Old knowledge and new evidence on "periconceptional folic acid supplementation"

Author: Yan Weili Professor and Researcher, Children's Hospital Affiliated to Fudan University

Reviewer: Huang Guoying, Professor and Chief Physician, Children's Hospital Affiliated to Fudan University

Folic acid is an important B vitamin (vitamin B9) necessary for embryonic development and the most important factor in single-carbon metabolism. The human body cannot synthesize it and can only obtain it from natural foods or through dietary supplements. The rapid development of the embryo after pregnancy greatly increases the mother's demand for folic acid. Dietary supplements can ensure adequate folic acid intake, which plays an important biological role in nucleic acid synthesis, methylation to donors, and human immune T cell activity. Folic acid supplementation during the peri-pregnancy period is not a general additional "tonic or health product", it is necessary.

Large population studies have confirmed that folic acid supplementation during the peri-conception period can prevent up to 80% of neural tube defects, a serious birth defect that causes death and disability. The World Health Organization (WHO) has three recommendations: ① Red blood cell folate is the best measurement indicator of the folate nutritional level of pregnant women during the peri-conception period; ② Women in the pregnancy preparation period need to supplement 400μg of folic acid every day for at least 3 months and continue throughout the pregnancy; ③ The red blood cell folate concentration must reach 400ng/ml (equivalent to 906 nmol/L) to fully play the role of preventing neural tube defects. my country has been implementing the strategy of folic acid supplementation during the peri-conception period since the 1990s. For a long time, the government has provided free folic acid to rural women preparing for pregnancy.

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However, based on the hard-core data from the latest large-scale population studies combined with previous studies, we need to let you know the following five things.

1. Achieving adequate red blood cell folate levels before pregnancy has a positive effect on preventing congenital heart disease

A maternal pre-pregnancy concentration of 400 ng/ml may reduce the risk of congenital heart disease in offspring by half, and the incidence of congenital heart disease in the population may be reduced by half.

2. The current folic acid supplementation rate among pregnant women (wives and husbands) in my country is low, and the red blood cell folic acid concentration is generally not up to standard.

We investigated the red blood cell folate levels of couples preparing for pregnancy in Shanghai and Kunshan, Jiangsu. The data showed that 90% of wives and 95% of husbands, respectively, did not reach the WHO recommended levels, and less than 20% of them took folic acid supplements regularly during the pregnancy preparation stage. It is speculated that the situation in other parts of my country is not optimistic either.

3. It is too late to start taking folic acid supplements after you know you are pregnant. You need to take it before pregnancy.

From the perspective of primary prevention of birth defects, peri-pregnancy folic acid supplementation should be changed to emphasize "pre-pregnancy folic acid supplementation to achieve the standard level of red blood cell folate". The closure of the fetal neural tube and the formation of important organs such as the heart usually occur around 1 month (28-30 days) of the embryo, while the earliest pregnancy confirmed by pregnancy test sticks is 7 weeks (42 days). It takes about 3 months (120 days) to obtain the maximum increase in red blood cell folate concentration by supplementing 400μg per day; only 30% and 60% of people can reach the standard concentration after supplementing for 4 weeks and 8 weeks; according to the dose of 800μg/d, the proportion of concentration reaching the standard after supplementing for 4 weeks and 8 weeks is 50% and 80% respectively. Obviously, folic acid supplementation after knowing pregnancy cannot effectively play a protective role. The best way is to check the red blood cell folate at least once during marriage registration or pre-pregnancy check to understand your own situation, supplement in time and strive to reach the standard concentration before pregnancy.

4. How much folic acid should be supplemented and for how long?

Supplementing with 400 to 800 micrograms of folic acid per day is a safe dose that has been verified by the adult population. Supplementing with a safe dose for a sufficient period of time (a ramp-up period of 2 to 3 months) and maintaining this dose after reaching the target can keep the red blood cell folate concentration at a stable and safe level. It is wise to retest the red blood cell folate concentration after 3 months of supplementation before becoming pregnant. Avoiding "cramming" in the short term can maximize the role of folic acid in preventing birth defects and avoid other adverse effects. WHO recommends starting folic acid supplementation at least 3 months before pregnancy and encourages continuation until 3 months after pregnancy.

5. Do you have a gene that is not conducive to the absorption and metabolism of folic acid? Don't worry too much

The MTHFR gene is one of several important enzymes in the folate metabolic pathway; when the coding sequence base of the 677th amino acid on this gene is the TT genotype, there is impaired metabolic capacity, and the red blood cell folate concentration of carriers can be 10% to 30% lower than that of the general population. It is not difficult to reach the level of the general population with sufficient doses (e.g. 800 μg/d) and sufficient supplementation time. Unless the improvement in red blood cell folate concentration after 3 months of folic acid supplementation is far lower than the expected level, it may involve rare mutations in related genes, otherwise there is no need to test this gene for everyone.

References

1. Chen H, Zhang Y, Wang D, et al. Periconception red blood cell folate and offspring congenital heart disease: nested case-control and Mendelian randomization studies[J]. Ann Intern Med. 2022, 175(9): 1212-1220.

2. Li M, Chen

3. Zhang Xue, Zhu Baosheng. Major birth defects and precision prevention[M]. Shanghai: Shanghai Jiaotong University Press, 2020.