Journal of Perinatology (2010) 30, S21–S30 r 2010 Nature America, Inc. All rights reserved. 0743-8346/10 www.nature.com/jp REVIEW Chorioamnionitis: a multiorgan disease of the fetus? M Gantert1,4, JV Been2,3,4, AWD Gavilanes2,3, Y Garnier1, LJI Zimmermann2,3 and BW Kramer2,3 1Department of Obstetrics and Gynecology, Klinikum Osnabru¨ck, Osnabru¨ck, Germany; 2Department of Pediatrics, Maastricht University Medical Centre, Maastricht, The Netherlands and 3School of Oncology and Developmental Biology, GROW, School of Mental Health and Neuroscience, University of Maastricht, Maastricht, The Netherlands membranes (PPROM). Obviously, in the former group the The bacterial infection of chorion and amnion is a common finding in direct cause is iatrogenic and may relate to fetal or maternal premature delivery and is referred to as chorioamnionitis. As the mother indications for intervention. These include severe intrauterine rarely shows symptoms of a systemic inflammation, the course of growth retardation, and maternal pre-eclampsia and hypertension, chorioamnionitis is frequently asymptomatic and chronic. In contrast, the elevated liver enzymes, low platelets (HELLP) syndrome. fetal inflammatory response syndrome represents a separate phenomenon, On the other hand, preterm deliveries in the larger group of including umbilical inflammation and increased serum levels of spontaneous preterm labor and PPROM are often associated proinflammatory cytokines in the fetus. Ascending maternal infections with intrauterine inflammation or chorioamnionitis.1,2 A close frequently lead to systemic fetal inflammatory reaction. Clinical studies have association between chorioamnionitis and spontaneous preterm shown that antenatal exposure to inflammation puts the extremely delivery exists.2 As a result, the proportion of preterm infants immature neonates at a high risk for worsening pulmonary, neurological exposed to chorioamnionitis increases with decreasing gestational and other organ development. Interestingly, the presence of age to up to 80% below 28 weeks of gestation.3,4 chorioamnionitis is associated with a lower rate of neonatal mortality in Ascending bacterial invasion of the uterine cavity is thought extremely immature newborns. In the following review, the pathogeneses of to be the most common route of infection, although bacteria are inflammation-associated perinatal morbidity are outlined. The concept identified only in the minority of cases.2 Organisms most frequently of fetal multiorganic disease during intrauterine infection is introduced associated with chorioamnionitis are mainly of low virulence, and discussed. including Ureaplasma spp. and Mycoplasma spp.2,5 Both the Journal of Perinatology (2010) 30, S21–S30; doi:10.1038/jp.2010.96 maternal and fetal immune system have an important role in Keywords: antenatal inflammation; organ injury; development; repair; chorioamnionitis, given the shown associations between adverse outcome polymorphisms in immunoregulatory genes and the risk of chorioamnionitis and preterm labor.6,7 A large subset of chorioamnionitis cases remain clinically silent. These may be Introduction diagnosed by culture or proteomic profiling of the amniotic fluid, by microbial culture or footprinting, or by histological examination Despite substantial progress in antenatal care, preterm birth of the placenta after birth.5 The latter is generally regarded as the remains a major health issue across the globe. In the Western ‘gold standard’ in the diagnosis of chorioamnionitis.5 More serious world, preterm birth accounts for 5 to 13% of all live births, with cases of chorioamnionitis may become clinically apparent and important regional differences.1 The incidence of preterm birth cause both general (fever, leukocytosis and raised C-reactive continues to rise steadily, exposing the society to increasing protein) and local symptoms (uterine tenderness and vaginal medical and social expenses.1 discharge). Although a combination of these symptoms is often Roughly, the causes of preterm birth can be divided into two given the syndromic description ‘clinical chorioamnionitis’, the groups: indicated preterm birth and preterm birth preceded by overlap with the histological diagnosis of chorioamnionitis spontaneous preterm labor or preterm prelabor rupture of has been shown to be only modest.8 Correspondence: Dr BW Kramer, Department of Pediatrics, Maastricht University Medical In chorioamnionitis, the presence of fetal signs of inflam- Center, School of Oncology and Developmental Biology, P. Debyelaan 25, Maastricht 6202 mation, such as funisitis or elevated cord blood interleukin-6 AZ, The Netherlands. E-mail: [email protected] (IL-6), is thought to reflect the more serious side of the continuum.9 When intrauterine inflammation