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Keywords:

  • Epilepsy;
  • Psychomotor development;
  • Antiepileptic drug;
  • Socioeconomic status;
  • Intrauterine growth

Abstract

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Summary:  Psychomotor development of 71 children born to mothers with epilepsy was prospectively studied and compared to those of 99 controls matched for age, maternal educational level and age, and socioeconomic status. Intrauterine growth retardation disappeared before age 3 years. Assessment at age 1.5 years revealed that exposure to seizures, high dose of antiepileptic drugs (AEDs) in utero, and small head circumference at birth affected development quotient (DQ) scores of motor or linguistic abilities or both. DQ scores of motor ability of children of mothers with complex partial seizures were lower than those with simple partial seizures when assessed at age 3 years. Assessments at age 1.5 years revealed that the total daily dose of AEDs correlated negatively with DQ scores of motor ability, and at age 3 years, maternal educational level affected DQ scores of some fields, including linguistic ability. The effects of AED exposure in utero and the occurrence of maternal seizures on the development of offspring were found to matter more at the younger age, but later on, the child care environment and, in particular, maternal ability of child-rearing, became more important. Our findings indicate that careful and regular follow-ups are needed to monitor the developmental stages of children of mothers with epilepsy, and the introduction of a day nursery should be suggested if necessary.

The improved diagnosis of and therapy for epilepsy, together with better social adjustment, have allowed most women with epilepsy to marry and bear children. Children of mothers with epilepsy have been reported to have higher incidence of psychomotor retardation than have control subjects. In earlier studies (1–4), development quotient (DQ) scores of children of mothers with epilepsy were lower than those of controls, although none of these studies was controlled for parental intelligence. Although some risk factors including small head circumference of infants at birth, total daily dosage of antiepileptic drugs (AEDs) taken by mothers during pregnancy, and complex partial seizures (CPSs) of the mother have been reported (4), the single most important variable in explaining the risk of poor developmental outcome was socioeconomic status (5). Therefore, the aim of this study was to make clear whether the reported risk factors correlate with poor developmental outcome when socioeconomic status is controlled.

SUBJECTS AND METHODS

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Seventy-one offspring born to mothers with epilepsy (E-group) and 99 born to healthy mothers (C-group) were investigated. The E- and C-groups were divided into two subgroups [i.e., younger group (Y-group, examined at age 1.5 years) and older group (O-group, examined at age 3 years)] for the psychomotor development test. The E-group consisted of 41 children of the Y-group and 30 children of the O-group. The corresponding numbers of children of the C-group were 45 and 54 children, respectively. Characteristics of mothers and their children are summarized in Table 1. Study subjects were controlled for parental annual income (3–6 million yen), maternal educational background (junior high school graduates, high school graduates, and university graduates), age at delivery, and gestational age of offspring. Forty-four mothers had generalized seizures, and 27 have partial seizures. Measurements of physical development were done at shorter intervals than those of psychomotor development. The development of children was assessed by using Enjoji's analytical development test (6), which evaluates the progress made in six developmental fields (i.e., motor ability consisting of body and hand movement, social ability including fundamental habits and human relationships, and linguistic ability consisting of speech and language understanding). Together with this test, structured interviews for the assessment of psychiatric symptoms and neurological examinations for assessment of neurological status were used. In the evaluation of the daily dosage of AEDs taken by mothers with epilepsy during pregnancy, the drug scoring system (Table 2) was adopted (7). For statistical analysis, Student's t test and Wilcoxon's test (2) were used.

