Chorioamnionitis and Chronic Lung Disease of Prematurity: A Path Analysis of Causality

 

 Buy Article Permissions and Reprints

Abstract

Current evidence suggests that additional pathogenetic factors could play a role in the development of chronic lung disease of prematurity, other than mechanical ventilation and free radical injury. The introduction of the concept of “fetal inflammatory response syndrome” offers a new perspective on the pathogenesis of chronic lung disease of prematurity. New statistical approaches could be useful tools in evaluating causal relationships in the development of chronic morbidity in preterm infants. The aim of this study was to test a new statistical framework incorporating path analysis to evaluate causality between exposure to chorioamnionitis and fetal inflammatory response syndrome and the development of chronic lung disease of prematurity. We designed a prospective cohort study that included consecutively born premature infants less than 32 weeks of gestation whose placentas were collected for histological analysis. Histological chorioamnionitis, clinical data, and neonatal outcomes were related to chronic lung disease. Along with standard statistical methods, a path analysis was performed to test the relationship between histological chorioamnionitis, gestational age, mechanical ventilation, and development of chronic lung disease of prematurity. Among the newborns enrolled in the study, 69/189 (36%) had histological chorioamnionitis. Of those with histological chorioamnionitis, 28/69 (37%) were classified as having fetal inflammatory response syndrome, according to the presence of severe chorioamnionitis and funisitis. Histological chorioamnionitis was associated with a lower birth weight, shorter gestation, higher frequency of patent ductus arteriosus, greater use of surfactant, and higher frequency of chronic lung disease of prematurity. Severe chorioamnionitis and funisitis were significantly associated with lower birth weight, lower gestational age, lower Apgar score at 5 minutes, more frequent use of mechanical ventilatory support and surfactant, as well as higher frequency of patent ductus arteriosus and chronic lung disease. The results of the path analysis showed that fetal inflammatory response syndrome has a significant direct (0.66), indirect (0.11), and overall (0.77) effect on chronic lung disease. This study demonstrated a strong positive correlation between exposure of the fetus to a severe inflammatory response and the development of chronic lung disease of prematurity.

