Pregnancy and Epilepsy

Summary: : Women with epilepsy account for approximately 0.5% of all pregnancies. Their pregnancies are high risk because of an increased frequency of maternal seizures, complications of pregnancy, and adverse pregnancy outcomes. The increase in seizure frequency is associated with a progressive decline in antiepileptic drug (AED) levels during pregnancy even with constant dosing. Fetal deaths after a generalized seizure, although rare, have been reported, and a marked decline in fetal heart rate has been demonstrated after such seizures during delivery. AEDs have been implicated in causing a twofold increase in the rate of congenital malformations, a variety of minor physical anomalies, mostly involving the midface, and a neonatal hemorrhagic disorder. The clinician caring for a pregnant woman with epilepsy is therefore faced with a dilemma and must carefully chart a middle ground providing effective seizure control while minimizing fetal exposure to AEDs     

孕前癫痫控制情况对孕期癫痫发作以及母婴结局的预测分析

目的探讨孕前6个月和孕前1年癫痫控制情况能否预测孕期癫痫发作风险以及母婴不良结局的发生,以指导女性癫痫患者(Women with epilepsy,WWE)最佳生育时机的选择。方法回顾性分析2016年8月—2020年1月期间在天津医科大学总医院癫痫门诊随诊的WWE 46例,共48次妊娠,分析妊娠期癫痫发作的危险因素,根据患者孕期无发作的时间分组,分析各组在妊娠期的癫痫发作情况、妊娠期并发症以及妊娠结局的差异。结果①48次妊娠中,妊娠期有癫痫发作者较无发作者出现胎膜早破的风险显著升高(34.6%vs.0.0%),差异具有统计学意义(P<0.01);妊娠期高血压(Pregnancy-induced hypertension,PIH)、妊娠期糖尿病(Gestational diabetes mellitus,GDM)、妊娠期贫血以及总妊娠期并发症发生率无统计学差异(P>0.05);子代平均出生体重略低,低出生体重、胎儿宫内窘迫发生率较高,但差异无统计学意义(P>0.05);②孕前6个月有癫痫发作与孕期癫痫发作显著相关[RR=4.28,95%CI(2.10,8.74),P<0.01];与孕前6个月无发作组对比,总不良妊娠结局发生率升高,差异有统计学意义[RR=2.00,95%CI(1.10,3.65),P<0.05];③孕前6个月无发作组与孕前≥1年无发作组妊娠期癫痫发作率分别为25.0%和20.0%,差异无统计学意义(P>0.05);相比孕前6个月无发作组,孕前≥1年无发作组发生PIH、妊娠期贫血的风险较低,后代发生低出生体重、早产、胎儿宫内窘迫的风险较低,但差异无统计学意义(P>0.05)。结论保证至少孕前6个月无发作将显著降低孕期癫痫发作的概率,且与较低的不良妊娠结局发生率显著相关。建议育龄期的女性癫痫患者在达到至少6个月癫痫无发作后再计划妊娠。     

A patient with DiGeorge syndrome with spina bifida and sacral myelomeningocele,who developed both hypocalcemia-induced seizure and epilepsy

DiGeorge syndrome – a component of the 22q11 deletion syndrome – causes a disturbance in cervical neural crest migration that results in parathyroid hypoplasia. Patients can develop hypocalcemia-induced seizures. Spina bifida is caused by failure of neurulation, including a disturbance in the adhesion processes at the neurula stage. Spina bifida has been reported as a risk factor for epilepsy.We report, for the first time, the case of a patient with DiGeorge syndrome with spina bifida and sacral myelomeningocele, who developed both hypocalcemia-induced seizures and epilepsy. The patient had spina bifida and sacral myelomeningocele at birth. At the age of 13 years, he experienced a seizure for the first time. At this time, the calcium concentration was normal. An electroencephalogram (EEG) proved that the seizure was due to epilepsy. Antiepileptic medications controlled the seizure. At the age of 29, the patient's calcium concentration began to reduce. At the age of 40, hypocalcemia-induced seizure occurred. At this time, the calcium concentration was 5.5 mg/dL (reference range, 8.7–10.1 mg/dL). The level of intact parathyroid hormone (PTH) was 6 pg/mL (reference range, 10–65 pg/mL). Chromosomal and genetic examinations revealed a deletion of TUP-like enhancer of split gene 1 (tuple1)—the diagnostic marker of DiGeorge syndrome. Many patients with DiGeorge syndrome have cardiac anomalies; however, our patient had none.We propose that the association among DiGeorge syndrome, spina bifida, epilepsy, cardiac anomaly, 22q11, tuple1, and microdeletion inheritance should be clarified for appropriate diagnosis and treatment.     

