Epilepsy is a serious brain disorder characterized by recurrent, unprovoked seizures. The incidence rate is high in early childhood, low in adulthood, and high again late in life.1 The overall incidence rates range between 40 and 70 per 100,000 person-years in industrialized countries.2 There are many causes of epilepsy in childhood, including brain tumors, cerebral palsy, and infections. However, for most of epilepsy cases, no clear antecedents have been identified. Studies of twins indicate that both genetic and environmental factors play a role in the etiology of epilepsy.3 Few studies have evaluated the effect of environmental factors originating in early life; some,4,5 but not all,6–10 have suggested that low birth weight, preterm birth, toxemias, vaginal bleeding, and duration of labor may be part of the etiology of epilepsy.
Apgar score evaluates newborns based on 5 signs: heart rate, respiratory effort, reflex irritability, muscle tone, and skin color during the first minutes of life.11 Each item is scored with a value of 0, 1, or 2, and a total score of 10 indicates that the baby is “in the best possible condition.”11 Studies have shown that low Apgar scores are associated with high risk of neonatal death, cerebral palsy, and mental retardation.12–16 One study has reported a higher risk of epilepsy among children with low Apgar scores, but did not address this association in detail.14
The aim of this study was to estimate the association between low Apgar scores and epilepsy in childhood and early adulthood by using a population-based cohort. An association between low Apgar scores and epilepsy would support the hypothesis that prenatal or perinatal factors play a role in the etiology of epilepsy.
We used data from the Danish Civil Registration System17 to identify all live newborns in Denmark between 1 January 1978 and 31 December 2002. They were followed from birth until the onset of epilepsy, death, emigration, or 31 December 2002, whichever came first. The information on deaths and emigration comes from the Danish Civil Registration System. All live-born children in Denmark are assigned a unique personal identification number (civil registry number), which is stored in the Civil Registration System. The civil registry number is used as an identification key to individual information in all national registers, and it enables accurate linkage of information between registers at the individual level. The study was approved by the Danish Data Protection Agency.
Assessment of Apgar Scores
Information on Apgar scores was obtained from the Danish Medical Birth Register.18 Information on Apgar scores at 5 minutes after birth was available during the entire study period, but information on Apgar scores at 1 minute after birth was accessible only for children born between 1978 and 1996. Midwives recorded Apgar scores after birth following standardized procedures. More than 95% of all births in Denmark take place in public hospitals, and midwives report Apgar scores to the registry from the remaining home births following the hospital procedures.
Assessment of Epilepsy
Information on epilepsy was obtained from the National Hospital Register that contains information on all discharges from Danish hospitals since 1977.19 Outpatients have been included in the register since 1995. Diagnostic information in the National Hospital Register was based on the International Classification of Diseases, 8th revision (ICD-8) from 1977 to 1993, and the International Classification of Diseases, 10th revision (ICD-10) from 1994 to 2002. Cohort members were classified with epilepsy if they had been hospitalized or had been in outpatient care with a diagnosis of epilepsy (ICD-8: 345; ICD-10: G40–G41). The time of onset of epilepsy was defined as the first day of contact with the hospital.
The incidence rate ratio of epilepsy was estimated by a log-linear Poisson regression model20 with the GENMOD procedure in SAS version 8.1 (SAS institute, Cary, NC). All incidence rate ratios were adjusted for age and its interaction with sex and for calendar year. Age and calendar year were treated as time-dependent variables.21 Age was categorized in 3-month intervals in the first year of life, in 1-year age levels from the first birthday to the 19th birthday, and then age intervals of 20–21 and 22–25 as the oldest 2 groups. Calendar year was categorized in a 1-year period from 1978–2002. P values were based on likelihood ratio tests and 95% confidence intervals (CIs) were calculated using Wald's test.21 The adjusted score test suggested that the regression models were not subject to overdispersion.22
The study included 1,538,732 live-born children. During 17,953,700 person-years of follow up, 16,455 children were diagnosed with epilepsy corresponding to an average incidence rate of 91.7 per 100,000 person-years. Table 1 shows the incidence rate of epilepsy according to the selected characteristics of the population.
The incidence rate of epilepsy increased consistently with decreasing 1- and 5-minute Apgar scores, especially for 5-minute Apgar scores (Table 2). In our study population, 2466 (0.16%) had a 5-minute Apgar score of 1 to 3 and 9047 (0.59%) of 4 to 6. The average incidence rate of epilepsy was 628 per 100,000 person-years for those with 5-minute Apgar scores of 1 to 3 and 86 for those with a 5-minute Apgar score of 10.
The incidence rate ratios of epilepsy decreased when the Apgar score improved from 1 to 5 minutes. However, the incidence rate ratios remained higher for infants with low 1-minute Apgar scores, even if their scores improved to 10 at 5 minutes compared with children with an Apgar score of 10 at both 1 and 5 minutes. Children with Apgar scores of 1 to 3 at both 1 and 5 minutes had the highest incidence rate ratio of 8.03 (95% CI = 6.19–10.42) compared with children with an Apgar score of 10 at both measures (Table 3).
