Introduction

It has been well established that children of mothers with epilepsy (CME), are at greater risk for a variety of adverse outcomes of pregnancy. Congenital malformations (Kaneko et al 1988, Tanganeli & Regesta 1992); low birth weight (Annegers et al 1974, Svigos 1984); congenital anomalies (Granstrom 1982, Leavitt et al 1992); fetal death and infant mortality rates ( Bjerkdal & Bahna 1973, Nelson & Ellenberg 1982); and mental retardation (Speidel & Meadow 1972, Nelson & Ellenberg 1982) are all at least twice as common for these children as the general population. With the possible exception of fetal death and infant mortality, effective interventions are generally available for most of these outcomes. Mental retardation or cognitive delay is less amenable to treatment. We have studied a group of children of mothers with epilepsy prospectively to determine the extent and risk factors for this problem.

Historical Trends

Beginning in the 1970's a small number of retrospective studies began to address the association of mental retardation and maternal epilepsy. In these studies offspring of parents with epilepsy were identified after birth through hospital records. The earliest report is that of Speidel & Meadow (1972) who found mental retardation in 1.5% of 427 children of mothers with epilepsy compared to 0.2% in controls. Children of mothers but not those of fathers with epilepsy were found to be delayed in reaching early developmental milestones (Beck-Mannagetta & Janz 1982). By the time they reached school age however, the children with maternal epilepsy appeared to have caught up with their peers.

In one of the few comparisons of children exposed to antiepileptic drugs (AED) with those with maternal epilepsy and no AED exposure, Majewski and colleagues (1981) found a higher rate of mental deficiency in the AED exposed children. In contrast, Steinhausen and co-workers (1982) found no impairment in intelligence, visual perception or psycholingustic abilities in 19 children of mothers with epilepsy. They compared their subjects scores with general population standards.

Though their subjects were identified retrospectively, Hill and colleagues (1982) followed children prospectively to school age. The mean IQ scores of children of mothers with epilepsy did not differ from those of mothers without epilepsy. The former were however, more likely to have IQ scores below 90 and to need special education. Similar observations by Vert and co-workers (1982) demonstrated fewer IQ's above 90 than expected in children of mothers with epilepsy.

Several investigators have reported that CME had higher rates of mental retardation than other children (Hill et al. 1974, Nelson & Ellenberg 1982, Speidel & Meadow 1972). Beck-Mannagetta and colleagues reported that 35% of AED exposed CME needed special education compared to 8% of controls (1982). Unfortunately most of these studies did not control for socioeconomic status or parental intelligence.

There have been 13 prospective studies of cognitive development of children of mothers with epilepsy (table 1). Only 2 of these also included children of fathers with epilepsy (Shapiro et al 1976, Koch et al 1983). Most of these studies recruited women with epilepsy from specialty clinics and may therefore over- represent patients with a more severe seizure disorder. Socioeconomic status was controlled for in 3 of the studies (Hanson et al 1976, Koch et al 1983, D'Souza et al 1991)

In general these data reveal lower developmental scores in children of mothers with epilepsy during the first 2 years of life. In two studies these children appeared to "catch up" with their non- epilepsy exposed peers after age 2 (Koch et al 1983, Nomura et al 1984).

Studies evaluating IQ scores in children over the age of 4 years, have generally found no difference between children of mothers with epilepsy and controls (Shapiro et al 1976, Gailey et al 1988) Though no control children studied by Gailey and colleagues had IQ scores below 85 when the analysis was done by removing the 4 of 148 children of mothers with epilepsy who had IQ scores below 85, no significant differences were seen. Two investigators found Intelligence quotients below 70 more often in children in mothers with epilepsy. Nelson and Ellenberg (1982) demonstrated rates of 6.2%, and Gailey et al (1988) described rates of 1.2%.

When one evaluates learning disabilities as opposed to global retardation, some differences between CME and control children emerge. Forty-eight percent of a group of 23 CME followed through age four showed psychometric test patterns consistent with learning disability (Hill et al 1982). A prospective Finnish study revealed that CME performed more poorly in tests of block design (below the 5th percentile on the WPPSI) and auditory closure (below the 5th percentile on the ITPA). Twenty three percent of CME compared to 7% of controls were thus classified as having specific cognitive dysfunction, which was found to be associated with maternal partial seizures, seizures occurring during pregnancy, and low levels of paternal education but not with exposure to AED (Gaily et al 1990).

