Antiseizure Medication Use for Epilepsy During Pregnancy: New Expert Guidance

The American Academy of Neurology (AAN), American Epilepsy Society (AES), and Society for Maternal-Fetal Medicine (SMFM) published an updated practice guideline in Neurology on teratogenesis, perinatal, and neurodevelopmental outcomes related to antiseizure medication (ASM) use in people with epilepsy who are pregnant.

In March 2018, a multidisciplinary panel was recruited to conduct a systematic review and develop the protocol for this guideline following the previous issuance of 2 relevant guidelines in 2009. After searching several databases from June 2007 to August 2022, the panel identified 82 articles for inclusion.

Researchers aimed to characterize the prevalence of major congenital malformations (MCMs), adverse perinatal outcomes, and adverse neurodevelopmental outcomes associated with intrauterine exposure to specific ASMs among children born to people with epilepsy of childbearing potential. They also sought to understand how prevalence may vary with monotherapy vs polytherapy and high doses vs low or medium doses.

Further, the researchers aimed to explore the effect of intrauterine exposure to folic acid on the prevalence of MCMs, as well as adverse perinatal and neurodevelopment outcomes, and understand how this varies by folic acid dose in children born to people with epilepsy of childbearing potential who received ASMs.

This updated guidance provides up-to-date evidence-based conclusions and recommendations for clinicians to effectively manage the treatment of patients with epilepsy during pregnancy.

Prescribing ASMs and Pregnancy-Related Outcomes

The selection of an ASM should be a joint decision between clinician and patient, and patient preferences should be taken into account. The optimal dose of an ASM prioritizes seizure control and fetal outcomes, should pregnancy occur.

In people with epilepsy of childbearing potential, clinicians must minimize the occurrence of convulsive seizures during pregnancy. In pregnant patients, clinicians should exercise caution when removing or replacing an ASM that is effectively controlling a patient’s seizures, even if it may not be optimal for the fetus.

Throughout pregnancy, ASM levels in people with epilepsy of childbearing potential should be monitored by clinicians.

Adjusting the dose of an ASM may be necessary when serum ASM levels are decreasing or when seizure control worsens.

Clinicians should inform patients of the limited data that exists on pregnancy-related outcomes when prescribing acetazolamide, eslicarbazepine, ethosuximide, lacosamide, nitrazepam, perampanel, piracetam, pregabalin, rufinamide, stiripentol, tiagabine, or vigabatrin.

ASMs and MCMs

Patients with epilepsy of childbearing potential should be informed by clinicians that the birth prevalence of any MCM in the general population is 2.4% to 2.9%, which provides a comparison framework for their individual risk.

Based on the patient’s epilepsy syndrome and the likelihood of achieving seizure control, and comorbidities, clinicians must consider the use of lamotrigine, levetiracetam, or oxcarbazepine in people with epilepsy of childbearing potential to reduce the risk for MCMs.

Valproic Acid and MCMs, Perinatal Outcomes

If clinically feasible, the use of valproic acid in people with epilepsy of childbearing potential must be avoided by clinicians to minimize the risk of MCMs or neural tube defects.

People with epilepsy of childbearing potential who are treated with or are considering starting valproic acid must be informed by clinicians that the risk for any MCM is the highest with valproic acid vs other studied ASMs.

If clinically feasible, clinicians must avoid the use of phenobarbital in people with epilepsy of childbearing potential to reduce the risk for cardiac malformations and should avoid the use of phenobarbital and topiramate in the same population to reduce the risk for oral clefts.

Furthermore, clinicians should avoid the use of valproic acid in this patient population to reduce the risk for urogenital and renal malformations.

The prevalence of intrauterine death does not differ among different ASMs exposures in monotherapy.

The use of valproic acid or topiramate in people with epilepsy of childbearing potential should be avoided to minimize the risk of offspring being born small for gestational age.

Obstetricians should recommend screening of fetal growth over the entire course of pregnancy among people with epilepsy of childbearing potential who are treated with valproic acid or topiramate to enable early identification of fetal growth restriction.

Recommended Fetal Screenings for MCMs, Congenital Heart Defects

Obstetricians should recommend fetal screening for MCMs (eg, a detailed anatomical ultrasound) for people with epilepsy of childbearing potential who are treated with any ASM during pregnancy. This will enable early detection and timely intervention of MCMs.

Obstetricians should also recommend screening cardiac investigations of the fetus among this patient population who are treated with phenobarbital during pregnancy to enable early detection and timely intervention of congenital heart defects.

ASMs and Neurodevelopmental Outcomes

Valproic acid use in people with epilepsy of childbearing may increase the risk for poor neurodevelopmental outcomes, including autism spectrum disorder (ASD) and lower IQ, in children born to this patient population.

Compared with intrauterine exposure to other studied ASMs (ie, carbamazepine, gabapentin, lamotrigine, levetiracetam, phenytoin, and topiramate), exposure to valproic acid is likely or possibly associated with a decrease in full scale, verbal, and non-verbal IQ.

Compared with intrauterine exposure to other studied ASMs (ie, carbamazepine, clonazepam, levetiracetam, and lamotrigine), intrauterine exposure to valproic acid is possibly associated with an increased risk for ASD.

Age-appropriate developmental screening in children exposed to any ASM in utero born to people with epilepsy of childbearing potential should be implemented by clinicians.

Folic Acid Supplementation Before and During Pregnancy

At least 0.4 mg of folic acid supplementation should be prescribed by clinicians daily preconceptionally and during pregnancy in people with epilepsy of childbearing potential who are receiving an ASM. The goal of folic acid supplementation is to reduce the risk for neural tube defects and possibly improve neurodevelopmental outcomes, including ASD and global IQ, in the offspring.

Potential Directions for Future Research

Although this updated practice guideline published by the AAN, AES, and SMFM addresses changes in guidance from the previously published guidelines in 2009, as well as previous knowledge gaps, future research to address remaining knowledge gaps is warranted.

One way in which studies can build on the current understanding of teratogenesis, perinatal, and neurodevelopmental outcomes after in utero exposure to ASM is by considering more novel and understudied therapies, including polytherapy.

“The risks of MCMs and adverse perinatal outcomes for newer and understudied ASMs (e.g., lacosamide, zonisamide, clobazam, and perampanel) require further research,” the researchers stated. “Future guidelines should consider even newer ASMs, such as cenobamate and fenfluramine, which were not included in our search strategy.”

To inform ASM choice among people with epilepsy, developmental screening requirements, and resource planning, longitudinal studies assessing long-term neurodevelopmental outcomes in children with intrauterine exposure to ASMs other than valproic acid are necessary.

A bolstered understanding of the pathophysiologic mechanisms underlying teratogenic effects of certain ASMs will help in the development of therapeutic strategies.

Dosing regimens can be informed by clarifying factors that impact the pharmacokinetics and pharmacodynamics of ASM metabolism in people with epilepsy of childbearing age during pregnancy and postpartum.

Definitions for exposures and outcomes, as well as which adjustment variables to include in any multivariable analyses should be standardized.

The optimal dose of folic acid supplementation, as well as timing of supplementation with respect to conception, should be clarified.

The effects of screening for fetal anomalies and growth restriction on perinatal outcomes needs to be characterized.

Future studies should include patient populations that are socioeconomically, racially, and ethnically diverse. Further, transgender, nonbinary, and intersex people with epilepsy of childbearing potential should be included in studies.

Overall, the researchers agreed that “When treating PWECP [people with epilepsy of childbearing potential], clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes should pregnancy occur, at the earliest possible opportunity preconceptionally.”

Disclosure: Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.