Epilepsy is one of the most common diseases in neurology, and its prominent clinical features are recurrence, unpredictability, and the long-term nature of drug treatment, which greatly affect the physical and mental health of epileptic patients. According to epidemiological data, there are about 50 million epilepsy patients worldwide, and nearly 9 million epilepsy patients in China, a significant proportion of whom are women of childbearing age with epilepsy. Because of the special physiological characteristics of women and the effects of epilepsy and antiepileptic drugs (AEDs) on pregnancy, delivery, fetal teratogenicity, and mental development of women with epilepsy, the treatment of women with epilepsy has become the focus of clinicians’ attention. Currently, several surveys in Europe and North America indicate that clinicians are still unfamiliar with the management of female patients with epilepsy and that a significant number of female patients do not receive the care and treatment they deserve. In this regard, the author focuses on the interrelationship between fertility, pregnancy, childbirth, and fetal development, which are of particular concern to women of childbearing age, with the hope of providing informative advice on the treatment of women with epilepsy in their childbearing years.
The fertility rate of women with epilepsy is only 60% to 80% of that of non-epileptic women, and about 1/3 of that of their non-epileptic siblings.
First, women with epilepsy are reluctant to conceive because of psychosocial factors, such as fear of hereditary epilepsy and fetal abnormalities. 2003, a British survey that included 2,000 women with epilepsy of childbearing age showed that about 1/3 of patients were reluctant to have children because of epilepsy.
Second, epilepsy itself has an effect on the reproductive endocrine system, which can lead to decreased fertility in patients with epilepsy. Seizures or epileptiform discharges have a direct effect on the hypothalamus, pituitary gland and ovaries, often leading to anovulatory menstrual cycles or menstrual disorders. The most common reproductive endocrine disorder in women with epilepsy is polycystic ovary syndrome (PCOD), which has a prevalence of 5% to 6% in the general population and a prevalence of 10% to 20% in the epileptic population.
Third, some AEDs may have an impact on the fertility of women with epilepsy. Isojarvi et al. reported that of 238 women with epilepsy treated with AEDs in Northern Finland, approximately 20% had no menstruation, hypomenorrhea, or menstrual cycle disorders; 12% were treated with sodium valproate, and 43% of them were found to have polycystic ovaries; 80% of women treated with sodium valproate before the age of 20 had polycystic ovaries. Among women treated with valproate before age 20, 80% had polycystic ovaries or hyperandrogenemia. It remains unclear whether polycystic ovaries and PCOD are due to seizures or AEDs.
Blood levels should be monitored during pregnancy and delivery. 1/3 ~ 1/4 of women with epilepsy have increased seizure frequency during pregnancy, which is not related to seizure type, seizure duration, or previous pregnancy experience, but may be related to increased plasma estrogen concentrations during pregnancy, water and sodium retention, anxiety or stress, and sleep deprivation. In addition, poor patient compliance with medication, altered gastric dynamics during pregnancy resulting in continuous nausea and vomiting, changes in AED distribution volume, altered protein binding and enhanced hepatic metabolism may cause a decrease in AED bioavailability and lead to an increased seizure frequency. Therefore, timely testing of AED blood levels during pregnancy and the perinatal period is necessary to guide treatment and optimize AED dosing.
Generalized tonic-clonic seizures during pregnancy often put the mother and fetus at risk for hypoxia, acidosis, and trauma. Although uncommon during pregnancy, persistent seizures can result in high maternal and fetal mortality when they occur. Generalized seizures during delivery have a serious impact on fetal heart rate and can result in neonatal hypoxia and low Apgar scores. There is no evidence that simple partial seizures, complex partial seizures, and aphasic seizures have a significant effect on the fetus.
Recently, the European Registry of Antiepileptic Drugs and Pregnancy investigated the course of pregnancy and delivery in nearly 2000 female patients with epilepsy and found that 58% of patients were seizure-free during pregnancy, 17% had increased seizure frequency, 16% had decreased seizures, and 3.5% had seizures during delivery. Although there is no strong evidence that women with epilepsy are at significantly increased risk for obstetric complications such as cesarean delivery, late pregnancy hemorrhage, premature contractions, preterm delivery, eclampsia, and gestational hypertension, it has been established that women with epilepsy who smoke during pregnancy are at significantly increased risk for preterm delivery.
The fetus and neonate of a woman with epilepsy are at greater risk for poor prognosis in pregnancy. 4% to 9% of fetuses and neonates have congenital malformations such as congenital heart disease (atrial or ventricular septal defects), cleft lip, cleft palate, neural tube defects (NTDs), and genitourinary malformations. The NTDs are mainly manifested by anencephaly, bulging brain and spina bifida, and about 85% of them are caused by multifactorial inheritance, but some patients are also associated with valproate and carbamazepine treatment. The occurrence of congenital malformations is due to the intermediate metabolites of AEDs binding to embryonic nucleic acids and interfering with normal embryonic development on the one hand, and the interference of AEDs with folate metabolism on the other. 6-20% of fetuses and newborns exhibit congenital microscopic anomalies of the eyes, ears, mouth, nose, and fingers, such as wide spacing between the eyes, small mouth, small nose, flat nose, low hairline, and hypoplastic nails.
There are more than 20 modern antiepileptic drugs, including first-generation drugs such as sodium phenobarbital, sodium phenytoin, carbamazepine and sodium valproate, and second-generation drugs such as topiramate, lamotrigine, oxcarbazepine and levetiracetam, etc. Fetal malformations caused by AEDs have become a great concern for doctors and patients. The Epilepsy and Pregnancy Registry was launched in the 1990s in Europe, the United States and other developed countries to conduct statistical studies on congenital malformations in offspring caused by single and combination antiepileptic drugs.