In the current prospective study of case and control groups, we have previously reported (Leavitt et al 1992) the results of testing at 2 months of age. Children of mothers with epilepsy showed more minor anomalies but no clear developmental differences.

The studies done to date reveal a variety of results generally but not in all cases, suggesting that as a group children of mothers with epilepsy are at greater risk for cognitive and developmental delay. The variation in reports is a function of the variation in study design and methods. Some studies have no control group. Others examine children exposed to a specific AED. Pre-1970 studies had no AED plasma concentrations hence not only was compliance uncertain but there was no possibility to compare high and low rates of exposure. The effect of the severity of maternal epilepsy has in addition not been evaluated.

METHODS

In an attempt to rectify some of these difficulties, the University of Washington's Child Development and Mental Retardation Center developed a prospective longitudinal controlled study of developmental outcomes of children of mothers with epilepsy Leavitt et al 1992). Women with epilepsy were recruited prior to conception or in the first trimester. They kept records of their seizure type and frequency. Their AED dose and plasma concentration were determined monthly. All women had a documented seizure disorder confirmed by a neurologist/epileptologist. Forty percent had only a single seizure type, 57% had 2 seizure types, and 3% had 3 seizure types. Thirty-six percent were completely seizure free during their pregnancy. All subjects were taking at least one AED. Seventy two percent were treated with monotherapy. No woman took more than 2 AED simultaneously. Table 2 describes the AED use of the women with epilepsy.

A control group of pregnant women without epilepsy or other medical illness was recruited from the University of Washington's prenatal clinics during their first or second trimester. They were matched with case subjects by years of education plus or minus 3 years, age, race and parity. Table 3 describes the demographic characteristics of the case and control population. The delivery outcomes of this population have previously been reported by the authors (Yerby et al. 1992)

At delivery all case children had cord blood samples collected to measure AED levels. All children were examined at intervals by a developmental pediatrician (Dr. Leavitt), and child psychologist (Dr. Robinson) both of whom were blinded as to maternal status. The children were seen at 8 weeks post partum, 1,2 and 3 years of age. At each visit the pediatrician performed a physical examination, took an interval history and measured growth parameters. At the 1, 2, and 3 year visits the children were examined by the psychologist for developmental testing. At 1 year of age all children were seen by an audiologist to rule out hearing impairment that could confound the outcome. Table 4 describes the evaluations performed at each visit.

The original cohort consisted of 107 women, 56 case and 51 control children. Attrition was low but some children were lost to follow up between each visit. At 1 year the total was 97 children (52 case and 45 controls). At 2 years the total was 83 (43 in the case group and 42 in the control group). By the 3 year visit we saw 76 children, (45 case and 31 controls).

RESULTS

IMMEDIATE PREGNANCY OUTCOMES

Immediate pregnancy outcomes were generally good for both the case and control group. Mean birthweight was 3.4 kg for case children and 3.6 kg for controls. Mean length was 51 cm for case children and 50.8 cm for control children. The mean head circumference was 34.3 cm in the case group, and 34.9 cm in the control group. None of these findings were statistically significantly different. Forty three percent of the case children and none of the controls were small for gestational age, however.

MAJOR MALFORMATIONS

Major malformations were found in 10 of 60 case children (17%). Five of these had microcephaly, defined as an OFC of < 5th percentile. The balance of case children consisted of 2 children with inguinal hernias requiring surgical repair, one pyloric stenosis, one choanal atresia, and one ventricular septal defect (VSD). If one excludes the children with microcephaly the malformation rate is 5 of 60 or 8%.

In the group of control children 3 of 50 (6%), had a major malformation. There was one case of microcephaly, a VSD which closed spontaneously, and hypospadias requiring surgery.

In neither group were there any children with oral facial clefts or neural tube defects.

OUTCOMES AT ONE YEAR

There were no significant differences in growth parameters (weight, height, and OFC) between the two groups. Minor anomalies were seen in both case and control children. Cases had a mean of 4.7 anomalies per child and controls 3.1 (p= 0.002). The most commonly seen minor anomalies in case children were: flat nasal bridge, broad aveolar ridge, metopic suture ridging, hypoplastic nails and pigmented nevi. In control children the distribution of anomalies was similar.

Objective measures were recorded where they could be performed. Mean inner canthal distance was 24.8 mm in the case, and 24.1 mm in control group. The mean philtrum length was 11.8 mm for case children and 11.9 mm for controls. There were no significant differences.

