ORIGINAL ARTICLE Association Between Early-life Factors and Risk of Child-onset Crohn’s Disease Among Victorian Children Born 1983–1998: A Birth Cohort Study Anne-Louise Ponsonby, BMedSci, MBBS, PhD,* ,† Anthony G. Catto-Smith, MBBS, MD,* ,‡,§ Angela Pezic, BAppSc,* Sandy Dupuis, BSc,* Jane Halliday, BSc, PhD,* ,§ Don Cameron, MBBS,* ,‡ Ruth Morley, BA, MB, BChir,* ,§ John Carlin, BSc PhD,* ,P and Terry Dwyer, MBBS, MPH, MD* ,† Background: The incidence of Crohn’s disease (CD) with onset before age 16 has increased. Several perinatal characteristics have been associated with CD. Our objective was to examine the temporal change in CD incidence by period of birth and the extent that this could be attributed to perinatal characteristics associated with higher CD risk. Methods: A record linkage study was conducted utilizing the perinatal records of Victorian births 1983–1998 inclusive and a state-based CD registry. Proportional hazards models were used to investigate the perinatal factors in relation to the onset of CD by age 16. Further, a nested case control study was conducted to examine the association between sibling exposure and CD risk. Results: The CD incidence rate for births 1983–1998 was 2.01 (95% confidence interval [CI] 1.79, 2.27) per 100,000 child- years. A birth cohort effect was demonstrated, with higher CD risk for 1992–1998 versus 1983–1991 births (hazard ratio [HR] 1.56; 95% CI 1.18, 2.06). Perinatal characteristics associated with higher CD risk included urban location, higher socioeco- nomic status, married mother, a congenital abnormality and de- livery by elective cesarean section. Sibling exposure during the first 6 years of life was not associated with CD risk. The in- creased CD incidence among more recent births was not ac- counted for by changes in these measured perinatal factors. Conclusions: The temporal increase in CD incidence documented for births up to 1990 has continued for children born after 1991 and was not accounted for by temporal changes in the measured peri- natal factors. (Inflamm Bowel Dis 2009;15:858 – 866) Key Words: Crohn’s disease, perinatal, risk factor, incidence, tem- poral increase P ediatric Crohn’s disease (CD) is a serious immunological disorder characterized by mucosal inflammation of the gut, with resultant strictures and fissures. The immune basis of the disease was first thought to involve predominantly Th1 activity but there is now increasing recognition of the impor- tance of defects in innate immunity 1 as well as other effector pathways in the adaptive cell-mediated system such as in Th17. 2 Genetic factors such as variants of the NOD/CARD15 and TLIA gene increase risk, 3 but the relatively low concor- dance in monozygotic twin pairs 4 and marked temporal shifts over time 5 indicate that environmental factors are important. An increasing incidence of CD has been observed in many modern countries over time. 5 In Victoria, Australia, we have previously reported that the incidence of pediatric-onset CD increased from 0.13/100,000 in 1971 to 2.01/100,000 in 1990, a more than 10-fold increase. 6 We also observed that the increase was more marked in urban rather than rural regions. 6 The etiology of CD remains unclear. Previous studies have reported that several perinatal characteristics of the infant may be associated with subsequent CD risk. These include prematurity, 7 higher socioeconomic family status at birth, 8 and higher maternal age. 9 In addition, case reports have identified a link between CD and various congenital abnormalities, 10,11 but population-based data on the associa- tion between congenital abnormalities and CD are not con- clusive. One line of etiological enquiry has been the role of the hygiene hypothesis in CD onset. 12 That is, that inadequate exposure to microorganisms in early life with resultant poorer microbial education of the immune system 13 is associated with higher CD risk. 12 This hypothesis has also been postu- Received for publication October 23, 2008; Accepted November 4, 2008. From the *Murdoch Childrens Research Institute, Melbourne, Victoria, Australia, † Menzies Research Institute, University of Tasmania, Hobart, Australia, ‡ Department of Gastroenterology and Clinical Nutrition, Royal Children’s Hospital, Melbourne, Victoria, Australia, § Department of Paedi- atrics, University of Melbourne, Melbourne, Victoria, Australia, P Depart- ments of Paediatrics and Public Health, University of Melbourne, Mel- bourne, Victoria, Australia. Funded by Murdoch Childrens Research Institute internal grant. Reprints: Anne-Louise Ponsonby, Murdoch Childrens Research Institute, Royal Childrens Hospital, Flemington Road, Parkville, Victoria, Australia 3052 (e-mail: anne-louise.ponsonby@mcri.edu.au). Copyright © 2008 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20842 Published online 23 December 2008 in Wiley InterScience (www. interscience.wiley.com). 858 Inflamm Bowel Dis ● Volume 15, Number 6, June 2009