Clinical Care of Pregnant Women with Epilepsy: Neural Tube Defects and Folic Acid Supplementation

Summary:  Women with epilepsy (WWE) have a risk of bearing children with congenital malformations that is approximately twice that of the general population. Most antiepileptic drugs (AEDs) have been associated with such risk. Valproate and carbamazepine have been associated specifically with the development of neural tube defects (NTDs), especially spina bifida. Other factors may contribute to the risk, including concomitant diseases such as diabetes mellitus, occupational exposure to teratogens, excessive prepregnancy weight, and various nutrient deficiencies. In the general population, maternal folate deficiency, in particular, has been linked with the development of NTDs, and periconceptional folate supplementation with a reduction of risk. It is unclear whether folate supplementation has a comparable protective effect for WWE. Data concerning the risk for congenital malformations associated with the newer AEDs (gabapentin, felbamate, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide) are still limited. Several pregnancy registries for women taking AEDs have been established. Comprehensive postmarketing surveillance, regionally or nationally, might be the ideal method of monitoring medication safety, but government support for such an undertaking has for the most part been lacking. Despite uncertainty about the efficacy of periconceptional folate supplementation in WWE, these women should receive such supplementation at dosage levels recommended for the general population of women of childbearing age. Seizure control must not be neglected in a pregnant woman with epilepsy since seizures are associated with harm to the fetus as well as the mother. Risk may be minimized by using a single AED at the lowest effective dosage.     

Foetal malformations and seizure control: 52 months data of the Australian Pregnancy Registry

The Australian Pregnancy Registry, affiliated European Register of Antiepileptic drugs in Pregnancy (EURAP), recruits informed consenting women with epilepsy on treatment with antiepileptic drugs (AEDs), those untreated, and women on AEDs for other indications. Enrolment is considered prospective if it has occurred before presence or absence of major foetal malformations (FMs) are known, or retrospective, if they had occurred after the birth of infant or detection of major FM. Telephone Interviews are conducted to ascertain pregnancy outcome and collect data about seizures. To date 630 women have been enrolled, with 565 known pregnancy outcomes. Valproate (VPA) above 1100 mg/day was associated with a significantly higher incidence of FMs than other AEDs (P < 0.05). This was independent of other AED use or potentially confounding factors on multivariate analysis (OR = 7.3, P < 0.0001). Lamotrigine (LTG) monotherapy (n = 65), has so far been free of malformations. Although seizure control was not a primary outcome, we noted that more patients on LTG than on VPA required dose adjustments to control seizures. Data indicate an increased risk of FM in women taking VPA in doses >1100 mg/day compared with other AEDs. The choice of AED for pregnant women with epilepsy requires assessment of balance of risks between teratogenicity and seizure control.     

