Seizure disorders, most commonly epilepsy, represent one of the most frequent serious neurological conditions encountered in pregnancy, affecting approximately 0.3-0.5% of all pregnancies. The intersection of epilepsy and pregnancy presents a complex clinical scenario that requires meticulous preconception planning, specialized antenatal care, and a collaborative, multidisciplinary approach. The primary objectives are to ensure the health and well-being of both the pregnant individual and the developing fetus by maximizing seizure control while minimizing the teratogenic risks associated with antiseizure medications (ASMs).
Preconception Counseling: The Foundation for a Healthy Pregnancy
The most critical period for a woman with epilepsy occurs before she even becomes pregnant. Preconception counseling is paramount and should be a standard of care.
- Seizure Control Optimization: The primary goal is to achieve the best possible seizure control before conception on the lowest effective dose of the most appropriate ASM. Uncontrolled tonic-clonic seizures pose a significant risk to both the mother (e.g., trauma, status epilepticus, SUDEP) and the fetus (e.g., miscarriage, fetal hypoxia, preterm delivery).
- Medication Review and Adjustment: A thorough review of the ASM regimen is essential. The guiding principle is monotherapy at the lowest effective dose. Polytherapy is associated with a significantly higher risk of major congenital malformations (MCMs) and developmental issues. If a patient has been seizure-free for an extended period (e.g., 2-5 years), medication withdrawal may be considered before pregnancy, but this decision must be weighed against the high risk of seizure recurrence.
- Folic Acid Supplementation: High-dose folic acid supplementation (at least 4-5 mg daily) is recommended starting at least three months before conception and continuing through the first trimester. While evidence for its efficacy in preventing ASM-related neural tube defects is not conclusive, it is a safe and potentially beneficial intervention that supports neural tube development.
- Risk Assessment and Education: Patients must be educated about the slightly increased baseline risk of congenital malformations in the general population (2-3%) and how specific ASMs modulate this risk. This shared decision-making process empowers the patient and sets realistic expectations.
Pharmacokinetic Changes During Pregnancy and Medication Management
Pregnancy induces profound physiological changes that can significantly alter the pharmacokinetics of ASMs, potentially jeopardizing seizure control.
- Altered Absorption and Distribution: Increased progesterone and estrogen can slow gastric emptying and intestinal transit time, affecting drug absorption. Furthermore, increased total body water and plasma volume lead to a larger volume of distribution, potentially lowering drug concentration. Increased body fat can also sequester fat-soluble drugs.
- Metabolism and Elimination: Hepatic enzyme activity is often induced during pregnancy, accelerating the metabolism of many ASMs (e.g., lamotrigine, levetiracetam, oxcarbazepine). Renal blood flow and glomerular filtration rate increase by 50-60%, enhancing the clearance of renally excreted drugs like levetiracetam and topiramate.
- Protein Binding: decreased serum albumin levels can increase the free (active) fraction of highly protein-bound ASMs (e.g., phenytoin, valproate, carbamazepine).
- Therapeutic Drug Monitoring (TDM): Regular monitoring of ASM serum levels is crucial, particularly for drugs with known significant pharmacokinetic shifts like lamotrigine and levetiracetam. Dosing should be adjusted based on clinical seizure control rather than rigid adherence to a preconception “therapeutic range.” The goal is to maintain the patient’s individual optimal level.
Teratogenicity and Fetal Risks
The risk of congenital malformations is a primary concern. This risk is influenced by the specific ASM, dosage, genetic factors, and potentially the underlying epilepsy itself.
- Major Congenital Malformations (MCMs): These are structural abnormalities with significant medical or cosmetic consequences. The risk is dose-dependently highest with valproic acid (6-10% or higher at high doses), particularly for neural tube defects, cardiac defects, cleft palate, and hypospadias. Other ASMs carry varying risks:
- Lower Risk: Lamotrigine and levetiracetam are generally associated with rates closer to the background population (~3%).
- Moderate Risk: Carbamazepine, oxcarbazepine, and phenytoin are associated with intermediate risks (~4-6%), including neural tube defects and cardiac anomalies.
- Neurodevelopmental Effects: Beyond physical malformations, in utero exposure to certain ASMs, especially valproate and to a lesser extent phenobarbital, is associated with an increased risk of cognitive impairment, lower IQ scores, and a higher incidence of autism spectrum disorder. This underscores the importance of avoiding valproate in women of childbearing potential whenever possible.
