Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes

Abstract

Background: Pregnant women with epilepsy frequently experience seizures related to pregnancy complications and are often prescribed anti-epileptic drugs (AEDs) to manage their symptoms. However, less is known about the comparative safety of AED exposure in utero. We aimed to compare the risk of congenital malformations (CMs) and prenatal outcomes of AEDs in infants/children who were exposed to AEDs in utero through a systematic review and Bayesian random-effects network meta-analysis.

Methods: MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception to December 15, 2015. Two reviewers independently screened titles/abstracts and full-text papers for experimental and observational studies comparing mono- or poly-therapy AEDs versus control (no AED exposure) or other AEDs, then abstracted data and appraised the risk of bias. The primary outcome was incidence of major CMs, overall and by specific type (cardiac malformations, hypospadias, cleft lip and/or palate, club foot, inguinal hernia, and undescended testes).

Results: After screening 5305 titles and abstracts, 642 potentially relevant full-text articles, and 17 studies from scanning reference lists, 96 studies were eligible (n = 58,461 patients). Across all major CMs, many AEDs were associated with higher risk compared to control. For major CMs, ethosuximide (OR, 3.04; 95% CrI, 1.23-7.07), valproate (OR, 2.93; 95% CrI, 2.36-3.69), topiramate (OR, 1.90; 95% CrI, 1.17-2.97), phenobarbital (OR, 1.83; 95% CrI, 1.35-2.47), phenytoin (OR, 1.67; 95% CrI, 1.30-2.17), carbamazepine (OR, 1.37; 95% CrI, 1.10-1.71), and 11 polytherapies were significantly more harmful than control, but lamotrigine (OR, 0.96; 95% CrI, 0.72-1.25) and levetiracetam (OR, 0.72; 95% CrI, 0.43-1.16) were not.

Conclusion: The newer generation AEDs, lamotrigine and levetiracetam, were not associated with significant increased risks of CMs compared to control, and were significantly less likely to be associated with children experiencing cardiac malformations than control. However, this does not mean that these agents are not harmful to infants/children exposed in utero. Counselling is advised concerning teratogenic risks when the prescription is written for a woman of childbearing age and before women continue with these agents when considering pregnancy, such as switching from polytherapy to monotherapy with evidence of lower risk and avoiding AEDs, such as valproate, that are consistently associated with CMs. These decisions must be balanced against the need for seizure control.

Systematic review registration: PROSPERO CRD42014008925.

Keywords: Adverse effects; Antiepileptic drugs; Congenital malformations; Epilepsy; Fetus; Knowledge synthesis; Miscarriage; Network meta-analysis; Pregnancy; Systematic review.

Fig. 1

Study flow

Fig. 2

Rank heat plot for overall major congenital malformations (CMs), combined fetal losses, prenatal growth retardation, and preterm birth. Rank-heat plot of 49 treatments (presented in 49 radii) and four outcomes (presented in four concentric circles). Each sector is colored according to the SUCRA value of the corresponding treatment and outcome using the transformation of three colors: red (0%), yellow (50%), and green (100%). carbam carbamazepine, clobaz clobazam, clonaz clonazepam, ethos ethosuximide, gabap gabapentin, lamot lamotrigine, levet levetiracetam, oxcar oxcarbazepine, pheno phenobarbital, pheny phenytoin, primid primidone, topir topiramate, valpro valproate, vigab vigabatrin

Fig. 3

Network plots for overall major congenital malformations, combined fetal losses, prenatal growth retardation, and preterm birth. Each treatment node is weighted according to the number of patients that have received the particular treatment, and each edge is weighted according to the number of studies comparing the treatments it connects. carbam carbamazepine, clobaz clobazam, clonaz clonazepam, ethos ethosuximide, gabap gabapentin, lamot lamotrigine, levet levetiracetam, oxcar oxcarbazepine, pheno phenobarbital, pheny phenytoin, primid primidone, topir topiramate, valpro valproate, vigab vigabatrin

Fig. 4

Network meta-analysis forest plots for each treatment versus control. Each rhombus represents the summary treatment effect estimated in the network meta-analysis on the odds ratio (OR) scale. The black horizontal lines represent the credible intervals (CrI) for the summary treatment effects, and the red horizontal lines represent the corresponding predictive intervals (PrI). In the absence of heterogeneity, the CrIs and PrIs should be identical. An OR > 1 suggests that control is safer, whereas an OR < 1 suggests that the comparator active treatment is safer. The vertical blue line corresponds to an OR = 1 (i.e., the treatment groups compared are equally safe). The total sample size (n) included in each treatment is also presented. a Overall major congenital malformations (78 studies, 35,016 cases, 48 treatments). b Combined fetal losses (31 studies, 13,487 cases, 28 treatments). carbam carbamazepine, clobaz clobazam, clonaz clonazepam, ethos ethosuximide, gabap gabapentin, lamot lamotrigine, levet levetiracetam, oxcar oxcarbazepine, pheno phenobarbital, pheny phenytoin, primid primidone, topir topiramate, valpro valproate, vigab vigabatrin

