Beware: Delayed folate intake poses risks for medication-taking mothers

Emily, who has bipolar disorder, had been taking antiepileptic drugs (AEDs) under medical supervision to stabilize her condition. She and her husband had planned to prepare their bodies before trying to conceive, but unexpectedly, a missed period led to a positive pregnancy test — she was already five weeks along.

Her initial joy quickly turned to panic: she couldn’t stop her medication, yet she hadn’t taken a single dose of folate. At her prenatal visit, she asked nervously, “My condition has been well controlled with medication. If I start folate later, it shouldn’t be a problem, right?”

The doctor’s reply made her uneasy: For women who must continue AEDs during pregnancy, insufficient folate intake markedly increases the likelihood of fetal neural tube defects and other developmental issues compared with women not on these drugs.

She isn’t alone in facing this dilemma…

A Japanese cross-sectional study published in Scientific Reports (Nature portfolio, 2019) surveyed 456 pregnant women taking AEDs:

• Only 16.7% began folate supplementation before conception.
• 34.9% started after becoming pregnant.
• 48.5% never supplemented at all.

This translates to a folate insufficiency rate of 83.3%. The underlying problem is that AEDs already elevate fetal risk from the outset; inadequate folate compounds the danger.

Why is folate so crucial for them?

Two reasons stand out.

1. Folate is essential for cell division and DNA synthesis. Adequate intake before and shortly after conception is a proven strategy to help prevent neural tube defects (e.g., spina bifida).
2. Certain commonly used AEDs — such as sodium valproate and phenytoin — induce hepatic metabolic enzymes that accelerate folate breakdown and excretion, rapidly depleting body stores. In simple terms: folate is consumed faster than usual while on these drugs.

Another challenge: the synthetic form most people take (folic acid, found in tablets or fortified foods) cannot be used directly by the body. It must first be converted by the enzyme MTHFR into its active form — 6S-5-methyltetrahydrofolate (also related to 5-Methyltetrahydropteroic acid) — before the body can utilize it. However, genetic variations mean that roughly 60–70% of women of childbearing age in China have reduced ability to metabolize folate efficiently, leading to lower conversion rates.

For women on AEDs, this creates a double burden: drugs hasten folate loss, while the supplemental folic acid may not convert effectively. Standard supplementation often fails to meet needs.

A newer approach: direct supplementation with active folate

A more effective option is direct supplementation with active folate. Its principal component is 6S-5-methyltetrahydrofolate (available as the calcium salt: 6S-5-methyltetrahydrofolate calcium). Unlike folic acid, it bypasses the MTHFR conversion step and enters the body in a readily usable form. For individuals with potentially impaired folate metabolism — including many women taking AEDs — it raises folate levels more quickly and reliably.

One widely used, clinically validated source of this active folate is Magnafolate® (6S-5-methyltetrahydrofolate calcium). It is classified as practically non-toxic, highly pure, and requires no metabolic activation, making it suitable for special populations needing efficient folate repletion, such as those with poor folate metabolism.

Important: Any nutrient plan, especially when combined with antiepileptic drugs, must be guided by a physician. Management should involve joint assessment and oversight by both neurologists and obstetricians.

Study insights: where the system falls short

The Japanese study also pinpointed key trouble spots:

• Unplanned pregnancy is the biggest issue. Planned pregnancies were over three times more likely to have adequate folate, as those women proactively sought preconception counseling and supplementation. Yet only 35.1% of the cohort planned their pregnancy, meaning most conceived without preparation, missing the optimal window (preconception 3 months).
• Some specialists overlook the issue. Folate adequacy among women prescribed AEDs by psychiatrists was just 9.1%; pediatricians prescribed to none who met adequacy criteria. This suggests some physicians focus on disease control but may neglect reproductive health and preconception nutrition, highlighting the need for better interdisciplinary communication.
• Certain medications warrant caution. About half of patients used sodium valproate. Clinical evidence indicates valproate increases the risk of fetal abnormalities; its use in women of childbearing potential requires strict evaluation by neurology/psychiatry specialists, and should be avoided unless essential. Alarmingly, over one-third of valproate users took it not for epilepsy or bipolar disorder, but for migraines — a particularly high-risk scenario in pregnancy.
• Personal risk factors matter. Younger age, smoking, alcohol use, and multiparity raise folate deficiency risk. Additionally, existing folate metabolism disorders diminish the effectiveness of ordinary folic acid supplements.

Take-home message

For women taking AEDs, folate supplementation is not a casual wellness choice — it is a carefully planned, high-priority health measure.

Key Recommendations

• For women on AEDs, preconception folate intake is critical.
• If ordinary folic acid conversion is inadequate, active folate may be chosen under medical guidance.
• Risk factors: unplanned pregnancy, prescriptions from psychiatry/pediatrics, smoking/alcohol.
• Ongoing care must involve both neurologist and obstetrician.

Magnafolate® is supplied solely as an active folate raw material (6S-5-methyltetrahydrofolate calcium) and does not directly diagnose or treat patients; all supplementation decisions require professional medical supervision.

Note: The patient story is a composite based on typical scenarios and research cases, intended to convey scientific information, not to represent a real individual.

References

1. Ikeda-Sakai K, et al. Inadequate Folic Acid Intake Among Women Taking Antiepileptic Drugs During Pregnancy in Japan: A Cross-Sectional Study. Scientific Reports, 2019.
2. Lian Zenglin, Liu Kang, Gu Jinhua, Cheng Yongzhi, et al. Biological Characteristics and Applications of Folate and 5-Methyltetrahydrofolate. China Food Additives, 2022, No. 2.