Birth outcomes in pregnant women with epilepsy: A Nationwide multicenter study from Türkiye.

OBJECTIVE: The present study was aimed at investigating the effects of anti-seizure medications (ASMs), patient demographic characteristics, and the seizure type and frequency on the development of congenital malformations (CMs) in the infants of pregnant women with epilepsy (PWWE). METHODS: PWWE followed up at the neurology outpatient clinic of 21 centers between 2014 and 2019 were included in this prospective study. The follow-up of PWWE was conducted using structured, general pregnant follow-up forms prepared by the Pregnancy and Epilepsy Study Committee. The newborns were examined by a neonatologist after delivery and at 1 and 3 months postpartum. RESULTS: Of the infants of 759 PWWE, 7.2% had CMs, with 5.6% having major CMs. Polytherapy, monotherapy, and no medications were received by 168 (22.1%), 548 (72.2 %), and 43 (5.7 %) patients, respectively. CMs were detected at an incidence of 2.3% in infants of PWWE who did not receive medication, 5.7% in infants of PWWE who received monotherapy, and 13.7% in infants of PWWE who received polytherapy. The risk of malformation was 2.31-fold (95% confidence interval (CI): 1.48-4.61, p < .001) higher in infants of PWWE who received polytherapy. Levetiracetam was the most frequently used seizure medication as monotherapy, with the highest incidence of CMs occurring with valproic acid (VPA) use (8.5%) and the lowest with lamotrigine use (2.1%). The incidence of CMs was 5% at a carbamazepine dose <700 mg, 10% at a carbamazepine dose ≥700 mg, 5.5% at a VPA dose <750 mg, and 14.8% at a VPA dose ≥750 mg. Thus the risk of malformation increased 2.33 times (p = .041) in infants of PWWE receiving high-dose ASMs. SIGNIFICANCE: Birth outcomes of PWWE receiving and not receiving ASMs were evaluated. The risk of CMs occurrence was higher, particularly in infants of PWWE using VPA and receiving polytherapy. The incidence of CMs was found to be lower in infants of PWWE receiving lamotrigine.

External validation of the AntiEpileptic Drug Monitoring in PREgnancy (EMPiRE) model for predicting seizures in pregnant women with epilepsy.

BACKGROUND: The AntiEpileptic Drug Monitoring in PREgnancy (EMPiRE) model is the only available tool for predicting seizures in pregnant women with epilepsy (WWE) using anti-seizure medications (ASMs); however, its predictive performance requires validation. This study aimed to evaluate the predictive ability of this model in pregnant Chinese WWE and its potential usefulness in clinical practice. METHODS: Data of the EMPiRE model were derived from the EMPiRE study, a prospective multicenter cohort study that recruited women on ASM monotherapy (lamotrigine, carbamazepine, phenytoin or levetiracetam) or polytherapy (lamotrigine with either carbamazepine, phenytoin or levetiracetam). Based on the applicable population of the EMPiRE model, we evaluated 280 patients registered in the Wenzhou Epilepsy Follow-up Registry Database from January 1, 2010, to December 31, 2020. A total of 158 eligible patients were included in the validation cohort. We collected data on the baseline characteristics of patients, eight predictors of the EMPiRE model and outcome events. The outcome was the occurrence of tonic-clonic or non-tonic-clonic seizures at any time in pregnancy up to 6 weeks postpartum. We used the equation of the EMPiRE model to obtain the predicted probabilities of seizures. The predictive ability of the EMPiRE model was quantified by the C-statistic (scale 0-1, values > 0.5 show discrimination), GiViTI calibration test and decision curve analysis (DCA). RESULTS: Of 158 eligible patients, 96 patients (60.8%, 96/158) experienced one or more seizures at any time between pregnancy and 6 weeks postpartum. The EMPiRE model showed good discrimination with a C-statistic of 0.76 (95% confidence interval [CI] 0.70-0.84). The GiViTI calibration belt showed that the predicted probabilities, which ranged from 16 to 96% (95% CI), were lower than the actual probabilities. DCA indicated that the highest net proportional benefit was obtained for predicted probability thresholds of 15-18% and 54-96%. CONCLUSIONS: The EMPiRE model could discriminate well between WWE with and without seizures during pregnancy and 6 weeks postpartum, but the risk of seizures may be underestimated. The limitations of the model for specific medication regimens may limit its real-world application. If the model is further improved, it will be incredibly valuable.

SUDEP and epilepsy-related mortality in pregnancy.

Although data are limited, research in 2004 estimated a 10-fold increase in mortality in pregnancy in the United Kingdom in women with epilepsy (WWE) compared to women without epilepsy. We highlight epilepsy mortality in pregnancy based on the 2011 report of the United Kingdom Confidential Enquiries into Maternal Deaths, relating its findings to previous reports and epilepsy-rates in pregnancy. Among 2,291,493 maternities (2006-2008), we estimated 0.6% or 13,978 were in WWE. Fourteen deaths were epilepsy-related, of which 11 (79%) were sudden and unexpected (SUDEP). Nine occurred during pregnancy and five were postpartum. Nine (64%) were in women taking lamotrigine, seven as monotherapy. We estimated that 1:1,000 women died from epilepsy (mostly SUDEP) during or shortly after pregnancy. Epilepsy-related mortality is a significant risk in pregnancy. Antiepileptic drug-related factors may be relevant. The high proportion of women taking lamotrigine may reflect United Kingdom prescribing practice. Recent observations from the European and International Registry of Antiepileptic Drugs and Pregnancy (EURAP), whereby women on lamotrigine, the levels of which significantly decrease in pregnancy, had more difficulties with epilepsy control, argue against this being the sole explanation. Given the potential risks, every attempt should be made to prevent seizures, particularly convulsive, during pregnancy and postpartum. This, we believe, includes being proactive in maintaining lamotrigine levels during pregnancy.

