Article ID: 24-00048
Objectives:To explore the outcomes of pregnant women with epilepsy and their neonates, including the incidence of neonatal withdrawal syndrome.
Methods:In total, 26 pregnancies in 20 mothers with epilepsy were retrospectively examined for the presence of complications before and during pregnancy, number of antiseizure medications taken, gestational weeks at delivery, mode of delivery, number of seizure episodes during pregnancy and postpartum, neonatal birth weight, Apgar score, pH of the umbilical cord arterial blood, neonatal abnormalities, and neonatal withdrawal syndrome.
Results:Overall, 25 of the 26 pregnancies resulted in live births, with 4 cases undergoing premature deliveries. Ten cases underwent cesarean section, with only one case undergoing cesarean section due to the fear of experiencing seizure during vaginal delivery. During pregnancy, two cases experienced one seizure episode. The rate of small for gestational age was 8.0%, and three neonates had congenital abnormalities. Withdrawal symptoms were observed in 75% of the neonates, but none of them obtained ≥8 points in the withdrawal checklist, the threshold for pharmacotherapy.
Conclusions:For women with epilepsy who receive medical management and establish good control prior to pregnancy, child birth may be relatively safe, with a low rate of neonatal withdrawal syndrome requiring pharmacotherapy.
Epilepsy is a condition that develops through abnormal intracerebral electrical excitement, with symptoms including tonic-clonic seizure, cataplexy, absence seizure, myoclonic seizure, behavior arrest, and dysesthesia. Epilepsy may occur in all age groups, from infants to older individuals, and 0.3%-0.8% of all pregnant women at any gestational week experience epilepsy1,2).
In women whose pregnancy is complicated with epilepsy, the risk of spontaneous abortion, preterm birth, antepartum hemorrhage, gestational hypertension, preeclampsia, cesarean section, and maternal death is higher than that in pregnant women without epilepsy3,4). Moreover, the risk of teratogenicity, neonatal neurodevelopmental disorders, and neonatal withdrawal syndrome is higher in neonates delivered by women taking antiseizure medications5,6). Neonatal withdrawal syndrome causes temporary neurological and gastrointestinal symptoms, including apnea, convulsions, abnormal muscle tone, somnolence, and tremors, as the transplacental transfer of antiseizure drugs ceases soon after birth. Neonates with withdrawal syndrome require strict management in the neonatal intensive care unit (NICU) and pharmacotherapy immediately after birth. Therefore, predicting the onset of neonatal withdrawal syndrome is crucial to ensure good management and prognostic improvement of mothers with epilepsy and their neonates.
We aimed to retrospectively investigate the background characteristics and outcomes of pregnant women with epilepsy and their neonates treated at our hospital as well as the incidence of neonatal withdrawal syndrome in this cohort. We also sought to explore appropriate management of pregnant women with epilepsy.
This case series study enrolled pregnant women with epilepsy and their neonates treated at the Japanese Red Cross Okinawa Hospital from April 2012 to November 2021. Mothers who did not receive obstetric services in their first trimester at our hospital and those who moved to other facilities before delivery were excluded.
Written informed consent was obtained from patients prior to study participation. The present study was approved by the Institutional Review Board of our hospital in November 2022 (#R-4.4).
We retrospectively examined the medical records of the mothers, including age at the time of delivery, complications during the prepregnancy and pregnancy periods, previous cesarean section, history of spontaneous abortion and premature birth, number of antiseizure medications taken, gestational weeks at delivery, mode of delivery, abortion, stillbirth, amount of intrapartum hemorrhage, and seizure(s) during pregnancy and postpartum.
We examined the medical records of the neonates, including birth weight, Apgar score, pH of the umbilical cord arterial blood, feeding method (breastfed and/or formula-fed), and incidence of congenital abnormalities.
We investigated the onset of withdrawal syndrome among neonates delivered by mothers taking antiseizure medications during pregnancy. Experienced neonatologists and NICU nurses evaluated the neonates for withdrawal symptoms immediately after birth and every 6 hours thereafter using the checklist developed by Isobe et al.7), which is a simplified version of the Finnegan checklist that is widely used in Japan (Table 1). Neonates diagnosed with other conditions whose symptoms are similar to those of neonatal withdrawal syndrome, including hypoglycemia, hypocalcemia, infection, and preterm birth, were excluded. The neonates were continuously assessed for neonatal withdrawal syndrome for at least 5 days after birth. Neonates with a score of ≥8 points were considered to require pharmacotherapy.
Neonatal withdrawal syndrome checklist
†sleep disorders, crying after feeding, continuous crying.
‡hyperactive Moro reflex.
§frequent yawn, abrasions of the nose, knee or heel, bradycardia.
During the study period, a total of 29 pregnancies in 23 mothers with epilepsy were managed at our hospital. We excluded three patients from the analysis, including two patients whose obstetric management at our hospital began in the second trimester and one who moved to another facility in the second trimester. Therefore, we examined a total of 26 pregnancies in 20 mothers. All cases were managed since prepregnancy by a neurosurgeon.
