Epilepsy in Pregnancy

A 24-year-old gravida 2, para 0-0-1-0 woman presented for outpatient consultation at 12 weeks’ gestation because of a history of epilepsy secondary to bilateral periventricular nodular heterotopia. She was diagnosed at 16 years of age after her first generalized tonic-clonic seizure, although she experienced petit mal seizures throughout her childhood. Her most recent hospitalization for seizure activity was 6 months prior to conception. She identifies her seizure triggers as sleep disturbance and poor oral intake. In the past, she has been prescribed levetiracetam, oxcarbazepine, zonisamide, and cenomabate. At the time of her visit, her antiepileptic drug (AED) regimen was comprised of lacosamide and clobazam.Ultrasound performed at 12 and 18 weeks’ gestation showed no fetal abnormalities and normal fetal biometry. Throughout the pregnancy, the patient overall did well with only 1 hospitalization for seizures and AED titration in the second trimester. At that time, she required the addition of a third AED, brivaracetam, given increased seizure frequency, with steady uptitration of dose to optimize seizure control. She continued to take her AEDs as prescribed and underwent regular fetal growth scans, demonstrating appropriate growth and fetal movement.She had an obstetrics anesthesia consult with a recommendation for early epidural placement, use of intravenous formulation of her AED regimen if unable to tolerate orally during induction, avoidance of medications that could lower her seizure threshold (such as tramadol), and the addition of cushioned padding to her hospital bed. As her pregnancy was thought to be increasing her seizure frequency, an early-term delivery was advised. She presented to labor and delivery for a scheduled induction at 37 weeks’ gestation with a detailed plan formulated by her neurology team, including strategies for acute management of an intrapartum seizure if one occurred. Her oral AEDs were continued throughout her labor. She optimized her sleep regimen by controlling labor pain with an epidural. She ultimately had an uncomplicated spontaneous vaginal delivery.A female infant was born at 37 weeks’ gestation weighing 3470 g with an Apgar score of 8 and 9 at 1 and 5 minutes, respectively. The hospital-based neonatology team was present at the time of delivery for immediate postnatal assessment. The newborn had an unremarkable neonatal course. The neonate received the standard dose of vitamin K intramuscularly.The postpartum course of the patient was uncomplicated. The doses of her AED medications were gradually decreased after delivery as directed by her neurology team to pre-pregnancy doses. Strategies to minimize sleep deprivation and seizure triggers were emphasized and undertaken.Epilepsy is a chronic noncommunicable neurological disorder that affects approximately 50 million people worldwide.1 It is characterized by spontaneous and recurrent seizures or brief episodes of involuntary movement. Epilepsy is one of the most common chronic disorders that affects individuals of childbearing age.2 It is estimated that more than half a million of individuals of childbearing age have an active diagnosis of epilepsy and that seizure disorders affect 0.3% to 0.8% of all pregnancies.3Seizure episodes result from abnormal electrical brain activity characterized by bursts of electrical discharges in a group of brain cells. They are heterogeneous in clinical presentation, from brief loss of awareness to jerking of muscles to severe and prolonged convulsions, largely owing to the brain sites affected by these discharges. They are sometimes accompanied by loss of control of bowel or bladder function. A diagnosis of epilepsy is defined by 2 or more unprovoked seizures.1 An epilepsy diagnosis can be made with a combination of tests that help distinguish the diagnosis from other conditions, including blood tests, electroencephalogram, neuropsychological testing, and brain imaging.A total of 6 potential known causes of epilepsy are recognized: acquired, structural, genetic, metabolic, infectious, and autoimmune. Understanding the cause of epilepsy can help identify its triggers, recognize conditions that may co-occur with epilepsy, and tailor treatment regimens.4 Yet, in approximately 50% of cases globally, the underlying etiology of seizures is not well understood.1,4 Certain events may be triggers to seizure episodes, including sleep disturbances, heightened stress, alcohol use or withdrawal, recreational drug use, hormonal or menstrual changes, pregnancy, illness and fever, flashing lights, dehydration, physical overexertion or hyperventilation, poor dietary habits such as skipping meals, and medication nonadherence.5At