Journal of Reproductive Immunology 79 (2008) 50–57 Review article Inflammatory processes in preterm and term parturition Inge Christiaens a,∗ , Dean B. Zaragoza a , Larry Guilbert a , Sarah A. Robertson b , Bryan F. Mitchell a , David M. Olson a a Perinatal Research Centre, Departments of Obstetrics and Gynecology, Pediatrics, Physiology, and Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada b Centre for Reproductive Health, Department of Obstetrics and Gynecology, University of Adelaide, Adelaide, Australia Received 19 December 2006; received in revised form 20 February 2008; accepted 15 April 2008 Abstract A role for the pro-inflammatory cytokines interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor alpha (TNF-) is evident in term and preterm delivery, and this is independent of the presence of infection. All uterine tissues progress through a staged transformation near the end of pregnancy that leads from relative uterine quiescence and maintenance of pregnancy to the activation of the uterus that prepares it for the work of labour and production of stimulatory molecules that trigger the onset of labour and delivery. The uterus is activated by pro-inflammatory cytokines through stimulation of the expression and production of uterine activation proteins (UAPs). One of these actions is the stimulation of prostaglandin (PG) synthesis. Particularly important for labour is PGF 2 and its receptor, PTGFR. In addition, pro-inflammatory cytokines are able to increase the synthesis of matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF) and the progesterone receptor C isoform, which leads to decreased tissue progesterone responsiveness. Some of these effects are replicated by PGF 2 , suggesting that it may act via its receptor to amplify the direct actions of cytokines. In turn, VEGF may enhance leukocyte recruitment to the uterus, and MMP-9 may promote activation of inactive pro-form cytokines. Pro-inflammatory cytokines also decrease the activity of 11-hydroxysteroid dehydrogenase, which likely increases intrauterine cortisol concentrations. In turn, cortisol may drive PG synthesis. Together these feed-forward mechanisms activate the uterus, trigger the production of uterine contractile stimulants and lead to labour and delivery. Crown Copyright © 2008 Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Pro-inflammatory cytokines; Pregnancy; Birth; Uterine activation; Preterm; Prostaglandins 1. Introduction Preterm birth (<37 weeks of gestation) is the lead- ing cause of mortality and morbidity in newborn infants. Data from the Canadian Perinatal Surveillance Report show that 81.6% of infants born preterm have a low birth weight (LBW; <2500 g at birth) and that 60% of all ∗ Corresponding author at: Perinatal Research Centre, 227 HMRC, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. Tel.: +1 780 492 0029; fax: +1 780 492 1308. E-mail address: Inge@ualberta.ca (I. Christiaens). neonatal deaths occur among LBW and preterm infants (Health-Canada, 1999). Further, preterm birth and LBW are associated with high neonatal and infant morbidity, including chronic respiratory illnesses, neurodevelop- mental problems and long-term impairment (Berkowitz and Papiernik, 1993; Kramer, 1987). Currently, over 60% of preterm deliveries are unexplained (Green et al., 2005), ascribable only to ‘idiopathic’ preterm labour or preterm premature rup- ture of fetal membranes. Some experts believe that these are associated with a (sub)clinical inflammatory response in the maternal and/or fetal tissues. Shim et al. (2004) showed that up to 70% of spontaneous 0165-0378/$ – see front matter. Crown Copyright © 2008 Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jri.2008.04.002