Intelligence of children of epileptic mothers

doi:10.1016/S0022-3476(88)80377-9

The Journal of Pediatrics

Volume 113, Issue 4, October 1988, Pages 677-684

https://doi.org/10.1016/S0022-3476(88)80377-9 Get rights and content

Intellectual performance was investigated in a group of 148 children of epileptic mothers enrolled in a prospective study during pregnancy, and in 105 control children; 121 of the 148 children (82%) were examined together with the control group at the age of 5 1/2 years. The intelligence of 116 study and 104 control children was assessed by both verbal (Wechsler Preschool and Primary Scale of intelligence) and nonverbal (Leiter International Performance Scale) methods. The prevalence of mental subnormality among the remaining 32 study children was calculated on the basis of psychologic assessments done outside our study, or school achievement, or both. Of the 148 study group children, 131 had been exposed in utero to antiepileptic drugs, most commonly phenytoin (103 exposed). The prevalence of mental deficiency in the study group (1.4%) was either the same or only slightly elevated in comparison with that in the general population. In the control group, there were no mentally deficient children. The mean intelligence quotients obtained at the 5 1/2-year examination were significantly lower in the study group than in the control group. There was no increased risk of low intelligence attributable to fetal exposure either to antiepileptic drugs below toxic levels or to brief maternal convulsions. In a few cases, there seemed to be a genetic connection between epilepsy in the mother and poor intellectual performance in the child. A high number of minor anomalies was associated with a lower mean intelligence quotient in both the study and the control groups. However, those features previously reported as typical of children of epileptic mothers, and those shown to be associated with phenytoin exposure in a previous phase of this study, did not predict low intelligence in the affected children.

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Cited by (117)