• References

• 1 Mittendorf R, Covert R, Montag AG , et al. Special relationships between fetal inflammatory response syndrome and bronchopulmonary dysplasia in neonates. J Perinat Med 2005; 33: 428-434
  CrossrefPubMedGoogle Scholar
• 2 Speer CP . Role of inflammation in the pathogenesis of acute and chronic neonatal lung disease. In: Bancalari E, ed. The Newborn Lung: Questions and Controversies in Neonatology Series. Pulmonary Volume, 1st ed. Philadelphia: Saunders; 2008 :166–186
  PubMed
• 3 Fujimura M, Takeuchi T, Kitajima H, Nakayama M. Chorioamnionitis and serum IgM in Wilson-Mikity syndrome. Arch Dis Child 1989; 64 ( 10 Spec No 1379-1383
  CrossrefPubMedGoogle Scholar
• 4 Watterberg KL, Demers LM, Scott SM, Murphy SM. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996; 97: 210-215
  CrossrefPubMedGoogle Scholar
• 5 Bland RD. Neonatal chronic lung disease in the post-surfactant era. Biol Neonate 2005; 88: 181-191
  CrossrefPubMedGoogle Scholar
• 6 Cornette L. Fetal and neonatal inflammatory response and adverse outcome. Semin Fetal Neonatal Med 2004; 9: 459-470
  CrossrefPubMedGoogle Scholar
• 7 Speer CP. Role of inflammation in the evolution of bronchopulmonary dysplasia. Drug Discov Today: Dis Mech 2006; 3: 409-414
  CrossrefPubMedGoogle Scholar
• 8 Speer CP. Chorioamnionitis, postnatal factors and proinflammatory response in the pathogenetic sequence of bronchopulmonary dysplasia. Neonatology 2009; 95: 353-361
  CrossrefPubMedGoogle Scholar
• 9 Ahn J. Beyond single equation regression analysis: path analysis and multi-stage regression analysis. Am J Pharm Educ 2002; 66: 37-42
  PubMedGoogle Scholar
• 10 Langston C, Kaplan C, Macpherson T , et al. Practice guideline for examination of the placenta. Arch Pathol Lab Med 1997; 121: 449-476
  PubMedGoogle Scholar
• 11 Redline RW. Inflammatory responses in the placenta and umbilical cord. Semin Fetal Neonatal Med 2006; 11: 296-301
  CrossrefPubMedGoogle Scholar
• 12 Kent A, Dahlstrom JE. Chorioamnionitis/funisitis and the development of bronchopulmonary dysplasia. J Paediatr Child Health 2004; 40: 356-359
  CrossrefPubMedGoogle Scholar
• 13 Pacora P, Chaiworapongsa T, Maymon E , et al. Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome. J Matern Fetal Neonatal Med 2002; 11: 18-25
  CrossrefPubMedGoogle Scholar
• 14 Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163: 1723-1729
  CrossrefPubMedGoogle Scholar
• 15 Mehta R, Nanjundaswamy S, Shen-Schwarz S, Petrova A. Neonatal morbidity and placental pathology. Indian J Pediatr 2006; 73: 25-28
  CrossrefPubMedGoogle Scholar
• 16 Zanardo V, Vedovato S, Cosmi E , et al. Preterm premature rupture of membranes, chorioamnion inflammatory scores and neonatal respiratory outcome. BJOG 2010; 117: 94-98
  CrossrefPubMedGoogle Scholar
• 17 Shatrov JG, Birch SC, Lam LT, Quinlivan JA, McIntyre S, Mendz GL. Chorioamnionitis and cerebral palsy: a meta-analysis. Obstet Gynecol 2010; 116 (2 Pt 1) 387-392
  CrossrefPubMedGoogle Scholar
• 18 Been JV, Rours IG, Kornelisse RF , et al. Histologic chorioamnionitis, fetal involvement, and antenatal steroids: effects on neonatal outcome in preterm infants. Am J Obstet Gynecol 2009; 201: 587-, e1–e8
  PubMedGoogle Scholar
• 19 Yoon BH, Romero R, Park JS , et al. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 2000; 182: 675-681
  CrossrefPubMedGoogle Scholar
• 20 Murthy V, Kennea NL. Antenatal infection/inflammation and fetal tissue injury. Best Pract Res Clin Obstet Gynaecol 2007; 21: 479-489
  CrossrefPubMedGoogle Scholar
• 21 Ambalavanan N, Carlo WA, D’Angio CT , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Cytokines associated with bronchopulmonary dysplasia or death in extremely low birth weight infants. Pediatrics 2009; 123: 1132-1141
  Google Scholar
• 22 Redline RW, Wilson-Costello D, Hack M. Placental and other perinatal risk factors for chronic lung disease in very low birth weight infants. Pediatr Res 2002; 52: 713-719
  CrossrefPubMedGoogle Scholar
• 23 Van Marter LJ, Dammann O, Allred EN , et al; Developmental Epidemiology Network Investigators. Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants. J Pediatr 2002; 140: 171-176
  CrossrefPubMedGoogle Scholar
• 24 McGowan EC, Kostadinov S, McLean K , et al. Placental IL-10 dysregulation and association with bronchopulmonary dysplasia risk. Pediatr Res 2009; 66: 455-460
  CrossrefPubMedGoogle Scholar
• 25 Speer CP. Inflammation and bronchopulmonary dysplasia: a continuing story. Semin Fetal Neonatal Med 2006; 11: 354-362
  CrossrefPubMedGoogle Scholar
• 26 Rojas MA, Gonzalez A, Bancalari E, Claure N, Poole C, Silva-Neto G. Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease. J Pediatr 1995; 126: 605-610
  CrossrefPubMedGoogle Scholar
• 27 Gonzalez A, Sosenko IRS, Chandar J, Hummler H, Claure N, Bancalari E. Influence of infection on patent ductus arteriosus and chronic lung disease in premature infants weighing 1000 grams or less. J Pediatr 1996; 128: 470-478
  CrossrefPubMedGoogle Scholar
• 28 Bancalari E, Claure N, Gonzalez A. Patent ductus arteriosus and respiratory outcome in premature infants. Biol Neonate 2005; 88: 192-201
  CrossrefPubMedGoogle Scholar
• 29 Viscardi RM, Muhumuza CK, Rodriguez A , et al. Inflammatory markers in intrauterine and fetal blood and cerebrospinal fluid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants. Pediatr Res 2004; 55: 1009-1017
  CrossrefPubMedGoogle Scholar
• 30 Fichorova RN, Onderdonk AB, Yamamoto H , et al; Extremely Low Gestation Age Newborns (ELGAN) Study Investigators. Maternal microbe-specific modulation of inflammatory response in extremely low-gestational-age newborns. MBio 2011; 2: e00280-e10
  PubMedGoogle Scholar
• 31 Leviton A, Allred EN, Kuban KC , et al. Microbiologic and histologic characteristics of the extremely preterm infant’s placenta predict white matter damage and later cerebral palsy. the ELGAN study. Pediatr Res 2010; 67: 95-101
  CrossrefPubMedGoogle Scholar
• 32 McGowan EC, Kostadinov S, McLean K , et al. Placental IL-10 dysregulation and association with bronchopulmonary dysplasia risk. Pediatr Res 2009; 66: 455-460
  CrossrefPubMedGoogle Scholar
• 33 Beaudet L, Karuri S, Lau J, Magee F, Lee SK, von Dadelszen P. Placental pathology and clinical outcomes in a cohort of infants admitted to a neonatal intensive care unit. J Obstet Gynaecol Can 2007; 29: 315-323
  PubMedGoogle Scholar