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Valproic Acid and Divalproex: High Risk of Birth Defects

Worst Pills, Best Pills Newsletter article November, 2018

Valproic acid (DEPAKENE) — also called valproate — was approved by the Food and Drug Administration (FDA) in 1978 to treat epilepsy, a brain disorder that causes recurring seizures.[1] The closely related drug divalproex (DEPAKOTE), which was approved by the FDA in 1983, is essentially two molecules of valproic acid hooked together and is converted to the active substance valproate after ingestion.[2] Divalproex is approved to treat seizures and bipolar disorder and to prevent migraines.
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Valproic acid (DEPAKENE) — also called valproate — was approved by the Food and Drug Administration (FDA) in 1978 to treat epilepsy, a brain disorder that causes recurring seizures.[1] The closely related drug divalproex (DEPAKOTE), which was approved by the FDA in 1983, is essentially two molecules of valproic acid hooked together and is converted to the active substance valproate after ingestion.[2] Divalproex is approved to treat seizures and bipolar disorder and to prevent migraines.

The serious adverse effects of valproate on fetal development during pregnancy have been well-recognized for many years. The drug can cause fetal valproate syndrome.[3] This syndrome is characterized by various defects including heart defects, facial and skeletal abnormalities, and cleft lip and palate, and delay in developmental milestones following birth. Some studies have shown that valproate can increase the risk of developing serious malformations by nearly fourfold.[4]

One of the most common birth defects caused by valproate is spina bifida, a condition that affects the development of the spine and spinal cord. Fetal exposure to valproate increases the risk of spina bifida by 10- fold to 20-fold.[5],[6],[7]

In addition to malformations present at birth, studies have shown that children with prenatal exposure to valproate have up to an 8-to-11–point decrease in IQ compared with children who had prenatal exposure to other epilepsy drugs.[8] Fetal exposure to valproate also is associated with an increased risk of autism.[9]

FDA-Required Black-Box Warning for Valproic Acid and Divalproex Regarding Birth Defect Risk*

Valproate can cause major birth defects, particularly neural tube defects (defects of the embryo’s developing brain, spinal cord or spine). In addition, valproate can cause decreased IQ scores following prenatal exposure.

Valproate should never be used in pregnant women to prevent migraines. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable.

Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (for example, migraine). Women should use effective contraception while using valproate.*

*Note: The FDA’s warning has been paraphrased in part from the FDA-approved product labeling.



FDA warnings

Since at least 2006, the product labeling for both valproic acid and divalproex has had an FDA-required black-box warning about the risk of major birth defects (see box, above). In 2009, the FDA issued a safety alert that reiterated the warnings about the drug’s ability to cause major birth defects including neural tube defects, skull and facial deformities, and cardiovascular malformations.[10]

In 2011 and 2013, the FDA released two safety communications about the use of valproate during pregnancy and the risk of decreased IQ scores and impaired cognitive development in children.[11],[12] In its 2013 communication, the agency advised that valproate should never be used in pregnant women to prevent migraines and should only be used in pregnant women to treat epilepsy or bipolar disorder if other medications are ineffective or otherwise unacceptable.

Barriers to preventing birth defects

There are several factors that make prescribing of valproic acid and divalproex to women and girls of childbearing age particularly risky. First, nearly half of all pregnancies in the U.S. are unplanned.[13] Second, many doctors do not properly inform female patients of childbearing age about the risk of birth defects associated with many medications.[14],[15] However, most women who are prescribed medication reported that they were confident that the prescribing health care provider would tell them if the medication potentially caused birth defects.[16]

Notably, valproate affects fetal development in the first few months of pregnancy, when many women do not know they are pregnant.[17] This is particularly problematic because the key steps in the development of the nervous system take place early on in the first trimester.

Concerningly, despite increasing recognition of valproate’s risks of birth defects, the number of women of childbearing age who were prescribed valproate for conditions other than epilepsy increased slightly between 1996-1998 and 2005-2007.

