PREVENTION OF SPINA BIFIDA AND ANENCEPHALIA: HOW TO PRESCRIBE FOLATES


OBJECTIF NUTRITION 83 (APRIL 2007)
by Prof. Michel Vidailhet, Faculty of Medecine (Nancy, France)

The severity of malformations (anencephalia, spina bifida) due to defective neural tube closure has lead, in view of their prevention, to the recommendation of periconceptional supplementation in folic acid. In the US, Canada and 37 other countries, this supplementation is accompanied by a systematic enrichment of dietary flour. The reasons for this policy are today confirmed by remarkable results published in the US and Canada, although the absence of negative side effects was questioned in several publications. The problem of effective and risk-free spina bifida and anencephalia prevention therefore appears to be difficult to resolve.

The EUROCAT network has recently published highly disappointing results, obtained in Europe for the prevention of neural tube closing defects (NTCDs) by periconceptional supplementation with folic acid. This generated renewed interest in the analysis of this problem, especially because the negative reports stand in opposition to the effectiveness of associating this type of supplementation with systematic flour enrichment, as practiced in the US, Canada and 37 other countries.

THE ROLE OF FOLIC ACID

The major importance of vitamin B9 during pregnancy, for the mother and the child, has been known for a long time. In the 1950s, the focus was mainly on its responsibility in gravidic megaloblastic anemia. From the point of view of the embryo and the fetus, the functions of vitamin B9 in the production of purines and pyrimidines, transfer of the methyl groups necessary for DNA methylation and protein synthesis explain its importance together with other micronutrients such as vitamin A. The specific role of folic acid in the occurrence of NTCDs was discovered in 1964-1965 by Hibbard and Smithells, who found anomalies in folate metabolism in the mothers of children born with these malformations. In the customary absence of the usual patent deficit of vitamin intake, scientists tried to associate perturbations in the metabolism or activity of folic acid, linked to genetic polymorphism, with teratogenesis likely to be prevented, in approximately half of the cases, by folic acid supplementation.


THE ADVANTAGES OF A PERICONCEPTIONAL SUPPLEMENTATION

These advantages seem clear when we realize the early nature of neural tube closure, which is completed on the 28th day following conception, at a time when women are most likely unaware of their pregnancy. From 1981 to 1996, 6 interventional studies using folic acid at doses ranging from 0.6 to 4 mg/day demonstrated a remarkable preventive effect on recurrence among women who have already had one child suffering from NTCD.

However, 30% of NTCDs remain resistant to folic acid, even at the very high dose of 4 mg/day, which shows the limitations of prevention.
Preventive effectiveness with respect to recurrence has led scientists to evaluate the general population of pregnant women. Butterworth and Bendich (1996) reviewed six retrospective case/control studies, one retrospective study among 22 women and most importantly one Hungarian interventional study, which lasted for 8 years. All these trials have shown the effectiveness of folic acid with a significant reduction in the risk of NTCDs as well as a certain preventive impact on other malformations, including cardiac defects, labiopalatine clefts and member malformations.
In the early 1990s, the collected data prompted the public health authorities in several countries to recommend systematic supplementation for all women in the periconceptional period. Supplementation involves synthetic folic acid with proven effectiveness, great bio-availability and a lower cost. In most European countries, supplementation intended for all women in their childbearing years is recommended in the amount of 0.4 or 0.5 mg/day and for women at a risk of recurrence (due to a history of NTCD in one of their children) in the amount of 4 mg/day. Information campaigns have been deployed in half of these countries, particularly in France in 2000 and 2004. The EUROCAT network, including 18 European countries and 36 registers, provides the epidemiological surveillance of congenital anomalies. In 2005, a review report on NTCDs covering the years 1980 to 2002 was published. Practically no changes in NTCD prevalence were observed in any of the countries, whether recommendations for supplementation during the periconceptional period were formulated or not. In the report, EUROCAT stressed the fact that, every year, 45 pregnancies in Europe are complicated by NTCDs and that the prevalence of these malformations had not declined since 1990. Because more than half of pregnancies are not planned and, when they are, most women remain poorly informed, the EUROCAT taskforce concluded that it was necessary to implement a policy of systematic folic acid enrichment of a staple food such as flour.

FLOUR ENRICHMENT IN THE US AND CANADA

The effectiveness of periconceptional supplementation has proven to be very limited. Similarly, follow-up on supplementation revealed to be relatively unsatisfactory, even among well-informed women, and even more so among younger, isolated primigravida women belonging to underprivileged socio-professional categories. In 1996, the US Food and Drug Administration (FDA) decided to implement the folic acid enrichment of all cereal products, such as flour (except for whole cereals), intended for human consumption. The enrichment became systematic as of January 1, 1998. Canada applied the same measure a few months later. The level of enrichment was established at 1.4 ppm (0.14 mg/1 g of cereals) by predicting, based on consumer surveys, an average supplemental intake of 0.1 mg/day, without exceeding 1 mg/day among heavy consumers. At the same time, folic acid enrichment was expected to bring other benefits for other types of malformations, together with a preventive effect on cardiovascular, particularly coronary, accidents among the older population thanks to a reduction in homocysteinemia. Enrichment is, of course, insufficient in itself to ensure optimal NTCD prevention. As a result, the specific supplementation of women in their childbearing years in the amount of 0.4 mg/day continued to be recommended.
Since 2000, numerous North-American publications have praised the effectiveness of this measure in various States: US, Newfoundland and Ontario (table 1). The results were more spectacular in the states where the initial folate status was more compromised and the rate of NTCD occurrence higher. This included Newfoundland where frequency dropped by 78%, and Ontario, where it declined by 48%.
A Chinese interventional study showed that supplementation with 0.4 mg/day reduced NTCD frequency to 0.6%. Some authors have thus estimated that the level of cereal enrichment chosen in the US was insufficient and should be raised to 2.5 ppm. Some claimed that NTCD frequency (1.12%) is twice as high as it should be.

