Paediatric Respiratory Reviews 15 (2014) 49–52
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Pro-Con Debate
Chorioamnionitis is essential in the evolution of bronchopulmonary dysplasia – The case in favour Wolfgang Thomas 1,*, Christian P. Speer 2,* 1 2
Mutterhaus der Borromaeerinnen, Department of Pediatrics, Feldstr. 6, 54290 Trier, Germany University of Wu¨rzburg, University Children’s Hospital, Josef-Schneider-Str. 2, 97080 Wu¨rzburg, Germany
EDUCATIONAL AIMS To illustrate a gestation-dependent effect of chorioamnionitis on BPD as major risk factor for spontaneous early preterm birth To demonstrate evidence for a direct gestation-independent effect of chorioamnionitis for BPD To highlight the role of chorioamnionitis as a postnatal risk factor for BPD
A R T I C L E I N F O
S U M M A R Y
Keywords: Chronic lung disease of infancy Prematurity Fetal inflammatory response syndrome
Bronchopulmonary dysplasia (BPD) is a major sequel of extremely premature birth. Multiple ante- and postnatal factors act in concert to injure the immature lung in the pathogenesis of the disease. Among them, chorioamnionitis - according to current evidence – plays a pivotal role. Pulmonary inflammatory processes seen in animal models of chorioamnionitis resemble those seen in premature infants who developed BPD. Chorioamnionitis can doubtlessly induce extremely preterm birth, thus contributing to a gestation-dependent risk of BPD. A gestation-independent association of chorioamnionitis with an increased risk of developing BPD has been demonstrated by a recent systematic review of clinical observational studies. Antenatal inflammation with signs of a systemic fetal response reduces the response to exogenous surfactant in infants with respiratory distress syndrome, leading to a longer need for mechanical ventilation. Moreover, chorioamnionitis increases the risk of early onset sepsis. Both mechanical ventilation and sepsis are, however, major postnatal risk factors for BPD. ß 2013 Elsevier Ltd. All rights reserved.
INTRODUCTION The pathogenetic role of chorioamnionitis in the development of bronchopulmonary dysplasia (BPD) has been addressed in a number of prospective observational clinical studies or retrospective case-control studies, which have been partially summarised in systematic reviews. These meta-analyses are suitable to generate hypotheses concerning the role of chorioamnionitis in the evolution of BPD but they do not prove a causal relationship between the two items. Animal studies have been applied as proof of concept that chorioamnionitis can cause pulmonary changes resembling human BPD. Nevertheless, it remains unclear if the results of these models can be transferred to extremely premature human infants. However, there is no clinically feasible way of
* Corresponding author. Tel.: +49 931 20127831; fax: +49 931 20127833. E-mail addresses: [email protected] (W. Thomas), [email protected] (C.P. Speer). * Tel.: +49 651 9472654. 1526-0542/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.prrv.2013.09.004
generating a higher level of evidence than currently available to demonstrate that chorioamnionitis is an important risk factor for the development of BPD. CHORIOAMNIONITIS AND EXTREMELY PREMATURE BIRTH ‘Chorioamnionitis’ is not a unique diagnosis but rather describes various manifestations of inflammatory processes affecting tissues of either mixed fetal-maternal or fetal origin [1]. Histological, microbiological and biochemical criteria have been used to define chorioamnionitis [2–4]. The term ‘fetal inflammatory response syndrome’ (FIRS) denotes the activation of the innate immune system of the fetus by infection/inflammation in utero, reflected by increased cord blood concentrations of proinflammatory cytokines and/or histological signs of funisitis/ chorionic vasculitis [4,5]. Both microbial colonization of placental tissue and histological evidence for placental and umbilical cord vessel inflammation have been shown to be associated with spontaneous early preterm birth [6,7]. In many of these cases pathogens of low virulence, such
50
W. Thomas, C.P. Speer / Paediatric Respiratory Reviews 15 (2014) 49–52
Figure 1. Simplified illustration of the role of chorioamnionitis for the development of bronchopulmonary dysplasia (BPD). Chorioamnionitis induces early preterm birth which leads to the immaturity of the lung as major prerequisite for BPD. It also induces a local pulmonary inflammatory process making the lung susceptible for further postnatal injuries. Among these postnatal risk factors, chorioamnionitis with systemic fetal inflammatory response (FIRS) has been shown to increase the likelihood of early onset sepsis and to deteriorate the response to exogenuous surfactant administration, which leads to a longer need for mechanical ventilation (MV) and supplemental oxygen (O2).
