Background Previous studies have suggested that in-utero exposure to infection is associated with an increased risk of childhood seizures, but there is a lack of evidence regarding in-utero exposure to influenza. The objective of this study was to investigate whether in-utero exposure to the H1N1 pandemic, influenza infection, or vaccination is associated with a higher risk of childhood seizures.

Methods Registry-based study including all children born in Norway between 01/10/2009 and 31/12/2015 (n=254,347). Data were linked from sources including the Medical Birth Registry, the Norwegian Immunisation Register, the primary care reimbursement system, and the Norwegian Patient Registry. We investigated three exposures: 1) in-utero exposure to the H1N1 pandemic (≥1 pregnancy day during the main H1N1 pandemic wave), 2) in-utero exposure to maternal influenza infection (diagnosis of influenza-like illness in primary care, and/or laboratory confirmed H1N1 infection), and 3) in-utero exposure to H1N1 vaccination. We used Cox Proportional Hazards modelling to compare the incidence of seizures (any seizure, febrile seizure, epilepsy) according to exposure status from birth until 31/12/2015. Hazard ratios were adjusted for parity, maternal age, multiplicity, sex and maternal smoking.

Results 24.4% (62,032) children were exposed in-utero to the H1N1 pandemic, of whom 3.7% (2,299) were exposed in-utero to maternal influenza. Among 77 671 children with ≥1 in-utero day during the vaccination period, 34.9% (n=27,138) were exposed to vaccination. The risk of febrile seizures was slightly increased after in-utero exposure to the pandemic (aHR 1.06, 95% CI 1.00–1.12), but there was no evidence of an increased risk of epilepsy (aHR 1.08, 95% CI 0.93–1.26). There was no evidence of an overall association between in–utero exposure to maternal H1N1 infection and childhood seizures (febrile seizures aHR 1.17, 95% CI 0.92–1.49; epilepsy aHR 0.93, 95% CI 0.50–1.75). However, when stratified by trimester of exposure we observed a 40% increased risk of febrile seizures after infection during the second trimester (aHR 1.42, 95% CI 1.02–1.99). In-utero exposure to vaccination was not associated with an increased risk of childhood seizures.

Discussion This large study benefits from virtually no loss to follow-up and mandatory vaccination reporting. The limitations includes our inability to validate outcome data, and the under-reporting of influenza infection.Our finding of no increased risk subsequent to in-utero exposure to H1N1 vaccination supports the safety of vaccination in pregnancy. Although we found no overall evidence that in-utero exposure to maternal H1N1 infection was associated with febrile seizures, a small increased risk of febrile seizures after second trimester exposure warrants further investigation.