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

The 56th Annual Meeting of the Japanese Teratology Society (President: Watanabe T) was held in Himeji, Hyogo Prefecture, Japan, from July 29–31, 2016. The highlight of the academic meeting this year was "New Developments and Future Perspectives of Teratology Study – Translational Study to Link Teratology to Nutrition" (Watanabe 2016). Congenital defects mean that the morphological and functional disorders present at birth are induced by genetic and/or environmental factors. The causes of most congenital anomalies are unknown, but they are thought to be produced by the genes interacting with environmental factors. It has been recently pointed out that the nutritional state of the dams during gestation, as an environmental factor, deeply affects fetal growth and development. This concept has been known as the “Developmental Origins of Health and Disease (DOHaD).” Folic acid is a water soluble vitamin and it is required as a coenzyme in one-carbon transfer reactions, which is essential for the metabolism of nucleic and amino acids, and the occurrence of methylation reactions. It also plays a central role in DNA synthesis through de novo purine biosynthesis necessary for mitotic cell division in almost all tissues. Therefore, inadequate intake of folic acid leads to megaloblastic changes in bone marrow. The mean cell volume in the peripheral blood smear is increased and macrocytic anemia is then developed by folic acid. Neural tube defect (NTD) is one of the most common birth defects in humans and is caused by both environmental and genetic factors. Previously, it was doubted that specific factors induced by the potato blight fungus might be causal factors for NTD in Europe. Afterwards, the prevalence of NTD in these regions was related to low socioeconomic levels and poor diets, suggesting that nutritional factors might be involved in the etiology. Smithells and colleagues reported an association between low folic acid levels and NTD in the late 1970s (Schorah & Smithells 1991). They confirmed that spina bifida and other NTDs can be prevented by the supplementation of folic acid in randomized clinical trials and other studies by the early 1990s (MRC Vitamin Study Research Group 1991; Czeizel & Dudás 1992). Based on these findings, in 1992, the United States Public Health Service recommended that all women of childbearing age who are capable of becoming pregnant consume 0.4 mg (400 μg) of folic acid per day for the purpose of reducing the risk of a pregnancy affected by NTD. Also in 1998, specified grain products were required to be fortified with folic acid at levels of 140 μg/100 g under Food and Drug Administration rules in the Department of Health and Human Services, USA. As a result, the risk of having a child with NTD in the general population in North America is presently less than 10:10 000 (Chitayat et al. 2016). The reported NTD prevalence (median) for each region: Americans (11.5 per 10 000 births), Africa (11.7), European (9.0) and South-East Asian (15.8) (Rosano et al. 1999). NTD prevalence among these countries in which fortification had been implemented showed declines. NTD is an important public health problem that can be prevented with folic acid supplementation and fortification of staple foods (Zaganjor et al. 2016). The policy of the folic acid fortification in grains is underway in many countries including the US, Canada, and South America and such population-wide approaches are effective. Recent studies demonstrate that folic acid is also related to controlling the onset of cardiovascular, cognitive decline and Alzheimer's diseases (Krause & Roupas 2015). Although the risks of masking vitamin B12 deficiency, asthma, and colorectal cancer with long-term excessive intake of folic acid are reported, the matching result is still not obtained in clinical trials and by the meta-data analysis (Selhub & Rosenberg 2016). In our country, the Japan Association of Obstetricians and Gynecologists have been monitoring congenital birth defects since 1972, based on nation-wide hospital-based monitoring. According to these databases, the prevalence of spina bifida in Japan was 4.0 and 5.1 per 10 000 births in 1999 and 2014, respectively. It has been slowly increasing, and the average of these past several years was about 6.0 per 10 000 births (Japan Association of Obstetricians and Gynecologists (JAOG): International Clearing House for Birth Defects Monitoring Systems (ICBDMS) Japan Center 2014). Based on the these data in Japan and foreign countries, the Ministry of Health and Welfare in Japan reported in 2000 that daily supplementation with 0.4 mg (400 μg) of folic acid, starting before conception and continuing through the first 3 months of pregnancy, prevented 28% of occurrences of NTD. The recommended dietary allowance (RDA) of folic acid was set at 200 μg/day for adults and 400 μg/day for pregnant women