as Ureaplasma urealyticum and Mycoplasma hominis are isolated from the maternal urogenital tract [8]. Clinical signs of inflammation/infection, like maternal fever, tachycardia, leukocytosis or elevated C-reactive protein, uterine tenderness, foul-smelling vaginal discharge or fetal tachycardia, can only be found in a minority of these cases. As a major risk factor for spontaneous preterm birth, chorioamnionitis unequivocally contributes to the gestation-dependent morbidity of extremely premature infants, including BPD (Figure 1) [1,9]. The assessment of chorioamnionitis as a gestation-independent risk factor for adverse respiratory outcome of these infants is hampered by methodological shortcomings of many studies addressing these issues [10]. Moreover, mainly two major pregnancy disorders lead to preterm birth: (1) inflammation and (2) placental dysfunction resulting from vascular malfunction [6]. Since both entities are closely associated with adverse neonatal outcome, the assessment of either of them as gestation-independent risk factor in very premature infants is impeded by the lack of a ‘normal’ control group. CHORIOAMNIONITIS AND BPD To date, BPD still represents the most common respiratory disease complicating the neonatal clinical course after very preterm birth [11,12]. It has clearly been shown that BPD is an inflammatory disease, at least in the initial phase of the disease [13,14]. Several proinflammatory mediators have been found increased in airway secretions of very low birth weight (VLBW) infants developing BPD. These mediators induce a pulmonary microvascular leakage leading to an influx of plasma proteins into the airspace, which is able to inactivate surfactant and perpetuate bronchoalveolar inflammation [15]. Such a prolonged inflammatory response in the fetal lung has been shown in an ovine model of chorioamnionitis, induced by the intraamniotic injection of lipopolysaccharide (LPS) [16,17]. In this model the pulmonary inflammation was accompanied by a disturbed vascularization and alveolarization, leading to a histological picture which very closely resembles the pattern seen in infants who have died with BPD [18].
In human stillborns, histological chorioamnionitis has also been shown associated with a higher pulmonary expression of proinflammatory cytokines, accompanied by an influx of neutrophils and an increased apoptosis of airway epithelial cells [19,20]. Watterberg and colleagues first described a decreased incidence of RDS but an increased rate of BPD after histological chorioamnionitis in a prospective observational study [21]. The authors concluded that the prenatal inflammatory process accelerates lung maturation but promotes pulmonary inflammation leading to lung injury in the long run; a hypothesis which has been confirmed by a number of in vitro and in vivo experiments as well as clinical studies [14]. However, the infants included in Watterberg’s study were rather mature infants and they were neither treated with prenatal steroids nor with exogenous surfactant. Both therapeutic strategies have dramatically ameliorated adverse neonatal outcomes after extremely premature birth and most likely mitigate the association between prenatal inflammation and neonatal respiratory disease [22,23]. That might at least partially explain the inconsistent findings of subsequent clinical studies addressing the association of histological chorioamnionitis with BPD [10,24–27]. However, one very recent pathway analysis in a single center, including 189 infants with a gestational age of less than 32 weeks, identified histological chorioamnionitis with evidence of FIRS as a major direct risk factor for BPD. The association between FIRS and the development of BPD could only partially be explained by lower gestational age or longer and more intensive mechanical ventilation in this study [28]. Interestingly, histological chorioamnionitis along with funisitis, reflecting FIRS, has been shown to reduce the response to exogenous surfactant in infants with RDS. In a prospectively enrolled cohort of 301 patients with a gestational age < 32 weeks, infants with histological signs of FIRS, who received surfactant, needed more supplemental oxygen and had a longer time to extubation than those without histological signs of fetal involvement. The reduced response to exogenous surfactant was associated with a higher risk of developing BPD [29]. Elevated concentrations of proinflammatory cytokines in the amniotic fluid of premature infants have been associated with the
