Valproic Acid During Pregnancy and After Delivery: A Narrative Review

Valproic acid (VPA) is a widely used anticonvulsant and mood stabilizer, effective in managing epilepsy, bipolar disorder, and migraine prophylaxis. It has demonstrated efficacy in controlling seizures, stabilizing mood, and reducing the frequency and severity of manic episodes.¹ Because epilepsy and bipolar disorder often emerge in late adolescence or early adulthood,^2,3 VPA is frequently prescribed to women of childbearing age.

Beyond teratogenic and neurodevelopmental risks, VPA has also been associated with endocrine dysfunction, particularly an increased risk of polycystic ovary syndrome (PCOS) in women with epilepsy. Studies suggest that VPA may contribute to hyperandrogenism, menstrual irregularities, and insulin resistance, likely due to its effects on steroidogenesis and luteinizing hormone secretion.^4,5 These potential adverse effects are important considerations when prescribing VPA to women of reproductive age, especially those with existing metabolic risk factors.

Its use, however, during the perinatal period—which includes pregnancy and the first year postpartum—is controversial due to well-documented risks to fetal development. VPA exposure has been consistently linked to major congenital malformations, cognitive impairment, and neurodevelopmental disorders, raising concerns about its safety during pregnancy.⁶ These risks create a dilemma for clinicians and patients, who must balance potential fetal harm against the need to manage the mother’s condition.

Prescription patterns and recommendations for VPA use during pregnancy vary significantly worldwide. While data on VPA use during pregnancy are limited, population-based studies from France and the United States provide key insights. In France, research shows that VPA was prescribed to 1.7% of pregnant women with epilepsy between 2007 and 2014, despite national guidelines advising against its use during pregnancy.⁷ Similarly, in the United States, only about 5% of pregnant women with epilepsy were reported to be prescribed VPA, indicating that the majority of women either discontinue the medication during pregnancy or are not started on it during pregnancy due to concerns about fetal safety.⁸

International guidelines support this trend, recommending that VPA be avoided during pregnancy unless other treatments are ineffective. The American Academy of Neurology and the American Epilepsy Society advise that VPA should not be used as a first-line treatment for women of childbearing potential and should only be considered when other medications fail to provide adequate seizure control.⁹ Similarly, the European Medicines Agency recommends that VPA be avoided in pregnancy due to its high risk of congenital malformations and developmental disorders, unless there is no suitable alternative treatment.¹⁰ These guidelines reflect the consensus that the risks associated with VPA use during pregnancy are substantial and necessitate careful consideration.

In spite of these general recommendations, real-world data on the use of VPA during pregnancy remain limited and suggest significant variability in clinical practice. A large-scale study from the United States, for example, found that while only a small percentage of women (3.2%) continued VPA during pregnancy, many faced substantial challenges in finding alternative treatments that provided comparable efficacy in controlling their symptoms.¹¹ Similarly, a study from the United Kingdom, Sweden, and Canada reported that many women discontinued VPA upon becoming pregnant, but a notable proportion resumed treatment during pregnancy due to relapse or lack of efficacy with other medications.¹²

Despite these concerns, VPA may be necessary in certain cases, and discontinuing it during pregnancy carries complex risks. For women with epilepsy, switching medications can increase the risk of breakthrough seizures, which poses direct risks to both the mother and the fetus, including trauma, hypoxia, and preterm labor.¹³ For women with bipolar disorder, discontinuation of VPA can lead to a relapse of mood symptoms, which has been associated with poorer maternal outcomes, including postpartum psychosis and increased risk of suicide.¹⁴ These challenges highlight the critical need for individualized treatment planning and close monitoring throughout pregnancy and the postpartum period.

This review examines the efficacy and safety of VPA during pregnancy and postpartum, focusing on fetal risks, neonatal outcomes, and breastfeeding considerations. By synthesizing current evidence, it aims to guide clinicians in informed decision-making and highlight areas for future research to improve maternal and child health.