Table 1. Clinical characteristics of mothers and their children
 E-groupC-group
Subjectsn = 71n = 99
Children
 Gestational ageFull termFull term
 Age of children at examination (month ± SD)Y: n = 41 16.3 ± 3.8n = 45 16.2 ± 3.8
 O: n = 30 39.2 ± 3.5n = 54 39.6 ± 2.9
Mothers
 Age at delivery (year±SD)26.5 ± 3.526.8 ± 3.6
 Seizure typeGeneralizedn = 44
 Partialn = 27
Annual income (¥10,000)300–600300–600
Table 2. Drug score (one unit)
 (mg/day)
  1. Group 1 : 0-9.9

  2. Group 2 : 10.0–14.9

  3. Group 3: 15.0–

Phenytoin 50
Phenobarbitone 50
Sulthiame 50
Primidone100
Carbamazepine100
Sodium valproate100
Acetazolamide125
Ethylphenacemide200
Ethosuximide250
Diazepam  5

RESULTS

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Physical development

Head circumference and body length at birth of the E-group were significantly smaller or shorter than those of the C-group, but these differences disappeared by ages 3 and 2 years, respectively (Fig. 1). Maternal AED dosage (the drug score) showed a negative correlation with head circumference of offspring, whereas maternal serum T4 in the third trimester of pregnancy, T3 and cortisol in serum taken from umbilical artery, and T4 in serum from umbilical vein had a positive correlation with head circumference at birth of the E-group (p < 0.05). Conversely, serum human chorionic gonadotropin (hCG) in the third trimester, progesterone in the umbilical artery, and hCG in the umbilical vein showed a negative correlation. The drug score negatively correlated with T4 and T3 levels (p < 0.05). Maternal folic acid during pregnancy showed a tendency to correlate positively with infant head circumference at birth. Details of these data were reported elsewhere (4).

image

Figure 1. Weight gain and increment of head circumference. Head circumference (circles, cm) and body weight (triangles, kg) of children were followed up from birth to age 3 years. Solid symbols indicate offspring born to mothers with epilepsy (E-group, n = 71). Open symbols indicate control children (C-group, n = 99). Symbols and vertical bars indicate mean ± SD of physical growth parameters. Significant difference between E- and C- group in body weight and head circumference disappeared by ages 2 and 3 years, respectively. Asterisks indicate significant difference between the E- and the C-groups at each examination period (*p < 0.05; **p < 0.01).

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Psychomotor development

The E-group showed significantly lower DQ scores in all fields tested than those of the C-group (Fig. 2).

image

Figure 2. Assessment of psychomotor development. Columns and vertical bars indicate DQ scores (mean ± SD). Dotted bars and open bars indicate the E-group (n = 71) and the C-group (n = 99), respectively. Asterisks at the tops of the columns indicate significant differences between the E- and the C-groups at each examination period (*p < 0.05; **p < 0.01).

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Maternal seizure type

Partial seizure types of the mother tended to correlate with lower DQ scores of offspring in social and linguistic abilities than did maternal generalized seizures. In the Y-group, a retardation of language understanding and body movement was noted (p < 0.05), in particular for infants of mothers with CPSs who developed seizures during pregnancy (n = 14), more than in those of mothers who experienced other types of seizures (p < 0.05; n = 4). The former group of mothers received higher dose of AEDs than the latter ones (p < 0.05). Occurrence of a generalized seizure during pregnancy (n = 4) tended to cause a lower DQ score in social and linguistic fields but failed to reach a statistically significant level.

In the O-group, the DQ score of motor ability of offspring born to mothers with CPSs was lower than that of offspring born to mothers with simple partial seizures (p < 0.05).

Intrauterine growth

The head circumference of infants at birth correlated positively with the DQ score for speech in the Y-group (y = 5.3 ×–79.0; p < 0.05), but not in the O-group.

Total daily AED dose taken by mothers during pregnancy

To analyze the effects of the maternal daily AED dosage on psychomotor development of offspring, the E-group was divided into three subgroups according to the drug score during pregnancy: subgroup 1, offspring exposed to the lowest dose of AEDs (drug score, 0–9.9); subgroup 2, offspring exposed to intermediate dose (drug score, 10–14.9); subgroup 3, offspring exposed to highest dose (drug score, ≥15). In the Y-group, DQ score of language understanding of subgroup 3 was significantly lower than that of subgroup 1 (p < 0.05). The DQ score of language understanding of the Y-group of mothers with generalized epilepsy correlated negatively with the drug score (y =–3.1 × 120; p < 0.05) but not in the O-group. In the O-group, DQ scores of motor ability of subgroup 2 were significantly higher than those of subgroup 3 (p < 0.05).

