Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy.

Motherisk Program, Hospital for Sick Children, Toronto, Ontario, Canada.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 03/1994; 271(10):767-70.
Source: PubMed


To compare pregnancy outcome prospectively after phenytoin and carbamazepine monotherapy with outcome in matched mother-child pairs exposed to nonteratogens to evaluate the relative fetal safety of these drugs.
A prospective, controlled, and blinded observational study.
Thirty-six mother-child pairs exposed to carbamazepine monotherapy and 34 pairs exposed to phenytoin monotherapy, all prospectively studied, were compared with mother-child pairs exposed to nonteratogens. The controls were matched for maternal age, time of consultation, obstetric history, and socioeconomic status.
The primary end point of interest was the children's global IQ measured by either the Bayley or the McCarthy scale according to their ages.
A teratology consultation program and two neurology services in Toronto, Ontario.
Children exposed to phenytoin in utero had a mean (+/- SD) global IQ 10 points lower (95% confidence interval, 4.9 to 15.8 points) than their matched controls (113.4 +/- 13.1 and 103.1 +/- 25.1; P = .038). The Reynell language development scores followed a similar trend, with children exposed to phenytoin scoring significantly lower than their controls. Phenytoin-exposed children had a global IQ of 84 or less significantly more often than the control group (P < .01). Children exposed in utero to carbamazepine did not differ from their controls on any of the neurobehavioral tests.
Our study suggests a clinically important negative effect of phenytoin on neurobehavioral development, independent of maternal or environmental factors, causing a substantial number of children to achieve a lower score than expected on cognitive tests. No similar effects could be shown after gestational use of carbamazepine.

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    • "The effects of other common AEDs, such as carbamazepine, on cognitive functioning of the offspring are less well defined, with some reports associating exposure with significant impairments in cognitive functioning [66] [67] and others that do not support this conclusion [63] [69] [86] [87] [103]. Those studies that do report effects of prenatal carbamazepine have suggested that there are developmental delays in offspring [66]. "
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    ABSTRACT: Epilepsy affects approximately 1% of children under the age of 15, making it a very common neurological disorder in the pediatric population (Russ et al., 2012 [1]). In addition, ~0.4-0.8% of all pregnant women have some form of epilepsy (Hauser et al., 1996a,b; Borthen et al., 2009; Krishnamurthy, 2012 [2-5]). Despite the potential deleterious effects of antiepileptic drugs (AEDs) on the developing brain, their use is still required for seizure control in pregnant women (Krishnamurthy, 2012 [5]), and they represent the standard approach for treating children with epilepsy (Chu-Shore and Thiele, 2010; Quach et al., 2010; Verrotti et al., 2011 [6-8]). Even when AEDs are effective, there are potential side effects, including cognitive and affective changes or altered sleep and appetite. The consequences of AED exposure in development have been studied extensively (Canger et al., 1999; Modi et al., 2011a,b; Oguni, 2011 [9-12]). Despite intensive study, there is still debate about the long-term consequences of early life AED exposure. Here, we consider the evidence to date that AED exposure, either prenatally or in early postnatal life, has significant adverse effects on the developing brain and incorporate studies of laboratory animals as well as those of patients. We also note the areas of research where greater clarity seems critical in order to make significant advances. A greater understanding of the impact of AEDs on somatic, cognitive and behavioral development has substantial value because it has the potential to inform clinical practice and guide studies aimed at understanding the genetic and molecular bases of comorbid pathologies associated with common treatment regimens. Understanding these effects has the potential to lead to AEDs with fewer side effects. Such advances would expand treatment options, diminish the risk associated with AED exposure in susceptible populations, and improve the quality of life and health outcomes of children with epilepsy and children born to women who took AEDs during pregnancy. This article is part of a Special Issue entitled "Translational Epilepsy Research".
    Epilepsy & Behavior 01/2013; 26(3). DOI:10.1016/j.yebeh.2012.10.031 · 2.26 Impact Factor
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    • "Phenytoin-exposed children had significantly lower IQ scores in a blinded-evaluator, case–control study (Vanoverloop et al., 1992). One prospective, blinded observational study demonstrated lower IQ for children with fetal phenytoin exposure compared with matched control (Scolnik et al., 1994), however no effect was seen when maternal IQ was taken into consideration (Loring et al., 1994). In a recent prospective observational multicenter studies of monotherapy, children at age 3 and again at age 4.5 years exposed to phenytoin in utero had better IQ outcomes than those exposed to valproate but did not differ from those exposed to carbamazepine or lamotrigine (Meador et al., 2009, 2012). "
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    ABSTRACT: The neurons in the developing mammalian brain are susceptible to antiepileptic drug (AED) effects. It is known that later in life deficits in cognitive performance as well as psychiatric deficits can manifest after early AED exposure. The extent of these deficits will be addressed. This review will attempt to draw parallels between the existent animal models and human studies. Through analysis of these studies, important future research will be elucidated and possible new and emerging therapies will be discussed.
    Frontiers in Neurology 12/2012; 3:182. DOI:10.3389/fneur.2012.00182
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    • "Carbamazepine appears to be the least developmentally neurotoxic compound among the major AEDs. Although in one study, mild mental retardation has been reported in children exposed in utero to carbamazepine (Ornoy and Cohen, 1996), no neurologic, or IQ differences were found by other investigators (van der Pol et al., 1991; Scolnick et al., 1994). "
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    ABSTRACT: Glutamate (Glu) and γ-aminobutyric acid (GABA) are major neurotransmitters in the mammalian brain which regulate brain development at molecular, cellular, and systems level. Sedative, anesthetic, and antiepileptic drugs (AEDs) interact with glutamate and GABA receptors to produce their desired effects. The question is posed whether such interference with glutamatergic and GABAergic neurotransmission may exert undesired, and perhaps even detrimental effects on human brain development. Preclinical research in rodents and non-human primates has provided extensive evidence that sedative, anesthetic, and AEDs can trigger suicide of neurons and oligodendroglia, suppress neurogenesis, and inhibit normal synapse development and sculpting. Behavioral correlates in rodents and non-human primates consist of long-lasting cognitive impairment. Retrospective clinical studies in humans exposed to anesthetics or AEDs in utero, during infancy or early childhood have delivered conflicting but concerning results in terms of a correlation between drug exposure and impaired neurodevelopmental outcomes. Prospective studies are currently ongoing. This review provides a short overview of the current state of knowledge on this topic.
    Frontiers in Neurology 08/2012; 3:120. DOI:10.3389/fneur.2012.00120
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