Methods

A comprehensive literature search was conducted using PubMed and Cochrane Library databases. Keywords included: “Pregnancy outcomes, Obstetric outcomes, Preterm birth, Low birth weight, Gestational hypertension, Preeclampsia, Congenital malformations, Teratogenic effects of anticonvulsants, Spina bifida, Neural tube defects, Valproate syndrome, Dose-dependent teratogenicity, Neurodevelopmental disorders AND Valproate, Autism spectrum disorder AND Valproate, ADHD risk and Valproate, Intellectual disability AND Valproate, Cognitive impairment AND Valproate, Speech delay AND Valproate, valproic acidexposure in pregnancy, Antiepileptic drugs pregnancy risks, Prenatal exposure to valproate, Alternative antiepileptic drugs in pregnancy, Clinical guidelines for valproate use in pregnancy, Neonatal outcomes, Small for gestational age, Microcephaly, Apgar score, Valproic acid breastfeeding, Valproic acid lactation transfer, AEDs in breast milk, Valproic acid milk-to-serum ratio, Maternal valproic acid levels while breastfeeding, Neonatal valproic acid exposure through breast milk, Antiepileptic drug pharmacokinetics in breastfeeding, Contraceptive use AND antiepileptic drugs.” Inclusion criteria consisted of original research articles, metanalyses, case reports, and clinical guidelines published in English from 1980 to 2024 which provided data on maternal and fetal outcomes and/or specifically addressed the use of valproic acid during pregnancy or in the postpartum period. Exclusion criteria consisted of non-English publications and studies without primary data (reviews, editorials). Additionally, studies were excluded if they were conference abstracts, animal studies, in vitro research, or if they were not available in full text or did not specifically focus on VPA use during pregnancy. After screening titles and abstracts, 60 articles met the inclusion criteria and were selected for full-text review.

Two independent reviewers conducted the initial screening of titles and abstracts from all identified studies. Full-text articles were subsequently evaluated to confirm their eligibility based on the predefined inclusion and exclusion criteria. Data extracted from the selected studies included key information on study characteristics (eg, design, population size, setting, duration), details of VPA exposure (including dosage and duration), and outcomes related to both maternal and fetal health, as well as any adverse effects reported.

Efficacy and Monitoring of Drug Levels

VPA is effective in managing multiple seizure types, including generalized tonic-clonic, absence, and myoclonic seizures. VPA monotherapy has shown efficacy comparable to other antiepileptic drugs, including carbamazepine, phenytoin, and phenobarbital, in treating both generalized and partial seizures.¹⁵ For absence epilepsy, VPA is as effective as ethosuximide, with both controlling seizures in approximately 75% of patients.¹⁶ However, VPA may be associated with attentional dysfunction in children treated for absence seizures.¹⁷

VPA is FDA-approved for treating acute mania in bipolar disorder and is frequently used as an alternative to lithium. While effective in managing manic episodes, its role in preventing depressive episodes and in long-term maintenance is less well-established compared to lithium.¹ Studies suggest VPA is more effective for acute mania than for prophylactic use in bipolar disorder.¹⁸ Serum VPA concentrations between 50-74 μg/mL are associated with a lower risk of recurrent mood episodes compared to levels below 50 μg/mL.¹⁹

Given its narrow therapeutic index, therapeutic drug monitoring (TDM) is essential to optimize efficacy and minimize adverse effects.The typical therapeutic range for VPA is 50-100 μg/mL, though higher levels may be required in refractory cases. Regular monitoring of serum levels, liver associated enzymes, ammonia, and complete blood counts is necessary due to risks of thrombocytopenia and hyperammonemia associated with VPA.¹⁵ Interestingly the hyperammonemia that is induced by VPA, due to inhibition of N-acetylglutamase synthetase, does not lead to a formal hepatotoxicity given that both liver-associated enzymes and INR levels are not impacted.²⁰ This is a paradoxical phenomenon in that the hyperammonemia caused by VPA use can ultimately lead to delirium despite not being hepatotoxic per se. Furthermore, the hyperammonemia can be resolved through use of carnitine.²¹ As such, individualized dosing based on clinical response and adverse effects is essential for safe, effective treatment.

