Folic acid and the prevention of neural tube defects (NTDs). Challenges and recommendations for public health.

Neural tube defects and folic acid in Japan: Prologue introduction ‐ Understanding of the current status of Japan and the proposal from Japanese Teratology Society

Focused Revision: Policy statement on folic acid and neural tube defects

Objective: To outline specific challenges facing public health in Canada that need to be addressed to ensure that all women of childbearing years can attain optimal folate status for prevention of NTDs.

Prevention of Fetal Neural Tube Defect with Folic Acid Supplementation

Four Years After Enhanced Folic Acid Fortification of the Canadian Food Supply — How Are We Doing?

A continuing, massive, global epidemic of folic acidpreventable spina bifida and anencephaly affects more than 200,000 children and their families each year (Botto et al., 1999). This unnecessary epidemic is the result of a tragic failure of global public policy. Health and food authorities around the world have either not required any folic acid fortification programs (as in Europe, Australia, and New Zealand), or they have implemented fortification programs that do not require enough folic acid to be added to flour (as in the United States and Canada). The article by De Wals and colleagues in this issue of the journal (see p 919) provides data from Quebec that help us to understand why the folic acid concentration in enriched flour in the United States and Canada needs to be increased and why folic acid fortification should be rapidly implemented in countries not currently requiring fortification. In a carefully researched and analyzed study, De Wals and colleagues find that before folic acid flour fortification, the rate of neural tube defects was about 2.0 per 1000; after fortification, the rate dropped to about 1.25 per 1000. The rapid reduction in the rate of neural tube defects in Canada has also been documented by other studies in North America (Honein et al., 2001; Persad et al., 2002; Ray et al. 2002; Williams et al., 2002). The folic acid fortification program required in 1998 by the health and food authorities in the United States and Canada has improved the lives of hundreds of children who were born without neural tube defects they might have otherwise had. Not only have these North American programs been shown to be effective in preventing neural tube defects, but also they have been shown to increase serum folate levels enough to virtually eliminate folate deficiency anemia—a substantial benefit not anticipated in pre-fortification discussions (Lawrence et al., 1999). In addition, fortification reduced concentrations of homocysteine in the adult population (Jacques et al., 1999). Although we have yet to learn the effect of such reductions, reasonable projections by Wald and colleagues suggest that fortification may have prevented up to 25% of heart attacks and strokes (Wald et al., 2002). If the reductions in homocysteine prevent even 10% of heart attacks and strokes, mandatory folic acid fortification of flour and other grain products has prevented 10 times as many adults from dying from cardiovascular disease as it has prevented babies from having birth defects. There have been no adverse effects reported for millions of Canadians and Americans who have been eating folic acidfortified products. We can conclude that the current fortification in Canada and the United States is safe and has been good for both adults and children. The data in the DeWals et al. article and data from the China study (Berry et al., 1999) suggest that increasing the concentration of folic acid in enriched grain products will produce even greater benefits. There is no general agreement on the prevalence of non-folic acid-preventable neural tube defects. The data from the China study (Berry et al., 1999) showed that the prevalence of neural tube defects was 0.6 per 1000 pregnancies for women who consumed 400 g of synthetic folic acid in a vitamin pill. It is reasonable to assume that the prevalence of non-folic acid-preventable neural tube defects is no more than 0.5 per 1000 pregnancies. Wald and colleagues use the available evidence to describe a doseresponse curve between increased folic acid consumption and decreases in neural tube defects that suggests the rate of the non-folic acid-preventable neural tube defects is less than 0.5 per 1000 pregnancies (Wald et al., 2001). The post-fortification prevalence observed in Quebec is about 1.25 per 1000, which the China data suggest can be lowered to 0.5 per 1000. The data from China and Quebec thus suggest that the post-fortification prevalence rate of neural tube defects in North America remains about twice what it should be. Yes, we have reduced the size of the epidemic, but there is still an epidemic that needs to be fully controlled. No one should be surprised that the decrease in neural tube defects after fortification was not larger. There was general agreement before fortification that the concentration selected would likely fail to accomplish as much prevention as a greater concentration could have. The pre-