Maternal educational background

Subjects were subdivided into three subgroups by maternal educational background. Among mothers of the E-group, 23 graduated from junior high school (Y-group, 13; O-group, 10), 43 from high school (Y-group, 27; O-group, 16), and five from university (Y-group, 1; O-group, four). The corresponding numbers of mothers of the control group were 17 (Y-group, eight; O-group, nine), 55 (Y-group, 24; O-group, 31), and 27 (Y-group, 13; O-group, 14), respectively.

As shown in Fig. 3, in the O-subgroup of the E-group, the educational background of the mother significantly affected the psychomotor development of the children, in particular, hand movement, human relationships, speech, and language understanding. For the Y-group, this relation was not analyzed because of the small number of university graduates in the E-group.

image

Figure 3. Effects of maternal educational level on psychomotor development of offspring Circles indicate offspring of mothers graduated from junior high school; diamonds indicate those of mothers graduated from high school, and triangles indicate those of mothers graduated from university. Solid symbols and open symbols indicate DQ scores of the E- and C-groups, respectively. Asterisks indicate significant differences between the E- and the C-groups at each maternal educational level (*p < 0.05; **p < 0.01). Small letters indicate statistical differences among different educational levels in the E- or C-group (a-b: p < 0.05; c-d: p < 0.01).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

An increased incidence of physical and mental subnormality was frequently reported during follow-up studies of children born to mothers with epilepsy. A clear dose-dependent effect was reported for phenobarbital (PB) and primidone (PRM) exposure in utero in terms of both low body weight and small head circumference, and a concentration-dependent effect for PB in terms of small head circumference (8). Antiepileptic drugs also cause pharmacologic side effects in the newborn, such as sedation, poor suckling, or withdrawal symptoms (9,10).

In the present study, residual effects of retarded intrauterine growth disappeared by age 3 years. However, intrauterine growth retardation, such as small head circumference at birth, which correlated negatively with total daily dose of AEDs taken by mother during pregnancy, affected the DQ score of speech of the Y-group but not of the O-group. In the Y-group, DQ scores of speech and language understanding were lower in the offspring whose mother developed CPSs than those whose mothers experienced other types of seizures, and a difference was found in drug score between these two groups (i.e., the former group showed a higher drug score than the latter).

Leavitt et al. (11) found that offspring born to mothers with epilepsy showed lower scores in measures of verbal acquisition at both ages 2 and 3 years. Losche et al. (5) demonstrated that exposure to polytherapy resulted in lower scores on the Bayley, McCarthy, and LOS Motor Tests, verbal and performance IQ measures of the WPPSI, visual perception (FTVP), and psycholinguistic abilities. Seizure frequency of the mother during pregnancy had a modest impact on the child's developmental outcome, whereas obstetric abnormality was less effective in predicting developmental outcome. Even stronger effects of socioeconomic status were noted, and sex was found to be less influential than polytherapy. Among children of mothers with partial epilepsy, DQ scores of motor ability of children of mothers with CPSs were lower than those of children of mothers with simple partial seizures in these subjects.

The question arises whether maternal seizures or AED exposure in utero are responsible for the delay in development observed. Leonard et al. (12) reported that regardless of the absence of seizures during pregnancy, children of mothers with epilepsy had lower Full-Scale IQ ratings than did normal control children and less efficient visuospatial ability. Children whose mothers had seizures were significantly worse than normal controls on measures of visuospatial memory, speeded motor tests, and reaction time. Polytherapy was associated with poor performance on verbal tests (particularly comprehension) and distractibility. These results indicate that AED exposure in utero associates negatively with cognitive effects and that the pattern of cognitive changes varies depending on whether the children were exposed to seizures, or whether the mothers were receiving mono- versus polytherapy (12). CPSs, rather than simple partial or primary generalized seizures, exerted a powerful influence on psychomotor development in the O-group but not in the Y-group, and mothers with CPSs registered higher drug scores than did those with other types of seizures. Exposure to seizures and mono- versus polytherapy also may suggest the influence of AED dose on the development of children, and from these data, a vicious circle can be postulated, in which the drug dose must be increased if maternal seizures are to be sufficiently controlled. Subsequently, if massive doses of AEDs are given, maternal intelligence decreases, and satisfactory mother–child interaction cannot be expected. As a consequence of this, the psychomotor development of the child is delayed.

