Research Article: Predicting seizures in pregnant women with epilepsy: Development and external validation of a prognostic model

Date Published: May 13, 2019

Publisher: Public Library of Science

Author(s): John Allotey, Borja M. Fernandez-Felix, Javier Zamora, Ngawai Moss, Manny Bagary, Andrew Kelso, Rehan Khan, Joris A. M. van der Post, Ben W. Mol, Alexander M. Pirie, Dougall McCorry, Khalid S. Khan, Shakila Thangaratinam, Lucy C Chappell

Abstract: BackgroundSeizures are the main cause of maternal death in women with epilepsy, but there are no tools for predicting seizures in pregnancy. We set out to develop and validate a prognostic model, using information collected during the antenatal booking visit, to predict seizure risk at any time in pregnancy and until 6 weeks postpartum in women with epilepsy on antiepileptic drugs.Methods and findingsWe used datasets of a prospective cohort study (EMPiRE) of 527 pregnant women with epilepsy on medication recruited from 50 hospitals in the UK (4 November 2011–17 August 2014). The model development cohort comprised 399 women whose antiepileptic drug doses were adjusted based on clinical features only; the validation cohort comprised 128 women whose drug dose adjustments were informed by serum drug levels. The outcome was epileptic (non-eclamptic) seizure captured using diary records. We fitted the model using LASSO (least absolute shrinkage and selection operator) regression, and reported the performance using C-statistic (scale 0–1, values > 0.5 show discrimination) and calibration slope (scale 0–1, values near 1 show accuracy) with 95% confidence intervals (CIs). We determined the net benefit (a weighted sum of true positive and false positive classifications) of using the model, with various probability thresholds, to aid clinicians in making individualised decisions regarding, for example, referral to tertiary care, frequency and intensity of monitoring, and changes in antiepileptic medication. Seizures occurred in 183 women (46%, 183/399) in the model development cohort and in 57 women (45%, 57/128) in the validation cohort. The model included age at first seizure, baseline seizure classification, history of mental health disorder or learning difficulty, occurrence of tonic-clonic and non-tonic-clonic seizures in the 3 months before pregnancy, previous admission to hospital for seizures during pregnancy, and baseline dose of lamotrigine and levetiracetam. The C-statistic was 0.79 (95% CI 0.75, 0.84). On external validation, the model showed good performance (C-statistic 0.76, 95% CI 0.66, 0.85; calibration slope 0.93, 95% CI 0.44, 1.41) but with imprecise estimates. The EMPiRE model showed the highest net proportional benefit for predicted probability thresholds between 12% and 99%. Limitations of this study include the varied gestational ages of women at recruitment, retrospective patient recall of seizure history, potential variations in seizure classification, the small number of events in the validation cohort, and the clinical utility restricted to decision-making thresholds above 12%. The model findings may not be generalisable to low- and middle-income countries, or when information on all predictors is not available.ConclusionsThe EMPiRE model showed good performance in predicting the risk of seizures in pregnant women with epilepsy who are prescribed antiepileptic drugs. Integration of the tool within the antenatal booking visit, deployed as a simple nomogram, can help to optimise care in women with epilepsy.

Partial Text: Women with epilepsy are 10 times more likely to die in pregnancy than those without the condition [1]—seizures are a common cause of death [2]. Despite warnings from consecutive reports of the Confidential Enquiry into Maternal Deaths (UK) on the failings in antenatal, intrapartum, and postnatal management of women with epilepsy, care of these women remains fragmented [3,4]. A lack of recognition of the women’s high-risk status by professionals in primary and in secondary care has been highlighted consistently as the main factor behind epilepsy-related maternal deaths [2,3,5]. Furthermore, up to 4 in 10 women discontinue their antiepileptic medication in pregnancy due to concerns about the effects of drugs on the fetus, thereby increasing their risk of seizures [6,7]. Many maternal deaths in women with epilepsy could be averted with timely specialist input [5]. Seizures in pregnancy also have a negative impact on daily living. For example, the loss of driving license following seizures affects employment, relationships, and quality of life [8–10].

We developed and validated the prognostic model for seizures in the prospective multicentre EMPiRE (AntiEpileptic drug Monitoring in PREgnancy) study, which recruited pregnant women with epilepsy on antiepileptic drugs at first antenatal visit from 50 maternity units in the UK between 4 November 2011 and 17 August 2014 [17]. The UK National Research Ethics Committee approved the EMPiRE study (11/WM/0164), written consent was obtained from participants, and the protocol can be accessed at The research reported here did not require further review by an ethics committee. We reported our prognostic study in line with the TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) recommendations, and present our findings as a nomogram, a graphical representation of the model to calculate an individual’s risk of seizure [18–20] (S1 TRIPOD Checklist).

The EMPiRE study recruited 560 pregnant women. The model development cohort included 399 women; the validation cohort included 128 women (S1 Appendix).



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