W. Thomas, C.P. Speer / Paediatric Respiratory Reviews 15 (2014) 49–52
development of BPD [30,31]. More recently, concentrations of matrix metalloproteinase 8 and white blood cell counts in amniotic fluid were shown to be higher in premature infants who developed BPD without RDS compared to infants with BPD after RDS [32]. These data suggest that intraamniotic inflammation has an impact on chronic respiratory disease in these patients. The finding that elevated cord blood concentrations of the proinflammatory interleukin-6 (IL-6) predicted BPD in infants born < 34 weeks of gestation better than elevated intraamniotic IL-6 allows the conclusion that FIRS contains an even more pronounced risk for BPD than local intraamniotic inflammation [33]. The role of infection of the maternal urogenital tract with microorganisms of low virulence, such as Ureaplasma, for spontanteous preterm birth has already been highlighted earlier. As a consequence, airways of many extremely premature infants are colonized with Ureaplasma urealyticum or parvum, which can induce a relevant pulmonary inflammation [34]. This colonization has clearly been associated with an increased risk for BPD, as outlined in a recent systematic review [35]. In addition, a considerable number of very preterm infants which has been identified with positive cord blood cultures of Ureaplasma urealyticum or Mycoplasma hominis were more likely to develop BPD [36,37]. Very recently, data from 59 observational and case-control studies including more than 15,000 patients have been summarised in a comprehensive systematic review [38]. This metaanalysis confirmed that chorioamnionitis represents a risk factor for the development of BPD. The diagnostic criteria for chorioamnionitis (histological, clinical, microbiological or combinations) varied substantially between the studies. The association with BPD was obvious for histological chorioamnionitis, which was assessed in the majority of studies included. A sub-analysis of 17 studies, which adjusted results for gestational age and birth weight, yielded a less accentuated, but still significant, interrelationship between chorioamnionitis and BPD [38]. The single most important risk factor for BPD is immaturity of the lung. However, according to the ‘‘multiple hit’’ hypothesis, the imminent risk for the disease associated with extremely low gestational age can be increased by a bunch of antenatal and postnatal factors [39]. In accordance with this hypothesis, a nested case control study demonstrated that histological chorioamnionitis in combination with mechanical ventilation and postnatal sepsis increased the risk of BPD [40]. A recent population-based study from Israel including almost 16,000 very low birth weight infants born in a period of eleven years identified early onset sepsis as one major postnatal risk factor for BPD [41]. Both histological and clinical chorioamnionitis have been associated with an increased risk of early onset sepsis in extremely premature infants [2,42,43]. These findings support the notion that exposure to infection/inflammation in utero plays a pathogenetic role for BPD also by increasing the risk of early postnatal systemic infection. In conclusion, chorioamnionitis is essential for the development of BPD as it clearly increases the likelihood of very premature birth as the single most important risk factor for the disease. It is able to induce a chronic inflammatory process of the immature lung making it more prone to postnatal injuries. Moreover, antenatal inflammation reduces the infant’s response to surfactant in RDS leading to higher supplemental oxygen requirements and a longer duration of mechanical ventilation. It is also associated with early onset sepsis in premature infants which is an additional postnatal factor contributing to an increased risk of BPD.
