Valproic Acid

The Basics

What is Valproic Acid?

Primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. Also useful for the prevention of seizures.

Brand names for Valproic Acid

Depakene

How Valproic Acid is classified

Anticonvulsants, Antimanic Agents

Valproic Acid During Pregnancy

Valproic Acid pregnancy category

Category N/ANote that the FDA has deprecated the use of pregnancy categories, so for some medications, this information isn’t available. We still think it’s useful to list historical info, however, given what a common proxy this has been in the past.

What we know about taking Valproic Acid while pregnant

For use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception . For use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. Women with epilepsy who become pregnant while taking valproate should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations). This risk is dose-dependent; however, a threshold dose below which no risk exists cannot be established. In utero exposure to valproate may also result in hearing impairment or hearing loss. Valproate polytherapy with other AEDs has been associated with an increased frequency of congenital malformations compared with AED monotherapy. The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see WARNINGS AND PRECAUTIONS and Data (Human)]. Epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores and a higher risk of neurodevelopmental disorders compared to children exposed to either another AED in utero or to no AEDs in utero [see WARNINGS AND PRECAUTIONS and Data (Human)]. An observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders [see Data (Human)]. In animal studies, valproate administration during pregnancy resulted in fetal structural malformations similar to those seen in humans and neurobehavioral deficits in the offspring at clinically relevant doses [see Data (Animal)]. There have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy. Pregnant women taking valproate may develop hepatic failure or clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death . Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal And/Or Embryo/Fetal Risk To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus . However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. Maternal Adverse Reactions Pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death . If valproate is used in pregnancy, the clotting parameters should be monitored carefully in the mother. If abnormal in the mother, then these parameters should also be monitored in the neonate. Patients taking valproate may develop hepatic failure [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. Hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy. Data Human Neural Tube Defects And Other Structural Abnormalities There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07% (6 to 7 in 10,000 births) compared to the risk following in utero valproate exposure estimated to be approximately 1 to 2% (100 to 200 in 10,000 births). The NAAED Pregnancy Registry has reported a major malformation rate of 9-11% in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy. These data show an up to a five-fold increased risk for any major malformation following valproate exposure in utero compared to the risk following exposure in utero to other AEDs taken as monotherapy. The major congenital malformations included cases of neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems . Effect On IQ And Neurodevelopmental Effects Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another AED in utero or to no AEDs in utero. The largest of these studies1 is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]) and phenytoin (108 [95% C.I. 104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to AEDs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed . Although the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on neurodevelopment, including increases in autism spectrum disorders and attention deficit/hyperactivity disorder (ADHD). An observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders. In this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]: 1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. The absolute risks for autism spectrum disorders were 4.4% (95% CI: 2.6%-7.5%) in valproateexposed children and 1.5% (95% CI: 1.5%-1.6%) in children not exposed to valproate products. Another observational study found that children who were exposed to valproate in utero had an increased risk of ADHD (adjusted HR 1.48; 95% CI, 1.09-2.00) compared with the unexposed children. Because these studies were observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder and ADHD cannot be considered definitive. Other There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. Animal In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following administration of valproate to pregnant animals during organogenesis at clinically relevant doses (calculated on a body surface area [mg/m²] basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate

Taking Valproic Acid While Breastfeeding

What are recommendations for lactation if you're taking Valproic Acid?

Valproic acid levels in breastmilk are low and infant serum levels range from undetectable to low. Breastfeeding during valproic acid monotherapy does not appear to adversely affect infant growth or development, and breastfed infants had higher IQs and enhanced verbal abilities than nonbreastfed infants at 6 years of age in one study.[1] If valproic acid is required by the mother, it is not necessarily a reason to discontinue breastfeeding. No definite adverse reactions to valproic acid in breastfed infants have been reported. Theoretically, breastfed infants are at risk for valproic acid-induced hepatotoxicity, so infants should be monitored for jaundice and other signs of liver damage during maternal therapy. A questionable case of thrombocytopenia has been reported, so monitor the infant for unusual bruising or bleeding. One author recommends monitoring infant serum valproate levels, platelets and liver enzymes during therapy.[2] Combination therapy with sedating anticonvulsants or psychotropics may result in infant sedation or withdrawal reactions.

Maternal / infant drug levels

Valproic acid levels in breastmilk are low and infant serum levels range from undetectable to low. Breastfeeding during valproic acid monotherapy does not appear to adversely affect infant growth or development, and breastfed infants had higher IQs and enhanced verbal abilities than nonbreastfed infants at 6 years of age in one study.[1] If valproic acid is required by the mother, it is not necessarily a reason to discontinue breastfeeding. No definite adverse reactions to valproic acid in breastfed infants have been reported. Theoretically, breastfed infants are at risk for valproic acid-induced hepatotoxicity, so infants should be monitored for jaundice and other signs of liver damage during maternal therapy. A questionable case of thrombocytopenia has been reported, so monitor the infant for unusual bruising or bleeding. One author recommends monitoring infant serum valproate levels, platelets and liver enzymes during therapy.[2] Combination therapy with sedating anticonvulsants or psychotropics may result in infant sedation or withdrawal reactions.

Possible effects of Valproic Acid on milk supply

Relevant published information was not found as of the revision date.

Possible alternatives to Valproic Acid