Parallel to these NTCD evaluations in the US, a follow-up of biological markers was also carried out. Comparisons of periods 1988-1994 and 2001-2002 (table 2) show a twofold multiplication of seric folates, a drop in the prevalence of low folatemia, an increase in erythrocyte folates and a drop in the prevalence of low erythrocyte folates. Concurrently, homocysteinemia drops while vitamin B12 status markers (seric B12, methylmalonic acid) show no changes.
No incidents imputable to folate enrichment could be reported, outside of a minimal increase in the frequency of multiple pregnancies, which was identified without constancy and the mechanism of which is furthermore under discussion. Inversely, a moderate but significant drop in the prevalence of other malformations was observed, for example in the transposition of the great arteries (12%), labiopalatal cleft (12%), upper member malformations (11%) and omphaloceles (21%). Finally, the CDCP (Center for Disease Control and Prevention) in the US observed a reduction in coronary and cerebrovascular accidents among individuals aged 40 and up. Today, 39 countries follow a policy of systematic flour enrichment, although this includes no industrialized countries of Europe, Asia or Oceania. Since 2002-2003, this has been the attitude adopted in England, the Netherlands and France, where the French Food Safety Agency (AFSSA) considers enrichment as probably necessary, but requested a prior evaluation in the Alsace region. This evaluation was never undertaken.


THE SAFETY OF SUPPLEMENTATION IS NOW QUESTIONED

An initial Swedish study concerned 85,000 individuals, who were followed for a period of several years, with 226 among them also appearing in a national register of colorectal cancer, and compared to 437 control subjects from the same cohort. The risk of colorectal cancer appeared lower among subjects with lower blood folate levels, with a significant odd-ratio (2; IC: 1.13-3.56). Although on the whole the risk level depending on folatemia follows a bell shaped curve, the increase in risk with folatemia becomes linear when the authors limit the evaluation to subjects followed for 4.2 years.
A second multi-center study conducted in the US concerned screening for prostate, lung, colon, rectal and ovarian cancer (PLCO Cancer Screening trial). The results, again limited to 25,400 women aged 55 to 74 participating in this study, showed a 20% increase in the risk of breast cancer among those receiving folic acid supplementation of more than 0.4 mg/day.
These results are in stark contrast to the previously published epidemiological trials, which were more in favor of folate enrichment, whether with respect to colorectal or breast cancer. The results are contradictory also with respect to the analysis of a majority of the experimental studies showing that mammary and intestinal carcinogenesis is inhibited in the case of folate deficiency. In fact, several groups, including that of Kim YI, had shown that the conditions, in which folate restriction or supplementation comes into play, are critical in regard to the observed results: the effects can range from protection to aggravation depending on the dose and the time when it is used. Although moderate supplementation with folic acid proves to have protective benefits on intestinal carcinogenisis, very high-dose or late supplementation tends to stimulate and not inhibit carcinogenecis, as microscopic tumor sites may already be in place. Recently, an article by Morris et coll. helped further fuel fears concerning flour enrichment with folates. Conducted in the US, this observational study showed that the effect of folate status on the cognitive functions of subjects aged 60 and up depends on the vitamin B12 status. Among subjects with a normal B12 vitamin status, a higher folate blood level was associated with a lower risk of cognitive decline. By contrast, in subjects with vitamin B12 deficiency, a high folate blood level seemed to increase the risk of cognitive decline, which was furthermore five times higher than in the subjects with normal vitamin B12 and folate levels.
Similarly to this editorial, the article´s authors think that flour enrichment in folic acid is largely responsible for this situation: by extrapolation, up to 1.8 million Americans could be concerned.
Flour enrichment in folic acid therefore seems to have been implemented (in 1996 in the US) with a certain measure of levity.

Conclusion

Although today the systematic enrichment of cereal flour appears to be an essential element of the successful NTCD prevention in North America, the results from two recent epidemiological studies, the quality of which cannot be doubted, show the possibility of increased risk of colorectal and breast cancer among certain individuals. These results, and the findings of another recent study by Morris et coll., preclude the implementation of extensive supplementation in the entire population of France. On another hand, the disappointing character of targeted supplementation during the periconceptional period, as demonstrated in the European EURO-CAT study, also applies to France. C. Stoll et al (2006), responsible for one of three French registers participating in EURO-CAT, observed no variations in the NTCD frequency between 1988 and 2002, which remained close to 1/1,000, including terminated pregnancies. Three reasons explain why it is today difficult to implement an effective targeted supplementation:
• the absence of indicators, especially genotypical, helping identify women at risk, with the exception of those who have already had a child affected by NTCD.
• the completion of neural tube closure on the 28th day after conception, at a time when a large majority of women are not aware of their pregnancy.
• the fact that approximately half of pregnancies, in France as well as other industrialized countries, are not planned.

While waiting for clearer epidemiological results concerning the evolution of colorectal and breast cancer risk, especially in countries with a flour enrichment policy in folic acid in place for 1 year, we can do no better than maintain the current recommendations, already circulated in France in 2000 and 2004, which are part of the National Nutrition and Health Program.

References