Fetal inflammatory injury as origin of long term disease: lessons from animal models

Background: Chorioamnionitis is a major risk factor for preterm birth in multifetal pregnancies. However, there is little clinical data whether chorioamnionitis is restricted to one amniotic compartment in multifetal pregnancies. Objective: To explore whether chorioamnionitis is confined to the exposed compartment and does not cross to the unaffected fetus in twin pregnancy. Methods: In twin pregnant sheep, one of the twins was exposed to either 2 or 14 days of intraamniotic lipopolysaccharide (LPS) while the co-twin was exposed to either 2 or 14 days of intra-amniotic saline (n = 3 for each exposure). Singletons were included in this study to compare the grade of inflammation with twins. All fetuses were delivered at 125 days of gestation (term = 150 days). Chorioamnionitis was confirmed by histological examinaReceived: November 17, 2011 Accepted after revision: March 12, 2012 Published online: May 17, 2012 Boris W. Kramer, MD, PhD Department of Pediatrics Maastricht University Medical Center, P. Debyelaan 25 NL–6202 AZ Maastricht (The Netherlands) Tel. +31 43 387 7246, E-Mail b.kramer @ mumc.nl © 2012 S. Karger AG, Basel 1661–7800/12/1022–0081$38.00/0 Accessible online at: www.karger. com/neo M. Gantert and R.K. Jellema contributed equally to this work. D ow nl oa de d by : U ni ve rs ite it M aa st ric ht 14 5. 29 . 2 54 . 3 2 6 /1 0/ 20 13 2 :3 5: 59 P M Gantert et al. Neonatology 2012;102:81–88 82 Introduction Preterm birth is the leading cause of perinatal morbidity and mortality in developed countries [1] . Most preterm infants survive due to advancing clinical support, but they are at high risk of neurodevelopmental impairment [2, 3] and respiratory [4] and gastrointestinal [5, 6] complications [7] . Intrauterine infection of the fetal membranes, as documented by histologic findings or culture is a frequent cause of preterm birth and is referred to as chorioamnionitis [1] . Chorioamnionitis can trigger a fetal immune response syndrome, which can initiate labor by increased uterine contractility and preterm premature rupture of the membranes [8] . The diagnosis of chorioamnionitis is an established risk factor for adverse outcome such as bronchopulmonary dysplasia, neonatal sepsis and injury to the neonatal brain, particularly cystic periventricular leukomalacia and later development of cerebral palsy and intraventricular hemorrhage [9, 10] . The risk of preterm birth is increased in multiple pregnancies irrespective of additional risk factors such as chorioamnionitis [1] . Clinical findings show that in the majority of cases, histological chorioamnionitis in twin pregnancy affects the presenting fetus [11, 12] . Under these circumstances clinicians have to decide whether delivery of the second fetus can be delayed to reduce morbidity associated with preterm birth. Delayed-interval delivery may be an option in a twin pregnancy complicated by chorioamnionitis if the inflammation is confined to only one amniotic compartment as reported by Bollen and Padwick [13] and Watson and McNelis [14] . Unfortunately, there is little evidence that shows whether chorioamnionitis crosses from the affected compartment to the unaffected compartment. Therefore, we performed a study in twin pregnant sheep and exposed only one amniotic compartment to lipopolysaccharide (LPS) to induce histological chorioamnionitis. We hypothesized that LPS-induced histological chorioamnionitis would be confined to the exposed compartment and not affect the neighboring fetus.