Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication

A new practice guideline provides updated, evidence-based conclusions and recommendations regarding the effects of antiseizure medications (ASMs) and folic acid supplementation on major congenital malformations (MCMs), adverse perinatal outcomes, and neurodevelopmental outcomes in children born to people with epilepsy of childbearing potential (PWECP). A multidisciplinary panel conducted a systematic review and developed practice recommendations following the American Academy of Neurology Clinical Practice Guideline Process Manual. Recommendations are supported by structured rationales integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence.

Introduction

Epilepsy, affecting over 50 million people globally, has a significant prevalence among people of childbearing potential. Infants born to PWECP are at increased risk of MCMs, adverse perinatal outcomes, and neurodevelopmental issues. Factors influencing these risks include genetic differences, environmental factors, seizure control, and intrauterine exposure to ASMs. Folic acid’s role in mitigating these risks remains uncertain. Optimizing epilepsy treatment is crucial for favorable outcomes for both individuals with epilepsy and their offspring.

Historical Context

In 2009, the American Academy of Neurology (AAN) released guidelines highlighting the higher risks associated with valproic acid compared to other ASMs like carbamazepine, phenytoin, and phenobarbital. Subsequent studies have expanded on these findings, particularly concerning newer ASMs like levetiracetam and topiramate.

Clinical Questions Addressed

1. Prevalence of MCMs associated with intrauterine exposure to specific ASMs.
2. Prevalence of adverse perinatal outcomes linked to specific ASMs.
3. Prevalence of adverse neurodevelopmental outcomes following ASM exposure.
4. Impact of folic acid on MCMs, adverse perinatal outcomes, and neurodevelopmental outcomes.

Analytic Process

The guideline development followed the AAN’s 2017 manual, involving a multidisciplinary panel with diverse expertise. The process included systematic reviews of literature databases, critical evaluation of studies, and grading of evidence. The panel used structured rationales to integrate evidence, principles of care, and clinical inferences to develop recommendations.

Evidence Review

The panel conducted comprehensive searches across several databases from June 1, 2007, to August 1, 2022, yielding thousands of articles. After rigorous screening and evaluation, 69 articles were included in the review. The evidence was graded based on bias risk, consistency, directness, precision, and publication bias.

Key Findings

• MCMs: The unadjusted birth prevalence of MCMs among children born to PWECP is higher with certain ASMs, particularly valproic acid.
• Perinatal Outcomes: Polytherapy exposure increases the risk of intrauterine death compared to monotherapy. Fetal growth restriction and SGA are associated with valproic acid and topiramate.
• Neurodevelopmental Outcomes: Valproic acid is linked to lower IQ and higher autism spectrum disorder (ASD) prevalence in offspring.
• Folic Acid: While folic acid supplementation does not significantly reduce MCM risk, it may improve neurocognitive outcomes. The optimal dosage remains at least 0.4 mg/d.

Practice Recommendations

1. Joint Decision-Making: Clinicians should engage in shared decision-making with PWECP, considering individual preferences in ASM selection and dosing.
2. Preconception Planning: Clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes preconceptionally. This ensures that if pregnancy occurs, the ASM regimen is already optimized
3. Minimize Seizures During Pregnancy: Clinicians must minimize convulsive seizures in PWECP during pregnancy to reduce risks to both the birth parent and fetus. Care should be taken when modifying ASMs during pregnancy, particularly those effective in controlling generalized tonic-clonic or focal-to-bilateral tonic-clonic seizures
4. ASM Choices: Lamotrigine, levetiracetam, or oxcarbazepine should be considered for PWECP to minimize the risk of MCMs. Valproic acid should be avoided if possible due to its higher risk of MCMs, neural tube defects (NTDs), and adverse neurodevelopmental outcomes
5. Folic Acid Supplementation: Clinicians should prescribe at least 0.4 mg of folic acid daily preconceptionally and during pregnancy to any PWECP treated with an ASM to decrease the risk of NTDs and possibly improve neurodevelopmental outcomes.

Seizure Control During Pregnancy

1. Minimize Convulsive Seizures: Clinicians must aim to reduce convulsive seizures during pregnancy.
2. Caution with ASM Changes: Exercise caution when altering effective ASMs during pregnancy.
3. Monitor ASM Levels: Regular monitoring of ASM levels throughout pregnancy is essential.
4. Dose Adjustments: Adjust ASM doses as needed based on serum levels and clinical presentation.
5. Limited Data Drugs: Counsel patients on limited pregnancy-related outcomes data for certain ASMs (e.g., acetazolamide, eslicarbazepine).

Major Congenital Malformations

1. Risk Communication: Counsel patients on the general population risk of MCMs (2.4%–2.9%).
2. Preferred ASMs: Consider lamotrigine, levetiracetam, or oxcarbazepine to minimize MCM risk.
3. Avoid Valproic Acid: Avoid valproic acid to reduce MCM and NTD risks.
4. Cardiac Malformations: Avoid phenobarbital to reduce cardiac malformation risks.
5. Oral Clefts: Avoid phenobarbital and topiramate to reduce oral cleft risks.
6. Urogenital and Renal Malformations: Avoid valproic acid to reduce these malformations.
7. Fetal Screening: Recommend detailed anatomical ultrasounds for early MCM detection.
8. Cardiac Screening: Recommend fetal cardiac investigations for those on phenobarbital.

Perinatal Outcomes

1. Polytherapy Risks: Recognize the higher intrauterine death risk with polytherapy compared to monotherapy.
2. Fetal Growth: Counsel patients on the potential for fetal growth restriction associated with valproic acid and topiramate.
3. SGA Risk: Highlight the increased risk of small-for-gestational-age (SGA) infants with valproic acid and topiramate.
4. Delivery Planning: Engage in early and ongoing discussions about delivery plans to mitigate perinatal risks.