Obstetric Outcomes After Valproic Acid Treatment During Pregnancy

VPA use during pregnancy is associated with significant teratogenic risks and adverse obstetric outcomes. Although additional research is needed to clarify these associations, we summarize several studies that have examined VPA’s impact on obstetric outcomes in Table 1. A prospective observational study by Diav-Citrin et al found that pregnancies with VPA exposure had a significantly higher rate of elective terminations (13.5% vs 2.9%) and lower rate of deliveries (76.3% vs 90.9%) when compared with pregnancies without exposure. VPA-exposed pregnancies also showed a median gestational age at delivery that was one week earlier than unexposed pregnancies, although both groups delivered at full term (P = 0.016). While the study found no significant differences in preterm birth, ectopic pregnancies, intrauterine fetal deaths, or miscarriages, larger studies are needed to fully assess VPA’s impact on neonatal outcomes.²²

VPA exposure is a significant risk factor for major congenital malformations (MCMs), with a prevalence of approximately 10%. These include neural tube defects, cardiovascular anomalies, urogenital malformations, skeletal abnormalities, orofacial clefts, and serious developmental disorders, which can occur in up to 40% of cases.^23,24 Notably, these risks are not reduced by high-dose folic acid supplementation.²⁴ In addition to its teratogenicity, VPA is linked to an increased risk of preterm birth, low birth weight, gestational hypertension, and preeclampsia with severe features compared to other antiepileptic drugs.^25,26 Fetal exposure has also been associated with growth retardation and neurodevelopmental disorders in up to 40% of cases.^27,28 Despite these risks, pregnancy rates among VPA users have remained stable, with higher rates observed in women with bipolar disorder or migraines compared to those with epilepsy.²⁵ However, contraceptive use amongst women taking valproic acid remains suboptimal at 22.3%, highlighting the need for improved counseling, pregnancy prevention strategies, and safer alternatives for women of childbearing age on VPA.²⁵ Given the high rates of adverse maternal and fetal outcomes, shared decision-making and comprehensive counseling are essential to optimize treatment and reduce exposure to VPA during pregnancy. Population-based monitoring and exploration of alternative therapeutic strategies are critical to improving outcomes in this vulnerable population.²⁹

Because VPA crosses the placental barrier and affects placental transport mechanisms, maternal use results in direct fetal drug exposure.^30-32 Fetal VPA concentrations are often higher than maternal levels, although they can vary significantly.³³ We present an overview of published findings on the short- and long-term implications of VPA exposure in utero.

Association Between In Utero Exposure to Valproic Acid and Congenital Malformations
The first trimester of pregnancy is critical for fetal development, as this is when major organs begin to form. This period of fetal vulnerability raises concerns about the teratogenic effects of VPA, particularly the risk of MCMs. This review synthesizes evidence from multiple cohort studies (see Table 2) to clarify the role of VPA exposure in MCM development.

Numerous clinical studies have investigated the teratogenicity of VPA. These studies consistently identify neural tube defects, such as spina bifida, as the most common malformations associated with in utero VPA exposure, along with cardiovascular defects and genitourinary anomalies.^8,34-36 These abnormalities occur due to the incomplete closure of the neural tube in early fetal development, leading to varying degrees of spinal cord and nerve exposure.

