In this population-based historical cohort study, we found a 40% increased risk of epilepsy associated with prenatal exposure to maternal infection. This association could be caused by the infection itself, its antecedents or consequences, or by antibiotic treatment. However, the similar magnitude of IR observed for different types of antibiotics argues against the role of specific types of infections or specific treatments. Our study extends the findings by Sun et al
,. based on data from the Danish National Birth Cohort (1996–2002) 
, that maternal infections of different types, measured by self-report collected twice during pregnancy and additionally at 6 months after delivery, were associated with epilepsy in offspring 
. While the Sun et al.
study examined a nationwide sample of births in Denmark in which participation was based on self-selection and our study encompassed all births in the two northern regions of Denmark, we cannot rule out at least some overlap between the two study populations during 1999–2002. Given the similarity of the settings, the overall consistency of results is reassuring. Our study confirmed, using objective measures of infection, the overall association, found earlier, between maternal systemic infection and risk of epilepsy regardless of infection site. However, we found no association with antifungal treatment, while Sun et al.
, found that self-reported maternal vaginal yeast infection was associated with more than a two-fold increased risk of childhood epilepsy. Given that most antifungals are administered locally, our finding supports the argument that systemic effects of disease or treatment underlie the association with epilepsy in offspring.
Furthermore, our finding is in line with two previous studies showing an association between intrapartum fever and increased risk of neonatal seizures 
. Another recent study based on the Danish National Birth Cohort found no association between self-reported elevated maternal body temperature (due to fever or sauna use) during pregnancy and increased risk of epilepsy in offspring 
. However, children with prenatal exposure to more than two maternal fever episodes, maternal fever with urinary symptoms, or maternal fever of 39.0°C or did have an increased risk of epilepsy –suggesting that the underlying causes of fever rather than elevated temperature play a role 
. Recently it has been suggested that inflammation may be involved in the mechanism linking fever and epilepsy 
. Experimental studies in rodents have shown that inflammatory reactions in the brain can enhance neuronal excitability 
, and anti-inflammatory treatments reduce seizures in experimental models. Cytokines are key players in the modulation of neuronal excitability, as well as in leukocyte recruitment, and inflammatory central nervous system infections 
, yet little is known about their role in the pathogenesis of epilepsy. It is possible that maternal cytokine production in response to an infection during pregnancy induces foetal neurological injury 
. Our finding of a nearly threefold increased IRR for epilepsy among children born to mothers with epilepsy suggested that infants genetically predisposed to epilepsy may be more susceptible to inflammatory reactions.
Strengths and limitations of the study
We conducted a large study in a well-defined population and within a uniform health care system. Our use of population-based registries permitted virtually complete follow-up for both exposure and outcome 
. A potential study weakness is our reliance on hospital diagnoses of epilepsy, of which an estimated 81% (95% CI: 75%–87%) can be confirmed by a medical-chart diagnosis according to the stringent criteria in the International League against Epilepsy classification 
. Presence of false positive records of epilepsy in registry data may partially explain the relatively low prevalence of antiepileptic drug use among mothers and offspring with an epilepsy diagnosis (between 65% and 70% in our study vs. 85% reported in other countries 
). At the same time, children in Denmark with conditions such as rolandic epilepsy or infantile spasms are not treated universally with antiepileptic drugs 
. However, our study yielded similar relative risk estimates for partial epilepsy and generalised epilepsy. As any diagnostic misclassification is unlikely to differ by preceding maternal infection status, the statistical expectation for the direction of a resulting bias is towards the null, unless an upward bias arises by chance 
We based our study on the assumption that use of antibiotics is a valid marker for infection since infections are the specific indication for antibiotics. A study in Denmark of 7606 patients who were prescribed antibiotics by one of 602 general practitioners found that only 0.7% received antibiotic prescription prophylactically, and only 0.6% of patients received such prescription for unknown or not specified infections. In the remaining 98.7% of the patients, a prescription to an antibiotic could be traced to a specific infection diagnosis 
. A Swedish study in patients who underwent inguinal hernia repair found that the risk of antibiotic treatment during the post-surgical period was of the same order of magnitude as infection rates reported in the Swedish Hernia Register and review studies and concluded that surveillance of postoperative antibiotic use may be considered as a resource-saving surrogate marker for surgical-site infections 
We do not know whether the pregnant women in our study actually took the drugs prescribed to them. We speculate that compliance was likely to be high, particularly for those redeeming more than one prescription, since financial and time expenditures were involved in obtaining the medications. Any misclassification of medication use due to noncompliance would be expected to attenuate our relative estimates because it is likely unrelated to diagnosis of epilepsy in children.
In conclusion, our data showed a slightly increased risk of epilepsy associated with prenatal exposure to maternal infections. Similar risk estimates for different categories of antibiotics suggest that the increased risk stems from the consequences of infection rather than the type of infection or drug.