Neurodevelopmental Outcomes

1. Cognitive Development: Inform patients about the association between valproic acid and lower IQ in offspring.
2. ASD Risk: Communicate the increased risk of autism spectrum disorder (ASD) associated with valproic acid.
3. Behavioral Issues: Discuss the potential for behavioral issues in children exposed to valproic acid and topiramate in utero.
4. Early Intervention: Recommend early neurodevelopmental assessment and intervention for children with prenatal exposure to ASMs, particularly valproic acid.

Folic Acid Supplementation

1. Routine Supplementation: Prescribe at least 0.4 mg of folic acid daily for all PWECP on ASMs preconceptionally and during pregnancy.
2. Higher Doses: Consider higher doses of folic acid (e.g., 4 mg) in specific cases, although evidence supporting this is less robust.
3. Neurodevelopmental Benefits: Emphasize potential improvements in neurodevelopmental outcomes with folic acid supplementation.

Implementation and Dissemination

1. Training: Provide training for healthcare providers on the latest guidelines and recommendations.
2. Resource Distribution: Distribute guideline summaries, infographics, and decision aids to facilitate implementation in clinical practice.

Patient Education

1. Informative Materials: Develop and distribute educational materials for PWECP to explain the risks and benefits of different ASMs and the importance of folic acid supplementation.
2. Support Systems: Encourage the establishment of support systems and counseling services for PWECP to aid in decision-making and management throughout pregnancy.

Monitoring and Follow-Up

1. Registry Participation: Encourage participation in epilepsy and pregnancy registries to collect data and improve future care.
2. Regular Reviews: Implement regular reviews and updates of treatment plans for PWECP, especially during pregnancy.
3. Outcome Tracking: Track and review outcomes for continuous improvement of epilepsy care in pregnant patients.

Future Research Directions

1. Longitudinal Studies: Conduct long-term studies to assess the impact of newer ASMs on perinatal and neurodevelopmental outcomes.
2. Dose-Response Relationships: Investigate dose-response relationships for ASMs to optimize dosing strategies.
3. Folic Acid Research: Further research into the optimal dosing of folic acid and its effects on both MCMs and neurodevelopmental outcomes.
4. Genetic Factors: Explore genetic factors that may influence ASM efficacy and teratogenic risks.

Folic Acid: Recommendations and Rationale

The ideal dosing and timing for folic acid supplementation in pregnant women with epilepsy and on antiepileptic drugs (PWECP) remain unclear. Evidence does not conclusively show that folic acid supplementation (at least 0.4 mg/d) prevents major congenital malformations (MCMs) in children born to PWECP. Earlier randomized controlled trials demonstrated a decrease in neural tube defects (NTDs) in the general population receiving periconceptional multivitamin supplementation before the widespread fortification of foods with folic acid in the United States. A systematic review of 14 studies involving 1,053 participants indicated that folic acid supplementation (up to 1 mg/d) could reduce the risk of NTDs by 23%, particularly in those with initially low serum folate levels.

Neurodevelopmental Outcomes

Preconception folic acid supplementation may improve neurodevelopmental outcomes in children born to PWECP. Studies suggest that at least 0.4 mg/d of folic acid is associated with reduced autistic traits at age 3 and a higher IQ at age 6. Lower plasma folic acid levels during weeks 17-19 of pregnancy in PWECP exposed to antiepileptic drugs correlate with a higher risk of autistic traits in their children. Increased folic acid intake from diet and supplements has shown statistically significant IQ improvements at age 6, an effect not observed in those relying solely on dietary folic acid.

Safety and Adverse Effects

The evidence regarding adverse events from folic acid supplementation in PWECP and their offspring is inconclusive. Some potential risks include an increased occurrence of twins, asthma, vitamin B12 deficiency masking, and new or worsening preexisting neoplasia. A study of 27,784 children indicated that periconceptional folic acid intake above 1 mg/d slightly increased the risk of childhood cancer.

Adherence and Pharmacokinetic Interactions

Adherence to folic acid supplementation is generally poor among PWECP, especially those on antiepileptic polytherapy. Higher doses required in the absence of high-dose formulations may further decrease adherence. Folic acid can also reduce phenytoin serum concentrations, presenting potential pharmacokinetic interactions.

Recommendations

1. For Reducing NTD Risk (Level B): Clinicians should prescribe at least 0.4 mg of folic acid daily before conception and during pregnancy for PWECP on antiepileptic drugs.
2. For Improving Neurodevelopmental Outcomes (Level A): Clinicians must prescribe at least 0.4 mg of folic acid daily before conception and during pregnancy for PWECP on antiepileptic drugs.
3. Counseling on Adherence (Level C): Clinicians should advise PWECP on the importance of adhering to recommended folic acid supplementation to minimize MCMs and poor neurodevelopmental outcomes.

Future Research Directions

Research should address several knowledge gaps to optimize reproductive outcomes for PWECP. These include understanding the risks of MCMs and adverse perinatal outcomes with newer antiepileptic drugs, evaluating long-term neurodevelopmental outcomes in children exposed to antiepileptic drugs in utero, and clarifying the complex risks associated with polytherapy. Understanding the mechanisms of teratogenic effects and the pharmacokinetics of antiepileptic drugs during pregnancy will inform dosing regimens. Future studies should also adopt more uniform definitions for exposures and outcomes and include diverse populations to better understand the varied needs of underrepresented groups.

For more detailed information, please visit: Practice Guideline From the AAN, AES, and SMFM