Epilepsy and seizures in pregnancy
Epilepsy is a common condition occurring in approximately 1% of the population. Women with epilepsy pose a difficult dilemma for their practitioner; all the antiepileptic drugs (AEDs) are pregnancy category C or D, but without the medication many patients will suffer seizures. Seizures during pregnancy may cause injury to the patient or fetus and may cause premature labor or rupture of membranes. The seizure frequency remains the same in the majority of patients with pre-pregnancy control being maintained. Preconception counseling to discuss the need for medication or to switch to a safer medication should be considered early and initiated by the practitioner since half of the pregnancies in the US are unplanned.
Diagnosing epilepsy and seizures
Epilepsy is defined as two or more unprovoked seizures. Generalized tonic clonic seizures (grand mal) last approximately 2 minutes with the entire body stiffening during the tonic phase followed by rhythmic body jerking during the clonic phase. During complex partial seizures patients stare or have impaired awareness, with one-sided body stiffening or fidgeting. The duration of these seizures is also approximately 2 minutes. A patient may become confused (postictal) after a complex partial seizure or it may progress into a tonic clonic seizure. Absence seizures (petit mal) occur less often in adults. These seizures last only a few seconds with eye blinking or staring and have no postictal confusion. Myoclonic jerks are quick single jerks of the body and are usually part of an epilepsy syndrome, juvenile myoclonic epilepsy. Simple partial seizures involve a confined area of cerebral cortex so consciousness is not impaired. Clinical symptoms of simple partial seizures depend on the location of seizure activity. If it is contained in the motor cortex, then a Jacksonian seizure of unilateral clonic activity will ensue. Auras are actually simple partial seizures and are localized to the temporal lobe when déjà vu or fear is experienced, or to the olfactory cortex when smell is experienced. Auras may progress into complex partial or generalized tonic clonic seizures. A detailed history from the patient and eyewitnesses can help determine the classification. An electroencephalogram (EEG) is abnormal in greater than 50% of patients with epilepsy but can be normal. A magnetic resonance image (MRI) of the brain is preferred over computed tomography (CT) since it can detect small areas of scarring or low-grade gliomas that are the seizure nidus and that CT may not detect.
Syncope is a common occurrence in the first trimester of pregnancy and can be confused with epilepsy and seizures. A good eyewitness account is paramount. Often the patient will describe tachycardia, tunnel vision, sweating and dizziness prior to fainting. After a syncopal event there should be no postictal confusion. New-onset epilepsy during pregnancy is uncommon and requires a detailed history and physical examination, and urgent evaluation with EEG and brain MRI to exclude an intracerebral hemorrhage or tumor. A history of febrile seizures, developmental delay, head trauma, meningitis or encephalitis, or a family history of epilepsy should raise the suspicion for a diagnosis of epilepsy. Later in the pregnancy, seizures may be associated with eclampsia.
Antiepileptic drug use during pregnancy
How AEDs interfere with fetal development and cause teratogenic effects is not completely known but clearly is medication dependent. Some mechanisms for teratogenicity may include folate depletion, epoxide formation, and suppression of neuronal signaling. This may lead to major malformation (neural tube, cleft lip/palate and cardiac are most common), minor malformations (nail and facial dysmorphism) or cognitive impairment in an exposed fetus. Fetal loss is also increased in women with epilepsy taking AEDs. Exposure to two or more AEDs during pregnancy greatly increases major malformation rates, probably by introducing multiple mechanisms of teratogenicity. The older AEDs are all FDA pregnancy category D while the new AEDs are category C at this time. Many believe all AEDs will eventually be category D once more data are collected. Folic acid supplementation may be beneficial.
Valproate appears to be more teratogenic than similar medications. Recent studies and worldwide AED prospective registry data have shown that the major malformation risk is approximately 11% (6–24%) as compared to 3–4% for most other monotherapy AED exposures. The teratogenic effects are also dose dependent with higher rates seen when taking doses over 1000 mg per day. Birth defects are varied but include neural tube defects, hypospadias, renal anomalies, cardiac and limb malformations. Switching to another AED prior to conception is advised.
