randomized, controlled trial of periconceptional multivitamin supplementation to test the efficacy of this treatment in reducing the incidence of a first occurrence of neural-tube defects. Women planning a pregnancy (in most cases their first) were randomly assigned to receive a single tablet of a vitamin supplement (containing 12 vitamins, including 0.8 mg of folic acid; 4 minerals; and 3 trace elements) or a trace-element supplement (containing copper, manganese, zinc, and a very low dose of vitamin C) daily for at least one month before conception and until the date of the second missed menstrual period or later. Pregnancy was confirmed in 4753 women. The outcome of the pregnancy (whether the fetus or infant had a neural-tube defect or congenital malformation) was known in 2104 women who received the vitamin supplement and in 2052 who received the trace-element supplement. Congenital malformations were significantly more prevalent in the group receiving the trace-element supplement than in the vitamin-supplement group (22.9 per 1000 vs. 13.3 per 1000, P = 0.02). There were six cases of neural-tube defects in the group receiving the trace-element supplement, as compared with none in the vitamin-supplement group (P = 0.029). The prevalence of cleft lip with or without cleft palate was not reduced by periconceptional vitamin supplementation. Periconceptional vitamin use decreases the incidence of a first occurrence of neural-tube defects.

ABSTRACTPurpose To examine the association between maternal coffee consumption during pregnancy and the occurrence of neural tube defects (NTDs) in offspring. Methods PubMed, Springer Link and Elsevier databases were searched up to August, 2014. Case-control and cohort studies published on the association between maternal coffee consumption during pregnancy and the occurrence of NTDs in offspring were included. Meta-analysis was applied to calculate the pooled effect estimates and their 95% confidence intervals (CIs) using a random-effects model. Results A total of six case-control studies and one cohort study were included. The pooled effect estimate of maternal coffee consumption during pregnancy was 0.86 for total NTDs (95% CI: 0.51– 1.45) and 1.30 (95% CI: 0.67– 2.52) for NTDs subtype of spina bifida. Conclusions Our findings suggested that maternal coffee consumption during pregnancy was not significantly associated with the occurrence of total NTD or the spina bifida subtype of NTD.

Background. The risk of recurrent neural-tube defects is decreased in women who take folic acid or multivitamins containing folic acid during the periconceptional period. The extent to which such supplementation can reduce the first occurrence of defects is not known. Methods. We conducted a randomized, controlled trial of periconceptional multivitamin supplementation to test the efficacy of this treatment in reducing the incidence of a first occurrence of neural-tube defects. Women planning a pregnancy (in most cases their first) were randomly assigned to receive a single tablet of a vitamin supplement (containing 12 vitamins, including 0.8 mg of folic acid; 4 minerals; and 3 trace elements) or a trace-element supplement (containing copper, manganese, zinc, and a very low dose of vitamin C) daily for at least one month before conception and until the date of the second missed menstrual period or later. Results. Pregnancy was confirmed in 4753 women. The outcome of the pregnancy (whether the fetu...

Cigarettes, alcoholic beverages, and street drugs contain substances potentially toxic to the developing embryo. We investigated whether maternal cigarette smoking, secondhand smoke exposure, and alcohol or street drug use contributed to neural tube defect (NTD) occurrence in offspring. 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 and delivered during 1995-2000. Control women were those who delivered live born infants in the same study area, without an apparent congenital malformation, randomly selected by year and facility. We interviewed women in person, 1-3 months postpartum, to solicit relevant information. Nonsmoking mothers exposed to secondhand smoke during the first trimester had an NTD odds ratio (OR) of 2.6 (95% confidence interval (CI)=1.6, 4.0) compared to those who neither smoked nor were exposed to secondhand smoke. Compared to the referent, the OR among women who smoked less than half a pack a day during the first trimester was 2.2 (95% CI=1.0, 4.8) and 3.4 (95% CI=1.2, 10.0) among those who smoked a half pack or more. Adjustment for maternal age, education, body mass index, and folate intake had a negligible effect on results. Alcohol and street drug use had no relation to NTD risk when adjusted for cigarette smoking. This study suggests that cigarette smoke including secondhand exposure is not only hazardous to the mother but may also interfere with neural tube closure in the developing embryo.

Neural-tube defects (NTDs) are common and serious congenital abnormalities of the central nervous system. Although some cases of NTDs are induced by hyperhomocysteinaemia, resulting from genetic polymorphism of a thermolabile enzyme, in the majority of cases the cause is unknown. Diet supplementation with a folic acid-containing multivitamin or high dose of folic acid alone in the periconception period reduced the recurrence of NTDs by 83 to 91% and 71%, respectively. Two Hungarian intervention studies demonstrated a high efficacy for periconception multivitamin supplementation (containing a physiological dose: 0.8mg of folic acid) in the primary prevention of the first occurrence of an NTD (approximately 92% reduction in the incidence of NTDs). However, a high dose of folic acid (approximately 6mg) alone during the periconception period was less efficient. Periconception folic acid-containing multivitamin supplementation reduces the occurrence of urinary tract and cardiovascular congenital abnormalities, and congenital limb deficiencies. The occurrence of orofacial cleftings may also be reduced by a high dose of folic acid. This preventive effect may be the result of other mechanisms of action (e.g. compensation of impaired mitosis caused by a folate deficiency). There are 3 options for ensuring appropriate multivitamin/folic acid consumption for women of childbearing age. First, providing a folate- and other vitamin-rich diet, which unfortunately may not be appropriate for this purpose. Second, and perhaps the best choice, the unique opportunity for multivitamin/folic acid supplementation during the periconception period. However, a major proportion of pregnancies are unplanned and, even in planned pregnancies, this type of primary prevention has not been widely used. Furthermore, it would require changes to the previous recommendations since a multivitamin containing a physiological dose of folic acid (0.5 to 0.8mg) seems to be more effective in reducing the occurrence of the first NTD and other congenital abnormalities than folic acid alone. Periconception multivitamin supplementation may also reduce the occurrence of recurrent NTDs. Thirdly, food (e.g. flour, bread) may be fortified with folic acid or 3 B vitamins (folic acid, B 12 and B6). This provides a practical means to ensure all women, especially those from lower socioeconomic backgrounds and/or with a low level of education who are more likely to have unplanned pregnancies, have an adequate folic acid intake.