Clinical characteristics, seizure control, and delivery outcomes in pregnant women with focal and generalized epilepsies.

OBJECTIVE: To prospectively investigate the course of epilepsy and assess seizure control during pregnancy in women with focal epilepsy (FE) compared with generalized epilepsy (GE), to ascertain the effects of epilepsy and its types on delivery and neonatal outcomes, and to compare adverse outcomes between pregnancies complicated by epilepsy and normal pregnancies. METHODS: 124 pregnant women with epilepsy (WWE) were enrolled in a prospective study. Obstetric and neonatal outcomes were compared with those of 277 healthy women in the control group. RESULTS: Occurrence of seizures during pregnancy was more often in FE (77.1 %) compared with GE (50.0 %) (Odds ratio [OR] 2.08; 95 % confidence interval [CI] 0.97-4.46, p = 0.06); the overall seizure freedom was significantly higher in women with GE compared with women with FE (p = 0.0038). Poor seizure control one year prior to the pregnancy and nonadherence to treatment were significantly associated with presence of seizures during pregnancy (p < 0.0001). Compared with pregnancies of women without epilepsy, WWE were at increased risk of cesarean section (CS) (p < 0.0001) and preterm birth (p = 0.03). Offspring of mothers with epilepsy were at higher risks of Apgar scores at 5 min ≤7 (p < 0.0001) and perinatal hypoxia (p = 0.03) compared with infants of unaffected women. Seizures during pregnancy were significantly correlated with the higher rate of CS, Apgar scores at 5 min ≤7, and perinatal hypoxia (p = 0.0069; p = 0.0098; and p = 0.0045, respectively). The risks of adverse outcomes were not significantly increased in women with FE compared to women with GE. CONCLUSION: Epileptic seizures in pregnancy are associated with increased risks of adverse delivery and neonatal outcomes. Hence, early assessment of seizure disorder, adequate seizure control prior to and during pregnancy, and effective treatment are required to prevent potential seizure-related complications and improve maternal and fetal outcomes.

Monitoring levetiracetam concentration in saliva during pregnancy is stable and feasible.

AIMS: This multicenter prospective cohort study (registration no. ChiCTR2000032089) aimed to investigate the relationship between saliva and plasma levetiracetam concentrations to determine whether saliva could be used for routine monitoring of levetiracetam during pregnancy. METHODS: The slot concentrations of levetiracetam in simultaneously obtained saliva and plasma samples were measured using UPLC-MS/MS. The correlations between saliva and plasma levetiracetam concentrations and the dose-normalized concentrations were compared among pregnant women in different stages and nonpregnant control participants with epilepsy. RESULTS: In total, 231 patients with 407 plasma and saliva sample pairs were enrolled from 39 centers. Linear relationships between salivary and plasma levetiracetam concentrations were reported in the enrolled population (r = 0.898, p < 0.001), including pregnant (r = 0.935, p < 0.001) and nonpregnant participants (r = 0.882, p < 0.001). Plasma concentrations were moderately higher than saliva concentrations, with ratios of saliva to plasma concentrations of 0.98 for nonpregnant women, 0.98, 1, and 1.12 for pregnant women during the first trimester, the second trimester, the and third trimester, respectively. The effective range of saliva levetiracetam concentration was found to be 9.98 µg/mL (lower limit) with an area under the curve (AUC) of 0.937 (95% confidence intervals, 0.915-0.959), sensitivity of 88.9%, specificity of 86.8%, and p < 0.001, to 24.05 µg/mL (upper limit) with an AUC of 0.952 (0.914-0.99), sensitivity of 100%, specificity of 92.3%, and p = 0.007. CONCLUSION: The saliva/plasma concentration ratio of levetiracetam remains constant during pregnancy and is similar to that in non-pregnant individuals. Monitoring levetiracetam concentration in saliva during pregnancy should be widely promoted.

Peripartum hemorrhage and other obstetric and neonatal outcomes in pregnant women with epilepsy: A single-center study.

OBJECTIVE: There are inconsistent results in different studies on maternal and fetal complications of pregnant women with epilepsy (PWWE). The differences may be in part due to racial characteristics. The aim of this study was to investigate if there is an increase in obstetric and neonatal complications, especially postpartum hemorrhage, in pregnant women with epilepsy in the Turkish population. METHODS: In a tertiary center, PWWE and the control group were compared in terms of obstetric and neonatal complications as well as postpartum hemorrhage. Among 46,789 deliveries, 154 eligible PWWE were matched 1: 3 with the control group. RESULTS: There was no increase in the possibility of peripartum hemorrhage and blood transfusion in PWWE. However, the probability of cesarean delivery was higher in PWWE (adjusted OR: 3.24 CI: 1.95-5.42, p < 0.001). Moreover, an increase in the possibility of fetal growth restriction, fetal death, admission to the neonatal intensive care unit and lower APGAR scores were found in PWWE. CONCLUSION: Although the risk of peripartum hemorrhage does not appear to be increased in PWWE, cesarean rates and fetal complications do increase. There is also a need for prospective studies examining long-term neonatal outcomes in pregnancies complicated by epilepsy.