Minor anomalies in offspring of epileptic mothers

doi:10.1016/S0022-3476(88)80162-8

The Journal of Pediatrics

Volume 112, Issue 4, April 1988, Pages 520-529

https://doi.org/10.1016/S0022-3476(88)80162-8 Get rights and content

In a prospective study, 121 children of mothers with epilepsy (study group) and 105 control children were examined in a blinded fashion at age 5 1/2 years for 80 minor physical anomalies, including nine typical features previously reported characteristic of fetal hydantoin syndrome. Of the study group, 106 children had been exposed to antiepileptic drugs (82 to phenytoin) during pregnancy; 44 (36%) mothers had had generalized convulsions during pregnancy. One hundred fourteen mothers and 87 fathers of study group children and 101 mothers and 58 fathers of control children were also examined. A significant excess of minor anomalies considered characteristic of hydantoin syndrome was observed in children of epileptic mothers and in epileptic mothers, compared with the control group. There was no excess of other minor anomalies studied. Several minor anomalies previously regarded as typical of fetal hydantoin syndrome were shown to be genetically linked to epilepsy. Only hypertelorism and digital hypoplasia were associated with phenytoin exposure. The current concept of the syndrome seems to be incorrect; most of the “typical” characteristics are not caused by phenytoin. None of the phenytoin-exposed children had all of the main characteristics of hydantoin syndrome (typical acrofacial features, intellectual deficiency, growth retardation, and microcephaly). The risk of developmental disturbance associated with intrauterine phenytoin exposure seems to be much lower than the 7% to 11% risk of fetal hydantoin syndrome reported earlier.

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Cited by (118)

