The Impact of Valproic Acid on Neonatal Outcomes

The potential impact of in utero VPA exposure on neonatal outcomes is an emerging area of research. While exposure to AEDs is associated with neonatal complications such as respiratory distress, small-for-gestational-age (SGA) status, hemorrhagic disorders, and increased mortality, data on the specific effects of VPA remain limited.^1,2 This article highlights current literature on neonatal outcomes and complications associated with maternal VPA use (Table 1).

A multicenter prospective cohort study found that 1-minute Apgar scores were more frequently reduced in neonates exposed to VPA; however, these scores typically normalized by 5 minutes, making the clinical significance unclear.³ Infants exposed to VPA in utero had the second highest rate of microcephaly after carbamazepine exposure, observed both at birth (P = 0.26) and at 12 months of age (P = 0.007).³ An increased risk of small head circumference has been reported; however, the prevalence of microcephaly in VPA-exposed neonates requires further investigation.^4,5

VPA exposure has been associated with significantly lower birth weight, defined as less than 2500 grams at birth.^5,6 Pennell et al (2012) found that full-term neonates exposed to VPA in utero had a higher risk of being small for gestational age (SGA) (7.7%) compared to those exposed to lamotrigine (3.6%) and phenytoin (0%). SGA neonates are at increased risk for both immediate and long-term complications, including neonatal morbidity, mortality, and developmental delays.

A small prospective study of 22 neonates exposed to VPA in utero reported that 59% developed hypoglycemia, primarily within the first hour after birth.⁵ Additionally, 45% of these infants exhibited VPA withdrawal symptoms, including irritability, hypertonia, seizures, and vomiting within the first 12-24 hours after birth. Further research on neonatal metabolism and VPA dependence is needed to better understand and prevent adverse outcomes.

This field of research is particularly important as pregnancy rates during VPA use have not changed and contraception utilization has remained low despite increased safety communications and labeling to inform patients about the possible risks of VPA during pregnancy. Given the association between VPA and reduced intrauterine growth, regular follow-up at a high-risk pregnancy clinic with serial ultrasounds is recommended.^6,7

Neurodevelopmental Consequences of Intrauterine Exposure to Valproic Acid

Although the risks of congenital malformations and neurodevelopmental disorders associated with VPA are well-documented, the underlying mechanisms remain under investigation. VPA is known to interfere with folate metabolism and other pathways critical to fetal development. Additional factors, including genetic susceptibility, dosage, and duration of exposure, may also contribute to its teratogenic effects.⁸ Strategies to mitigate these risks include using the lowest effective dose, high-dose folic acid supplementation, and considering alternative medications when feasible.⁹

VPA is rarely recommended for pregnant women unless their epilepsy or bipolar disorder cannot be controlled with alternative medications, due to its significant neurodevelopmental risks to the fetus. Extensive clinical data support these risks, with key studies summarized in Table 2. Neurodevelopmental risks are highest when VPA is taken during the first trimester.¹⁰ VPA monotherapy during the first trimester is associated with an increased risk of congenital malformations, including spina bifida, atrial septal defects, cleft palate, hypospadias, polydactyly, and craniosynostosis.^10,11 These effects appear dose-dependent, with daily doses below 600 mg showing limited teratogenic potential.¹¹ The risk of malformations increases when VPA is used in combination with other AEDs.¹¹ These risks highlight the importance of counseling women of reproductive age taking VPA about potential pregnancy-related complications.

VPA is the most widely recognized AED associated with adverse neurodevelopmental outcomes, including pervasive developmental disorders, intellectual disability, and speech delays.^12,13 It has also been shown to carry greater risk in pregnancy than any other AED studied.^13,14 One study evaluated the cognitive impact of prenatal exposure to sodium valproate in school-aged children, finding a dose-dependent negative impact on verbal intellectual abilities and working memory.¹⁵ One Danish study estimated that neonatal exposure to valproate was associated with an approximately 4.5-fold increased risk of intellectual disability and an up to 6-fold increased risk when looking at both the risk of intellectual disability and the risk of delayed childhood milestones, compared with children with no prenatal valproate exposure.¹⁶

Although research is limited, prenatal VPA exposure is associated with an increased risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD).^11,16,17 In a population-based cohort study that included 913,302 children, of the children exposed to valproate during pregnancy, 8.4% were diagnosed with ADHD, compared with 3.2% of those unexposed.¹⁶ Valproate exposure was associated with a 48% increased relative risk of ADHD with a 15-year risk ofthe child developing ADHD being 4.6% in unexposed children and 11.0% in those exposed.¹⁶ Furthermore, sex of the neonate might also serve as an effect modifier to the concept of VPA serving as a behavioral teratogen.¹⁸ While, in general, males tend to have a higher incidence of ADHD and ASD than females, there seemed to be no significant difference between males and females exposed to VPA and the subsequent development of either ADHD or ASD.¹⁸ This indicates that sex might influence the effect of VPA with females being particularly sensitive to the effects of the drug.¹⁸