for the first time in Dietary Reference Intakes (DRI) for Japanese, 6th revision, in 1999. In the DRI 2005 version, the RDA of folic acid for pregnant women was set at 440 μg/day, which was taken from meals and any other sources combined. However, in the DRI 2010 and 2015 version, RDA of folic acid for pregnant women was revised to 480 μg/day, and women in the reproductive age group were advised to take daily the extra level of 400 μg of pteroylmonoglutamic acid (folic acid) as a dietary supplement and vitamin-enriched food to reduce the risk of NTD (Ministry of Health, Labour and Wealth of Japan 2015). The methylation reactions in the one-carbon metabolism are related with some enzymes. The production of 5-methyltetrahydrofolate by 5, 10-methylenetetrahydrofolate reductase (MTHFR) is an important functional and regulatory step in the regeneration of methionine from homocysteine. MTHFR is influenced by both gene polymorphism and folic acid intake. The TT genotype of MTHFR C677T showed significantly lower serum folate and higher homocysteine than the CC and CT genotypes (Hiraoka et al. 2004). Also, this polymorphism, which results in a thermolabile form of the enzyme, is regarded as a genetic risk factor for NTD and coronary artery diseases (Botto & Yang 2000; Li et al. 2016). The genotype should be also considered when setting the intake of folic acid. The system of Health Claims was started in 2001 in Japan, and “Folic acid is good for the normal development of the fetus” was approved as a nutritional display for folic acid. In the maternity passbook, the warning information for pregnant women is written as follows: “Periconceptional folic acid significantly reduces the risk of neural tube defects. It is important to keep it in mind to enable efficient intake, and achieve optimal levels of folate by eating folic acid-rich foods such as vegetables or fruits.” However, the incidence of pregnant women taking folic acid supplement is still not high at all in Japan, based on reports. Also, the addition of folic acid for staple foods, such as rice and grains, is not admitted by the government. In the Japanese Teratology Society, this issue about NTD and folate was taken up for the first time in the 43rd Annual Meeting (President: Kamiishi H) in 2003, where the symposium titled “Prevention of neural tube defects and other congenital birth defects with periconceptional folic acid supplementation” was held. Also, this matter was proposed in a general meeting in the 54th Annual Meeting (President: Arishima K) in 2014, and the special committee of the president mission consisting of nine dear committees (Chairperson: Iseki S) was established under this society. This pressing question has been discussed by the board of directors (Chief: Otani H) and the special committee for 2 years. We planned the symposium titled “Folic Acid and Neural Tube Defects” (co-chaired by Shiota H & Aoyama H) held in the 56th Annual Meeting (Watanabe 2016). The theme of this symposium is related to the main topics of this annual meeting. Especially, in the symposium entitled “Neural Tube Defects and Folic Acid,” five speakers talked about recent findings in Japan. The central problem concerning folic acid and NTD was discussed by three speakers in a sponsored seminar titled “The Need of Folic Acid in Pregnant Women” (chaired by Kagawa Y) as well. During the symposium and seminar at the annual meeting this year, we mainly focused on the importance of folic acid intake and the reduced risk of NTD, and we concluded that a great deal of effort in the academic society and the government is required to provide information on NTD as well as folic acid intake. Therefore, we requested seven speakers in this meeting to gather up the main points of their lectures, as general remarks. Also, one researcher who is active at the forefront of this field today was also invited and was asked to give a review about NTD and folate from the viewpoint of his specialized field. Finally, we must restate that a great deal of effort in the academic society and the government is required to provide information on NTD as well as folate intake. This question referred to the discussion of a general meeting last year, and the Japan Teratology Society adopted a message for the Minister of Health and Welfare and the nation of Japan in a general meeting. The message “Proposal for supplemental intake of folic acid to reduce the risk of neural tube defects” from this society is shown as an announcement in a former issue of this journal (The Japanese Teratology Society 2017), which will be sent to the Ministry of Education, Culture, Sports, Science and Technology. We strongly hope that the actions of this society leads to decreased risk of NTD, elucidation of the onset mechanism of NTD and the increased awareness of Japanese society including women in the reproductive age. None.

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