An interval review of congenital malformations associated with prenatal exposure to anti-epileptic drugs (J. Weston and colleagues, Cochrane Database Systematic Reviews, e-published on November 7, 2016; 11:CDO10224) corroborates previously reported findings pertaining to teratogenicity of carbamazepine and valproic acid (both indicated for treatment of acute mania, and both deemed to convey prophylactic activity with respect to suppression of manic recurrence), and both effective for migraine prophylaxis and for alleviation of acute neuropathic pain). Known to confer higher-than-population risks of neural tube defects (such as spina bifida and anencephaly) and to do so before today’s technology can confirm pregnancy, neither drug would likely be approved were its application for approval of a new drug (IND) submitted today. Contrariwise would neither likely have been approved had today’s alternatives (gabapentin, pregabalin, topiramate, and lamotrigine) preceded them. Reviewed every decade or so, the latest vetting of antiepileptic drugs leaves unrevised the reassuring ordination of its predecessor.
The authors searched registries of epileptic patients, registries of controlled clinical trials, and large medical databases for prospective, controlled cohort studies of women with epilepsy who had been treated with anti-epileptic pharmacotherapy during pregnancy, and compared rates of major congenital malformations in their infants with those of two control groups of infants: those born to epileptic mothers without prenatal exposure to anti-epileptic drugs, and those born to non-epileptic mothers unexposed to antiepileptic drugs during pregnancy.
The authors analyzed studies of prenatal exposure to a diversity of old- and new-generation antiepileptic drugs, including phenytoin, primidone, phenobarbital, carbamazepine, valproic acid, oxcarbazepine, levetiracetam, gabapentin, topiramate and lamotrigine, and compared rates of major congenital malformations following gestational exposure to each with that of a patient sample of the general population.
Compared with baseline population rates of major congenital malformations ranging from three to five percent, the authors observed the highest rate among offspring of valproic acid-treated women (10.32 percent). Infants with prenatal exposure to valproic acid had significantly higher risks of major congenital malformations than did infants born to epileptic women who received no antiepileptic drugs and women without epilepsy.
Prenatal exposure to valproic acid was associated with significantly higher risks of congenital malformations than was prenatal exposure to each of the other antiepileptic drugs when compared head-to-head. Moreover, valproic acid-related congenital malformations were significantly more likely to consist of neural tube defects, orofacial and craniofacial defects, and skeletal and limb malformations. The risk of valproic–acid-related congenital malformations appeared dose-related.
The lowest risks of congenital malformations following prenatal exposure were conferred by lamotrigine and levetiracetam (each similar to those of infants in each of the control groups with no prenatal antiepileptic exposure (those born to untreated epileptic women or women without epilepsy)). (So, too, were risks following prenatal exposures to gabapentin, oxcarbazepine, topiramate, and zonisamide, withal calculated from smaller samples with greater variability than those of lamotrigine and/or levetiracetam, and therefore considered less favorable for clinical use, pending study of larger samples.)
Infants with prenatal exposure to carbamazepine had twice the risk of developing congenital malformations compared with infants born to women without epilepsy and 1.5-times higher risk than those born to untreated epileptic women.
Infants with prenatal exposure to phenytoin had a rate of major congenital malformations that waš 2.4-times higher than that of either of the untreated control groups.
Among the antiepileptic drugs compared, lamotrigine has so far accumulated the most abundant and strongest evidence of effectiveness for depression associated with bipolar disorder, type II. The authors’ finding—that it is one of two antiepileptic treatments with the lowest risk of congenital malformations following prenatal exposure (and that that risk is no higher than that accompanying absence of exposure)—corroborates the potential favorability of lamotrigine as first-line treatment by reducing the denominator of the benefit:risk paradigm.