Managing epilepsy in pregnancy

There are close to one and half million women with epilepsy (WWE) in reproductive age group in India. WWE have several unique gender-specific problems in the biological and social domains. Women experience more social stigma from epilepsy and have more difficulty with education and employment. They have more difficulty to get married and sustain successful family life. Reproductive hormones like estrogen and progesterone have opposing effect on seizure threshold. WWE have increased risk of infertility. About 10% of their babies may have major congenital malformations. Most of the adverse biological outcomes for WWE are related to adverse effects of antiepileptic drugs (AEDs). Traditional AEDs like phenobarbitone and sodium valproate are probably associated with increased risk of fetal malformations or other adverse fetal outcomes. Polytherapy and use of high dose of any AED is associated with higher risk fetal complications. It is very important that all WWE have a preconception evaluation done by a neurologist, when the need to continue AEDs or possibility of reducing AED load could be assessed. All WWE need to take folic acid 5 mg daily during preconception period and pregnancy. They should undergo a detailed screening for fetal malformations between 12 and 18 weeks of pregnancy. The neurologist, gynecologist, imageologist and pediatrician need to work as a team while managing pregnancy in WWE. It is important to reassure WWE and their relatives that pregnancy is safe in WWE and their children are healthy in more than 90% instances.     

Pregnancy and teratogenicity of antiepileptic drugs

Maternal use of antiepileptic drugs (AEDs) during pregnancy has been associated with an increased risk of congenital abnormalities in the fetus. This is partly attributable to AEDs. We aimed to analyse seizure frequency and the rate and type of any congenital malformation related to pregnancies in women with epilepsy in this prospective study. Eighty four pregnant women with epilepsy on AEDs were followed for congenital malformations. Z test was used for statistical analysis. Pregnancy did not influence the seizure frequency in 64 (76.2%) pregnancies. The seizure frequency increased in 16 (19.04%) pregnancies. In 4 (4.76%) pregnancies the number of seizures decreased during pregnancy. Overall percentage of congenital malformations in infants of mothers with epilepsy treated with AEDs was 10%, versus 3.65% in the general Turkish population. Percentages of malformations in children of pregnancies in women with epilepsy on antiepileptic drugs (AEDs) were; 6.52% (3/46) for carbamazepine (CBZ), 14.28% (2/14) for phenytoin (PHT), 13.33% (2/15)for valproic acid (VPA) and 20% (1/5) for phenobarbital (PB). This comfirms previous reports that all four AEDs (CBZ, PHT VPA, PB) are associated with an increased risk of congenital malformations, although CBZ seems to be the the safest agent in monotherapy.     

Pregnancy in the woman with epilepsy: maternal and fetal outcomes

Pregnancy in women with epilepsy is associated with increased obstetric risks and increased adverse neonatal outcomes. Prior to conception, folic acid should be administered and the antiepileptic drug (AED) regimen should be optimized. Effective control of maternal seizures with the least risk to the fetus is the goal, preferably using AED monotherapy. Periodic monitoring of total and free AED levels is recommended. The "fetal anticonvulsant syndrome" has been described with all of the AEDs and includes major malformations, minor anomalies, microcephaly, cognitive impairment, intrauterine growth retardation, and infant mortality. The most common major malformations are cleft lip/palate, heart defects, and neural tube defects. Prenatal screening should be offered. Supplemental vitamin K(1) should be given to the mother and newborn to prevent neonatal hemorrhagic disorder. Careful planning and management of any pregnancy in women with epilepsy are essential to increase the likelihood of a healthy outcome for the mother and infant.     

Management of epilepsy in pregnancy: a report from the International League Against Epilepsy Task Force on Women and Pregnancy

The risks associated with use of antiepileptic drugs during pregnancy are a major concern for all women with epilepsy with childbearing potential. These risks have to be balanced against foetal and maternal risks associated with uncontrolled seizures. This report from the International League Against Epilepsy Task Force on Women and Pregnancy aims to provide a summary of relevant data on these risks as a basis for expert opinion recommendations for the management of epilepsy in pregnancy. The report reviews data on maternal and foetal risks associated with seizures as well as teratogenic risks associated with antiepileptic drug exposure, including effects on intrauterine growth, major congenital malformations, and developmental and behavioural outcomes. The impact of pregnancy on seizure control and on the pharmacokinetics of antiepileptic drugs are also discussed. This information is used to discuss how treatment may be optimized before conception and further managed during pregnancy.