Epilepsy is a common neurological disorder in women of childbearing age, with a prevalence of 0.15% to 0.17%. There are 9 million epilepsy patients in China, and the incidence of pregnancy-related epilepsy is about 0.26%-0.99%. 13% of women with epilepsy have their first seizure during pregnancy, and 40% of them have seizures only during pregnancy. Seizures and antiepileptic drugs (AEDs) can have many adverse effects on pregnant women, including trauma, miscarriage, preterm delivery, and neuropsychiatric changes, and can also lead to fetal birth defects and acquired cognitive impairment. Therefore, preconception diagnosis and preconception counseling are very important.
I. Management of epilepsy during pregnancy
The management of patients with epilepsy before conception, during pregnancy, during delivery and after delivery should be strengthened, which requires close cooperation between obstetricians and neurologists.
Preconception counseling is necessary for patients with epilepsy, including genetic issues, teratogenicity of AEDs, folic acid and vitamin K1 supplementation, delivery, breastfeeding, and neonatal care. Proper preconception counseling can reduce the risk of epilepsy itself and the risk of AEDs treatment. Barrier contraception is recommended for six months prior to pregnancy, modulation of AEDs use, and planning of pregnancy with effective seizure control. Seizure-inducing drugs such as penicillins and quinolone antibiotics should be avoided during pregnancy. Correct bad habits, avoid smoking and drinking alcohol. Ensure adequate nutrition and sleep.
Pregnant patients with epilepsy should undergo rigorous prenatal checkups to detect serious fetal malformations. Serological screening should be performed at 14-19 weeks of gestation, and systemic ultrasound should be performed at 18-24 weeks of gestation to exclude neural tube development defects, cleft lip and palate, spina bifida or limb mutilation and other structural abnormalities. An echocardiogram will be performed to remove any abnormalities of the fetal heart. If necessary, amniocentesis will be performed to detect alpha-fetoprotein, acetylcholinesterase and chromosomes. Termination of pregnancy is recommended if there are frequent seizures or even recurrent grand mal seizures during pregnancy or if you are in a continuous state of epilepsy.
Most women with epilepsy can deliver normally through the birth canal, but if there are recurrent seizures or persistent status epilepticus in the second trimester, a cesarean section should be chosen. However, the indication for cesarean section can be relaxed considering the cautious attitude of doctors and patients towards delivery. There is no restriction on the type of surgical anesthesia, but it should be noted that some sedatives can induce epilepsy.
Some AEDs are associated with an increased risk of neonatal hemorrhage due to a decrease in vitamin K-dependent clotting factors caused by drugs such as carbamazepine and phenobarbital. Therefore, the American Academy of Neurology recommends that a history of preterm delivery, co-administration of antiepileptic drugs, use of hepatic enzyme-inducing antiepileptic drugs (e.g., carbamazepine, oxcarbazepine, phenytoin sodium, phenobarbital, topiramate), and alcohol abuse should be treated with oral vitamin K 10-20 mg/d from 36 weeks of gestation until delivery. Newborns routinely receive vitamin K1 treatment at birth, and fresh frozen plasma is given when there is a tendency to bleed.
5. Breastfeeding AEDs generally enter breast milk in a simple diffusion manner. Infant blood concentration is related to the amount of drug in breast milk and the half-life of the drug in the newborn. Because the concentration of AEDs in breast milk is lower than in serum, the total amount of drug obtained by the infant through breast milk is much lower than that obtained by the fetus through the placenta during pregnancy. Also, the protein binding rate of phenobarbital, carbamazepine and sodium valproate is very high, thus the concentration in breast milk is generally negligible. Therefore, breastfeeding is encouraged in patients with epilepsy while taking AEDs. However, due to the lack of glycolysis in early infancy, the drug clearance mechanism is immature, e.g., lamotrigine has a certain accumulation effect after absorption through breast milk. In addition, the mother should not care for the infant alone. It is advisable to use the device or IUD for contraception after delivery.
6. supplementation of folic acid folic acid is a coenzyme necessary for the development of hematopoietic cells and the maintenance of central nervous system function. Some AEDs such as carbamazepine interfere with the absorption of folic acid, while sodium valproate inhibits the enzyme methionine synthase, which promotes the conversion of homocysteine to methionine, a process that requires folic acid as a cofactor. Therefore, folic acid supplementation may significantly reduce the risk of neural tube developmental defects in this population. Because neural tube development defects occur very early in pregnancy, many organizations, including the American Academy of Neurology, recommend that all women taking the hepatic enzyme inducers AEDS (e.g., carbamazepine, sodium valproate, phenobarbital, etc.) should take 4-5 mg of folic acid supplementation daily during the first 1-3 months of pregnancy, and women taking other antiepileptic drugs should take 0.4-0.8 mg of folic acid supplementation daily during the first 1-3 months of pregnancy.