Given the multitude of significant neurodevelopmental risks associated with neonatal exposure to VPA, clinicians should exercise caution when prescribing the medication to women of childbearing age and follow the most updated clinical guidelines. This is particularly important when counseling women on contraceptive use since it is estimated that roughly only 22% of women on VPA are also on contraceptives, most commonly oral contraceptives.⁷ Clinicians should avoid prescribing VPA when possible and consider alternatives such as lamotrigine, levetiracetam, or oxcarbazepine, which pose lower neurodevelopmental risks to the fetus.¹⁹ In the case that VPA is the only medication effective in treating the patient and it is not clinically feasible to switch to another ASM, then clinicians should prescribe at least 0.4 mg of folic acid supplementation daily preconceptionally and during pregnancy to reduce the risk of neural tube defects and potentially improve neurodevelopmental outcomes in the child.¹⁹ While evidence on the effectiveness of folic acid in mitigating VPA-associated neurodevelopmental risks remains inconclusive, supplementation is still recommended due to its overall benefits in pregnancy.

Infant Valproic Acid Exposure Through Lactation
Clinical guidelines generally consider breastfeeding safe for women taking VPA, as no definitive adverse reactions have been reported in breastfed infants.²⁰ VPA levels in breast milk are typically low, and infant serum concentrations range from low to undetectable.²⁰ However, despite its widespread use as an antiepileptic, research on VPA concentrations in breastfed infants remains limited.

Table 3 summarizes clinical studies evaluating infant VPA exposure through breastfeeding. A prospective cohort study examined VPA transfer from mothers to colostrum and breastfed infants in 90 participants between 1993 and 2018.²¹ VPA concentrations were measured in maternal serum, breast milk, and infant serum between the second and fifth postnatal days. VPA concentrations in breast milk were significantly lower than in maternal serum, with a mean milk-to-serum ratio of 0.04. Infant serum VPA concentrations showed significant correlations with maternal serum levels, daily VPA dose, and breast milk concentrations.²¹

Another prospective cohort study investigated AED transfer from mothers to breastfed infants by measuring drug concentrations in blood samples collected between 5 and 20 weeks postpartum.²² The study analyzed 164 matched infant–mother concentration pairs from 138 infants.²² Nearly half (49%) of AED concentrations, including VPA, in infant blood samples were below the detection limit.²² The median infant-to-mother concentration ratios for 7 AEDs and one metabolite ranged from 0.3% to 44.2%, with VPA averaging 21.4% (range: 17.9% to 24.9%).²²

A retrospective study of 30 breastfeeding women examined VPA transfer using data collected between 1996 and 2017.²¹ Maternal serum VPA concentrations averaged 39.0 mg/L, while levels in breast milk and infant serum were significantly lower, at 1.6 mg/L and 4.2 mg/L, respectively.²¹ The mean milk-to-maternal serum and infant-to-maternal serum ratios were 0.03 and 0.11, respectively, with most milk (67%) and infant (33%) VPA levels below quantification limits.²¹ No significant correlation was observed between maternal serum, breast milk, and infant serum VPA concentrations.²¹ Compared with in utero exposure, VPA exposure through breastfeeding appears minimal. Since most breast milk and infant serum VPA concentrations remain below therapeutic levels for epilepsy, routine monitoring of breastfed infants is generally unnecessary unless clinical concerns arise.^21-23

Discussion
The aim of this narrative review is to provide a clinical overview of VPA’s impact on pregnancy and postpartum outcomes and to outline current recommendations for its use in these contexts. Our key findings underscore the well-established evidence that VPA exposure during pregnancy is associated with an increased risk of MCMs, neurodevelopmental disorders, and adverse obstetric and neonatal outcomes. This review also highlights gaps in mitigation strategies and complementary interventions for managing VPA use during pregnancy and the postpartum period. These gaps complicate clinical decision-making, particularly when weighing the risks of discontinuing or switching medications against the potential for disease relapse in women with severe or refractory epilepsy and bipolar disorder.

We summarize the key findings related to the risks and benefits of VPA use during pregnancy and postpartum, including lactation, and discuss their implications for clinical practice and patient management. Additionally, we identify limitations in the current literature and suggest areas for future research.

VPA has consistently been linked to various congenital malformations and neurodevelopmental disorders, underscoring its teratogenic potential. Although ongoing research continues to explore the full spectrum of risks associated with in utero exposure, existing studies have demonstrated associations with adverse pregnancy and neonatal outcomes, including preterm birth, low birth weight, and neonatal withdrawal symptoms. Despite these risks, VPA remains a commonly prescribed medication during pregnancy due to its efficacy as an antiepileptic and mood stabilizer, particularly when alternative treatments fail to provide adequate symptom control.^11,24-26 Therefore, the potential consequences of VPA discontinuation, such as breakthrough seizures and mood relapse, must be carefully considered when counseling patients who are pregnant or planning pregnancy.^27,28