The risk of a neural tube defect (NTD)‐affected pregnancy increases about 10 fold as red blood cell (RBC) folate status decreases from a sufficient status to a deficient status (<340 nmol/L), with the optimal RBC folate concentration for the prevention of NTD having been recently defined as >906 nmol/L by the World Health Organization. Since the implementation of mandatory folic acid fortification in the U.S. population, RBC folate concentrations have increased and NTD prevalence has decreased about35%. There are three primary sources of folic acid in the U.S. diet: folic acid supplements (typically 400 μg ‐ 1,000 μg per dose), ready‐to‐eat breakfast cereals (allowed but not required to include 400 μg per serving) and cerealgrain flour labeled as enriched (140 μg per 100g; resulted in ~140 μg increase in daily average usual intake). It is critical to determine if this demonstrated effective intervention has reached its full potential. To determine if women in the U.S. were still at risk of folate sensitive NTDs even in the presence of folic acid fortification we used RBC folate concentration distributions from the 2007–2012 National Health and Nutrition Examination Survey (NHANES) among U.S. women of childbearing age (12–49 years) to estimate NTD prevalence by source of folic acid intake. We applied a prediction model developed using Bayesian methods to estimate the risk of NTD‐affected pregnancies at specific RBC folate concentrations. The overall predicted NTD risk was 6.9 per 10,000 births (95%uncertainty interval [UI] 5.0–9.0) based on a median RBC folate concentration of 1220 nmol/L (log of the variance σ =0.400). RBC folate concentrations were higher for supplement users compared to non‐users, however, there was no difference in their predicted NTD risk. This is consistent with the NTD risk observed between folic acid supplement users and non‐users among existing epidemiological studies. However, women whose only reported source of folicacid was cereal grain products labeled as enriched had RBC concentrations (median1075 nmol/L) that suggest significantly elevated predicted NTD risks (8.8 NTD sper 10,000; 6.7–11.1 95% uncertainty interval) compared to women who consumed additional sources of folic acid (i.e. ready‐to‐eat cereal and/or supplements)in their diet (median NTD prevalence: 4–6 per 10,000 births). Population level estimated NTD prevalence was driven by slight shifts in distribution at the lower RBC folate concentration because NTD risk increases very rapidly with decreasing folate concentrations. Additional analyses are underway to determine usual folic acid intake among women with optimal RBC folate concentrations. Folate‐sensitive NTD prevention interventions could be considered to target U.S. women of reproductive age consuming cereal grain products labeled as enriched as their only source of folic acid.Support or Funding InformationNo external support.

To conduct surveillance for neural tube defects (NTDs) in a high-risk region of the United States and to prevent occurrence and recurrence of NTDs through the periconceptional use of folic acid supplements. Active and passive methods were used for surveillance of NTD-affected pregnancies and births during a 6-year period (October 1992-September 1998). Individual genetic counseling was used to prevent NTD recurrences and a public awareness campaign was used to reduce NTD occurrences. State of South Carolina. All cases of spina bifida, anencephaly, and encephalocele identified among 278 122 live births and fetal deaths to South Carolina residents during 1992-1998 were included. Changes in occurrence and recurrence rates during a 6-year period. Over the 6 years of surveillance, the prevalence rates for NTDs decreased from 1.89 to.95 cases per 1000 live births and fetal deaths. The prevalence decrease is explained primarily by a decrease in cases of spina bifida. Isolated NTDs accounted for 297/360 (82%) NTDs and 63/360 (18%) had at least 1 other structural anomaly. Females predominated among isolated NTDs but the sex distribution was equal among NTD cases with other anomalies. Prevalence rates for whites (1.48 cases per 1000 live births and fetal deaths) were higher than rates for blacks (.87 cases per 1000 live births and fetal deaths). There were no NTD recurrences in 113 subsequent pregnancies to mothers of infants with isolated NTDs who took periconceptional folic acid. The rate of periconceptional folic acid use among women of childbearing years increased from 8% to 35% during the 6-year project period. The prevalence of NTDs in a high-risk region has declined coincident with the increased periconceptional use of folic acid supplements among women of childbearing age.neural tube defects, high-risk region, birth defects, folic acid, spina bifida, anencephaly, encephalocele.

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.

Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies.

Folic acid deficiency plays a central role in the aetiology of many congenital anomalies including neural tube defects. Protective effect of folic acid on embryo may be acquired only if taken periconceptionally. The aim of the study was to investigate the awareness about folic acid among women of childbearing age in Bratislava, Slovakia. There were 130 respondents involved in the research (106 pregnant women, 24 female students of medical faculty). Using questionnaire we acquired following data: pregnancy details, interest in diet before and during pregnancy, recommendations regarding nutrition and supplementation pre- and post-conception, knowledge about folic and other acid in 2004 and 2009. More than half of the respondents knew the sources of folic acid. The interest in the nutrition facts of the food dropped from 91 % to 58.5 %. The number of pregnant women advised about correct nutrition and folic acid supplementation before and during pregnancy increased from 16 % to 37 %. Planning the next gravidity with folic acid supplementation became greater than 21 % (38 % in 2009). Nevertheless, only 46 % of these women believed that proper food content with folic acid may prevent congenital anomalies. In a group of students planning to take folic acid periconceptionally the number raised up to 62.5 %. The results revealed low knowledge about the effect of folic acid on developing embryo among women of childbearing age. Effective intervention programs are needed with the aim to improve periconceptional intake of folic acid in 2004 and 2009. The results in both periods show low knowledge about this essential vitamin (Tab. 1, Fig. 8, Ref. 31).