The present study was controlled for familial socioeconomic status, maternal age, gestational age of offspring, and age at assessment of development. Maternal educational background is considered to be one of the most important determinant factors because the level of maternal education might be influenced by the familial attitude toward the education of children (circumstances of child-rearing) and also the parental intelligence (mother's child-rearing ability). In the present study, the maternal background of education clearly influenced the psychomotor development of offspring at age 3 years, although the present study does not permit drawing any conclusions about the results of the Y-group because of small number of university graduate mothers with epilepsy.

Therefore, AED dosage, small head size at birth, and occurrence of seizures may exert a baneful influence on psychomotor development of children at a younger age, but later on, psychomotor development may be much more dependent on the child-care environment, making it unlikely that the intrauterine growth affects the psychomotor development of the child in the long run. Mothers with a treatment-resistant seizure type, such as CPSs, often require high doses of AED or polytherapy. In such cases, the seizure itself and side effects of AEDs make the mother's ability for child-rearing to decrease. Thus, child-rearing ability of the family, especially of the mother, becomes more important for the psychomotor development of offspring in the long run because no retardation of offspring of fathers with epilepsy has been reported (13). For the purpose of providing a good rearing environment, careful and regular follow-ups are needed to follow up the developmental stages of children, and the introduction of a day nursery should be considered if necessary.

Further studies are needed to analyze the risk factors (including new AEDs) for the psychomotor development of children of mothers with epilepsy with larger numbers of cases and with a wide range of developmental and psychological tests.

REFERENCES

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Speidel BD, Meadow SR. Maternal epilepsy and abnormalities of the fetus and newborn. Lancet 1972; 2: 83943.DOI: 10.1016/S0140-6736(72)92209-X
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    Hill RM, Verniaud WM, Horning MG, et al. Infants exposed in utero to antiepileptic drugs: a prospective study. Am J Dis Child 1974; 127: 64553.
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    Fujioka K. Psychomotor development in the offspring of epileptic mother: significance of environment in child care [in Japanese]. J Jpn Epilepsy Soc 1984; 2: 2534.
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    Kaneko S, Hirano T, Muramatsu E, et al. Fetal and neonatal effects of antiepileptic drugs: the physical and psychomotor developments in the offspring of epileptic parents. In: FujiiT, AdamsPM, eds. Functional teratogenesis. Tokyo : Teikyo University Press, 1987: 20515.
  • 5
    Losche G, Steinhausen HC, Koch S, et al. The psychological development of children of epileptic parents, II: the differential impact of intrauterine exposure to antiepileptic drugs and further influential factors. Acta Paediatr 1994; 83: 9616.
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    Enjoji M. Analytical development test of infants. Tokyo : Keio-Tsushin, 1962.
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    Battino D, Kaneko S, Andermann E, et al. Intrauterine growth in the offspring of epileptic women: a prospective multicenter study. Epilepsy Res 1999; 36: 5360.
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    Kaneko S, Fukushima Y, Sato T, et al. Breast feeding in epileptic mothers. In: SatoT, ShinagawaS, eds. Antiepileptic drugs and pregnancy. Amsterdam : Excerpta Medica, 1984: 3846.
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    Hirano T, Kaneko S, Nagasawa K, et al. Complications in neonates born to epileptic mothers. In: SatoT, ShinagawaS, eds. Antiepileptic drugs and pregnancy. Amsterdam : Excerpta Medica, 1984: 11422.
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    Leonard G, Andrmann E, Pitno A, et al. Cognitive effects of antiepileptic drug therapy during pregnancy on school age offspring. Epilepsia 1997; 38(suppl 3):170.
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    Hirano T, Kaneko S, Fukushima Y, et al. Retardation in psychomotor development of offspring of epileptic parents: importance of the rearing environment. Folia Psychiatry Neurol Jpn 1985; 39: 3435.