The Bayley Mental Developmental Index (MDI) was significantly different between case and control groups p < .004. Case children had a mean score of 112.2 and controls 119.9. The Bayley Psychomotor Developmental Index (PDI) was not different between the groups with case children scoring a mean of 102.5 and controls 105.9. The lower limits of scores for the case children was lower than for the control group (50 compared to 66). Growth parameters and Bayley scores for the children at age one are seen in table 5.

OUTCOMES AT TWO YEARS

At two years of age, the physical growth parameters (weight, height, and OFC) were not significantly different between case and control groups. There was a significant difference in the Bayley MDI scores. Control children had a mean of 122 while the case children's mean was 111 (p< .004). The PDI scores were not significantly different the means being 103.5 and 104.7 in the case and control groups respectively (table 6.). The Bates-Bretherton Early Language Inventory demonstrated a marked difference in the mean number of vocabulary words in each group. Mothers with epilepsy reported a mean number of 190 words compared to control group mothers who reported a mean of 298 words (p< 0.016).

OUTCOMES AT THREE YEARS

As during the other interval visits no statistically significant difference was seen in the weight, height, and OFC of the two groups of children. Mean weights were: 14.6 and 14.7 kg, heights were 95.2 and 95.3 cm, and OFC 49.7 and 50.3 cm in case and control children respectively.

Objective measures of facial parameters also did not reveal any significant differences between children of mothers with epilepsy and controls (table 7.).

Composite IQ scores were derived from the Stanford-Binet IV as well as separate domain scores for verbal reasoning, abstract visual reasoning, quantitative reasoning, and short term memory. Children of mothers with epilepsy attained statistically lower verbal reasoning scores (102 vs 112) and composite scores (103 and 109) in comparison with control children.

Mothers with epilepsy attained significantly lower scores than controls on the Peabody Picture Vocabulary Test, but their children did not. Women with epilepsy had mean scores of 95, the controls 113 ( p< 0.001). Children of mothers with epilepsy had mean scores of 103, their controls 106.

The mean length of utterance (MLU), recorded as the children played with toys was significantly different between the groups. The mean of case children's MLU means were 3.6. Control children's means were 4.5 (p< 0.001). There was no difference in the Vineland Motor Scale between the groups (table 8).

OUTCOMES of CHILDREN EXPOSED to MONOTHERAPY v. POLYTHERAPY

To examine the relative impact of drug exposure, we next compared developmental outcomes at 3 years of age of children of mothers with epilepsy who were exposed to a single AED in utero and those exposed to polytherapy. In 2 areas, abstract visual reasoning and the composite score the monotherapy group scored higher than the polytherapy group 105 v. 98, and 105 v. 98 respectively.

The IQ scores derived from the Peabody Picture vocabulary revealed slightly higher scores for the monotherapy exposed children (104) than the polytherapy group (98), but this was not statistically significant. Mothers with epilepsy taking polytherapy however, scored significantly lower (85) than those on monotherapy (99), (p< 0.01). Other variables were not significantly different between these groups (table 9).

OUTCOMES of CHILDREN EXPOSED to MONOTHERAPY v. CONTROLS

For most variables there were no significant differences between children of mothers on monotherapy vs controls, though control children tended to score slightly higher (table 10). The verbal reasoning scores and Mean Length of Utterance were significantly lower for CME. Control's mean scores were 112 for verbal reasoning, while case children's were 103 (p< 0.006). The Mean Length of Utterance was 4.5 for the controls and 3.6 for the case children (p< 0.004).

Control mothers also maintained higher Peabody Picture Vocabulary scores than monotherapy case mothers (113 v. 99, p< 0.004). There was no significant difference between the monotherapy exposed children and controls.

OUTCOMES of CHILDREN EXPOSED to POLYTHERAPY v. CONTROLS

When we compared scores between the group of children exposed to polytherapy in utero with controls virtually every variable demonstrated a significant difference. The only variables in which this was not the case were the child's Peabody Picture Vocabulary and the Vineland Motor. Even then the case scores were higher than those of the controls (table 11).