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[17]
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[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
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placental infiltrations, other markers of inflammation, and outcomes in 23- to 32-week preterm newborn infants. Am J Obstet Gynecol 2006;195:803–8. Leviton A, Allred EN, Kuban KC, Hecht JL, Onderdonk AB, O’Shea TM, Paneth N. Microbiologic and histological 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. Yoon BH, Romero R, Kim CJ, Jun JK, Gomez R, Choi JH, Syn HC. Amniotic fluid interleukin-6: A sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity. Am J Obstet Gynecol 1995;172:960–70. Gotsch F, Romero R, Kusanovic JP, Mazaki-Tovi S, Pineles BL, Erez O, Espinoza J, Hassan SS. The fetal inflammatory response syndrome. Clin Obstet Gynecol 2007;50:652–83. McElrath TF, Hecht JL, Dammann O, Boggess K, Onderdonk A, Markenson G, Harper M, Delpapa E, Allred EN, Leviton A. Pregnancy disorders that lead to delivery before the 28th week of gestation: An epidemiologic approach to classification. Am J Epidemiol 2008;168:980–9. Onderdonk AB, Delaney ML, DuBois AM, Allred EN, Leviton A. Detection of bacteria in placental tissues obtained from extremely low gestational age neonates. Am J Obstet Gynecol 2008;198. 110 e111–e117. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med 2000;342:1500–7. Muglia LJ, Katz M. The enigma of spontaneous preterm birth. N Engl J Med 2010;362:529–35. Been JV, Zimmermann LJ. Histologicalal chorioamnionitis and respiratory outcome in preterm infants. Arch Dis Child Fetal Neonatal Ed 2009;94:F218–25. Jobe AH. The new bronchopulmonary dysplasia. Curr Opin Pediatr 2011; 23:167–72. Philip AG. Bronchopulmonary dysplasia: then and now. Neonatology 2012; 102:1–8. Speer CP. Chorioamnionitis, postnatal factors and proinflammatory response in the pathogenetic sequence of bronchopulmonary dysplasia. Neonatology 2009;95:353–61. Speer CP. Neonatal Respiratory Distress Syndrome: An Inflammatory Disease? Neonatology 2011;99:316–9. Groneck P, Go¨tze-Speer B, Oppermann M, Eiffert H, Speer CP. Association of pulmonary inflammation and increased microvascular permeability during the development of bronchopulmonary dysplasia: a sequential analysis of inflammatory mediators in respiratory fluids of high-risk preterm neonates. Pediatrics 1994;93:712–8. Kramer BW, Kramer S, Ikegami M, Jobe AH. Injury, inflammation and remodeling in fetal sheep lung after intra-amniotic endotoxin. Am J Physiol Lung Cell Mol Physiol 2001;283:L452–9. Willet KE, Jobe AH, Ikegami M, Newnham J, Brennan S, Sly PD. Antenatal endotoxin and glucocorticoid effects on lung morphometry in preterm lambs. Pediatr Res 2000;48:782–8. Husain AN, Siddiqui NH, Stocker JT. Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia. Hum Pathol 1998;29:710–7. Schmidt B, Cao L, Mackensen-Haen S, Kendziorra H, Klingel K, Speer CP. Chorioamnionitis and inflammation of the fetal lung. Am J Obstet Gynecol 2001;184:173–7. May M, Marx A, Seidenspinner S, Speer CP. Apoptosis and proliferation in lungs of human fetuses exposed to chorioamnionitis. Histopathology 2004;45:283– 90. Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996;97:210–5. Been JV, Degraeuwe PL, Kramer BW, Zimmermann LJ. Antenatal steroids and neonatal outcome after chorioamnionitis: A meta-analysis. BJOG 2011;118: 113–22. Yost CC, Soll RF. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev 2000. CD001456. Dempsey E, Chen MF, Kokottis T, Vallerand D, Usher R. Outcome of neonates less than 30 weeks gestation with histological chorioamnionitis. Am J Perinatol 2005;22:155–9. Lahra MM, Beeby PJ, Jeffery HE. Intrauterine inflammation, neonatal sepsis, and chronic lung disease: A 13-year hospital cohort study. Pediatrics 2009;123:1314–9. Lau J, Magee F, Qiu Z, Hoube J, Von Dadelszen P, Lee SK. Chorioamnionitis with a fetal inflammatory response is associated with higher neonatal mortality, morbidity, and resource use than chorioamnionitis displaying a maternal inflammatory response only. Am J Obstet Gynecol 2005;193:708–13. Ogunyemi D, Murillo M, Jackson U, Hunter N, Alperson B. The relationship between placental histopathology findings and perinatal outcome in preterm infants. J Matern Fetal Neonatal Med 2003;13:102–9. Dessardo NS, Mustac E, Dessardo S, Banac S, Peter B, Finderle A, Maric M, Haller H. Chorioamnionitis and chronic lung disease of prematurity: a path analysis of causality. Am J Perinatol 2012;29:133–40. Been JV, Rours IG, Kornelisse RF, Jonkers F, de Krijger RR, Zimmermann LJ. Chorioamnionitis alters the response to surfactant in preterm infants. J Pediatr 2010;156:10–5. Ghezzi F, Gomez R, Romero R, Yoon BH, Edwin SS, David C, Janisse J, Mazor M. Elevated interleukin-8 concentrations in amniotic fluid of mothers whose neonates subsequently develop bronchopulmonary dysplasia. Eur J Obstet Gynecol Reprod Biol 1998;78:5–10.