VPA use during pregnancy is also associated with a specific craniofacial abnormality known as “valproate syndrome.” Since its identification in 1984, numerous studies have described infants exposed to VPA in utero with characteristic facial features, including a long thin upper lip, shallow philtrum, small upturned nose, flat nasal bridge, and downturned corners of the mouth. Other AEDs such as phenytoin and carbamazepine, however, have been associated with similar findings and this syndrome is now accepted as the “antiepileptic drugs syndrome.”³⁶

These associations highlight the need to examine the prevalence of MCMs in pregnancies with and without VPA exposure. A systematic review of 59 studies found that the incidence of MCMs in pregnancies exposed to VPA monotherapy was 10.7%, nearly 5 times higher than in unexposed pregnancies (2.3%).³⁴ These findings were corroborated in an analysis of 1565 pregnancies from eight cohort studies, which demonstrated that fetuses exposed to VPA monotherapy were 2 to 7 times more likely to develop atrial septal defect, cleft palate, hypospadias, polydactyly, and/or craniosynostosis and 12 to 16 times more likely to develop spina bifida compared to fetuses without AED exposure.³⁵

Evidence suggests that VPA’s teratogenic risk is dose-dependent. A large prospective cohort study using data from the EURAP Epilepsy and Pregnancy Registry observed that the prevalence of MCMs increased exponentially with dose. The prevalence of MCMs was 5.6% at doses ≤ 700 mg/day, increased to 10.4% at 700-1500 mg/day, and peaked at 24.2% for doses > 1500 mg/day.³⁷ Similarly, an Australian study of 450 women demonstrated that the mean dose of VPA was significantly higher in pregnancies with MCMs (1975 mg) compared with those without (1128 mg).³⁸

Compared with alternative AEDs, studies consistently demonstrate that VPA is associated with significantly higher risk of MCMs. A 2018 prospective cohort study using data of 7355 pregnancies from the EURAP international registry found that VPA pregnancies had a MCM prevalence of 10.3%, which was greater than MCMs associated with exposure to phenobarbital (6.5%), phenytoin (6.4%), carbamazepine (5.5%), topiramate (3.9%), oxcarbazepine (3.0%), lamotrigine (2.9%), and levetiracetam (2.8%).³⁹ A recent prospective cohort study of 10,121 pregnancies across 40 countries found MCMs occurred in 9.9% of fetuses with VPA exposure, which was much higher than fetuses with phenytoin (6.3%), phenobarbital (6.8%), carbamazepine (5.4%), topiramate (4.9%), lamotrigine (3.1%), oxcarbazepine (2.9%), and levetiracetam (2.5%) exposure. Importantly, while AED polytherapy has been previously suggested to play a role in MCM development, recent studies have found that the inclusion of certain AEDs such as VPA in these multidrug treatment plans is the more likely cause of heightened risk of MCMs.^40,41

Even at doses ≤ 650 mg/day, VPA carries a significantly higher risk of MCMs compared with most other AEDs. Clinicians should assess these risks prior to prescribing VPA in pregnancy and strongly consider known safer alternatives in terms of MCMs, such as oxcarbazepine, lamotrigine, and levetiracetam.^39,42 The risk of MCMs associated with VPA should be routinely discussed with patients of childbearing potential as part of informed consent. These discussions should balance the potential teratogenicity of VPA with the risk of disease breakthroughs.³⁸ In pregnancies that require VPA use, individualized treatment plans should be implemented to minimize dose and provide routine prenatal care.^35,37

A discussion on this data will follow in a subsequent article.

Mr Maristany is a fourth-year medical student at University of Miami Miller School of Medicine in Miami, FL. Ms Vyas is a fourth-year medical student at University of Miami Miller School of Medicine in Miami, FL. Ms Sa is a fourth-year medical student at University of Miami Miller School of Medicine in Miami, FL. Ms Nousari is a fourth-year medical student at University of Miami Miller School of Medicine in Miami, FL. Dr Buciuc is a third-year resident at University of Miami Miller School of Medicine and Jackson Memorial Health System in Miami, FL. Dr Oldak is a consultation-liaison psychiatry fellow at Brigham and Women’s Hospital / Dana-Farber Cancer Institute / Harvard Medical School in Boston, MA.