What You Can Do

If you are a woman of childbearing age and have seizures or bipolar disorder, you should avoid using valproate unless other medicines fail to adequately control your condition or cause unacceptable adverse effects. Also, you should use effective contraception while using valproate. Do not stop taking anti-seizure medications without first consulting your doctor because sudden cessation of anti-seizure medication can lead to the recurrence of seizures.

If you are a woman of childbearing age and taking valproate for migraines, talk to your doctor about switching to another medication to manage your symptoms.



References

[1] AbbVie. Drug label: valproic acid (DEPAKENE). May 2018. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=b43ff78c-8e7d-475c-8095-773d03c94437&type=pdf&name=b43ff78c-8e7d-475c-8095-773d03c94437. Accessed September 10, 2018.

[2] AbbVie. Drug label: divalproex (DEPAKOTE). May 2018. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=acc183a0-4a81-4023-bd6b-fbe477846dca&type=pdf&name=acc183a0-4a81-4023-bd6b-fbe477846dca. Accessed September 10, 2018.

[3] National Institutes of Health, National Center for Advancing Translational Sciences. Fetal valproate syndrome. https://rarediseases.info.nih.gov/diseases/5447/fetal-valproate-syndrome. Accessed September 10, 2018.

[4] Koren G, Nava-Ocampo AA, Moretti ME, et al. Major malformations with valproic acid. Can Fam Physician. 2006;52(4):441-442, 444, 447.

[5] Centers for Disease Control and Prevention. International notes, valproic acid and spina bifida: A preliminary report–France. MMWR Morb Mortal Wkly Rep, 1982;31(42):565–566.

[6] Gotlib D, Ramaswamy R, Kurlander JE, et al. Valproic acid in women and girls of childbearing age. Curr Psychiatry Rep. 2017;19(9):58.

[7] Jentink J, Loane MA, Dolk H, et al. Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med. 2010;362(23):2185-2193.

[8] Food and Drug Administration. FDA drug safety communication: Valproate anti-seizure products contraindicated for migraine prevention in pregnant women due to decreased IQ scores in exposed children. May 6, 2013. https://www.fda.gov/Drugs/DrugSafety/ucm350684.htm. Accessed September 10, 2018.

[9] Christensen J, Gronborg TK, Sorensen MJ, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013;309(16): 1696-1703.

[10] FDA warns pregnant women taking Depakote, Depakene. Psych Central. https://psychcentral.com/news/2009/12/05/fda-warns-pregnant-women-taking-depakote-depakene/9977.html. Accessed September 10, 2018.

[11] Food and Drug Administration. FDA drug safety communication: Valproate anti-seizure products contraindicated for migraine prevention in pregnant women due to decreased IQ scores in exposed children. May 6, 2013. https://www.fda.gov/Drugs/DrugSafety/ucm350684.htm. Accessed September 10, 2018.

[12] Food and Drug Administration. FDA drug safety communication: Children born to mothers who took valproate products while pregnant may have impaired cognitive development. June 30, 2011. https://www.fda.gov/Drugs/DrugSafety/ucm261543.htm. Accessed September 10, 2018.

[13] Finer LB, Zolna MR. Shifts in intended and unintended pregnancies in the United States, 2001–2008. Am J Public Health. 2014;104(Suppl 1):S43-48.

[14] Wisner KL, Leckman-Westin E, Finnerty M, Essock SM. Valproate prescription prevalence among women of childbearing age. Psychiatr Serv. 2011;62(2):218-220.

[15] Schwarz EB, Mattocks K, Brandt C, et al. Counseling of female veterans about risks of medication-induced birth defects. J Gen Intern Med. 2013;28(Suppl 2):S598-S603.

[16] Ibid.

[17] Jentink J, Loane MA, Dolk H, et al. Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med. 2010;362(23):2185-2193.