While it is widely recognized that valproate is a teratogen, its impact on fetal neurodevelopment and the subsequent risk of neurobehavioral disorders is less widely discussed. 

In the United States, about half of all pregnancies are unplanned. Furthermore, rates of unintended pregnancy are even higher among women with psychiatric illness. Thus, inadvertent exposures to psychiatric medications are relatively common.

While there is information to support the use of many different types of psychiatric medications during pregnancy, valproate is one that carries significant risk. We continue to recommend that valproate be avoided in all women of reproductive age who are capable of becoming pregnant. Nonetheless, we continue to see women in our clinic who are taking valproate or who have become pregnant while taking this medication.

While other countries have seen reduced use of valproate in reproductive-aged women and a reduction in valproate-exposed pregnancies, rates of valproate-exposed pregnancies have not decreased in the United States over the past 15 years, despite enhanced Food and Drug Administration (FDA) safety communications Furthermore, the use of contraception in this population continues to be relatively low.

In a recent commentary, Suleiman and colleagues argue for stricter regulations in the United States regarding the use of valproate in women of childbearing age.

Clinical Context and Evidence of Risk

Valproate is a well-established teratogen, associated with a spectrum of major congenital malformations. The risk of neural tube defects is 10- to 20-fold higher in valproate-exposed children compared to the general population. Other congenital anomalies associated with prenatal valproate exposure include craniofacial abnormalities (such as cleft lip and palate), congenital heart defects, genitourinary anomalies, limb defects, and characteristic dysmorphic facial features as seen in fetal valproate syndrome. For more information, see our posts on Anticonvulsants in Pregnancy: Focus on Valproic Acid. 

In addition, there is robust and consistent evidence that prenatal valproate exposure greatly increases the risk of neurodevelopmental disorders. The most recent meta-analyses show that prenatal exposure to valproate more than triples autism risk (aHR ~3.10), with even greater risk associated with exposure to higher doses of valproate. In addition, prenatal valproate exposure is associated with a modestly increased ADHD risk (aHR ~1.62).

Given these risks, valproate should be avoided in pregnancy and should not be used in women of child-bearing age, except in the rarest circumstances, and only with the most robust safeguards in place.

Current Warnings on Safety

The FDA requires that information on the safety of medication use during pregnancy be included in package labeling. In 2006, the FDA introduced a black box warning for valproate addressing its teratogenicity. This warning specifically highlights the risk of birth defects (including neural tube defects, cardiovascular malformations, and craniofacial anomalies), and was later expanded to include neurodevelopmental risks such as decreased IQ and increased risk of autism and ADHD when used during pregnancy. In addition, regulatory agencies may implement risk management programs. 

In the United States, there are also Risk Evaluation and Mitigation Strategies (REMS) that may be used to help prevent medication-related harm. While many anticonvulsants—including valproic acid, carbamazepine, and topiramate—carry teratogenic risk, currently only one anticonvulsant (used in the combination of topiramate-phentermine, Qsymia, for weight loss) has a REMS.

Although regulatory agencies in Europe have demonstrated success in reducing valproate exposures in pregnancy through aggressive measures, prescription and exposure rates have not declined significantly in the United States. In a recent commentary, Suleiman and colleagues argue that it is time for stricter U.S. regulations that are aligned with the evidence-based consensus on the use of valproate in women of child-bearing age.

Key Recommendations

While the FDA black box warning has been in place for nearly 20 years, valproate continues to be prescribed at unacceptably high rates in the United States. Suleiman and colleagues discuss the need for, and obstacles to, enhanced risk mitigation involving teratogenic anticonvulsants, especially valproate. This is particularly crucial in an era of increasingly strict abortion restrictions.

The authors call for a formal Risk Evaluation and Mitigation Strategy (REMS) program for valproate in the United States, similar to European regulations and the iPLEDGE program currently used for isotretinoin. This would include:

• Specific informed consent outlining the risks of teratogenicity, to be signed by both patient and provider. 
• Mandatory contraceptive counseling, including a pregnancy prevention guide for all reproductive-age individuals receiving valproate. 
• Regular documented confirmation of effective contraception or documentation of reasons pregnancy is not possible (for example, menopause or hysterectomy). 
• Reliable, periodic pregnancy testing prior to initiation and at every outpatient visit if the patient is capable of pregnancy. 
• Clear, visual warnings on all valproate packaging. 

Despite longstanding warnings and clear evidence of harm, valproate continues to be inappropriately prescribed to women of reproductive potential, resulting in preventable exposures and significant risks associated with exposure. Given the persistently high rates of pregnancies exposed to valproate in the United States, it is critical to advance more stringent regulatory safeguards and risk mitigation programs. Stricter measures and a coordinated approach are urgently needed to prevent avoidable harm and to protect the health of women and their children.

Ruta Nonacs, MD PhD

Reference:

Suleiman M, Silver DF, Forray A, et al. Beyond the boxed warning: a call for regulation of psychiatry’s most teratogenic drug. J Clin Psychiatry 2025; 86(4):25com16026.