Fig. 5

Network meta-analysis forest plots for each treatment versus control. Each rhombus represents the summary treatment effect estimated in the network meta-analysis on the odds ratio (OR) scale. The black horizontal lines represent the credible intervals (CrI) for the summary treatment effects, and the red horizontal lines represent the corresponding predictive intervals (PrI). In the absence of heterogeneity, the CrIs and PrIs should be identical. An OR > 1 suggests that control is safer, whereas an OR < 1 suggests that the comparator active treatment is safer. The vertical blue line corresponds to an OR = 1 (i.e., the treatment groups compared are equally safe). The total sample size (n) included in each treatment is also presented. a Prenatal growth retardation (16 studies, 18,177 cases, 23 treatments). b Preterm birth (17 studies, 17,133 cases, 23 treatments). carbam carbamazepine, clobaz clobazam, clonaz clonazepam, ethos ethosuximide, gabap gabapentin, lamot lamotrigine, levet levetiracetam, oxcar oxcarbazepine, pheno phenobarbital, pheny phenytoin, primid primidone, topir topiramate, valpro valproate, vigab vigabatrin

Fig. 6

Network meta-analysis forest plots for each treatment versus control. Each rhombus represents the summary treatment effect estimated in the network meta-analysis on the odds ratio (OR) scale. The black horizontal lines represent the credible intervals (CrI) for the summary treatment effects, and the red horizontal lines represent the corresponding predictive intervals (PrI). In the absence of heterogeneity, the CrIs and PrIs should be identical. An OR > 1 suggests that control is safer, whereas an OR < 1 suggests that the comparator active treatment is safer. The vertical blue line corresponds to an OR = 1 (i.e., the treatment groups compared are equally safe). The total sample size (n) included in each treatment is also presented. a Cardiac malformations (51 studies, 21,935 cases, 40 treatments). b Hypospadias (31 studies, 12,365 cases, 32 treatments). carbam carbamazepine, clobaz clobazam, clonaz clonazepam, ethos ethosuximide, gabap gabapentin, lamot lamotrigine, levet levetiracetam, oxcar oxcarbazepine, pheno phenobarbital, pheny phenytoin, primid primidone, topir topiramate, valpro valproate, vigab vigabatrin

Fig. 7

Network meta-analysis forest plots for each treatment versus control. Each rhombus represents the summary treatment effect estimated in the network meta-analysis on the odds ratio (OR) scale. The black horizontal lines represent the credible intervals (CrI) for the summary treatment effects, and the red horizontal lines represent the corresponding predictive intervals (PrI). In the absence of heterogeneity, the CrIs and PrIs should be identical. An OR > 1 suggests that control is safer, whereas an OR < 1 suggests that the comparator active treatment is safer. The vertical blue line corresponds to an OR = 1 (i.e., the treatment groups compared are equally safe). The total sample size (n) included in each treatment is also presented. a Cleft lip/palate (29 studies, 18,987 cases, 33 treatments). b Club foot (23 studies, 8836 cases 27 treatments). carbam carbamazepine, clobaz clobazam, clonaz clonazepam, ethos ethosuximide, gabap gabapentin, lamot lamotrigine, levet levetiracetam, oxcar oxcarbazepine, pheno phenobarbital, pheny phenytoin, primid primidone, topir topiramate, valpro valproate, vigab vigabatrin

Fig. 8

Network meta-analysis forest plots for each treatment versus control. Each rhombus represents the summary treatment effect estimated in the network meta-analysis on the odds ratio (OR) scale. The black horizontal lines represent the credible intervals (CrI) for the summary treatment effects, and the red horizontal lines represent the corresponding predictive intervals (PrI). In the absence of heterogeneity, the CrIs and PrIs should be identical. An OR > 1 suggests that control is safer, whereas an OR < 1 suggests that the comparator active treatment is safer. The vertical blue line corresponds to an OR = 1 (i.e., the treatment groups compared are equally safe). The total sample size (n) included in each treatment is also presented. a Inguinal hernia (13 studies, 12,216 cases, 29 treatments). b Undescended testes (10 studies, 6270 cases, 17 treatments). c Minor congenital malformations (9 studies, 614 cases, 17 treatments). carbam carbamazepine, clobaz clobazam, clonaz clonazepam, ethos ethosuximide, gabap gabapentin, lamot lamotrigine, levet levetiracetam, oxcar oxcarbazepine, pheno phenobarbital, pheny phenytoin, primid primidone, topir topiramate, valpro valproate, vigab vigabatrin