Associations between particular types of fetal malformation and antiepileptic drug exposurein utero

Abstract

Associations between particular types of fetal malformation and antiepileptic drug exposure in utero Objective -To study associations between patterns of fetal malformation and individual antiepileptic drugs taken during pregnancy. Methods -Multiple variable logistic regression and other statistical analyses of data relating to 1733 fetuses from 1703 pregnancies (147 of which were not exposed to antiepileptic drugs during pregnancy). Results -There were statistically significant (P < 0.05) associations between (i) valproate exposure and spina bifida, malformations of the heart and great vessels, digits, skull bones, and brain, but not hypospadias, cleft palate/lip and mouth abnormalities, (ii) topiramate exposure and hypospadias and brain maldevelopments, and (iii) carbamazepine (CBZ) exposure and renal tract abnormalities. Conclusions -The valproate findings are mostly in keeping with the published literature, but the topiramate finding regarding hypospadias and the association between CBZ exposure and various renal tract abnormalities raise questions of organ specific teratogenesis. More extensive data are desirable, particularly in relation to topiramate, which is being used increasingly as a migraine prophylactic in women of childbearing potential.

Serum levels of valproic acid during delivery in mothers and in umbilical cord - correlation with birth length and weight

“…Valproic acid is a known human teratogen. Exposure in pregnancy is associated with approximately a three-fold increase in the rate of major malformations, mainly spina bifida, and only rarely, in increased risk for anencephaly, cardiac, craniofacial, skeletal and limb defects, and a possible set of dysmorphic features called the "valproate syndrome" associated with decreased intrauterine growth [17][18][19][20][21][22][23] . Intrauterine growth restriction associated with the maternal use of both VPA monotherapy and combination therapy have been described [24][25][26][27][28][29] .…”

Antiepileptic drug combinations not involving valproate and the risk of fetal malformations

“…Then, in 2010 and 2011, three articles appeared in the literature, including one from our group, each demonstrating that the critical factor that determined the increased malformation risk associated with AED polytherapy was not the use of two drugs simultaneously per se, but the inclusion of valproate-by this time known to be a dose-dependent teratogen-in the combinations. [6][7][8] Because prescribing practice in pregnant women with epilepsy has changed over the last decade and valproate is now being employed less often and at lower doses, 9,10 we wished to reexamine the relationship between AED polytherapy and the risk of fetal malformations, focusing on AED combinations that did not involve valproate. Specifically it was hypothesized that AEDs other than valproate may contribute to an increased malformation risk of AED polytherapy in pregnancy.…”

Valproate fetopathy

“…6,7 The most frequent anomalies in valproate fetopathy are neural tube defects, dysmorphic facial appearance, cardiac anomalies, limb, especially radial and thumb anomalies, and genitourinary anomalies. 8 The characteristic facial anomalies include arched eye brows, epicanthal folds, broad nasal bridge, small nose with anterverted nostrils and occasionally cleft palate and trigonencephaly due to premature closure of the metopic suture. 1,5 The most characteristic facial findings are small nose (57%) and epicanthal folds (31%).…”