Question from a Member:
Do you have any thoughts on using divalproex for women of childbearing age? Today, one of my colleagues started a 43-year-old female who is 8 months postpartum on divalproex.
I have been very reserved about starting females on divalproex…I try to avoid starting divalproex in this population unless absolutely needed.
In this article we will:
1. Follow the convention of using “valproate” as a generic term that includes divalproex, valproic acid, and valproate sodium.
2. Use both phrases: “female of childbearing potential” and “woman of childbearing potential.” The distinction is, of course, that “female” refers to biological sex and “woman” to gender identity. But FDA-approved documents like the Prescribing Information continue to use both terms.
What does “childbearing potential” mean?
The term “childbearing potential” is used by the FDA in its broadest sense. Any female who could conceivably become pregnant, even if that is unlikely, is considered to be “of childbearing potential.” So, “childbearing potential” is considered to exist from the onset of menarche to the postmenopause (or documented sterilization).
For example, childbearing potential is considered to exist even if the person is not sexually active at all, has exclusively lesbian relationships, is using any type of contraception (oral, injectable, IUD, etc.), and so on.
In this article, we’ll answer the following questions:
1. What are the risks associated with valproate use during pregnancy?
2. Should valproate NEVER be used in a female of childbearing potential? Or are there some situations in which it can be prescribed?
3. Can’t females of childbearing potential stop the valproate as soon as they realize that they are pregnant?
4. Would folic acid supplementation help if valproate is prescribed to a female of childbearing potential?
Have you prescribed valproate to one or more female patients of childbearing potential? If so, I would appreciate your sharing with us the circumstances that led to this. Thank you!
What are the risks of valproate use during pregnancy?
Here are a few important things about the risks that we should frame our understanding of the issues:
1. We are fairly certain that there is an increased risk of congenital malformations if valproate is used during the first trimester of pregnancy. In addition to human studies, similar congenital malformations have also been found in animal studies involving valproate exposure during pregnancy.
2. It is not just a small increase in risk; it is substantial. In newborns who were exposed to valproate during the first trimester of pregnancy, the risk of major congenital malformations may be 3 times that in the general population (Vigod et al., 2025).
3. This increased risk of congenital malformations with valproate is much higher than with carbamazepine and lamotrigine (Vigod et al., 2025).
4. The risks associated with valproate are not limited to the first trimester. As discussed below, valproate use is not safe at any time during pregnancy.
First trimester
Valproate use during the first trimester of pregnancy is associated with a substantially increased risk of major congenital malformations, mainly neural tube defects and cardiac defects (Vigod et al., 2025), though other congenital malformations can also occur.
1. Neural tube defects like spina bifida. The neural tube is a hollow structure that develops early in embryonic development and develops into the brain and spinal cord. If the neural tube does not close as it normally does, serious congenital malformations called neural tube defects occur.
2. Cardiovascular malformations
3. Other major congenital malformations, including craniofacial defects, hypospadias, and limb malformations (Divalproex ER Prescribing Information).
Second and third trimesters
Valproate use in the second and third trimesters is associated with an increased risk of:
1. Neurodevelopmental delay (Vigod et al., 2025).
2. Decreased IQ scores (Divalproex ER Prescribing Information).
3. Neurodevelopmental disorders including autism spectrum disorder, intellectual disability (IQ < 70), and ADHD (Andrade et al., 2025; Divalproex ER Prescribing Information).