We have really enjoyed our weekly virtual rounds.  It’s been a great opportunity to meet other perinatal psychiatrists in the community, and discussions with new people always brings up interesting clinical questions.  Last week we received a question regarding the use of folic acid supplementation in women taking lamotrigine (Lamictal). 

The U.S. Public Health Service and the American College of Obstetricians and Gynecologists (ACOG), recommend that all women of reproductive age take 400 micrograms (400 mcg) or 0.4 milligrams of folic acid every day. Multivitamiased risk of neural tube defects, as well as other structural abnormalities.  While it is believed that these negative outcomes may be related to the anticonvulsants’ effects on folate transport and metabolism, it is likely that the picture is more complicated.  Although it is recommended that women on valproic acid should take an increased daily dose (4-5 mg) of folic acid, we do not know if this level of folic acid supplementation decreases the risk of neural tube defects or other malformations in women taking valproic acid or other anticonvulsant drugs. 

What About Lamotrigine?

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.

Patel N, Viguera AC, Baldessarini RJ.  Mood-Stabilizing Anticonvulsants, Spina Bifida, and Folate Supplementation: Commentary.  J Clin Psychopharmacol. 2018 Feb;38(1):7-10.

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.