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

Abstract

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.

Lamotrigine in Breast Milk and Nursing Infants: Determination of Exposure

“…2,3 This transition is propagated by the burgeoning lamotrigine reproductive safety data. Briefly, the overall risk of major fetal malformations after first-trimester prenatal exposure to lamotrigine is 2.6% (83 of 3176 exposures, including 0.32% [8 of 2537] for midline cleft formations), [4][5][6][7][8][9][10] rates that are within the range of births not involving drug exposures. A recent report by the North American Pregnancy Registry noted a relatively high rate of midline facial clefts (0.89% of 564 exposures) 8 ; however, the collective rate of orofacial clefts in the other registries was only 0.15% (2 of 1937 exposures).…”

“…A recent report by the North American Pregnancy Registry noted a relatively high rate of midline facial clefts (0.89% of 564 exposures) 8 ; however, the collective rate of orofacial clefts in the other registries was only 0.15% (2 of 1937 exposures). [4][5][6][7]9,10 The United Kingdom Epilepsy and Pregnancy Register reported higher risk of malformations at maternal daily doses exceeding 200 mg, 10 although this was not confirmed in a subsequent analysis of the manufacturer's registry. 7 The transplacental passage of lamotrigine both in placental perfusion and umbilical cord blood at delivery indicates that fetal exposure is equal to maternal plasma concentrations.…”

Teratogenicity of Antiepileptic Drugs

“…There is evidence in literature to suggest that the ratio of major malformation increases due to VPA monotherapy or polytherapy including VPA, especially with higher doses, and has a negative impact on the long-term cognitive development of the child. 18,[33][34][35][36][37][38] There was one child with autism while 28 children were below the age of two, hence impossible to diagnose at the time of the study. Therefore, the ratio of autism in our sample needs to be revised at a later date.…”

Economic evaluation of anti-epileptic drug therapies with specific focus on teratogenic outcomes

“…Therefore, it is important for the prescribers to already keep in mind potential future wishes to become pregnant when choosing between antiepileptic therapies in younger girls. Carbamazepine, valproic acid and lamotrigine are the most used anti-epileptic drugs, both among pregnant and non-pregnant women 5,6 . All three agents are first choice options for partial epilepsy.…”