The incidence of hospitalizations with epilepsy increased consistently with decreasing gestational age and birth weight. The association was modified by age at diagnosis of epilepsy; the incidence rate ratio of epilepsy decreased with age at diagnosis, but remained elevated into early adulthood. Children with likely impairment of fetal growth had an increased incidence rate ratio of epilepsy, even if they had a birth weight within the “normal” range.
In general, children with a low birth weight include children who are constitutionally small, have a short gestational age at birth, or are growth-restricted (28
). In an attempt to disentangle these factors, we calculated the expected birth weight based on the birth weight of their older siblings to provide a better estimate of the biologic growth potential (29
) and reduce the risk of misclassifying children who are constitutionally small as growth-restricted (30
). We estimated the risk of epilepsy as a function of the ratio between the observed birth weight and this expected birth weight. Among children who achieved their expected birth weight, the risk of epilepsy increased consistently with decreasing gestational age indicating that preterm birth is an independent risk factor for childhood epilepsy.
Total brain tissue volume increases linearly in the third trimester of fetal life, with a four-fold increase in cortical grey matter between 29 and 41 weeks and a five-fold increase in myelinated white matter between 35 and 41 weeks (31
). Premature birth itself may lead to subtle neuropathologies, including cerebral white matter gliosis, hippocampal sclerosis and subarachnoid haemorrhage, as shown in non-human primates (31
). Furthermore, children born preterm are more often exposed to infections, pre-eclampsia, eclampsia, and smoking which may increase the risk of epilepsy (19
). The association between gestational age and the risk of epilepsy may, therefore, reflect the effect of both immaturity and that of a suboptimal intrauterine environment.
Cerebral palsy and congenital malformations especially in central nervous system are associated with an increased risk of epilepsy (33
). We and others have shown that children with a low Apgar scores have an increased risk of epilepsy and that the risk of epilepsy increases with decreasing Apgar scores (34
). In this analysis we found that the risk of epilepsy related to low birth weight or shorter gestational age was not mediated by cerebral palsy, congenital malformation or low Agpar scores. An early study showed that low birth weight, preterm birth, and smallness for dates at term were not significantly related to the risk of seizure disorders in children free of cerebral palsy (5
). However, the highest risk of afebrile seizures in children who did not have cerebral palsy was in those who were smallness for dates (5
In our analysis, the association between low birth weight and shorter gestational age and the risk of epilepsy was particularly strong within the first five years of life, perhaps because the immature brain is more susceptible to seizures when exposed to risk factors operating in prenatal life than the immature brain (36
). Children with a low birth weight or born preterm also have an increased risk of febrile seizure (10
). We can not exclude that some of those febrile seizure have been miscoded as epilepsy, although this bias is likely to be small.
In this study we focused on children born with a short gestational age or children who did not fulfill their growth potential, but postterm delivery is also a risk factor for perinatal complications. A recent study showed that children born postterm had an increased risk of epilepsy in the first year of life (37
), but our results failed to show similar results.
Our study is based on a large population-based cohort that was followed for up to 24 years with virtually no loss of follow-up (20
). Thus, bias due to selection of study participants cannot explain our findings. The quality of the gestational age assessment is, however, not optimal; estimates from LMP may be biased by early pregnancy bleeding, irregular periods, use of contraceptive methods and recall problems (38
) and estimates from ultrasound may be biased by exposures that impair early fetal growth (39
). A validation study in Denmark showed that, between 1982 and 1987, 64% of gestational age estimates from the medical records was based on the LMP, 35% on early ultrasound, and 1% on clinical estimates (40
) but, in recent years, ultrasound measurements have been increasingly used (41
). On the other hand, information on gestational age was recorded before the diagnosis of epilepsy and misclassification is thus most likely to be non-differential, which often attenuates effect measures (42
). It is, however, possible that children born preterm or small may have been more likely to receive a diagnosis of epilepsy compared to babies born at term or with normal growth, especially if these factors increased their probability of being hospitalized or diagnosed with seizures.
This study only included singletons and thus the results cannot be applied to children born of multiple deliveries, for whom the significance of preterm and low birth weight are likely to be different.
Diagnoses of epilepsy were obtained from the Danish Hospital Registry, which holds information on discharge diagnoses from Danish hospitals of all inpatients since 1977 and all outpatients since 1995. The positive predictive value of the diagnosis of epilepsy in the Danish Hospital Register has been assessed according to the criteria (which requires ≥ 2 unprovoked seizure episodes) of International League Against Epilepsy (43
) and found to be 81 percent (95 percent CI: 75, 87) (44
). Unfortunately, we did not have information on completeness of the epilepsy diagnosis in the Danish National Hospital Register. We believe that severe cases of epilepsy are more likely to be hospitalized. Including outpatients in the register in 1995 was followed by a 17% increase in incidence rates of epilepsy (45
). When we restricted the analyses to data from 1995-2002, we found the same trend of association between gestational age and birth weight and the risk of epilepsy. An incomplete registration of epilepsy would cause underestimation of the cumulative incidence of epilepsy, but rate ratios would be affected only if it registration depended on exposure status, which is possible. However, this mechanism would result in higher IRR estimates of epilepsy during early childhood, but it is unlikely to explain the long-term impact of gestational age and birth weight on risk for epilepsy.
Our study was limited by lack of detailed clinical data on types of epilepsy. Our validation study showed that the data on epilepsy classification was imprecise (44
) and more than half of the epilepsy cases in the first year of life received a code of “unspecified” or “other.”(37
) Thus, more studies are needed to evaluate whether the association with birth weight, gestational age, and intrauterine growth is restricted to certain types of epilepsy.
Our study showed that gestational age at birth and intrauterine growth restriction are associated with the subsequent risk of epilepsy. Environmental factors operating in fetal life or short gestation in itself may play a causal role in the development of epilepsy, especially among young children.