PAPER

Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register

J Morrow¹, A Russell², E Guthrie³, L Parsons⁴, I Robertson⁵, R Waddell⁶, B Irwin⁶, R C McGivern⁷, P J Morrison⁸ and J Craig⁹

¹ Department of Neurology, Royal Group of Hospitals, Grosvenor Road, Belfast, UK
² Department of Clinical Neurophysiology, Southern General Hospital, Glasgow, UK
³ General Practitioner, Dumbarton Road, Glasgow
⁴ Department of Neurology, St Albans City Hospital, Waverley Road, St Albans, Herts, UK
⁵ Sharoe Green Unit, Lancashire Teaching Hospitals NHS Trust, Preston, Lancashire, UK
⁶ Royal Group of Hospitals, Grosvenor Road, Belfast
⁷ Northern Ireland Regional Medical Physics Agency, Royal Group of Hospitals, Grosvenor Road, Belfast
⁸ Department of Medical Genetics, Belfast City Hospital Trust, Belfast & School of Biological Sciences, University of Ulster, Coleraine, UK
⁹ Department of Neurology, Royal Group of Hospitals, Grosvenor Road, Belfast

Correspondence to:
Correspondence to:
Dr James I Morrow
Department of Neurology, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA, UK; jim.morrow{at}royalhospitals.n-i.nhs.uk

Objective: To assess the relative risk of major congenital malformation (MCM) from in utero exposure to antiepileptic drug (AEDs).

Methods: Prospective data collected by the UK Epilepsy and Pregnancy Register were analysed. The presence of MCMs recorded within the first three months of life was the main outcome measure.

Results: Full outcome data were collected on 3607 cases. The overall MCM rate for all AED exposed cases was 4.2% (95% confidence interval (CI), 3.6% to 5.0%). The MCM rate was higher for polytherapy (6.0%) (n = 770) than for monotherapy (3.7%) (n = 2598) (crude odds ratio (OR) = 1.63 (p = 0.010), adjusted OR = 1.83 (p = 0.002)). The MCM rate for women with epilepsy who had not taken AEDs during pregnancy (n = 239) was 3.5% (1.8% to 6.8%). The MCM rate was greater for pregnancies exposed only to valproate (6.2% (95% CI, 4.6% to 8.2%) than only to carbamazepine (2.2% (1.4% to 3.4%) (OR = 2.78 (p<0.001); adjusted OR = 2.97 (p<0.001)). There were fewer MCMs for pregnancies exposed only to lamotrigine than only to valproate. A positive dose response for MCMs was found for lamotrigine (p = 0.006). Polytherapy combinations containing valproate carried a higher risk of MCM than combinations not containing valproate (OR = 2.49 (1.31 to 4.70)).

Conclusions: Only 4.2% of live births to women with epilepsy had an MCM. The MCM rate for polytherapy exposure was greater than for monotherapy exposure. Polytherapy regimens containing valproate had significantly more MCMs than those not containing valproate. For monotherapy exposures, carbamazepine was associated with the lowest risk of MCM.

Abbreviations: AED, antiepileptic drug; EUROCAT, European Surveillance of Congenital Anomalies; MCM, major congenital malformation

Keywords: epilepsy; pregnancy; teratogenicity; antiepileptic drugs

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