Bringing clarity to the role of MTHFR variants in neural tube defect prevention

Soon after the implementation of folic acid fortification in cereal grain products in 1998, several reports appeared in the medical literature showing a reduction in the prevalence of neural tube defects (NTDs). However, a number of investigators observed an ongoing background trend for decreased prevalence of NTDs that began before the implementation of fortification. It is therefore possible that the apparent reduction produced by folic acid fortification actually results from continuation of that trend. Previous studies obtained prevalence ratios consistent with a beneficial effect of fortification through use of a summary of prevalence before and after fortification. Their data, however, do not include an analysis of the magnitude and direction of the change in prevalence over time. This population-based study was designed to determine whether the trend for decline in the prevalence of NTDs observed before fortification (1989-1996) continued after fortification (1998-2003) in 8 central California counties. The study population included all live births, and stillbirths delivered in 8 central California counties from 1989 to 2003. The authors recorded the total number of NTD cases each year. Over the entire study period (1989-2003), 690 of the 886,985 total deliveries were NTD cases. This corresponds to an average prevalence of 77.8 cases per 100,000 deliveries. The authors compared the slopes of two regression lines, pre and postfortification, to provide an estimate of the annual change in NTD prevalence, and to compare the pre and postfortification changes in NTD prevalences over time. Analysis of the slope data for all NTDs combined showed that before fortification NTD prevalences were decreasing by 7.5 (slope: 27.5; 95% confidence interval [CI]: 212.4, 22.5) cases per 100,000 deliveries per year. After fortification, NTD prevalences were no longer decreasing. The postfortification slope exceeded the prefortification slope by 12.6 (95% CI: 2.6, 22.6) cases per 100,000 deliveries per year. These findings do not appear to result from low intake of folic acid during the postfortification period or differences in maternal race, ethnicity, or obesity. The authors conclude from these findings that the observed decline in NTD prevalence before fortification did not continue after fortification in selected central California counties. The data provide no evidence that fortification with folic acid reduced the prevalence of NTDs in this selected population.

Objective To investigate the level of serum folic acid, red blood cell (RBC) folic acid among childbearing-aged women and provide information for carrying out suping folic acid to prevent birth defects. Methods From January 2010 to October 2011, a total of 261 childbearing-aged women were included into this study. Their age, and related clinical data were collected and analyzed. The study protocol was approved by the Ethical Review Board of Investigation in Human Being of Yunnan Population and Family Planning Research Institute of Science and Technology. Informed consent was obtained from each participate. And 4 mL venous blood was drawn. Serum and RBC folic acid concentrations were detected by electrochemiluminescence immunoassay. Results The average level of serum folic acid was (9.74±3.23) ng/L and RBC folic acid was (529.79±205.44) ng/L.The prevalence of low serum folic acid and RBC folic acid concentrations were 8.43%(22/261), and 5.36%(14/261), respectively. Taking the optimal level of folic acid to prevent neural tube defects (NTDs) as the determine, the prevalence of low serum folic acid and RBC folic acid concentrations were 67.82%(177/261) and 73.95%(193/261), respectively. Conclusions The serum and RBC folic acid levels among more than half of childbearing-aged women in Kunming region below the recommended level for the prevention of NTDs. So the actual intake of folic acid should be strength. Key words: folic acid; serum; red blood cell; child-bearing aged women; neural tube defect

The prevalence of neural tube defects (NTDs) in northern China is among the highest in the world. A massive folic acid supplementation program as a specific countermeasure was introduced in 2009. Examining trends in NTD prevalence may provide evidence for future intervention. Data for 2000 to 2014 in five counties in northern China were obtained through a population-based birth defects surveillance system. All live births, stillbirths of over 20 gestational weeks, and pregnancy terminations because of NTDs at any gestational age were recorded. The prevalence of NTDs by gestational weeks (< 28 vs. ≥ 28), by calendar year, and by subtype was presented. From 2000 to 2014, a total of 234,225 births and 2027 cases of NTDs were recorded. The prevalence of total NTDs was extremely high during 2000 to 2004, but it began to decrease continuously thereafter, from a peak of 120.0/10,000 in 2004 to a low of 31.5/10,000 in 2014. A significant decrease (60%) was observed from 78.8/10,000 in 2009 to 31.5/10,000 in 2014, 5 years after the folic acid supplementation program was introduced. All three major subtypes, namely anencephaly, spina bifida, and encephalocele, showed a decline over this period. Although the perinatal (≥ 28 gestational weeks) prevalence of NTDs decreased progressively, the pre-perinatal (< 28 gestational weeks) prevalence of NTDs remained high until 2011 and then decreased. The prevalence of NTDs remains high despite a substantial and continuous decrease over the past 15 years. To further reduce NTD risk in the population, fortification staples with folic acid should be considered.