A common question in preconception counseling is: "I take folic acid daily as prescribed, and my blood tests show 'normal' levels—so why do I keep experiencing pregnancy loss?"

This question points to a critical yet often overlooked issue: the problem is not inadequate intake, but impaired folate metabolism.

A 2019 study published in the American Journal of Obstetrics & Gynecology (a leading journal in obstetrics with an impact factor of 9.8) addressed this precise concern.

I. The Key Factor Is Metabolic Efficiency, Not Supplemental Dosage

Researchers prospectively followed 1,228 women with a history of one or two prior miscarriages who were consistently supplementing with 400 µg of folic acid daily. The findings revealed:

·        No statistically significant association between serum folate concentration and subsequent miscarriage risk.

·        A clear dose-dependent relationship with homocysteine (Hcy): among women with two prior losses, each 2 µmol/L increase in Hcy (e.g., from 6 µmol/L to 8 µmol/L) was associated with a 43% increase in miscarriage risk.

These results demonstrate that with adequate folic acid intake, pregnancy outcomes depend on folate metabolic capacity, not serum levels alone.

Folic acid must be converted to its biologically active form, 6S-5-methyltetrahydrofolate (5-MTHF), to serve as a methyl donor in the remethylation pathway that clears homocysteine. This conversion requires key enzymes including dihydrofolate reductase (DHFR) and 5,10-methylenetetrahydrofolate reductase (MTHFR).

II. The Underlying Cause: Common Genetic Polymorphisms in MTHFR

Population studies in China indicate that approximately 78.4% of individuals carry MTHFR gene polymorphisms (such as C677T and A1298C variants), which reduce enzyme activity to 30–70% of normal function.

This metabolic bottleneck impairs the generation of usable 5-MTHF, leading to inefficient homocysteine clearance and accumulation of hyperhomocysteinemia (HHcy)—a metabolically harmful state.

For women attempting conception, elevated Hcy levels can:

·        Disrupt embryo implantation by impairing trophoblast vascularization and uteroplacental perfusion

·        Exacerbate oxidative stress, compromising the early embryonic microenvironment

·        Promote a prothrombotic state, hindering uterine spiral artery remodeling and compromising placental function

III. Clinical Approach: Screen Hcy and Optimize With Active 5-MTHF

For patients with recurrent pregnancy loss or Hcy levels ≥8 µmol/L, standard folic acid supplementation is often insufficient to overcome metabolic inefficiencies and lower Hcy effectively.

In such cases, direct supplementation with active folate (6S-5-MTHF)—which bypasses MTHFR-dependent conversion—has been shown to reduce Hcy levels efficiently. Products with established safety profiles (e.g., Magnafolate) provide bioavailable 5-MTHF directly into the methionine cycle.

Evidence-Based Recommendations:

1.      Preconception Screening: Measure both serum Hcy and folate levels to identify metabolic bottlenecks.

2.      Personalized Supplementation: For those with metabolic impairment or HHcy, replace standard folic acid with active 5-MTHF.

3.      Adjunctive Support: Co-administer vitamins B12 and B6 under medical supervision to optimize one-carbon metabolism.

4.      Professional Oversight: All supplementation strategies require physician guidance to prevent potential adverse effects from unsupervised high-dose regimens.

References

1.      Mumford SL, et al. Preconception folate status and reproductive outcomes among a prospective cohort of folate-replete women. Am J Obstet Gynecol. 2019;220(4):399.e1-399.e10.

2.      Yang B, et al. Geographical Distribution of MTHFR Gene Polymorphisms in China. PLoS One. 2013;8(3):e57917.

3.      Biological Characteristics and Applications of Folate and 5-Methyltetrahydrofolate. China Food Additives. 2022(2).