To review the impact of folic acid fortification of flour on the prevalence of neural tube defects (NTD). Systematic review of the literature on MEDLINE via PubMed, Scopus, OvidSP and LILACS (Latin American and Caribbean Health Sciences Literature) reporting the impact of folic acid fortification of flour on the prevalence of NTD in 2000-2011. Focusing on Santiago of Chile's birth defects registry (1999-2009) and the monitoring of flour fortification, we analysed the prevalence (NTD cases/10 000 births) pre and post flour fortification and the percentile distribution of folic acid content in flour (2005-2009). We explored the potential association between median folic acid in flour (mg/kg) and the prevalence of NTD. Chile, Argentina, Brazil, Canada, Costa Rica, Iran, Jordan, South Africa and the USA. Live births and stillbirths. Twenty-seven studies that met inclusion criteria were evaluated. Costa Rica showed a significant reduction in NTD (∼60 %). Prevalence in Chile decreased from 18·6 to 7·3/10 000 births from 1999 to 2007 and showed a slight increase to 8·5 in 2008-2009, possibly due to changes in fortification limits. When we related the prevalence of NTD with levels of flour fortification, the lowest prevalence was observed at a folic acid level of 1·5 mg/kg. Fortification of flour with folic acid has had a major impact on NTD in all countries where this has been reported. Chile showed a 55 % reduction in NTD prevalence between 1999 and 2009. There is a need to constantly monitor the levels of flour fortification to maximize benefits and prevent the potential risk of folic acid excess, moreover to be vigilant for any new adverse effects associated with excess.

We studied the association between multivitamin use during the periconceptional period and the occurrence of neural tube defects using data from the Atlanta Birth Defects Case-Control Study. There were 347 babies with neural tube defects who were live born or stillborn to residents of metropolitan Atlanta from 1968 through 1980. The 2829 control-babies born without birth defects were randomly selected through birth certificates. Periconceptional multivitamin use was defined as reported use for each of the three months before conception through the first three months of pregnancy. Mothers who reported not using multivitamins any time during the six-month period were defined as nonusers. Fourteen percent of mothers reported periconceptional multivitamin use and 40% reported nonuse. Multivitamin users were different from nonusers in a number of demographic, health-related, and life-style characteristics. We found an overall apparent protective effect of periconceptional multivitamin use on the occurrence of neural tube defects, with a crude estimated relative risk of 0.40 (95% confidence interval, 0.25 to 0.63). At this time, it is not possible to determine whether this apparently lower risk is the direct result of multivitamin use or the result of other characteristics of women who use multivitamins.

Folate has received international attention regarding its role in the risk-reduction of birth defects, specifically neural tube defects (NTDs). In 1998, health officials in Canada, like the United States, mandated the addition of folic acid to white flour and select grain products to increase the folate intake of reproductive-aged women. Subsequent to this initiative there has been an increase in blood folate concentrations in Canada and a 50% reduction in NTDs. Many countries, including Korea, have not mandated folic acid fortification of their food supply. Reasons vary but often include concern over the masking of vitamin B12 deficiency, a belief that folate intakes among womenare adequate, low priority relative to other domestic issues, and the philosophy that individuals have the right not to consume supplemental folic acid if they so choose. Prior to folic acid fortification of the food supply in Canada, the folate intakes of women were low, and their blood folate concentrations while not sufficiently low to produce overt signs of folate deficiency (eg. anemia) were inconsistent with a level known to reduce the risk of an NTD-affected pregnancy. The purpose of this article is to describe the role of folate during the periconceptional period, pregnancy, and during lactation. The rationale for, and history of recommending folic acid-containing supplements during the periconceptional period and pregnancy is described as is folic acid fortification of the food supply. The impact of folic acid fortification in Canada is discussed, and unresolved issues associated with this policy described. While the incidence of NTDs in Canada pre-folic acid fortification were seemingly higherthan that of Korea today, blood folate levels of Korean women are strikingly similar. We will briefly explore these parallels in an attempt to understand whether folic acid fortification of the food supply in Korea might be worth consideration

We evaluated the relationship between preconception folic acid supplementation and the occurrence of neural tube defects (NTDs) in offspring, using data from the Japan Environment and Children's Study (a nationwide prospective birth cohort study) database. Of 92 269 participants with single pregnancies, 74 cases (offspring or fetuses) had NTDs, including 32 cases of spina bifida, 24 cases of anencephaly, and 19 cases of encephalocele. A total of 7634 participants (8.27%) used preconception folic acid supplementation, and of these, 621 (0.67%) also took in dietary folic acid at ≥480 μg/day. Multivariate logistic regression analyses demonstrated no association between preconception folic acid supplementation and NTDs in offspring or fetuses (odds ratio [OR] 0.622; 95% confidence interval [CI]: 0.226-1.713). Moreover, the participants who combined preconception folic acid supplement use with dietary folic acid intake ≥480 μg/day demonstrated no incidence of NTDs in offspring or fetuses. Our analysis is limited by the absence of the data on the daily amount of supplementary folic acid intake, requiring careful attention to the interpretation. Additional surveys are required in Japan to resolve those limitations for further comprehensive assessment.