Risk of Cerebral Palsy and Childhood Epilepsy Related to Infections before or during Pregnancy Chun S. Wu 1 *, Lars H. Pedersen 1,2 , Jessica E. Miller 3 , Yuelian Sun 1 , Elani Streja 3 , Peter Uldall 4,5 , Jørn Olsen 1,3 1 Department of Public Health, Aarhus University, Aarhus, Denmark, 2 Department of Obstetrics and Gynecology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark, 3 Department of Epidemiology, School of Public Health, University of California Los Angeles, Los Angeles, California, United States of America, 4 The Cerebral Palsy Registry in Denmark, National Institute of Public Health, University of Southern Denmark, Odense, Denmark, 5 Paediatric Clinic, The Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Abstract Background and Aim: Maternal infections during pregnancy have been associated with several neurological disorders in the offspring. However, given the lack of specificity for both the exposures and the outcomes, other factors related to infection such as impaired maternal immune function may be involved in the causal pathway. If impaired maternal immune function plays a role, we would expect infection before pregnancy to be associated with these neurological outcomes. Methods/Principal Findings: The study population included all first-born singletons in Denmark between January 1 1982 and December 31 2004. We identified women who had hospital-recorded infections within the 5 year period before pregnancy, and women who had hospital-recorded infections during pregnancy. We grouped infections into either infections of the genitourinary system, or any other infections. Cox models were used to estimate adjusted hazard ratios (aHRs) with 95% confidence interval (CI). Maternal infection of the genitourinary system during pregnancy was associated with an increased risk of cerebral palsy (aHR = 1.63, 95% CI: 1.34–1.98) and epilepsy (aHR = 1.27, 95% CI: 1.13–1.42) in the children, compared to children of women without infections during pregnancy. Among women without hospital-recorded infections during pregnancy, maternal infection before pregnancy was associated with an increased risk of epilepsy (aHR = 1.35, 95% CI: 1.21–1.50 for infections of the genitourinary system, and HR = 1.12, 95% CI: 1.03–1.22 for any other infections) and a slightly higher risk of cerebral palsy (aHR = 1.20, 95% CI: 0.96–1.49 for infections of the genitourinary system, and HR = 1.23, 95% CI: 1.06–1.43 for any other infections) in the children, compared to children of women without infections before (and during) pregnancy. Conclusions: These findings indicate that the maternal immune system, maternal infections, or factors related to maternal immune function play a role in the observed associations between maternal infections before pregnancy and cerebral diseases in the offspring. Citation: Wu CS, Pedersen LH, Miller JE, Sun Y, Streja E, et al. (2013) Risk of Cerebral Palsy and Childhood Epilepsy Related to Infections before or during Pregnancy. PLoS ONE 8(2): e57552. doi:10.1371/journal.pone.0057552 Editor: Claire Thorne, UCL Institute of Child Health, University College London, United Kingdom Received September 12, 2012; Accepted January 22, 2013; Published February 27, 2013 Copyright: ß 2013 Wu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The study was supported by the Danish Medical Research Council (FSS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: cw@soci.au.dk Introduction Maternal infections during pregnancy have been associated with a wide variety of neurological and psychiatric disorders in the offspring, such as cerebral palsy [1–3], epilepsy [4–6] autism [7– 10] and schizophrenia [11], respectively. These associations have also been observed in animal studies. [12,13] However, the lack of specificity related to both the exposures and the outcomes suggests that underlying factors correlated with maternal infections may play a role. Considering a family history of autoimmune disease is associated with autism in the offspring [14], underlying factors with other outcomes could also be related to impaired maternal immune function. If so, we would expect to see associations between maternal infections occurring before pregnancy, as an indicator of impaired immune function, and the risk of childhood neurological disorders, even in mothers without reported infec- tions during pregnancy. In regards to genetic causation, paternal infection may also be associated with an increased risk of these outcomes in the offspring. We conducted a population-based cohort study to examine whether the risk of cerebral palsy and epilepsy in the offspring is related to maternal (or paternal) infections occurring either during pregnancy or within the five year period before pregnancy. The underlying hypothesis is that maternal infections occurring before pregnancy increases the risk of cerebral palsy and epilepsy in the offspring. Under the hypothesis we would expect no associations between paternal infections and the outcomes under study. PLOS ONE | www.plosone.org 1 February 2013 | Volume 8 | Issue 2 | e57552