Balancing the risks and benefits of VPA therapy in women of childbearing age presents a complex clinical challenge. A tailored approach is necessary, with an emphasis on preconception planning to transition patients to safer alternatives whenever possible. Maternal VPA exposure has been strongly associated with higher rates of major congenital malformations, fetal growth restriction, preterm birth, and neurodevelopmental disorders.^28-31 These risks are not mitigated by high-dose folic acid supplementation.²⁹ In addition to structural malformations, VPA exposure has been linked to increased maternal complications, such as severe preeclampsia.^7,32 When seizure control or mood stabilization cannot be achieved with safer alternatives, VPA may be necessary. In such cases, risk mitigation strategies should include using the lowest effective dose, providing regular fetal monitoring through ultrasonography, ensuring multidisciplinary prenatal care, and offering comprehensive patient counseling to support informed decision-making.

VPA’s teratogenic and neurodevelopmental risks are well-documented, particularly when exposure occurs during the first trimester. This period is associated with an elevated risk of congenital malformations, including spina bifida, atrial septal defects, and craniosynostosis, with evidence suggesting a dose-dependent relationship—lower doses (< 600 mg daily) may reduce teratogenic risk.¹¹ Prenatal VPA exposure also substantially increases the risk of intellectual disability, ASD, and ADHD, with some studies reporting a 4.5-fold increase in the risk of intellectual disability and a 48% higher relative risk of ADHD.^{11,16 ,17} While ASD and ADHD are generally more prevalent in male infants, studies have not found significant sex differences in the neurodevelopmental effects of VPA exposure, suggesting that female infants may have heightened sensitivity to its effects.¹⁸ Given these risks, clinicians should prioritize the use of alternative medications, such as lamotrigine, when feasible, and ensure that women of reproductive age receiving VPA are counseled on contraception and folic acid supplementation to help mitigate adverse outcomes.

In contrast to its well-established risks during pregnancy, VPA is generally considered safe during breastfeeding due to minimal drug transfer through breast milk. Studies consistently report low milk-to-maternal serum ratios (0.03–0.04) and low to undetectable VPA concentrations in infant serum.²³ A prospective cohort study found that nearly half of infant blood samples had undetectable levels of antiepileptic drugs, including VPA.²³ Retrospective data support these findings, indicating that postnatal exposure through breastfeeding is significantly lower than in utero exposure. As a result, routine monitoring of breastfed infants is generally unnecessary unless clinical concerns arise. These findings highlight the importance of distinguishing between prenatal and postnatal exposure risks when counseling patients on VPA use and underscore the need for individualized care plans.

Despite robust evidence linking VPA to adverse pregnancy outcomes, several limitations remain, particularly the reliance on observational data in many studies. There are notable gaps in established guidelines for managing patients who must continue VPA during pregnancy due to the severity of their underlying condition or lack of access to evidence-based alternatives. While current recommendations—such as using the lowest effective dose and high-dose folic acid supplementation—offer some guidance, more detailed protocols are needed to help clinicians optimize maternal and fetal outcomes in these high-risk cases.^29,33

This issue is especially relevant in the context of increasing barriers to contraception and abortion access, which may lead to a higher prevalence of unplanned pregnancies among women taking VPA.⁷ Addressing these barriers is crucial for improving maternal and fetal health outcomes, as it allows women to have greater autonomy over pregnancy timing and enables preconception optimization of care. Even with reliable contraception, unplanned pregnancies can occur due to the inherent failure rates of contraceptive methods. Therefore, access to comprehensive reproductive health care, including safe abortion services, remains essential. Additionally, further research is needed to evaluate the effectiveness of dose adjustments and adjunctive interventions, such as folic acid supplementation, in mitigating the risks associated with continued VPA use during pregnancy and postpartum. While high-dose folic acid is recommended, its efficacy in reducing adverse outcomes is uncertain, and more studies are needed to determine the optimal dosing and timing.²⁹

Although safer alternatives to VPA—such as lamotrigine, levetiracetam, and oxcarbazepine—are preferred for managing epilepsy and bipolar disorder during pregnancy due to their lower teratogenic and neurodevelopmental risks,^33,34 switching medications may not always be feasible. This is particularly true for women with treatment-refractory conditions or those who have experienced relapse on alternative therapies. Additionally, polypharmacy should be avoided whenever possible, as it may increase the risk of adverse outcomes.³⁵ More research is needed to evaluate the risks and benefits of switching medications, especially in women with refractory epilepsy or bipolar disorder.^33,34

Part of this risk-benefit evaluation involves addressing the heightened risk of mood destabilization and seizure recurrence in the postpartum period, particularly when VPA is discontinued during pregnancy.³⁶ In such cases, reinstating VPA postpartum may be necessary to prevent relapse, but clinicians should carefully weigh the benefits against potential risks of neonatal exposure through breastfeeding. Further research is needed to clarify the pharmacokinetics of VPA transfer into breast milk and its potential long-term effects on infant development, particularly regarding neurodevelopmental outcomes.^21,22

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.

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