IQ at 6 years after in utero exposure to antiepileptic drugs

Abstract

Objective: To delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs.Methods: Children born to women with epilepsy (n 5 243) and women without epilepsy (n 5 287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at 6 years of age. Maternal and child demographics were collected and entered into statistical models.Results: The adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] 24.9 to 214.6; p , 0.001) for children exposed to high-dose (.800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5-19.7; p , 0.001). Valproate at doses ,800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (25.6, 95% CI 211.1 to 20.1; p 5 0.04) and a 6-fold increase in educational intervention (95% CI 1.4-18.0; p 5 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (24.2, 95% CI 20.6 to 27.8; p 5 0.02) and increased frequency of IQ ,85.Conclusions: Consistent with data from younger cohorts, school-aged children exposed to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine. Antiepileptic drugs (AEDs) are associated with teratogenic risk to the development of the fetus, with the prevalence of major congenital malformations differing by treatment type and dose. Determining the association between exposure to AEDs and child cognitive functioning represents a challenge, and a number of different methodologies have been utilized in its investigation including case studies, 2-4 retrospective studies, 5,6 and prospective studies. 7-15 Despite limitations, 16 there is growing evidence that exposure to sodium valproate (VPA) in utero is associated with significantly poorer functioning. [10][11][12]15,17 Prospective studies consistently document that VPA is associated with an increase in risk of cognitive impairment in young children, 10,12,15 but any longer-term effects are unlikely to be comprehensively documented until the children studied are of school age, when cognitive development is more stable.10 In a comparison across AED monotherapies, a significantly poorer IQ in school-aged children exposed in utero to

Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy

“…There is not, however, a single agreed boundary at which "low" versus "high" is drawn. Recent data from the United Kingdom long-term follow-up study highlighted concern about verbal abilities and educational needs in children exposed to low-dose valproate, 33 which could suggest that there is no "safe" dose for valproate. This group is an important one, clinically, and additional neurodevelopmental research is required to clarify the consequences of low-dose valproate exposure on the unborn child.…”

Clobazam‐induced pedal edema: “An unrecognized side effect of a common antiepileptic drug”

“…Antiepileptic drugs (AEDs) such as gabapentin, pregabalin, and valproate are known to cause pedal edema. 2,3 Although the mechanism of pedal edema in patients taking gabapentin and pregabalin is thought to be the antagonistic action of these drugs on the calcium channels in the peripheral vasculature, the exact mechanism in the case of valproate is not yet known. The mechanism by which clobazam causes pedal edema has not yet been evaluated.…”

Evidence for spared attention to faces in 7-month-old infants after prenatal exposure to antiepileptic drugs

“…Besides the need for assessing the general effects of AED exposure on early development [7,9,10,[25][26][27], it has become important to assess changes in specific cognitive processes, and in particular, those related to visual functions. Recent developments in eye-tracking-based testing of infant cognition [28][29][30] have opened new possibilities for automated testing of infants' visual acuity, visuospatial orienting (gaze shifts to a novel visual stimulus), and attention to salient social stimuli, such as faces [31][32][33][34][35].…”