Pregnancy in Epilepsy: Moms Have Risks too

Abstract

Risk of Perinatal and Maternal Morbidity and Mortality Among Pregnant Women With Epilepsy

Razaz N, Igland J, Bjørk MH, Joseph KS, Dreier JW, Gilhus NE, Gissler M, Leinonen MK, Zoega H, Alvestad S, Christensen J, Tomson T. JAMA Neurol. 2024;81(9):985-995.

Importance: Maternal epilepsy is associated with adverse pregnancy and neonatal outcomes. A better understanding of this condition and the associated risk of mortality and morbidity at the time of delivery could help reduce adverse outcomes. Objective: To determine the risk of severe maternal and perinatal morbidity and mortality among women with epilepsy. Design, Setting, Participants: This prospective population-based register study in Denmark, Finland, Iceland, Norway, and Sweden took place between January 1, 1996 and December 31, 2017. Data analysis was performed from August 2022 to November 2023. Participants included all singleton births at 22 weeks’ gestation or longer. Births with missing or invalid information on birth weight or gestational length were excluded. The study team identified 4 511 267 deliveries, of which 4 475 984 were to women without epilepsy and 35 283 to mothers with epilepsy. Exposure: Maternal epilepsy diagnosis recorded before childbirth. Prenatal exposure to antiseizure medication (ASM), defined as any maternal prescription filled from conception to childbirth, was also examined. Main Outcomes and Measures: Composite severe maternal morbidity and mortality occurring in pregnancy or within 42 days’ postpartum and composite severe neonatal morbidity (eg, neonatal convulsions) and perinatal mortality (ie, stillbirths and deaths) during the first 28 days of life. Multivariable generalized estimating equations with logit link were used to obtain adjusted odds ratio (aOR) and 95% confidence interval (CI). Results: The mean (SD) age at delivery for women in the epilepsy cohort was 29.9 (5.3) years. The rate of composite severe maternal morbidity and mortality was also higher in women with epilepsy compared with those without epilepsy (36.9 vs 25.4 per 1000 deliveries). Women with epilepsy also had a significantly higher risk of death (0.23 deaths per 1000 deliveries) compared with women without epilepsy (0.05 deaths per 1000 deliveries) with an aOR of 3.86 (95% CI, 1.48-8.10). In particular, maternal epilepsy was associated with increased odds of severe preeclampsia, embolism, disseminated intravascular coagulation or shock, cerebrovascular events, and severe mental health conditions. Fetuses and infants of women with epilepsy were at elevated odds of mortality (aOR, 1.20; 95% CI, 1.05-1.38) and severe neonatal morbidity (aOR, 1.48; 95% CI, 1.40-1.56). In analyses restricted to women with epilepsy, women exposed to ASM compared with those unexposed had higher odds of severe maternal morbidity (aOR, 1.24; 95% CI, 1.10-1.48) and their neonates had an increased odd of mortality and severe morbidity (aOR, 1.37; 95% CI, 1.23-1.52). Conclusion and Relevance: This multinational study shows that women with epilepsy were at considerably higher risk of severe maternal and perinatal outcomes and increased risk of death during pregnancy and postpartum. Maternal epilepsy and maternal use of ASM were associated with increased maternal morbidity and perinatal mortality and morbidity.

Commentary

In recent years, the approach to optimal management of epilepsy during pregnancy has been transformed by knowledge of the teratogenic and neurodevelopmental risks of in-utero antiseizure medication (ASM) exposure informed by international pregnancy registries.^1,2 Unfortunately, expanded insight into fetal, infant, and child outcomes has not been matched by a commensurate exploration of risks to the pregnant person with epilepsy. Even the basic question as to whether epilepsy carries unique risk to pregnant women's health has remained under debate. Some studies have quoted a 5- to 10-fold increased risk of maternal mortality in epilepsy, but other investigations have found no elevation of risk with conclusions limited by sample size and weaknesses in study design.^2–6 The largest prior investigation, a retrospective study of perinatal maternal morbidity and mortality based on data from the U.S. Nationwide Inpatient Sample comparing close to 70,000 women with epilepsy to over 20,000,000 controls, indicated that about 1 in 1000 pregnancies in women with epilepsy result in maternal death. ⁴ That study, however, relied on ICD-10 codes assigned during the hospitalization for delivery. This raised concern that an unknown percentage of observed mortality might be attributable to acute symptomatic seizures related to conditions like eclampsia or peri-partum cerebrovascular events versus, potentially overstating the risk faced by women with chronic epilepsy present prior to pregnancy. There was further critique that those inclusion criteria could also lead to under ascertainment of women with well-controlled pre-existing epilepsy that might not be captured in the coding of obstetrics records, particularly if antiseizure medication was not prescribed at the time of labor and delivery. In addition, it has been uncertain if an epilepsy diagnosis might be a proxy for other factors contributing to poor maternal outcomes including social determinants of health, lack of insurance, and limited access to prenatal care. A 2022 study by Gyamfi-Bannerman et al using an insurance claims database to identify women with a diagnosis of epilepsy prior to pregnancy found no increased mortality risk, although the sample size was smaller at about 18,000 women with epilepsy. ⁵