present, several AEDs exist to help treat epilepsy. For medically refractory epilepsy, other options for management include responsive neurostimulation, vagus nerve stimulation, deep brain stimulation, and surgical management. The safety of neuromodulating therapies during pregnancy is largely unknown.While epilepsy is not a contraindication to pregnancy, preconception planning to optimize epilepsy control and surveillance of the pregnancy is critical to optimize pregnancy outcomes (Figure 1).2 Although more than 90% of pregnancies complicated by epilepsy proceed without major complications, a recent meta analysis by Kuang et al noted increased rates of several complications in the pregnant person and fetus. These include small but significant risks for cesarean delivery, induction of labor, hypertensive disorders of pregnancy, eclampsia, postpartum hemorrhage, spontaneous abortion, congenital anomalies, preterm birth, fetal growth restriction, and low fetal birth weight.6–8Seizure control plays an important role in the management of pregnancies complicated by epilepsy. The best predictor for seizure control during pregnancy is a seizure-free period 9 months to 1 year before pregnancy.9 In contrast, those who experienced seizures in the year prior to pregnancy appear to be 3 to 4 times more likely to continue having seizures during pregnancy than those who have had that period of seizure freedom preceding the pregnancy.2 Ideally, adults with epilepsy should delay pregnancy until seizures are well controlled on a stable AED regimen. Adjustments to the AED regimen and dose adjustments may be required, as serum levels may fluctuate during pregnancy because of changes in metabolism and an increased volume of distribution in the pregnant person.9 Unrecognized reductions in drug serum concentrations account for most breakthrough seizures during pregnancy.A person with epilepsy is at increased risk for having offspring with congenital malformations compared to the general population, including neural tube defects, cardiac anomalies, orofacial clefts, and skeletal defects. Individuals with epilepsy have a higher rate of congenital malformations of offspring at baseline; additionally, exposure to AEDs in the first trimester increases the risk of teratogenicity (Figure 2). The risk is heightened with polytherapy, especially when containing valproate, phenobarbital, or phenytoin. As a result, these agents should be avoided during pregnancy, if possible.9 To mitigate the risk of fetal complications related to AEDs, exposure to the least number of AEDs at the lowest possible dosage is recommended. Most importantly, the implications of AEDs must be weighed carefully with the paramount importance of seizure control in the pregnant person.2Pregnant patients with epilepsy are at higher risk of fetal diagnosis of neural tube defects. These defects are characterized by incomplete closure of the embryonic neural tube, including anencephaly and spina bifida, and are linked to low folic acid levels.2 Medical therapy for epilepsy includes antiseizure medications that are liver enzyme inducers that can reduce the serum folate level or are direct folate antagonists. As a result, like the general population, the American Academy of Neurology practice guideline recommends periconceptional folic acid supplementation with 0.4 mg per day.10 Notably, data are currently insufficient to strongly support higher dosages for folate supplementation in this population.2,10,11Similarly, enzyme-inducing antiseizure medications such as first-generation AEDs (eg, carbamazepine, phenytoin, and phenobarbital/primidone) have also been linked to a potential risk of hemorrhagic disease of the newborn by resulting in vitamin K deficiency.11 However, a large prospective study of pregnant patients with epilepsy taking enzyme-inducing antiseizure medications found no significant difference in the incidence of hemorrhagic disease in the newborn compared with the control group.12 Therefore, the data are currently insufficient to recommend antenatal vitamin K supplementation for all pregnant patients with epilepsy taking enzyme-inducing antiseizure medications. The standard 1-mg parenteral vitamin K supplementation given to neonates at the time of birth is recommended.11 Given the increased risks of congenital malformations among pregnancies complicated by epilepsy, fear of teratogenicity and lack of patient counseling may lead patients with epilepsy to abruptly stop or reduce antiseizure medications without physician discussion. Abrupt cessation of AEDs makes patients more vulnerable to status epilepticus and causes an increased risk of sudden unexplained death in epilepsy patients.11,13,14Status epilepticus is a medical