References

1. Bowden CL, Brugger AM, Swann AC, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA. 1994;271(12):918-924.

2. Kessing LV, Andersen PK, Mortensen PB, Bolwig TG. Recurrence in affective disorder. I. Case register study. Br J Psychiatry. 1998;172:23-28.

3. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia. 1993;34(3):453-468.

4. Rasgon NL. The relationship between polycystic ovary syndrome and antiepileptic drugs: a review of the evidence. J Clin Psychopharmacol. 2004;24(3):322-334.

5. Verrotti A, D’Egidio C, Mohn A, et al. Antiepileptic drugs, sex hormones, and PCOS. Epilepsia. 2011;52(2):199-211.

6. Stjerna S, Huber-Mollema Y, Tomson T, et al. Cognitive outcomes after fetal exposure to carbamazepine, lamotrigine, valproate or levetiracetam monotherapy: data from the EURAP neurocognitive extension protocol. Epilepsy Behav. 2024;159:110024.

7. Blotière PO, Weill A, Dalichampt M, et al. Development of an algorithm to identify pregnancy episodes and related outcomes in health care claims databases: an application to antiepileptic drug use in 4.9 million pregnant women in France. Pharmacoepidemiol Drug Saf. 2018;27(7):763-770.

8. Hernández-Díaz S, Smith CR, Shen A, et al. Comparative safety of antiepileptic drugs during pregnancy. Neurology. 2012;78(21):1692-1699.

9. Harden CL, Pennell PB, Koppel BS, et al. Management issues for women with epilepsy--focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73(2):126-132.

10. Valproate and related substances. European Medicines Agency. 2018. Accessed July 16, 2025. https://www.ema.europa.eu/en/medicines/human/referrals/valproate-related-substances-0

11. Vajda FJE, O'Brien TJ, Lander CM, et al. Critical relationship between sodium valproate dose and human teratogenicity: results of the Australian register of antiepileptic drugs in pregnancy. J Clin Neurosci. 2004;11(8):854-858.

12. Rodriguez-Cabezas L, Clark C. Psychiatric emergencies in pregnancy and postpartum. Clin Obstet Gynecol. 2018;61(3):615-627.

13. Angus-Leppan H, Arkell R, Watkins L, et al. New valproate regulations, informed choice and seizure risk. J Neurol. 2024;271(8):5671-5686.

14. Viguera AC, Whitfield T, Baldessarini RJ, et al. Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation. Am J Psychiatry. 2007;164(12):1817-1824.

15. Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs. 2002;16(10):695-714.

16. Glauser T, Ben-Menachem E, Bourgeois B, et al; ILAE Subcomission on AED Guidelines. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551-563.

17. Masur D, Shinnar S, Cnaan A, et al; Childhood Absence Epilepsy Study Group. Pretreatment cognitive deficits and treatment effects on attention in childhood absence epilepsy. Neurology. 2013;81(18):1572-1580.

18. Macritchie KA, Geddes JR, Scott J, et al. Valproate for acute mood episodes in bipolar disorder. Cochrane Database Syst Rev. 2003;(1):CD004052.

19. Chen YB, Liang CS, Wang LJ, et al. Comparative effectiveness of valproic acid in different serum concentrations for maintenance treatment of bipolar disorder: a retrospective cohort study using target trial emulation framework. EClinicalMedicine. 2022;54:101678.

20. McCall M, Bourgeois JA. Valproic acid-induced hyperammonemia: a case report. J Clin Psychopharmacol. 2004;24(5):521-526.

21. Eubanks AL, Aguirre B, Bourgeois JA. Severe acute hyperammonemia after brief exposure to valproate. Psychosomatics. 2008;49(1):82-83.

22. Diav-Citrin O, Shechtman S, Bar-Oz B, et al. Pregnancy outcome after in utero exposure to valproate. CNS Drugs. 2008;22(4):325-334.