- Syndromes: Specific patterns of malformations have been described, such as the “fetal valproate syndrome” (characterized by facial dysmorphism, cardiac and limb defects) and “fetal hydantoin syndrome.”
Antenatal Care and Monitoring
Pregnancy in a woman with epilepsy should be managed as a high-risk pregnancy by a team including a neurologist, maternal-fetal medicine specialist, and primary obstetrician.
- Enhanced Surveillance: This includes detailed fetal anomaly ultrasounds at 18-20 weeks to screen for structural abnormalities, such as neural tube defects and cardiac anomalies. Fetal echocardiography may be recommended, especially with valproate or carbamazepine exposure.
- Vitamin K Supplementation: Enzyme-inducing ASMs (e.g., phenytoin, carbamazepine, phenobarbital, topiramate) can interfere with vitamin K metabolism in the newborn, increasing the risk of hemorrhagic disease of the newborn. Maternal oral supplementation with vitamin K1 (10-20 mg daily) during the last month of pregnancy is typically recommended.
- Seizure Management: Any change in seizure frequency or pattern must be promptly investigated. The first step is usually to check ASM levels and adjust doses accordingly. Status epilepticus is a medical emergency requiring immediate hospitalization and treatment, as it carries high maternal and fetal mortality.
Labor, Delivery, and the Postpartum Period
The peripartum period requires specific planning and vigilance.
- Labor and Delivery: Stress, sleep deprivation, pain, and hyperventilation during labor can lower the seizure threshold. It is vital that the neurologist and obstetric team have a clear plan. ASMs should be continued on schedule throughout labor; if oral intake is not possible, intravenous formulations must be used (e.g., levetiracetam, lacosamide, phenytoin/fosphenytoin). Vaginal delivery is encouraged, and cesarean section is reserved for standard obstetric indications or if seizures are frequent and uncontrolled near term.
- The Postpartum Period: This is a high-risk time for seizure recurrence due to rapid physiological readjustment (dropping progesterone levels, fluid shifts, sleep disruption). ASM doses that were increased during pregnancy often need to be reduced back to preconception levels gradually over several weeks, guided by TDM and clinical assessment. Breastfeeding is strongly encouraged for nearly all women on ASMs, as the benefits vastly outweigh the minimal risks of drug exposure through milk. Lamotrigine and levetiracetam achieve relatively high milk-to-plasma ratios, so infants should be monitored for drowsiness, but cessation of breastfeeding is rarely necessary.
Conclusion
A pregnancy complicated by a seizure disorder is eminently manageable with proactive, specialized, and collaborative care. The cornerstone of success lies in meticulous preconception planning to optimize therapy and educate the patient. Throughout gestation, vigilant monitoring of both maternal seizure control and fetal well-being, with thoughtful adjustments to ASM regimens, allows the vast majority of women with epilepsy to have safe pregnancies and deliver healthy babies. By embracing a team-based approach and leveraging current evidence, healthcare providers can effectively navigate the complexities and empower their patients to achieve optimal outcomes.
References
- Harden, C. L., Pennell, P. B., Koppel, B. S., Hovinga, C. A., Gidal, B., Meador, K. J., … & Le Guen, C. (2009). Management issues for women with epilepsy—focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breastfeeding. Epilepsia, 50(5), 1247-1255.
- Tomson, T., Battino, D., Bonizzoni, E., Craig, J., Lindhout, D., Perucca, E., & Vajda, F. (2018). Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. The Lancet Neurology, 17(6), 530-538.
- Practice Bulletin No. 201: Prenatal and Perinatal Human Immunodeficiency Virus Testing. (2018). Obstetrics and Gynecology, 132(3), e138-e142. (Reaffirmed 2021). *Note: While this specific bulletin is on HIV, ACOG guidelines and committee opinions on epilepsy in pregnancy are often referenced similarly; check ACOG’s website for the most current “Obstetric Management of Women with Epilepsy”).
- Medicines and Healthcare products Regulatory Agency (MHRA). (2021). Antiepileptic drugs: updated advice on valproate use in women and girls of childbearing potential. [Online] Available at: MHRA website.
- Pennell, P. B. (2020). Antiseizure medications during pregnancy: what do we know and what do we need to know? Epilepsy Currents, 20(5), 259-261.
- Veroniki, A. A., Cogo, E., Rios, P., Straus, S. E., Finkelstein, Y., Kealey, R., … & Tricco, A. C. (2017). Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC Medicine, 15(1), 1-18.