emergency defined as 2 or more sequential seizures without recovery of consciousness between seizures lasting more than 30 minutes with continuous seizure activity. It is managed by the use of short-acting antiseizure medications administered intravenously, assessment of airway status, administration of oxygen, and identification of inciting factors. Convulsions in pregnant patients may cause falls, blunt trauma, and harm to the fetus from exposure to a hypoxemic environment that may lead to transient fetal distress.3 Moreover, a 10-fold elevated risk of mortality has been estimated in pregnant patients with epilepsy in the peripartum period in comparison to pregnant patients without epilepsy; most of such deaths in pregnant patients are attributed to sudden unexplained death of epilepsy.13,14Seizure burden may increase during labor and delivery, although this is estimated to occur in only 1% to 2% of pregnancies in patients with epilepsy.3 Seizures should continue to be treated with the usual rescue therapy, a short-acting benzodiazepine administered intravenously.3 If benzodiazepines are required to achieve seizure control for a period greater than 2 to 3 days, then the medication should be gradually weaned to avoid withdrawal seizures. If patients experience significant nausea or vomiting that limits oral administration of scheduled AEDs, use of antiemetics should be maximized, and intravenous formulations of home AED regimens should be utilized instead.Epilepsy is not a contraindication to neuraxial anesthesia, and early placement may be considered to optimize pain control and rest for the patient. Patients who are pregnant may also receive narcotic pain medications to manage early labor pain. Tramadol is a medication that may lower the seizure threshold, and its use can be minimized.15Fortunately, most neonates will have no sequelae from a diagnosis of epilepsy in the birth parent. For neonates who are breastfeeding, family members and the pediatrician should be aware of potential side effects of certain AED excreted in the breastmilk, such as phenobarbital, primidone, clobazam, and clonazepam, which can be associated with poor neonatal weight gain, poor feeding, breathing problems, and excessive sleepiness.11The postpartum period may place patients with epilepsy at increased risk for seizures because of sleep deprivation, heightened stress, and alterations to AEDs. Some safety measures that can be undertaken include feeding the infant while sitting on the floor, changing and dressing the infant on a pad on the floor or using a changing table with a safety strap, bathing the infant in a tub only when someone else is present or giving a sponge bath on a pad on the floor when alone, and using a stroller in the house rather than carrying the baby.Importantly, people with epilepsy should be encouraged to breastfeed. The current evidence suggests that the potential benefits of breastfeeding outweigh the theoretical risks of exposure to AED via breastmilk.11 It is important to note that breastfeeding may disrupt the maternal sleep schedule and trigger seizure activity.16 To offset this, patients with epilepsy may consider pumping breastmilk or supplementing with bottle feedings.Finally, studies have demonstrated that a high rate of pregnancies, approximately 65% to 80%, in this patient population are unintended and are at higher risk of contraception failure compared to the general population, which is thought to be driven by drug to drug interactions that could compromise contraceptive efficacy.2,3,17,18 Due to drug interactions, progesterone-only pills, combined oral contraceptive pills, and subdermal progesterone implants may have reduced effectiveness with concomitant use of enzyme-inducing AEDs such as phenytoin, carbamazepine, topiramate, and oxcarbazepine. However, both depot medroxyprogesterone acetate injections and levonorgestrel-containing and copper intrauterine devices received the highest contraceptive safety rating by the Centers for Disease Control and Prevention for patients with seizure disorders regardless of the use of antiseizure medications.2,17,19SummaryThis patient with epilepsy had a reassuring maternal and neonatal outcome that was optimized with preconception planning; close multidisciplinary care with obstetrics, pediatrics, neurology, and anesthesia; and control of her epilepsy with increasing doses of AEDs as her volume of distribution and creatinine clearance increased throughout the pregnancy.American Board of Pediatrics Neonatal-Perinatal Content SpecificationKnow maternal medical disorders and medications affecting the fetus and newborn infantRecognize prenatal substance exposure issues, including neonatal withdrawal syndromes