Neurodevelopment of Children Exposed In Utero to Phenytoin and Carbamazepine Monotherapy

ArticleinJAMA The Journal of the American Medical Association 271(10):767-70 · March 1994with14 Reads
DOI: 10.1097/00006254-199408000-00004 · Source: PubMed
Abstract
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.
    • "The majority of studies evaluating carbamazepine have demonstrated no effect on cognition with prenatal exposure (Scolnik et al., 1994; Wide et al., 2002; Vinten et al., 2005; Meador et al., 2013), although lower intelligence scores have been reported (Ornoy and Cohen, 1996). "
    [Show abstract] [Hide abstract] ABSTRACT: Antiepileptic drugs (AEDs) have been known to have teratogenic effects for a little over 50 years. While early reports focused on fetal malformations, there has been an increasing amount of data over the last few decades exploring the cognitive outcomes of offspring exposed to AEDs in utero. Although the challenges of confounding factors and varied methodologies have led to inconsistent results, the negative impact of some of the agents, such as valproate, have become clear. Further studies are needed to evaluate the cognitive effects of prenatal exposure to many AEDs which have not been tested, to clarify the effects of existing AEDs which have yielded mixed results, and to better understand the effects of polytherapy. Research in animal models is warranted to screen AEDs for their effects on cognition in exposed offspring and to further our understanding of the underlying mechanisms by which AEDs exert their harmful effects on the developing brain. And finally, new AEDs without these harmful effects and agents which can prevent or reverse the negative consequences imparted by AED therapy on cognition should be sought. Copyright © 2015 Elsevier B.V. All rights reserved.
    Article · May 2015
    • "Among studies of illicit drugs, there have been reports of associations between lower general language scores and maternal use of cocaine in pregnancy [10,11] . A study of anticonvulsants used prenatally among women with epilepsy demonstrated an association between phenytoin and both the verbal comprehension and expressive language scores on the Reynell scales, which was not found with a different anticonvulsant [12]. Another study found an association between sodium valproate exposure in the 1 st trimester with language im- pairment [13] . "
    [Show abstract] [Hide abstract] ABSTRACT: Although speech and language deficits are common in children and strongly associated with poor educational and social outcomes, little attention has been paid to the antecedents. In this study we used the information from the Avon Longitudinal Study of Parents and Children to examine preconception and prenatal environmental risk factors that were related to communication difficulties in children using the Children's Communication Checklist (CCC). We used an exposome-wide approach to identify environmental factors univariably associated with the CCC. Taking account of the False Discovery rate, we used a P value of 0.000157 to identify 621 of 3855 items tested. These were then subjected to a series of stepwise linear regression analyses, firstly within 10 domains: personal characteristics, health, development, education, socio-economic variables, lifestyle, home and social environments, life events and chemical and other exposures; and then with the predictive variables from each domain. The final model consisted of 19 variables independently associated with the communication scale. These variables suggested 6 possible mechanisms: stressors primarily associated with socio-economic disadvantage although other lifestyle choices such as a social network of family or friends can ameliorate these effects; indicators of future parenting skills primarily associated with aspects of parental personality; aspects of the home environment; poor maternal health with a novel finding concerning maternal hearing loss; and maternal education which was partially mediated by the child's IQ. Finally, there may be a mechanism via the maternal diet in pregnancy in particular the consumption of fatty or processed foods. This is the subject of ongoing investigation.
    Full-text · Article · Mar 2015
    • "significantly lower on intelligence quotient and language tests (Scolnik et al., 1994). Treatment of adult male Sprague-Dawley rats with an anti-METH monoclonal antibody (mAb) before (pretreatment model) or after (overdose model) METH administration can significantly reduce METH concentrations in the brain and other organs (Byrnes-Blake et al., 2003; Laurenzana et al., 2003; Byrnes-Blake et al., 2005). "
    [Show abstract] [Hide abstract] ABSTRACT: We hypothesized that treatment of pregnant rat dams with a dual reactive monoclonal antibody (mAb4G9) against (+)-methamphetamine (METH, KD =16 nM) and (+)-amphetamine (AMP, KD =102 nM) could confer maternal and fetal protection from brain accumulation of both drugs of abuse. To test this hypothesis, pregnant Sprague-Dawley rats (on gestational day 21) received a 1 mg/kg intravenous METH dose, followed 30-min later by vehicle or mAb4G9 treatment. The mAb4G9 dose was 0.56 mole-equivalent in binding sites to the METH body burden. Pharmacokinetic analysis showed baseline METH and AMP elimination half-lives were congruent in dams and fetuses, but the METH volume of distribution in dams was nearly double the fetal values. The METH and AMP area under the serum concentration-versus-time curves from 40 min to 5 h (AUC 40min-5hr) after mAb4G9-treatment increased >7,000% and 2,000%, respectively in dams. Fetal METH serum AUC 40min-5hr did not change, but AMP AUC 40min-5hr decreased 23%. The increased METH and AMP concentrations in maternal serum resulted from significant increases in mAb4G9 binding. Protein binding changed from ~15% to >90% for METH and AMP. Fetal serum protein binding appeared to gradually increase, but the absolute fraction bound was trivial compared to the dams. MAb4G9 treatment significantly reduced METH and AMP brain AUC 40min-5hr values by 66% and 45% in dams, and 44% and 46% in fetuses (P<0.05), respectively. These results show anti-METH/AMP mAb4G9 therapy in dams can offer maternal and fetal brain protection from the potentially harmful effects of METH and AMP.
    Article · May 2014
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