Table 2 shows maternal background characteristics. The median maternal age at delivery was 30 years. Regarding complications, except for epilepsy, five cases underwent cesarean section previously and three had chlamydia cervicitis. Depression, schizophrenia, bronchial asthma, atrial septal defect, history of cerebral hemorrhage, and history of traumatic subarachnoid hemorrhage were detected in one patient each.
Before pregnancy, 4 of the 12 patients treated with valproate were successfully switched to levetiracetam or lamotrigine. Additionally, 2 of the 3 patients who transitioned from multiple drugs to a single agent showed successful transition after expressing a desire to conceive. Consequently, during pregnancy, the number of patients taking valproate, levetiracetam, lamotrigine, phenobarbital, carbamazepine, clonazepam, gabapentin, and others were 8, 6, 3, 3, 4, 1, 1, and 3, respectively. Regarding the number of antiseizure medications, 4 patients took no medication, 17 were taking 1 drug, 3 were taking 2 drugs, and 2 were taking 3 drugs.
Furthermore, 61.5% of patients took folic acid during pregnancy. All mothers who were taking valproate or multiple medications took folic acid. In all cases, the folic acid dose during pregnancy was 5 mg/day.
Regarding maternal outcomes, 1 pregnancy ended in early spontaneous abortion, whereas 25 pregnancies resulted in live births. A total of 4 pregnancies resulted in premature births, whereas 21 of the 25 pregnancies (84%) experienced term deliveries. Ten cases (40%) underwent cesarean section, with nine cases undergoing elective or emergency cesarean section due to obstetrical indications, such as previous cesarean section, weak labor, malrotation, nonreassuring fetal status, and exacerbation of hypertensive disorders of pregnancy. In one case, cesarean section was performed because the patient refused to deliver via normal vaginal birth due to the fear of experiencing epileptic seizure during labor. During the pregnancy period and within 1 month after giving birth, two patients experienced seizure only once during the pregnancy period (Table 3).
The outcomes of 25 neonates who were born alive are shown in Table 4. The neonates’ median birth weight was 3,002 g and the rate of small for gestational age was 8.0% (2/25). None of the infants had an Apgar score of <7 points at 5 minutes or an umbilical cord arterial blood pH of <7.1. Regarding neonatal congenital abnormalities, polydactyly of the left leg was detected in one neonate after birth. One neonate who showed hypotonia, poor suck, and imperfectly descended testis after birth was diagnosed with Prader-Willi syndrome through genetic testing. Another neonate showed poor weight gain in the early infancy period, repeated respiratory infections, and episodes of convulsions. This case was diagnosed with Pol Ⅲ-related leukodystrophy using magnetic resonance imaging and genetic testing at 2 years of age.
For the evaluation of withdrawal syndrome, among the 22 neonates whose mothers took antiseizure medications during pregnancy, 4 born before 37 gestational weeks and 2 with congenital abnormalities (Prader-Willi syndrome and Pol Ⅲ-related leukodystrophy) were excluded from the analysis. Therefore, we evaluated 16 neonates, of whom 12 (75.0%) showed withdrawal symptoms. Based on the withdrawal syndrome checklist, five cases had a maximum withdrawal symptom score of 1 point, two had 2 points, and five had 3 points. No cases showed a withdrawal symptom score of ≥8 points, the threshold for pharmacotherapy (Table 4). Regarding the number of antiseizure medications taken by the mothers of these neonates (n = 16), ten (62.5%), four (25.0%), and two (12.5%) neonates were born to mothers who took one, two, and three drugs, respectively.
Regarding the feeding method for all 25 neonates, 23 (92%) were breastfed, and only 2 were exclusively formula-fed.
Maternal background characteristics
Maternal outcomes
HDP:hypertensive disorders of pregnancy NRFS:nonreassuring fetal status CAM:chorioamnionitis
Neonatal outcomes
Although pregnancy may aggravate epilepsy, most patients with epilepsy do not experience a change in the frequency of seizures during pregnancy8). Only 1%-2% of pregnant women with epilepsy experience seizure during labor and delivery; therefore, >90% of them give birth via normal delivery without any apparent complications2,8). In the present study, the incidence of epileptic seizure during the pregnancy period and within 1 month after birth was low, as only 2 of the 26 cases (7.7%) experienced 1 seizure episode during this period.
Regarding obstetric complications in women with epilepsy, some studies have reported that the risk of miscarriage, stillbirth, preterm birth, hypertensive disorder, fetal growth restriction, birth of neonates with congenital malformations, neonatal asphyxia-related complication, and low Apgar score at 5 minutes is significantly higher in women with epilepsy than in those without epilepsy9,10). In our study, 25 of the 26 pregnancies resulted in live births, with 4 cases undergoing premature delivery; the term delivery rate was 84%. Previous studies have reported a higher rate of cesarean section in women with epilepsy than in those without epilepsy9,10). The vaginal delivery rate in our study was relatively low, as women who underwent cesarean delivery accounted for 40% of the total study population. However, the obstetrical indications for cesarean section in 9 of the 10 cases included weak labor, malrotation, nonreassuring fetal status, previous cesarean section, and exacerbation of hypertensive disorders of pregnancy. Only one case underwent cesarean section due to the fear of experiencing seizure during vaginal delivery after the onset of labor pain. In the present study, all mothers were treated by a neurosurgeon before pregnancy. Mothers with unplanned pregnancies showed a lower rate of administering antiseizure medication and had higher incidences of seizures during pregnancy, spontaneous fetal loss, preterm birth, and birth of neonates with major congenital malformations than those with planned pregnancy11,12). These findings revealed the importance of prepregnancy treatment for epilepsy and planned pregnancy to achieve better seizure control and pregnancy outcomes.