OUTCOMES with EXPOSURE to SPECIFIC AED

We further segregated the case group by specific AED used in monotherapy. Children exposed to monotherapy with carbamazepine and phenytoin had scores that were indistinguishable from those of the control group. Children exposed to phenobarbital monotherapy had slightly lower (but not statistically significant) mean scores than the control group. The children exposed to valproate monotherapy tended to have lower mean scores than the controls, and there was a significant difference in: verbal reasoning, short term memory, and the composite score. The verbal reasoning subscale mean score of the valproate group was 92.3, and that of controls was 111.7. The short term memory mean score was 92.7 in the valproate group and 106.9 in the control group. The mean composite score in the valproate group was 91.0, whereas that in the control group was 108.8. All three of these differences were significant at p < 0.05 (table 12).

DISCUSSION

Children exposed to intrauterine AED in this study were in general doing well. Their physical parameters were comparable to those of children of non-epileptic mothers and, although they demonstrated somewhat more frequent major and minor malformations, most of these had few implications for their development or health trajectories. At age two, however, an important finding was reduced OFC in the case children.

At all three assessment ages, children of mothers with epilepsy consistently attained lower scores than did the control children on some (not all) measures of cognitive development. At the two-year visit, for example, mothers reported vocabulary size in the case group to be half that of the controls, and the observed mean length of utterance was also shorter for the case group. At the three-year visit, ccase children attained significantly lower scores in verbal reasoning on Stanford-Binet IV and, again , a shorter average mean length of utterance.

This finding is, however, difficult to interpret in light of the higher mean education of the control mothers (15 years vs. 12 years for case mothers) and their higher Iqs on the PPVT (113 vs 99). The conditions that result in epilepsy for mothers may well affect maternal verbal competence in a variety of ways; not only may maternal language be affected by the same condition that underlies the seizures or by the medication itself, but educational participation may have been reduced during the mother's childhood, social experience may have been restricted for fear of seizures, and so on. In fact, as reported in Table X, small to moderate correlations exisit between parental education and maternal vocabulary (PPVT IQ) on the one hand, and child performance on the other. Neither heritability of verbal-cognitive ability nor maternal influence on the child's developmental experience can be ruled out in this situation, with the result that caution should be exercised in interpreting the finding of somewhat lower verbal competence in the case group of children exposed to uterine AED.

Although the mothers exposed to polytherapy attained lower PPVT IQ than mothers on monotherapy, a dose response effect also appears in these children. Polytherapy-exposed children scored much lower than monotherapy-exposed children in mean length of utterance as well as Stanford-Binet IV verbal reasoning and composite scores. It should be kept in mind that the lower scores found with polytherapy may be secondary to the severity of the maternal epilepsy and not simply to a direct efect of the medication.

This study does, of course have some limitations. The sample size is rather small, though larger than most of its predecessors. The longitudinal nature of the study resulted in the progressive loss of subjects over time. The loss was greater in the control group, who had fewer incentives to participate in a study than did the cases. Mobility of the popoulation in a society in which the average family moves every three years, also increased attrition, since nearly four years ensued between enrollment and completion of the three year-visit.

Controls were matched with women with epilepsy by the highest year of completed schooling, plus or minus three years. This procedure resulted in a control group with higher levels of educationthan the case group. Few women in either group had not graduated from high school (14.5% of cases and 12% of controls), but 11.6% of the cases and 20% of the controls were college graduates. These educat4ional differences make it somewhat difficult to imterpret the findings of the study but do not vatiate the fact that sdeficiences in language development can have a profound impact on a child's academic and social success. Physicians caring for such children should monitor langusge development closely so that early interventions can be planned if needed.

CONCLUSION

Children of mothers with epilepsy consistently score less well than control children on a variety of measures of cognitive development. The differences are significant in the areas of language development, and are more striking when the children are exposed to polytherapy than monotherapy.

Physical developmental parameters weight, length, and head circumference were not significantly different. Children of mothers with epilepsy do however, tend to have more congenital anomalies than controls particularly: flat nasal bridges, broad aveolar ridges, metopic sutural ridges, and hypoplastic nails. CME have an average of 4.7 anomalies compared to 3.1 for controls.

Maternal epilepsy and intrauterine exposure to AED are the primary differences between the groups of children. It is possible that maternal education could also be a factor. A larger sample could clarify which variables are of greatest importance. We encourage more work in this area but also believe it would be an error to simply pass off these differences to maternal education. It is clear that CME have lower scores on a variety of measures of cognitive development particularly language. These differences suggest that they are at greater risk for academic difficulty than control children particularly if they are exposed to polytherapy. It is important therefore, for physicians caring for such children to monitor their development and plan early interventions if their language acquisition falls behind.

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Mark S. Yerby M.D., M.P.H.
North Pacific Epilepsy Research
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