In 2011, a study of nearly 7000 cases in the North American Antiepileptic Drug and Pregnancy Registry showed that the incidence of anticonvulsant syndrome in the sodium valproate monotherapy group was 9.3%, the teratogenicity rate of phenobarbital was 5.5%, topiramate was 4.2%, carbamazepine was 3.0%, phenytoin sodium was 2.9%, levetiracetam was 2.4%, and lamotrigine was 2.0%. The rate of teratogenicity is 2.0%.
The largest of these is the European Registry of Antiepileptic Drugs and Pregnancy, which was established in 1999 and now includes 42 countries with 700 patients. From 1999 to 2010, 14,461 cases were included in the registry, and the incidence of anticonvulsant syndrome was found to be 5.6% in the carbamazepine monotherapy group, and the teratogenic rates were 9.7%, 2.9%, and 7.4% for valproate, lamotrigine, and phenobarbital, respectively. It was also found that AEDs were the most common cause of cardiac malformations, and some AEDs had a dose-dependent teratogenic effect; the risk of congenital malformations was 4 times higher in fetuses with a history of parental malformations.
Weighing the pros and cons of breastfeeding, breastfeeding can strengthen the resistance of newborns and prevent diseases of the digestive and respiratory tracts and other organs. The milk concentration of AEDs is inversely proportional to their plasma protein binding rate in the mother, and the current ratio of milk concentration to maternal plasma concentration (M/S) for AEDs is 5% to 10% for valproate, 36% to 40% for carbamazepine, 6% to 20% for phenytoin, 40% for phenobarbital, and 71% for paroxetine. 40%, paroxetine 71%, and ethosuximide 90%. The M/S of newer generation AEDs are higher, with oxcarbazepine at 50%-64%, lamotrigine at 60%, topiramate at 66%-110%, and levetiracetam at 100%-300% .
Although breast milk concentrations may be lower in some AEDs, the reduced serum protein binding and slowed hepatic metabolism rates in neonates maintain serum drug levels in the therapeutic concentration range in all neonates. When breastfeeding female patients with epilepsy treated with phenobarbital and paroxetine, the newborn often shows sedative effects and feeding difficulties. Hematologic and liver function abnormalities in breastfed infants have been reported less frequently.
Overall, breastfeeding is not an absolute contraindication for newborns of women with epilepsy. When deciding whether to breastfeed a newborn, various factors should be considered, such as the desire to breastfeed, the type, amount, and dosage of AEDs, and the condition of the newborn, to fully weigh the pros and cons of breastfeeding.
Despite the adverse effects of seizures on women, timely, appropriate and proper treatment can lead to a normal pregnancy and a healthy next generation for more than 90% of women.
The use of medication during pregnancy In women with epilepsy, if the seizures have stopped 2-5 years before conception, if the EEG is normal, and if there are no neurological signs of a single type of seizure in the past, the medication can be considered to be gradually discontinued, otherwise the medication must be continued. Treatment principles: choose the most effective medication according to the type of seizure, preferably with a single drug at the lowest effective dose, and take small amounts several times a day; test the plasma drug concentration every 3 months, preferably the free concentration of the drug, and adjust the dose if necessary. If patients experience pregnancy reactions, such as nausea and vomiting, timely intervention is necessary to ensure caloric intake and AED absorption.
As for the choice of AED during pregnancy, the American Academy of Neurology as well as the Epilepsy Society recommend the following.
☆ Try to avoid the application of sodium valproate and multiple antiepileptic drug combinations during the first trimester of pregnancy to reduce the risk of anticonvulsant syndrome.
☆ Avoid, as much as possible, the use of sodium valproate and multiple antiepileptic drug combinations throughout pregnancy to prevent fetal cognitive decompensation.
☆ Avoid treatment with phenobarbital and sodium phenytoin throughout pregnancy as much as possible to prevent fetal cognitive decompensation.
Folic acid supplementation therapy Animal experiments have found that reduced serum and red blood cell folate levels are associated with spontaneous abortion and fetal malformations. For example, phenytoin sodium, carbamazepine and phenobarbital can reduce folate absorption, and sodium valproate, although not producing folate deficiency, can interfere with the conversion of folate to the active metabolite folinic acid. Since the major organs and systems of the fetus are largely formed in the first trimester, and the posterior neural foramen and hard palate close at 27 d and 47 d of gestation, respectively, folic acid supplementation prior to and during early gestation is necessary. Clinical observations have also shown that pre-pregnancy folic acid supplementation reduces the risk of fetal malformations and neural tube defects.The optimal dose of AED is not known, and the American Epilepsy Society currently recommends that all female epilepsy patients of childbearing age should take folic acid at a dose of at least 0.4 mg/d before planning a pregnancy to prevent neural tube defects; for female patients with a family history of neural tube defects, the recommended dose is 5 mg/d. Whether high-dose folic acid application affects seizures has not been studied.
In addition, the selection of AEDs for female epileptic patients of childbearing age should also take into account whether long-term AED application affects patient cosmesis, such as gingival hyperplasia, facial acne, increased facial and arm hair, hair loss, and weight gain, which often affects patient compliance with medication.
Conclusion Research on women and epilepsy in China lags far behind that in Europe and the United States, especially as a national epilepsy and pregnancy registry has not yet been established, and there is a lack of data from domestic studies on AEDs and the risk of fetal anticonvulsant syndrome. Therefore, it is of strategic importance to establish a national AED and pregnancy registry in China and to conduct a large-scale prospective study on the risk of fetal congenital malformations associated with seizures and AEDs: on the one hand, it can provide guidance for the treatment of female epileptic patients of childbearing age in China, and on the other hand, it can provide constructive suggestions for the improvement of eugenic policies in China.