Regarding the teratogenicity of antiseizure medications, valproate showed the strongest effect, whereas lamotrigine and levetiracetam showed low teratogenicity (Fig. 1). In particular, the use of valproic acid increases the risk of facial anomalies or central nervous system dysfunction, known as “valproate syndrome,” among infants. In our study, among the children born to mothers with epilepsy, three had congenital abnormalities, including Prader-Willi syndrome, Pol Ⅲ-related leukodystrophy, and polydactyly. In this study, a neonate diagnosed with Prader-Willi syndrome was born to a mother who took lamotrigine only during pregnancy, and a neonate with Pol III-related leukodystrophy was born to a mother who took carbamazepine, clonazepam, and gabapentin during pregnancy. The association among these two diseases, maternal epilepsy, and use of antiepileptic drugs remains unknown, as there are no reports showing any association. Polydactyly is a common complication with a high incidence rate among neonates born to mothers taking antiseizure medications13,14). A mother who delivered a neonate with polydactyly had discontinued her antiseizure medications, such as phenobarbital and phenytoin, at 1 year before pregnancy and did not take any antiseizure medications during pregnancy. In our study, 4 of the 12 patients treated with valproate successfully switched to levetiracetam or lamotrigine, which are drugs with lower teratogenic effects, after expressing a desire to conceive. This prepregnancy shift to drugs with low adverse effects for the well-being of the fetus possibly led to relatively good neonatal outcomes.
Maternal antiseizure medications are a risk factor for neonatal withdrawal syndrome. Ebbesen et al.15) reported that 10 of the 22 (45.5%) neonates born to mothers who took valproate alone or valproate and carbamazepine developed withdrawal symptoms, and pharmacotherapy was required in 3 neonates. Thisted et al.16) reported that 9 of the 17 (53%) neonates born to mothers who took valproate developed withdrawal symptoms, and 4 neonates were administered with diazepam. In our study, 75% of the evaluated neonates showed withdrawal symptoms, but none of them scored ≥8 points in the withdrawal syndrome checklist, the threshold for pharmacotherapy. Studies have reported that neonatal withdrawal syndrome is more common in neonates born to mothers with polypharmacy than in those born to mothers who took a single drug17,18). None of the neonates in our study required pharmacotherapy, which could be due to the fact that 62.5% of all cases used a single maternal drug.
The antiseizure medications taken by the mothers may have caused some neonatal symptoms through breast feeding. However, the transfer of several types of psychotropic and antiseizure medications to breast milk may be actually minimal, as no adverse neurodevelopmental effects were noted in either breastfed or formula-fed neonates19). In fact, breast feeding is not contraindicated for most antiseizure medications. Some studies have reported that breastfed infants had a lower incidence of neonatal withdrawal syndrome and a lower pharmacotherapy rate than formula-fed infants. These studies also suggested that breast feeding is protective against neonatal withdrawal syndrome due to the small amounts of drug secretion in breast milk, which might provide a natural taper to neonates18,20). The other reason that no neonate required pharmacotherapy might be the high proportion of breastfed neonates.
Our study had several limitations. First, this is a case series study involving a few patients recruited from a single facility. Second, we could not examine pharmacological effects according to the type and dose of antiseizure medication, as our sample size was too small. Third, we could not clearly determine whether the observed neonatal symptoms were caused by withdrawal or by the drug’s effects across the placenta because the urine, blood, and meconium of the neonates were not examined. Fourth, blood concentrations of antiseizure drugs were measured in only a few mothers; thus, we could not examine the association between maternal blood drug concentration and neonatal withdrawal syndrome. Fifth, a long-term prognostic investigation of the neonates was not conducted. Children born to women with epilepsy were reported to have lower mean IQ scores, which remained low after adjusting for multiple confounding factors, including maternal education level, maternal age, year of birth, and birth weight21). In another report, in-utero exposure to antiseizure medication was suggested to be related to an increased risk of developing autism spectrum disorder22,23). However, to achieve good outcomes for women with epilepsy who wish to bear children and their future neonates, preconception management is crucial.
In conclusion, for women with epilepsy receiving medical treatment who have good seizure control before pregnancy, child birth may be relatively safe, with a low rate of neonatal withdrawal syndrome requiring pharmacotherapy. As these neonates may develop neurodevelopmental disorders, long-term follow-up is needed. Moreover, breastfeeding is considered useful to prevent the development of neonatal withdrawal syndrome and facilitate positive mother and infant bonding.
Teratogenicity of antiseizure medications
The authors would like to thank Enago (www.enago.jp) for the English language review.
All authors declare no conflict of interest regarding the publication of this article.
