Your new patient is a 16-year-old high school student who received a diagnosis of chronic migraine two years ago. She has recently become sexually active. How would you counsel this patient?
Your new patient is a 16-year-old high school student who received a diagnosis of chronic migraine two years ago. She is currently on valproate and says she has had a significant reduction in migraine days since she started it about a year ago. Before that, she suffered from migraines 20 days per month, which caused her to miss school. During that time, her grades dropped from As and Bs to Cs and a few Ds.
She is now back to her former level of functioning at school and has just made the honor roll. Her former doctor started her on valproate after trials of onabotulinum toxin A, topiramate, amitryptiline, and propranolol were ineffective. She has a new boyfriend and has recently become sexually active. She says they always use condoms, but she is not on birth control.
How would you counsel this patient?
While valproate is FDA-approved for the treatment of seizures, bipolar disorder, and the prevention of migraines, the FDA has issued several warnings about its use in women of child-bearing age. Valproate has been linked to severe congenital malformations, especially neural tube defects. Other possible defects include limb defects, facial and skull defects, cleft lip and palate, as well as cardiac, renal, and urogenital defects. The FDA advises that women of childbearing potential should not receive valproate unless essential for the treatment of a medical condition and states that “this is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (eg, migraine).1”
Moreover, in 2011, the FDA warned that children exposed to valproate in utero are at increased risk for impaired cognitive development. And in 2013, the FDA issued a statement that valproate is contraindicated for migraine prevention in pregnant women because of findings that suggest that the offspring might have a decreased IQ.3 The FDA has also advised that the benefits of valproate should be carefully weighed against the risks, and an alternative medication with lower risk to the fetus should be used if the drug is not deemed essential. The FDA further stated: “If the decision is made to use valproate in women of childbearing age, effective birth control should be used.”2
Other professional organizations have also taken a hard line against valproate in women of child-bearing potential.1 In 2017, the American Epilepsy Society issued a position statement endorsing the FDA’s stance about the use of valproate in women of childbearing potential.4
And, in perhaps the most drastic action so far, in March 2018, the European Medical Association and European Headache Federation (EMA/EHF) introduced actions effectively banning valproate in women of childbearing age, unless they meet the conditions of a Pregnancy Prevention Program. The EMA/EHF stated that valproate is contraindicated for bipolar disorder during pregnancy and should be considered last line for migraine prevention in children, teens, and women of childbearing potential.
The drug should not be started even in prepubescent girls, unless no other alternative is available. These restrictions are now legally binding across the European Union.5,6 The action was taken based on findings that suggest lack of awareness about the risks of valproate during pregnancy, despite 2014 recommendations intended to limit its use.
The Pregnancy Prevention Program requires an assessment of a woman’s potential for becoming pregnant and whether she will comply with contraception during treatment, pregnancy tests before starting treatment, counseling about the risks of valproate and the need for effective birth control as well as at least one annual treatment review with a specialist using a risk acknowledgement form. Pregnancy planning should also occur before discontinuation and switching to another medication. In the case of unplanned pregnancy, the woman should seek immediate consultation about discontinuing valproate.
You discuss this information with the patient and advise her that continued use of valproate is not advisable. You inform her that in May 2018 a new drug, erenumab was FDA-approved for migraine prevention, based on research that suggests that the drug may decrease migraine days in chronic migraine. Because the drug is new, insufficient evidence exists about its safety during pregnancy in humans, but animal data suggested no adverse effects to offspring. You further advise her to start birth control, which may also improve her migraines. If she chooses to stay on valproate, you emphasize the importance of effective contraception, as well as taking folic acid.
Take Home Points
• Valproate use during pregnancy has been linked to impaired cognitive development and lower IQ in offspring, as well as several birth defects, especially neural tube defects
• The FDA has stated that valproate is contraindicated for migraine prevention in pregnant women
• The European Union has strict regulations against valproate use in women of childbearing potential, who must follow a Pregnancy Prevention Plan
• Women of childbearing potential who take valproate should adhere to effective contraception and take folic acid
1. US Food and Drug Administration. Valproate full prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018081s046_18082s031lbl.pdf. Accessed November 5, 2018.
2. US 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 November 5, 2018.
3. US 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 November 5, 2018.
4. American Epilepsy Society. Position Statement on the Use of Valproate by Women of Childbearing Potential. https://www.aesnet.org/sites/default/files/file_attach/Position%20Statement%20on%20the%20Use%20of%20Valproate%20by%20Women%20of%20Childbearing%20Potential.pdf. Accessed November 5, 2018.
5. European Medicines Agency. Valproate and Related Substances. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Valproate_and_related_substances/human_referral_prac_000066.jsp&mid=WC0b01ac05805c516f. Accessed November 5, 2018.
6. Vatzaki E, Straus S, Dogne JM, et al. Latest clinical recommendations on valproate use for migraine prophylaxis in women of childbearing age: overview from European Medicines Agency and European Headache Federation. J Headache Pain. 2018;19:68.