In our community of perinatal psychiatrists, we have recently seen many questions regarding the use of folic acid supplementation in women taking lamotrigine (Lamictal).  While all recognize that all women of childbearing age should receive folic acid supplementation, there is considerable variation regarding the dose that should be recommended for women taking lamotrigine (Lamictal).

Folic Acid Supplements Recommended for All Women of Childbearing Age

Folic acid is a B-vitamin needed for proper cell growth and is found in many multivitamins, as well as many food sources, such as lentils, dried beans and peas, and dark green vegetables.  Women with low serum levels of folate have an increased risk of having a child with neural tube defects.  By taking the recommended dosage of folic acid daily, women reduce the risk of neural tube defects by 50% – 70%. In addition, women who take folic acid supplements are less likely to give birth to a child with an autism spectrum disorder.

Because about half of all pregnancies are unplanned, the CDC, the U.S. Public Health Service and the American College of Obstetricians and Gynecologists (ACOG), recommend that every woman of reproductive age take 400 micrograms (400 mcg) or 0.4 milligrams of folic acid every day. Most multivitamins contain 400 micrograms or 0.4 milligrams of folic acid. Most prenatal vitamins have approximately 800 micrograms or 0.8 milligrams of folic acid.

HIgher Doses of Folic Acid Recommended for Women Taking Anticonvulsants

Some, but not all, anticonvulsants can decrease folate levels.  Children exposed to certain anticonvulsants, including valproic acid (Depakote) and carbamazepine (Tegretol), during the first trimester of pregnancy have an increased risk of neural tube defects, as well as other structural abnormalities.

This finding led to the recommendation that women on valproic acid should take an increased daily dose (4-5 mg) of folic acid.  While folic acid supplementation has been shown to decrease the overall risk of neural tube defects in the general population, we do not know if folic acid supplementation decreases the risk of neural tube defects or other malformations in women taking anticonvulsant drugs.  

Furthermore, we do not have any information regarding the optimal dosage of folic acid.  It is hypothesized that correcting the folate deficiency seen in women taking certain anticonvulsants would be corrected by supplementing with higher doses (4-5 mg) of folate before and during pregnancy and, thus, would decrease the risk of neural tube defects may be decreased by supplementation with higher doses of folic acid.  The 4-5 mg recommended daily dosage of folic acid has not been shown to be harmful to the pregnant woman or her fetus.

Anticonvulsants  that do not induce cytochrome P450 enzymes, such as lamotrigine (Lamictal), are not associated with low levels of folic acid.  Lamotrigine has weak folate properties in vitro, but does not appear to have any effect on serum or red blood cell folate levels in humans (as observed in 14 patients on short-term treatment and in an additional 14 patients treated for up to 5 years).    The use of lamotrigine during pregnancy has not been associated with an increased risk of neural tube defects; however, the recommendation regarding higher doses of folic acid supplementation is often, but not always, broadened to include women taking any anticonvulsant, including lamotrigine.  (The package insert for lamotrigine does not recommend using higher doses of folic acid.)

The Take-Home Message

I wish I had one, or at least one that was more specific.  I have looked extensively (and obsessively) at the various recommendations regarding the use of folic acid supplementation during pregnancy in women taking lamotrigine and was hoping to find some clarity.  Given that lamotrigine is one of the most commonly prescribed anticonvulsants during pregnancy, it is somewhat surprising that the recommendations are so nonspecific.  It seems that there are two approaches here.  Some recommend that folic acid at doses of 4-5 mg causes no harm and may help, so why not use it?  Others feel that there is no increased risk of neural tube defects with prenatal exposure to lamotrigine, so we should use the dose of folic acid recommended for all childbearing women: 400-800 mcg.

But perhaps even more important than the exact dosage of folic acid is making sure that all women of childbearing age get some sort of folate supplementation.  The studies which have looked at periconceptual use of folic acid have demonstrated relatively low rates of folic acid use in women taking anticonvulsants.   In a recent study which included seven European countries, women taking AEDs were not consistently co-prescribed high-dose folic acid in the 3 months prior to pregnancy; the rates ranged from 1.0% in Italy to 33.5% in Wales.

 

Ruta Nonacs, MD PhD

Charlton R, Garne E, Wang H, Klungsøyr K, et al. Antiepileptic drug prescribing before, during and after pregnancy: a study in seven European regions.  Pharmacoepidemiol Drug Saf. 2015; 24(11): 1144-54.

Goh YI et al. Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. J Obstet Gynaecol Can 2006;28(8): 680-9.

Wilson RD; Genetics Committee, Wilson RD, Audibert F, et al.  Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies. J Obstet Gynaecol Can. 2015 Jun;37(6): 534-52.