Phenobarbital has recently been shown to have a higher birth defect rate compared to other AEDs: 6.5% versus 3–4%. Birth defects with phenobarbital include cleft lip and/or palate, and cardiac abnormalities. Primidone is metabolized into two byproducts, one of which is phenobarbital. Therefore, it should be considered equally teratogenic. With the advent of newer AEDs, phenobarbital’s use has waned in recent years although due to its low cost it is still used extensively worldwide. If this drug is to be withdrawn prior to pregnancy, it must be tapered off slowly (months) to prevent withdrawal seizures.
Phenytoin exposure in utero has been associated with a fetal hydantoin syndrome (craniofacial anomalies, limb defects) and has a major malformation rate of approximately 4%, cardiac abnormalities being most prevalent. Its mechanism of toxicity may be due to the epoxide byproduct.
Carbamazepine is the AED of choice for partial-onset seizures. Although it is category D, malformation rates are approximately 2.5% with cleft lip/palate 0.5% and neural tube defect ∼1% predominating. Higher malformation rates were seen in the past and rates may have decreased with the ubiquitous use of folate supplementation. Oxcarbazepine is chemically similar to carbamazepine but does not form the 10, 11 epoxide when metabolized. Regardless of this fact, it does not appear to be safer than carbamazepine during pregnancy.
Lamotrigine has the most pregnancy data of the newer agents, with more than 1000 monotherapy exposures registered. Although birth defect rates are comparable to other AEDs (∼3%), one registry found an increase in cleft lip and/or palate (0.89%) and another registry found a dose-dependent birth defect rate for doses greater than 200 mg a day. Lamotrigine levels in particular fall dramatically during pregnancy and require frequent level checks (monthly or more) and reduction of the dose in the first 2 weeks post partum to prevent toxicity.
Leviteracetam is a widely used newer AED. Its major malformation rate is approximately 3.5%. Premature births and low birthweights have been described with its use. Topiramate, zonisamide, gabapentin and pregabalin have limited pregnancy data available. Benzodiazepines can cause a syndrome similar to fetal alcohol syndrome.
There is much debate regarding the appropriate vitamin supplementation for pregnant women with epilepsy taking AEDs. Women taking AEDs need more than the FDA recommended 0.4 mg of folic acid to prevent neural tube birth defects but the optimal dose (1–4 mg) is not known. In addition, taking a high dose of folate, 4 mg a day, prior to conception does not guarantee protection against birth defects. Supplementing with oral vitamin K 10 mg a day in the last month of pregnancy may prevent neonatal hemorrhagic syndrome due to its deficiency from AED liver enzyme induction.
A high-risk perinatologist should follow women on these AEDs. Amniocentesis should be offered early to women with carbamazepine and valproate exposures. Triple screen testing should be offered to all others. A high-level anatomy scan in the second trimester is crucial in detecting abnormalities.
Managing seizures during pregnancy and delivery
Seizures can harm both the mother and fetus during pregnancy. Seizures have been associated with premature rupture of membranes, premature labor, abruption, fetal bradycardia and hypoxia. Generalized tonic clonic seizures pose the greatest risk to the mother and fetus although complex partial seizures can also cause similar injury and prolonged fetal bradycardia. Injury to the mother occurs during falls associated with the seizure, resulting in abdominal or head trauma, bone fractures, thermal burns, and aspiration. Therefore seizures should be prevented with appropriate therapy.
Seizure control during pregnancy often reflects seizure control prior to conception but breakthrough seizures occur for a number of reasons. The most common reason is stopping AEDs abruptly when the pregnancy is discovered. Stopping phenobarbital in particular will provoke withdrawal seizures and can provoke status epilepticus. Nausea and vomiting due to morning sickness or hyperemesis gravidarum will prohibit proper ingestion and absorption of medication, leading to seizures. In those patients who are prone to seizures after sleep deprivation, seizures may also occur as sleep deteriorates in the third trimester due to discomfort.