There has also been a lack of clarity about what might drive maternal morbidity and mortality in epilepsy, including the cause(s) of death, the role of seizures, ASM, and co-morbidities. The U.S. Inpatient Sample-based study found women with epilepsy to have significantly higher rates of co-morbidities known to influence maternal mortality including diabetes, chronic renal disease, hypertension, psychiatric disorders, and substance abuse. ⁴ No analysis was included to determine to what extent comorbidity could have contributed to excess mortality in the epilepsy sample. A 30-year retrospective review from the United Kingdom on maternal death occurring during pregnancy and the early postpartum period found the majority were directly attributable to uncontrolled seizures. ⁷ Specifically, in 92 mortalities in women with epilepsy, 38 were SUDEP, 19 from aspiration during seizures, and 8 seizure-related drownings. If maternal mortality was driven by breakthrough seizures, one might expect that optimized medication compliance and management could prevent death, yet we have had little evidence-based insight into this issue. While some published studies have compared women with epilepsy on versus off ASM, there was no data on seizure control to inform if this was primarily differentiating active epilepsy from epilepsy in longstanding remission, or relative seizure control in these groups. There has also been a lack of data on potential contributions of specific ASM, medication compliance or serum drug levels. To add to the confusion, the Gyamfi-Bannerman study that used insurance claims to determine both epilepsy diagnosis and the presence of a filled prescription for ASM, found that serious pregnancy complications were more common in women with epilepsy not taking ASM versus those on ASM. ⁵

The article by Razaz et al specifically addresses many of the controversies and gaps in our understanding of risks to pregnant people with epilepsy. This was a retrospective population-based study of women from Denmark, Finland, Norway, and Sweden—countries that have universal health care, where all women had access to prenatal care. ⁸ To ensure that epilepsy was present prior to pregnancy, the diagnosis was defined based on ICD codes in the record in the 10 years prior to conception. For women registered in Norway, Denmark, and Finland inclusion as a person with epilepsy also required a filled prescription for ASM. Morbidity and mortality outcomes were assessed between 22 weeks’ gestation and 42 days’ postpartum based on inpatient ICD codes. In a total sample size of around 4.5 million, about 35,000 were women with epilepsy of whom 46% were prescribed ASM during pregnancy. Women with epilepsy were at an almost 4 fold increased risk of death. They were also 1.23 times more likely to have serious birth complications requiring hospitalization, particularly cerebrovascular accidents (OR, 6.69). These risks remained even when eclampsia was specifically excluded. Women with epilepsy had a greater burden of comorbidity, however, the elevated odds of mortality remained after adjusting for obesity, smoking, number of comorbid conditions, and frequency of pre-pregnancy hospitalizations. The authors noted they could not exclude the role of medical and psychiatric conditions, and these were generally more prevalent in the epilepsy group versus controls. Women with epilepsy using ASM during pregnancy were at higher risk of severe pre-eclampsia, hemorrhage, and stroke compared to women with epilepsy with no ASM. The highest complication rate was observed in women taking valproate; however, as the authors noted, ASM use may be a confounder for less well-controlled epilepsy. Increased risk of morbidity and mortality was still present in the subset of women whose epilepsy was diagnosed within a year of pregnancy, which should remove the modifying effect of outcomes in epilepsy in longstanding remission. With the concern of significantly increased risk of adverse pregnancy outcomes, the authors include a reminder that 96% of pregnancies in women with epilepsy were without mortality, serious morbidity, or adverse perinatal outcome.

Further investigation is still needed to stratify risk in women with epilepsy who are planning pregnancy, actively pregnant, or in the early postpartum period. It remains challenging to know how to balance the risk of ASM on the fetus with the risk of seizures on maternal health and wellness. Hopefully, future studies will provide information about the impact of seizure type and frequency during pregnancy and opportunities to modify risk by addressing medical and psychiatric co-morbidity. While an increased risk of maternal mortality in 1 in 1000 women with epilepsy demands intervention, we can be reassured that the overwhelming majority will have pregnancies without serious maternal or fetal adverse outcomes. Neurologists and obstetricians need further insight and guidance in knowing who—and when—to refer for high-risk pregnancy care.