is present, the fetus This paper resulted from the Evidence vs Experience in Neonatal Practices conference, 19 to 20 June 2009, sponsored by Dey, LP. may be exposed through direct contact with amniotic fluid or 4These authors contributed equally to this work. through the placental–fetal circulation. The consequent fetal Chorioamnionitis: a multiorgan disease of the fetus? M Gantert et al S22 response to chorioamnionitis has been referred to as the fetal perinatal brain injury might increase the risk for the development inflammatory response syndrome (FIRS).9 Many studies have of psychiatric disorders such as schizophrenia later in life.11 associated chorioamnionitis with adverse neonatal outcome in Chorioamnionitis and vasculitis in the umbilical cord (funisitis) newborn infants and the most pronounced effects were often have a high incidence in preterm deliveries and are probably present in infants with signs of FIRS. Although earlier studies have the most important risk factor of both preterm labor and birth, focused mainly on the respiratory and neurological outcomes, and preterm cerebral white matter disease (WMD) (Figure 1). additional fetal sequelae of chorioamnionitis have more recently Furthermore, hypoxia–ischemia in association with chorio- been described in several other organ systems. Moreover, evidence amnionitis markedly increases the vulnerability of the immature is increasing that the effects of chorioamnionitis on health and brain to the deficits mentioned above.12 Diffuse or focal WMD, disease may extend well beyond the neonatal period.10 In the usually described as periventricular leukomalacia, has been shown current review we aim to give an overview on the concept of to be the predominant feature of brain damage in premature chorioamnionitis as a multiorgan disease of the fetus, and discuss newborns of <32 weeks of gestation.11 Magnetic resonance potential long-term consequences and therapeutic options for imaging studies at corrected term age showed that 21% of early intervention. extreme preterm infants have moderate-to-severe WMD, and this was predictive of cerebral palsy at the corrected age of 2 years.13 In clinical studies, antenatal exposure to inflammation has been associated with an increased risk for periventricular Multiorgan overview 14–16 Brain leukomalacia and cerebral palsy. Moreover, neurodevelop- Clinical observations. Specific stages of brain development mental delay has been linked with previous exposure to chorioamnionitis by some studies, although others have failed could be affected at different gestational ages with different 10 prognoses that manifest throughout the entire lifespan. In term to reproduce these findings. and preterm newborns in particular, perinatal brain damage is a fundamental cause of developmental delay and lifelong Animal experimental evidence. Experimentally, inflammatory neurological disabilities, such as mental retardation, cerebral processesFinduced by intra-amniotic or intravenous fetal palsy as well as school and behavioral difficulties. In addition, endotoxin administrationFimpair myelination.17 We showed Figure 1 Chorioamnionitis as a multiorgan disease of the fetus. The fetus is being exposed to contaminated amniotic fluid that is aspirated and/or slicked by the fetus. The direct and indirect exposure has been associated with effects on several organs that are depicted in the figure. Journal of Perinatology Chorioamnionitis: a multiorgan disease of the fetus? M Gantert et al S23 global central nervous system compromise after chorioamnionitis inflammatory response is frequently associated with perinatal induced by the intra-amniotic administration of lipopolysaccharide hypoxia–ischemia.11 (LPS) in the fetal sheep.18 Chorioamnionitis induced microglial Recently, a new effect of neuroinflammation was revealed. activation, astrogliosis and apoptotic cell death and differentially Neuroinflammation is not only neurotoxic, as already shown, affected the whole ovine central nervous system. Regional responses but may also be beneficial for neural repair.31 For instance, TNF-a varied as a function of its maturational stage; for example, brain might lead to structural repair through the upregulation of and cerebellar, but not spinal premyelinating oligodendrocytes, astroglial brain-derived neurotrophic factor31 and macrophages were found to be vulnerable at the gestational age of 125 days can be involved in optic axonal regeneration.32 Furthermore, LPS- (term being 150 days).18 In addition, Garnier et al.19 showed induced sublethal inflammation may affect developing central microglial activation in the periventricular and subcortical white nervous system vulnerability, offering neuroprotection to a severe matter and increased S100B protein blood levels in a model