Incidence rate ratios of epilepsy differed in preterm and term infants according to 5-minute Apgar scores (P for interaction <0.001). The highest incidence rate ratios were found among term infants (Table 4).
Infants with 5-minute Apgar scores of less than 10 had higher incidence rate ratios of epilepsy throughout childhood and early adulthood compared with those with a score of 10. The highest incidence rate ratios were found, however, during the first year of life (Fig. 1).
The association between 5-minute Apgar scores and epilepsy did not change after excluding infants with cerebral palsy (n = 600), with confirmed or suspected congenital malformations (n = 812), with parental history of epilepsy (n = 629), or with any of the 3 conditions (Table 5).
From 1995 to 2002, 9500 people were diagnosed with epilepsy, including 1466 (15%) only in an inpatient setting, 3443 (36%) only in an outpatient setting, and 4591 (48%) in both settings. The incidence rates of epilepsy increased when outpatients were included, especially for children with an Apgar score of 10, whereas incidence rate ratios of children with low Apgar score decreased slightly (Table 6).
The incidence rate of epilepsy increased consistently with decreasing 1- and 5-minute Apgar scores for children born at term or born preterm. The incidence rates of epilepsy decreased when the Apgar scores increased from 1 to 5 minutes, but they remained higher than those of children who had an Apgar score of 10 at both measures. The incidence rate ratios of neonates with low 5-minute Apgar score were particularly high in early childhood and continued to be high throughout the study period of up to 25 years. This association was not confounded by cerebral palsy, congenital malformations, or a parental history of epilepsy.
The association between Apgar scores and epilepsy has been the subject of few studies. A case–control study indicated that low Apgar score is a risk factor for first unprovoked afebrile seizures among children,23 and one large population-based study showed that children with a 5-minute Apgar score below 7 had a higher risk of epilepsy.14 Our results are consistent with those of the 2 previous studies.14,23 Our study further showed that changes in Apgar scores from 1 to 5 minutes played a role, and we also found an association that persisted into early adulthood.
Apgar score is a nonspecific assessment of the neonates shortly after birth, and low Apgar scores are not specific to birth asphyxia.24,25 Congenital malformations, infections, and administration of drugs to the mother can also lead to low scores.26–29 We know of only few studies on the effect of early perinatal environmental factors and the risk of epilepsy.4–10 Most of these studies did not find strong associations,6–10 but some studies indicate that neonatal encephalopathy, neonatal seizures, and epilepsy may be related to brain lesions occurring in the antepartum period.30–32 The combination of low Apgar scores and symptoms of neonatal encephalopathy carried an increased risk of a variety of later minor disabilities, including epilepsy, among children with normal birth weights, no congenital malformation, and no major neurologic abnormalities.33 Unfortunately, we have no information about neonatal encephalopathy to add to these findings.
The major strengths of our study are the large sample size, the long follow-up time, the low loss to follow up, the reliable information on hospitalization, and the fact that data came from a uniform healthcare system that is free of charge for all patients. Children with low Apgar scores may be followed more closely for adverse outcomes than those with a normal score for a short time after birth, but probably not for months or years. Apgar scores were recorded prospectively and the diagnosis of epilepsy was made independently of these scores, making differential misclassification an unlikely explanation for the association. It is more likely that nondifferential misclassification attenuates the true association.
The main weakness of the study is that we had limited clinical data. Epilepsy is a heterogeneous disorder, and different seizure types and syndromes may have different etiologies. We were not able to evaluate whether that was the case for the association with Apgar scores. The information of epilepsy in our study came from ICD codes. The validity of the epilepsy diagnosis has been assessed according to International League Against Epilepsy criteria34 in 188 randomly selected inpatients and outpatients registered with epilepsy in the National Hospital Register.35 The epilepsy diagnoses met the definition as recurrent, unprovoked epileptic seizures in 153 patients corresponding to a positive predictive value of 81% (95% CI = 75–87%), which is comparable with other population-based register studies.36 Among the 35 persons who did not fulfill the criteria, 14 had had a single episode of seizures. Thus, our estimate of the positive predictive value is conservative, because some of these persons will probably develop epilepsy. There were 2 major changes in the hospital register system during the time of follow up. ICD-10 replaced ICD-8 in 1994, and outpatients were included in the register system from 1995. The association between Apgar score and epilepsy decreased slightly when outpatients were included.
The Apgar scoring is made by midwives following standardized procedures, but unfortunately, the interrater reliability of Apgar score has not been estimated in Denmark. The distribution of 5-minute Apgar score in our study was, however, similar to those of previous studies from other industrialized countries.14,33 Some children in our study arbitrarily received an Apgar score of zero if they were transferred to another department immediately after birth (0.4% for 1- and 0.2% for 5-minute Apgar score) and some children had missing Apgar scores for unknown reasons (0.6% for 1- and 1.1% for 5-minute Apgar score). These children had a slightly higher rate of epilepsy than those with an Apgar score of 10.
Our findings call for more research focusing on a fetal and perinatal origin of epilepsy. Potential causal candidates could be infections, maternal lifestyle factors, maternal complications during pregnancy, and factors related to the delivery process.
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