23. Macfarlane A, Greenhalgh T. Sodium valproate in pregnancy: what are the risks and should we use a shared decision-making approach? BMC Pregnancy Childbirth. 2018;18(1):200.

24. Mawer G, Briggs M, Baker GA, et al. Pregnancy with epilepsy: obstetric and neonatal outcome of a controlled study. Seizure. 2010;19(2):112-119.

25. Smolinski NE, Sarayani A, Thai TN, et al. Prenatal exposure to valproic acid across various indications for use. JAMA Netw Open. 2024;7(5):e2412680.

26. Danielsson KC, Gilhus NE, Borthen I, et al. Maternal complications in pregnancy and childbirth for women with epilepsy: time trends in a nationwide cohort. PLoS One. 2019;14(11):e0225334.

27. Galappatthy P, Liyanage CK, Lucas MN, et al. Obstetric outcomes and effects on babies born to women treated for epilepsy during pregnancy in a resource-limited setting: a comparative cohort study. BMC Pregnancy Childbirth. 2018;18(230).

28. Medicines related to valproate: risk of abnormal pregnancy outcomes. Medicines and Healthcare Products Regulatory Agency. January 22, 2015. Accessed July 16, 2025. https://www.gov.uk/drug-safety-update/medicines-related-to-valproate-risk-of-abnormal-pregnancy-outcomes

29. Angus-Leppan H, Liu RSN. Weighing the risks of valproate in women who could become pregnant. BMJ. 2018;361:k1596.

30. Albani F, Riva R, Contin M, et al. Differential transplacental binding of valproic acid: Influence of free fatty acids. Br J Clin Pharmacol. 1984;17(6):759-762.

31. Nau H, Schäfer H, Rating D, et al. Placental transfer and neonatal pharmacokinetics of valproic acid and some of its metabolites. In: Janz D, Bossi L, Dam M, et al, eds. Epilepsy, Pregnancy, and the Child. Raven Press; 1982:367-372.

32. Tetro N, Imbar T, Wohl D, et al. The effects of valproic acid on early pregnancy human placentas: pilot ex vivo analysis in cultured placental villi. Epilepsia. 2019;60(5):e47-e51.

33. Kacířová I, Grundmann M, Brozmanova H. Valproic acid concentrations in nursing mothers, mature milk, and breastfed infants in monotherapy and combination therapy. Epilepsy Behav. 2019;95:112-116.

34. Meador K, Reynolds MW, Crean S, et al. Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res. 2008;81(1):1-13.

35. Jentink J, Loane MA, Dolk H, et al. Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med. 2010;362(23):2185-2193.

36. Ornoy A, Echefu B, Becker M. Valproic acid in pregnancy revisited: neurobehavioral, biochemical and molecular changes affecting the embryo and fetus in humans and in animals: a narrative review. Int J Mol Sci. 2024;25(1):390.

37. Tomson T, Battino D, Bonizzoni E, et al; EURAP study group. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011;10(7):609-617.

38. Vajda FJE, Hitchcock A, Graham J, et al. The Australian Register of Antiepileptic Drugs in Pregnancy: the first 1002 pregnancies. Aust N Z J Obstet Gynaecol. 2007;47(6):468-474.

39. Tomson T, Battino D, Bonizzoni E, et al; EURAP study group. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol. 2018;17(6):530-538.

40. Meador KJ, Baker GA, Browning N, et al; NEAD study group. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med. 2009;360(16):1597-1605.

41. Vajda FJE, O'Brien TJ, Graham JE, et al. Antiepileptic drug polytherapy in pregnant women with epilepsy. Acta Neurol Scand. 2018;138(3):115-121.

42. Battino D, Tomson T, Bonizzoni E, et al; EURAP Collaborators. Risk of major congenital malformations and exposure to antiseizure medication monotherapy. JAMA Neurol. 2024;81(5):481-489.