Drugs and Environmental Agents in Pregnancy and Lactation: Teratology, Epidemiology
2016, Obstetrics: Normal and Problem Pregnancies
Neurologic Disorders in Pregnancy
2016, Obstetrics: Normal and Problem Pregnancies
Impact of early life exposure to antiepileptic drugs on neurobehavioral outcomes based on laboratory animal and clinical research
2013, Epilepsy and Behavior
Citation Excerpt :
Some of the earliest studies to identify a potential effect of AEDs on cognitive function in the offspring come from studies of phenytoin, where it was shown that there was an increased risk to cognitive function following prenatal exposure [19,24]. These findings were, in part, confirmed by follow-up studies in which trends were found toward decreased IQ in children (aged 4, 5, and 7 years) exposed to phenytoin in utero [20,34,80–85]. In a significant proportion of those studies, phenytoin was used as part of a polytherapy, so the direct contribution of phenytoin to cognitive outcomes could not be assessed.
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”.
Neurodevelopmental effects of anti-epileptic drugs
2010, Epilepsy Research
Citation Excerpt :
A possible increased risk of developmental delay in offspring born to mothers with epilepsy taking anti-epileptic drugs has long been noted, but not attributed to any specific anticonvulsant. ( Gaily et al., 1988; Granstrom and Gaily, 1992; Speidel and Meadow, 1972). Many potential contributory factors have been considered such as maternal seizure type, number of seizures during pregnancy, IQ and education of parents, in addition to AED exposure (Table 1).
Use of medication with a desired effect on the central nervous system (as with anti-epileptic drugs) in children will undoubtedly cause concern about neurodevelopment. Data are emerging to suggest an effect of anticonvulsants on the developing brain of the unborn child when administered to mothers with epilepsy. This obviously requires detailed evaluation, especially when considering the risks of epilepsy itself. In the child with epilepsy, many of the early onset epilepsies are associated with developmental compromise as part of their clinical profile, and therefore determining the relative effects of the underlying cause, seizures and medication can be difficult. Although data are available with regard to some anti-epileptic drugs (AEDs) they remain lacking particularly in the very young with regard to efficacy as well as neurodevelopmental effects of the newer anti-epileptic drugs. Ongoing evaluation is required to ensure the best clinical practice in each individual.
Risk of major congenital malformations in the offsprings of women with epilepsy is not related to family history
2009, Epilepsy Research
Citation Excerpt :
A genetic predisposition to malformations may also be operating as only less than ten percent of infants exposed to AEDs in utero develop malformations. Earlier studies had suggested that some of the minor dysmorphic features observed in the offsprings of WWE could have a genetic basis (Gaily et al., 1988). Studies that focused on genetic liability to malformation when mother has epilepsy have been few in the past, although a causal relationship had been raised in some of the earlier papers (Meadow, 1970).
We aimed to ascertain whether family history of major congenital malformations (MCMs) was increased in women with epilepsy (WWE) compared to controls (spouses) and whether family history of MCM was associated with occurrence of MCM in the offspring.
Women enrolled in the Kerala Registry of Epilepsy and Pregnancy were probands of this study. The control group comprised of unaffected spouses and their families. We interviewed the probands and spouses to construct detailed pedigree charts with information on MCM. All live born infants of WWE underwent clinical examination, echocardiography and ultrasonography.
Data were collected for 11,777 family members of probands (n = 573) and 10,832 family members of controls (n = 550). Family history of MCM was positive for 84 probands (0.71%) and 64 controls (0.59%). Corresponding figures for first degree relatives were 32 out of 2717 for probands (1.18%) and 27 out of 2992 for controls (0.90%). Among the second degree relatives 52 out of 9060 for probands (0.71%) and 64 out of 10,832 for the controls (0.50%) had history of MCM. These differences were not statistically significant (p value = 0.29, 0.37 and 0.42, respectively). There was no significant difference in the frequency of MCM between probands with generalized epilepsy and localization related epilepsy. Out of the 426 live born infants of the probands, 44 had MCM; two with family history and 42 without family history (OR 0.74; 95% CI 0.19–3.26).
WWE of Asian Indian origin have no familial tendency for MCM and the offsprings with family history have no increased risk of MCM.
Motor and mental development of infants exposed to antiepileptic drugs in utero
2008, Epilepsy and Behavior
We prospectively evaluated the mental (MeDQ) and motor (MoDQ) developmental quotients of 395 (67.5% of the eligible) infants of mothers with epilepsy (IME) (mean age: 15 months) enrolled in the Kerala Registry of Epilepsy and Pregnancy between 1998 and 2004. The same developmental pediatricians, blinded to antiepileptic drug (AED) exposure, evaluated the children using the Indian adaptation of the Bayley Scale of Infant Development: Their mean MeDQ was 89.1 ± 29.9 and mean MoDQ was 90.7 ± 26.9. The MeDQ and MoDQ were impaired (<84) for 150 (37.6%) and 133 (33.5%) IME, respectively. Maternal age, type of epilepsy, seizure frequency, or use of folic acid did not correlate with the mean MeDQ or MoDQ. Maternal education was significantly correlated with the MoDQ, but not with the MeDQ, of the infants. Infants not exposed to AEDs (n = 32) had a higher MeDQ (mean: 92.3, 95% CI: 81.4–103.2) and MoDQ (mean 94.7; 95% CI 84.9–104.5) than those exposed to AEDs (MeDQ—mean: 88.6, 95% CI: 85.5–91.6; MoDQ—mean: 90.0, 95% CI: 87.3–92.8). Those exposed to polytherapy had significantly lower developmental quotients than those exposed to monotherapy. Cumulative AED scores during pregnancy had an inverse relationship with developmental quotients. On multiple regression analysis, polytherapy was a stronger predictor of lower developmental quotients than dosage. Compared with carbamazepine monotherapy, valproate monotherapy was associated with significantly lower MeDQ and MoDQ in IME (93.1 and 95 vs 86.9 and 86.1), but the differences between other AEDs were not significant for IME exposed to valproate monotherapy. A limitation of the study is that the influence of maternal intelligence on developmental quotients was not evaluated.

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

Preliminary results presented in part at the 16th Epilepsy International Congress, Hamburg, Sept. 6–9, 1985 (published in: Wolf P, Dam M, Jane D, Dreifuss FE, eds. Advances in epileptology; vol. 16. New York: Raven Press, 1987;567–71).

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Original articleMinor anomalies in offspring of epileptic mothers*

Lancet

Lancet

J Pediatr

J Pediatr

Lancet

Am J Obstet Gynecol

J Pediatr

J Pediatr

J Pediatr

Distal limb hypoplasia in the fetal hydantoin syndrome

Birth Defects

Minor congenital anomalies and dermatoglyphic alterations in the offspring of epileptic women: a clinical investigation of the teratogenic effects of anticonvulsant medication

Relationship between antiepileptic drug exposure of the infant and developmental potential

Antiepileptika während der Schwangerschaft

Dtsch Med Wochenschr

Minor anomalies in the offspring of epileptic parents

The influence of antiepileptic drugs on minor anomalies 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

Congenital anomalies in children of epileptic mothers and fathers

Neuropediatrics

Teratogenicity of anticonvulsant drugs. II. A prospective study

Am J Med Genet

Malformations and minor anomalies in the offspring of epileptic parents: a retrospective study

Original article
Minor anomalies in offspring of epileptic mothers*