Researchers discovered that a common epilepsy medication called valproic acid can damage the placenta—the organ that feeds a baby during pregnancy. However, a study in rats suggests that a special type of vitamin B (called bioactive folate) might protect against this damage. The researchers found that when pregnant rats took valproic acid, their placentas became thin and damaged. But when they also gave the rats bioactive folate supplements, the placental damage was significantly reduced. While this is promising news for pregnant women who need epilepsy medication, more research in humans is needed before doctors can recommend this approach.

The Quick Take

  • What they studied: Whether a special type of vitamin B (bioactive folate) could protect a baby’s placenta from damage caused by valproic acid, a medication used to treat epilepsy.
  • Who participated: Pregnant laboratory rats were divided into three groups: a control group that received no medication, a group that received valproic acid, and a group that received valproic acid plus bioactive folate supplements.
  • Key finding: Rats that received bioactive folate supplements along with valproic acid had significantly better placental health compared to rats that only received the medication. The placenta remained thicker, had better cell structure, and showed fewer signs of inflammation and damage.
  • What it means for you: If you’re a pregnant woman who needs to take valproic acid for epilepsy, this research suggests that bioactive folate supplements might help protect your baby. However, this study was done in rats, not humans, so you should talk to your doctor before making any changes to your supplements or medications.

The Research Details

This was an animal study using pregnant rats to understand how valproic acid affects the placenta and whether bioactive folate could help. The researchers divided the rats into three groups: one group received no treatment (control), another received a dose of valproic acid on day 10 of pregnancy, and the third group received valproic acid plus daily bioactive folate supplements. The researchers then examined the placentas under a microscope to see the damage and measured chemical markers of inflammation and stress in the tissue.

The scientists also used computer modeling to understand how valproic acid might interfere with the body’s folate metabolism—the process that uses B vitamins to support healthy cell growth and function. This helped explain why bioactive folate might be protective.

This research approach is important because it allows scientists to study how medications affect pregnancy in a controlled way that wouldn’t be ethical to do in humans. By using rats, which have similar pregnancy biology to humans, researchers can identify potential problems and test solutions before considering human studies. The combination of looking at tissue damage, measuring inflammatory chemicals, and using computer modeling provides strong evidence for how the protection works.

This study was published in a peer-reviewed scientific journal, meaning other experts reviewed it before publication. The researchers used standard laboratory techniques and measured multiple markers of placental health, which strengthens their findings. However, because this is an animal study, the results may not directly apply to humans. The study also doesn’t specify exactly how many rats were used, which would help readers assess the strength of the findings.

What the Results Show

Valproic acid caused significant damage to the placenta in rats. The placental tissue became much thinner, with disorganized layers that couldn’t function properly. The researchers observed loss of important cell types, including decidual cells (which anchor the placenta) and glycogen cells (which provide energy). Blood vessels in the placenta were also damaged, which would reduce oxygen and nutrient delivery to the baby.

When bioactive folate was added to the treatment, the damage was substantially reduced. The placental layers remained thicker and better organized, the important cell types were preserved, and blood vessel damage was minimized. These improvements suggest that bioactive folate protected the placenta from the harmful effects of valproic acid.

The researchers also measured chemical markers of inflammation and oxidative stress (cellular damage from harmful molecules). Valproic acid alone caused these markers to increase significantly, indicating inflammation and cellular stress. Bioactive folate supplementation substantially reduced these harmful markers, suggesting it protected cells from damage.

The computer modeling analysis revealed that valproic acid binds weakly to a protein called MTR, which is involved in folate metabolism and methylation (a chemical process important for cell function). This weak binding may disrupt normal folate processing in the body. Bioactive folates like 5-MTHF and folinic acid appear to bypass these disrupted pathways, which explains why they’re more protective than regular folic acid. This finding suggests that the form of folate matters—bioactive forms work better than synthetic forms when folate metabolism is impaired.

Previous research has shown that valproic acid can cause birth defects and harm fetal development, but the exact mechanisms weren’t fully understood. This study provides new insight into how valproic acid damages the placenta specifically. The finding that bioactive folates are superior to regular folic acid is important because most prenatal vitamins contain synthetic folic acid, not the bioactive forms studied here. This suggests that current supplementation strategies might not be optimal for pregnant women taking valproic acid.

This study was conducted in rats, not humans, so the results may not directly apply to human pregnancies. The dosages used in rats may not translate exactly to human doses. The study doesn’t specify the number of animals used, which makes it harder to assess how reliable the findings are. Additionally, the study only looked at one time point in pregnancy (day 10 in rats), so we don’t know if the protection continues throughout pregnancy or if there are other critical periods. Finally, this research doesn’t address whether bioactive folate supplementation is safe for all pregnant women or if there are any potential side effects.

The Bottom Line

Based on this animal research, bioactive folate supplementation (specifically 5-MTHF or folinic acid) appears promising for protecting placental health in pregnancies where valproic acid is necessary. However, this is preliminary evidence from animal studies. Confidence level: LOW for human application. If you’re pregnant and taking valproic acid, discuss with your doctor whether bioactive folate supplementation might be appropriate for you. Do not change your medications or supplements without medical guidance.

This research is most relevant to pregnant women who need valproic acid to control epilepsy and their healthcare providers. Women planning to become pregnant while taking valproic acid should also be aware of this research. This is less relevant to women taking valproic acid for other conditions (like bipolar disorder) who are not pregnant, though they may want to discuss it with their doctors if they’re considering pregnancy. This research should NOT be used by people to self-treat or change their medication without medical supervision.

In the animal study, placental protection was observed with daily supplementation throughout pregnancy. In humans, if bioactive folate supplementation is eventually recommended, benefits would likely need to be sustained throughout pregnancy to be effective. You would not see immediate changes—the protection would develop gradually over weeks of consistent supplementation. Any human studies would need to follow pregnancies through delivery to assess real-world benefits.

Want to Apply This Research?

  • If your doctor recommends bioactive folate supplementation, track daily supplement intake (5-MTHF or folinic acid dose and time taken) and any pregnancy-related symptoms or concerns. Log this consistently to ensure compliance and to share with your healthcare provider at appointments.
  • Set a daily reminder to take bioactive folate supplements at the same time each day (ideally with a meal). If prescribed, keep a simple checklist or use your app’s medication reminder feature to ensure you don’t miss doses, since consistent supplementation appears important for protection.
  • Work with your healthcare provider to monitor placental health through regular ultrasounds and prenatal check-ups. Track any symptoms that might indicate placental problems (unusual bleeding, decreased fetal movement, etc.) and report them immediately. Maintain regular communication with your doctor about supplement tolerance and any side effects.

This research was conducted in laboratory rats and has not been tested in humans. Valproic acid is an important medication for controlling epilepsy, and the decision to take it during pregnancy should only be made with your doctor, weighing the benefits against potential risks. Do not start, stop, or change any medications or supplements during pregnancy without consulting your healthcare provider. While this research suggests bioactive folate may be protective, it is not yet standard medical practice. Always follow your doctor’s recommendations for prenatal care and supplementation. If you are pregnant or planning to become pregnant and take valproic acid, discuss this research with your neurologist and obstetrician to determine the best approach for your individual situation.