Second, the effect of pregnancy on epilepsy
The frequency of seizures can change during pregnancy, which is related to changes in maternal psychological factors, hormone levels, medication compliance and pharmacokinetics. It is thought that only about 1/3 of patients have an increase in seizure frequency during pregnancy, while most patients have no significant change or even a decrease. Epilepsy is not a contraindication to pregnancy, and the vast majority of women with well-controlled seizures can have a normal pregnancy and delivery and have a healthy child. The risk of seizures is higher during early pregnancy and delivery in terms of the time frame of the pregnancy. The blood concentration of some AEDs (e.g. lamotrigine, oxcarbazepine, and tolterazepine) decreases during pregnancy due to weight gain, plasma volume redistribution, hepatic metabolism, and increased renal clearance, resulting in increased seizure frequency and worsening degree of seizures, while carbamazepine has the least decrease in blood concentration during pregnancy. In terms of seizure type, partial seizures have a higher risk of deterioration than generalized seizures, and a small percentage of patients have grand mal seizures during pregnancy.
The effect of epilepsy on pregnancy
Epilepsy is not a hereditary disease, but it has a tendency to be inherited. The risk of epilepsy in the offspring of a mother with epilepsy is two to four times higher than that of a normal population. The law does not explicitly prohibit women with epilepsy from having offspring, but those with epilepsy due to a clear genetic disorder should not have children. The fertility of childbearing epileptics is generally unaffected. However, seizures and AEDs may interfere with the hypothalamic-pituitary-gonadal axis, resulting in abnormal secretion of sex hormones that can lead to menstrual disorders and anovulatory dysfunction. In addition, the incidence of polycystic ovary syndrome has been reported to be increased in patients taking sodium valproate. All of these may lead to infertility. On the other hand, CYP450-inducing AEDs such as carbamazepine can increase the metabolic rate of hormones in contraceptives, reducing their effectiveness and leading to unintended pregnancy. In addition, AEDs affect cognitive function in patients with epilepsy by decreasing neuronal excitability and enhancing inhibitory neurotransmitters. Patients with epilepsy during pregnancy also have altered mental status and quality of life, including depression. Pregnancy and delivery are generally unaffected in patients with epilepsy, and the incidence of pregnancy complications and comorbidities is similar to that of the general population. Among the studies on pregnancy and epilepsy, the most important concern in obstetrics and neurology is the effect of AEDs on the fetus, among which the teratogenicity of AEDs has been studied most extensively and intensively. The rate of congenital malformations in fetuses taking AEDs during pregnancy is now thought to be about three times higher than in normal pregnancies. The higher the number of drugs and the higher the dose, the higher the risk. The rate of fetal malformation is highest with the combination of multiple drugs (including sodium valproate); the rate of fetal malformation is highest with trimethoprim and sodium valproate in monotherapy, and it is correlated with the dose, and the rate of fetal malformation is higher when the dose of sodium valproate reaches 800-1000 mg/d (drug concentration >70µg/mL). The teratogenicity of the new generation antiepileptic drugs levetiracetam, oxcarbazepine, lamotrigine, and gabapentin may be relatively low. However, most studies have not adequately considered other factors influencing teratogenicity, such as seizure type, seizure frequency, and family history of birth defects in infants. The most common fetal malformations associated with AEDs include facial abnormalities such as cleft lip and palate, congenital heart disease, neural tube defects, and genitourinary defects. In general, each AED is teratogenic, but there is no specificity in the type of malformation caused. The mechanism of fetal malformation caused by AEDs is currently considered to be related to folic acid deficiency, slowed fetal heart rate and altered fetal hemodynamics due to AEDs, abnormal oxidative metabolite mechanism, and genetics. In addition, AEDs can also cause fetal growth restriction, low birth weight and neonatal hemorrhage syndrome, the perinatal mortality rate is two times higher than normal pregnancy.