The treatment of epilepsy in pregnancy: The neurodevelopmental risks associated with exposure to antiepileptic drugs
2016, Reproductive Toxicology
A number of antiepileptic drugs (AEDs) have been confirmed as teratogens due to their association with an increased malformation rate. The majority of research to date does not find an association between prenatal exposure to monotherapy carbamazepine, lamotrigine or phenytoin and neurodevelopmental outcome in comparison to control children and noted higher abilities in comparison to children exposed to valproate; but further work is needed before conclusions can be drawn. Data for levetiracetam was limited to one study, as was the evidence for topiramate. Sodium valproate exposure appeared to carry a dose dependent risk to the developing brain, with evidence of reduced levels of IQ, poorer verbal abilities and increased rate of autistic spectrum disorder both in comparison to control children and children exposed to other AEDs. The severity of the neurodevelopmental deficits associated with prenatal exposure to valproate highlight the critical need to consider neurodevelopmental outcomes as a central aspect of teratological research.
Children (10-12 years age) of women with epilepsy have lower intelligence, attention and memory: Observations from a prospective cohort case control study
2015, Epilepsy Research
To compare the cognitive outcome of children of women with epilepsy (CWE) with matched controls (CWO).
CWE (10–12 years) under follow up in Kerala Registry of Epilepsy and Pregnancy (n = 190) were evaluated with WISC-IV, Trail Making Test (TMT), Rey Auditory Verbal Learning Test (RAVLT) and compared with age and sex matched children of women without epilepsy – CWO (n = 149) drawn from schools in the same region. The dosage was expressed as prescribed daily dose/daily-defined dose (PDD/DDD) ratio in order to make comparisons.
The Full Scale IQ of CWE (77.9 ± 14.6) was 8.5 points lower than that of CWO (86.4 ± 13.4), which was statistically significant (p = 0.001). They performed lower on TMT Part A & B and RAVLT. The FSIQ mean ± SD; PDD/DDD ratio and number of monotherapy exposure for different anti-epileptic drugs were phenobarbital: (74.5 ± 14; 1.1 ± 0.8; 22), valproate: (82.8 ± 12.4; 0.3 ± 0.1; 36), carbamazepine: (82.2 ± 13.9; 0.6 ± 0.3; 41), phenytoin: (82.6 ± 13.5; 0.8 ± 0.3; 11). The FSIQ for those exposed to phenobarbital was significantly (p = 0.01) lower than others. The significant predictors of FSIQ differed at lower and higher ends of its spectrum. These predictors were low body mass index and low maternal education for FSIQ < 80 and low maternal education, low maternal IQ and high anti-epileptic drug dosage for FSIQ < 86. High anti-epileptic drug dosage, low maternal IQ, and low paternal education were the predictors for FSIQ < 92.
The IQ, attention and memory were significantly lower for 10–12 year old CWE when compared to CWO. The important predictors of low FSIQ were antiepileptic drug dosage, maternal IQ, and parental education.
Cognitive outcomes of prenatal antiepileptic drug exposure
2015, Epilepsy Research
Citation Excerpt :
Another study had similar findings for prenatal phenytoin exposure with lower scores for full scale IQ, verbal IQ and the Visual Motor Integration Test, which was also controlled for socioeconomic status but not for maternal IQ (Vanoverloop et al., 1992). However, there have also been studies in which intellectual outcomes were not affected by phenytoin, such as was found in 2005 by Vinten et al. with a small sample size, but controlling for maternal IQ, as well as by Gaily et al. (1988) and Shapiro et al. (1976), with consideration for maternal IQ and socioeconomic status, respectively. The NEAD study found that children exposed in utero to phenytoin did not differ from those exposed to carbamazepine or lamotrigine, but fared better than with valproate (Meador et al., 2013).
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.
Developmental neurotoxicity and anticonvulsant drugs: A possible link
2014, Reproductive Toxicology
Citation Excerpt :
The study concluded that CBZ exposure may lead to mild decrease in IQ [102]. In agreement with these findings, children exposed to CBZ and evaluated at early outcomes, showed impaired fine-motor and personal-social skills at 18 months and also an increased risk to develop aggressive behaviors at 36 months [84]. Prenatal exposure to CBZ had a significant impact on verbal but not on non-verbal abilities [15].
In utero exposure to antiepileptic drugs (AEDs) may affect neurodevelopment causing postnatal cognitive and behavioral alterations. Phenytoin and phenobarbital may lead to motor and learning dysfunctions in the pre-exposed children. These disorders may reflect the interference of these AEDs with the development of hippocampal and cerebellar neurons, as suggested by animal studies. Exposure to valproic acid may result in inhibition of neural stem cell proliferation and/or immature neuron migration in the cerebral cortex with consequent increased risk of neurodevelopmental impairment, such as autistic spectrum disorders. A central issue in the prevention of AED-mediated developmental effects is the identification of drugs that should be avoided in women of child-bearing potential and during pregnancy. The aim of this review is to explore the possible link between AEDs and neurodevelopmental dysfunctions both in human and in animal studies. The possible mechanisms underlying this association are also discussed.
Impact of early life exposure to antiepileptic drugs on neurobehavioral outcomes based on laboratory animal and clinical research
2013, Epilepsy and Behavior
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], [3], [4], [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], [7], [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], [10], [11], [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 “The Future of Translational Epilepsy Research”.
Anti-epileptic drugs and brain and behavioural development in animal models and humans
2010, Fetal and Maternal Medicine Review

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Supported by the Rinnekoti Research Foundation, Espoo, Finland, the Foundation for Pediatric Research, and the Orion Foundation.

Preliminary results of study presented in part at the Congress of the European Federation of Child Neurology Societies, Siena, Italy, April 11–13, 1985.

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Original articleIntelligence of children of epileptic mothers*

Lancet

J Pediatr

J Am Acad Child Psychiatry

J Pediatr

J Pediatr

J Pediatr

Am J Obstet Gynecol

Am J Obstet Gynecol

A study of the psychomotor development of the offspring of epileptic mothers

Follow-up study on growth and neurologic development of children born to epileptic mothers

Relationship between antiepileptic drug exposure of the infant and developmental potential

Somatic parameters, diseases and psychomotor development in the offspring of epileptic parents

The teratogenicity of hydantoins and barbiturates in humans, with considerations on the etiology of malformations and cerebral disturbances in the children of epileptic parents

Biol Res Pregnancy Perinatol

Minor physical anomalies and hyperactive behaviour in young children

Minor physical anomalies and academic performance in young school-children

Dev Med Child Neurol

Neurodevelopmental significance of minor and major congenital anomalies in neonatal high risk children

Neuropediatrics

Dictionary of epilepsy. Part I. Definitions

Serum folate concentrations during pregnancy in women with epilepsy: relation to antiepileptic drug concentrations, number of seizures, and fetal outcome

Br Med J

Original article
Intelligence of children of epileptic mothers*