The Journal of Clinical Psychiatry recently published a series of articles on the use of valproic acid in women of childbearing age. We all agree that valproic acid is a teratogen and is associated with unacceptably high rates of major congenital malformations, including neural tube defects, neurodevelopmental disorders, and other adverse outcomes.
Where there seems to be a divergence of opinions, however, is whether or not valproic acid should be used at all in women of childbearing age. Several other countries have put strict limitations on the use of valproic acid in reproductive aged women; the United States has not.
Chittaranjan Andrade, MD, et al:
Use of Valproate in Women: An Audit of Prescriptions to 10,001 Psychiatry, Neurology, and Neurosurgery Outpatients
During September to November 2019, researchers examined prescriptions for 10,001 consecutive outpatients seen in the Departments of Psychiatry, Neurology, and Neurosurgery at the National Institute of Mental Health and Neurosciences in Bangalore, India, a large, tertiary care referral center
A large proportion of women (647/3,837 or 16.9%) received a prescription for valproate (mean dose?=?898 mg/d). Women between the ages of 15 and 45 years accounted for 71.1% of these prescriptions. In comparison, 403 (10.5%) of 3,837 women received a prescription for carbamazepine. Women were more likely to receive a prescription for valproate in the Departments of Neurology and Neurosurgery than in the Department of Psychiatry (29.1% vs 14.4%, respectively).
Camille Tastenhoye, MD et al:
Valproate Prescribing Practices in Individuals of Childbearing Age at a Tertiary Care Women’s Hospital
Researchers from the University of Pittsburgh reviewed a database of electronic medical records from a tertiary care women’s hospital and identified women of childbearing age (12–52 years) who received valproate during medical admission (January 1, 2019, to December 31, 2019). They identified 15 unique patients treated with valproate.
Documented indications for valproate use included bipolar disorder (7/15), seizure disorders (7/15), and migraine treatment (2/15). The home dosage of valproate was continued in 14 encounters. Six encounters had a documented negative urine pregnancy test. Three out of 15 patients were pregnant. One patient was prescribed high-dose folate prior to admission; however, the other 14 patients had no documented folate supplementation. There were no documented risk-benefit discussions.
The reality is that if you treat individuals of reproductive potential, you will find yourselves on the front lines of perinatal health care. The ideal time to select a psychotropic for pregnancy is well before conception, planned or not. Unplanned pregnancies are common, and women with psychiatric disorders may be more likely than the general population to have unplanned pregnancies.
Tastenhoye and her co-authors argue that valproic should not be used in women of reproductive age, and that physicians would benefit from additional education about the risks of valproate use in women of childbearing age.
Joseph F. Goldberg, MD
Living in a Pharmacologically Imperfect World
In this commentary, Dr. Goldberg argues that when it comes to treating women of childbearing age, valproic acid is but one imperfect treatment option on a list of other imperfect options. He notes that second generation atypical antipsychotic medications carry a risk of weight gain, and some may increase risk for gestational diabetes. Lithium may be an option, although it does carry a risk, albeit small, for cardiovascular malformations. While lamotrigine does not appear to carry any teratogenic risk, it may not be as effective in preventing recurrent mania. Furthermore, it is not clear whether women who respond well to valproic acid will respond equally well to these alternatives.
Certainly, if and when a better and safer alternative to valproate exists, it warrants preferred status. However, the risk for relapse and functional impairment in bipolar disorder remains high even with state-of-the-art care, making it a risky proposition to advise an absolute moratorium on any treatment that could help to avert its inordinately high morbidity and mortality.
Thus, Dr. Goldberg would prefer to leave valproic acid on the table.
Marlene Freeman, MD:
Prescribing Guideline for Valproic Acid and Women of Reproductive Potential: Forget It Exists
In this commentary, Dr. Freeman notes that valproic acid is a known teratogen that can cause a range of major fetal malformations, including neural tube defects, before most women are aware they are pregnant. She notes the well-established literature indicating that prenatal exposure to valproic acid is associated with worse neurodevelopmental outcomes and recent data that prenatal exposure to valproic acid may have transgenerational risks, contributing to an increased risk of malformations in the children of exposed individuals. She argues that better education of prescribers is simply not enough.
There is no nuance to this: Valproic acid should not be prescribed to women of childbearing potential for psychiatric disorders. While some countries have sought to regulate its use and disseminate the dangers of use during pregnancy more prominently, there is no sufficient threading of this needle. Not today, when we have so many other options as mood stabilizers than we did decades ago.
Just forget it exists.
Some Final Thoughts
While on the surface these may seem like dramatically divergent opinions, they are not. At the heart of the discussion is the realization that bipolar disorder is an often difficult-to-treat illness with significant morbidity. It is commonplace for individuals with bipolar disorder to have a long list of medications they have tried and failed, and they often struggle to find a regimen that maintains their stability.
Sometimes that regimen may include valproic acid. Given the risks associated with valproic acid during pregnancy and the high frequency of unplanned pregnancy, valproic acid should never be a first choice in a woman of reproductive age. Rather, we should consider treatment options in the context of a pregnancy in the future, and our first line options should include medications that are appropriate for a given clinical situation while at the same time considering data on reproductive safety.
Ruta Nonacs, MD PhD
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