Treatment of epilepsy during pregnancy
In addition to the tendency of spontaneous remission, a significant number of patients with epilepsy can have no recurrence for life after regular treatment. The majority of patients do not require lifelong medication. Since most pregnancies in patients with epilepsy are unplanned, they may be taking AEDs at the time of discovery or have their first seizure during pregnancy. Seizure control and improvement of the patient’s quality of life are the main goals of epilepsy drug therapy. When complete seizure control is not possible, the best treatment is to minimize the frequency of seizures and to keep adverse drug reactions within a tolerable range. It should be emphasized that the risk of pregnancy in patients with epilepsy is mainly due to the risk of grand mal seizures and uncontrolled seizures, while the risk of fetal teratogenicity from drugs is secondary; the total teratogenic effect of AEDs is currently considered to be about three times that of normal pregnancy. The type of malformation caused by AEDs is non-specific, and neural tube malformation can be excluded by prenatal diagnosis such as serological screening and systemic ultrasound; the use of drugs is teratogenic to the fetus especially in early pregnancy; the patient has the right to choose to continue the pregnancy under the principle of informed consent.
(I) Recommended strategies for interictal period
1. Whether to treat medication: Most patients should choose appropriate medication once the diagnosis is clear. However, the use of AEDs during pregnancy involves fetal teratogenic consequences and should be decided with caution. It is currently believed that recurrent, severe seizures can cause more damage to the mother and fetus than AEDs. Therefore, patients and their families should be informed of the side effects of AEDs and the possible consequences of not treating them, and the decision to treat or not rests with the patient and her family.
ILAE and domestic guidelines suggest that valproate is preferred for adults with generalized seizures, carbamazepine for partial seizures, valproate or lipitor for atonic seizures, and valium for persistent epilepsy. All other AEDs should be used as a backup in case of ineffectiveness of the drug of choice. There is a lack of evidence-based treatment for AEDs in women of childbearing age. For women of childbearing age who are planning to become pregnant, their seizure type should be re-evaluated and the best drug therapy should be selected based on the type of seizure and the effect of the chosen drug on pregnancy. From the limited data available, the more recommended antiepileptic drugs are levetiracetam, lamotrigine, carbamazepine and Toltea, which are relatively less teratogenic. The obvious teratogenic drugs trimethoprim and phenytoin sodium are contraindicated. Given the high teratogenicity of sodium valproate, it should not be used as a first-line antiepileptic drug during pregnancy. In addition, carbamazepine and sodium valproate are associated with neural tube developmental defects and should be screened for.
3. Monotherapy and maintenance of the lowest effective dose: If the patient is receiving multiple AEDs, try to change to monotherapy before pregnancy. After discontinuation of the drug, you need to continue to take the drug to control before considering pregnancy. Pregnancy medication is gradually increased from a small dose to an effective dose. If the dose is high, it can be changed to multiple small doses or use extended-release tablets to reduce the peak concentration of the drug. Since most AEDs are alkaline, taking the drug after meals can reduce gastrointestinal reactions.
4, the drug should be closely followed up during the period of use: because the average blood concentration of AEDs varies, some AEDs need to increase the dose. Therefore, it is important to monitor the blood concentration of patients during pregnancy, and adjust the drug dose according to the blood concentration and seizure control after 3 to 5 years of complete control, and consider discontinuing the drug after 1 to 2 years of the cessation of aphasic seizures. It is important to stop the medication slowly, from the beginning of the dose reduction to the complete discontinuation of the medication should be at least six months to one year. Therefore, it is better to have a pregnancy when the seizures have stopped for more than 2 to 3 years and the medication has been stopped for 6 to 12 months without seizures. It is not advisable to discontinue the medication in case of pregnancy during the medication period.
(B) Seizure treatment
Epileptic seizures are self-limiting, and most patients do not need special treatment. In case of tonic-clonic seizures, attention should be paid to prevent trauma and complications. Support the patient to lie flat or on the side to prevent bruises or injuries. Prevent tongue bite and keep breathing open. When convulsions occur, put soft objects on the joints to prevent bruises during seizures; do not press the limbs to avoid fractures and dislocations. After the convulsions stop, turn the patient’s head to the side to let the secretions flow out and prevent asphyxiation. For patients who exhibit autonomic symptoms, do not forcibly restrain them to prevent injury or self-injury, provided that it is safe to do so. For treatment of persistent status epilepticus, the principles are to maintain stable vital signs and cardiopulmonary support; to terminate the persistent seizures and to reduce the damage to neurons in the brain. The first choice of treatment is Valium 10mg intravenously at a rate of <2mg/min until the convulsions stop. If necessary, use intravenous anesthesia or inhalation anesthesia, keep the airway open, diuretic dehydration to reduce cerebral edema, and correct acidosis.