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[31] Yoon BH, Romero R, Jun JK, Park KH, Park JD, Ghezzi F, Kim BI. Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia. Am J Obstet Gynecol 1997;177:825–30. [32] Lee J, Oh KJ, Yang HJ, Park JS, Romero R, Yoon BH. The importance of intraamniotic inflammation in the subsequent development of atypical chronic lung disease. J Matern Fetal Neonatal Med 2009;22:917–23. [33] Yoon BH, Romero R, Kim KS, Park JS, Ki SH, Kim BI, Jun JK. A systemic fetal inflammatory response and the development of bronchopulmonary dysplasia. Am J Obstet Gynecol 1999;181:773–9. [34] Groneck P, Go¨tze-Speer B, Speer CP. Inflammatory bronchopulmonary response of preterm infants with microbial colonisation of the airways at birth. Arch Dis Child Fetal Neonatal Ed 1996;74:F51–5. [35] Schelonka RL, Katz B, Waites KB, Benjamin Jr DK. Critical appraisal of the role of ureaplasma in the development of bronchopulmonary dysplasia with metaanalytic techniques. Pediatr Infect Dis J 2005;24:1033–9. [36] Goldenberg RL, Andrews WW, Goepfert AR, Faye-Petersen O, Cliver SP, Carlo WA, Hauth JC. The Alabama Preterm Birth Study: umbilical cord blood Ureaplasma urealyticum and Mycoplasma hominis cultures in very preterm newborn infants. Am J Obstet Gynecol 2008;198. 43.e1–5.
[37] Romero R, Garite TJ. Twenty percent of very preterm neonates (23–32 weeks of gestation) are born with bacteremia caused by genital mycoplasmas. Am J Obstet Gynecol 2008;198:1–3. [38] Hartling L, Liang Y, Lacaze-Masmonteil T. Chorioamnionitis as a risk factor for bronchopulmonary dysplasia: A systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2012;97:F8–17. [39] Bland R. Neonatal chronic lung disease in the post-surfactant era. Biol Neonate 2005;88:181–91. [40] Van Marter LJ, Dammann O, Allred EN, Leviton A, Pagano M, Moore M, Martin C. Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants. J Pediatr 2002;140:171–6. [41] Klinger G, Levy I, Sirota L, Boyko V, Lerner-Geva L, Reichman B, in collaboration with the Israel Neonatal Network. Outcome of early-onset sepsis in a national cohort of very low birth weight infants. Pediatrics 2010;125:e736–40. [42] Alexander JM, Gilstrap LC, Cox SM, McIntire DM, Leveno KJ. Clinical chorioamnionitis and the prognosis for very low birth weight infants. Obstet Gynecol 1998;91:725–9. [43] Strunk T, Doherty D, Jacques A, Simmer K, Richmond P, Kohan R, Charles A, Burgner D. Histologic chorioamnionitis is associated with reduced risk of lateonset sepsis in preterm infants. Pediatrics 2012;129:e134–41.
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Pro-Con Debate
Chorioamnionitis is essential in the evolution of bronchopulmonary dysplasia – The case in favour Wolfgang Thomas 1,*, Christian P. Speer 2,* 1 2
Mutterhaus der Borromaeerinnen, Department of Pediatrics, Feldstr. 6, 54290 Trier, Germany University of Wu¨rzburg, University Children’s Hospital, Josef-Schneider-Str. 2, 97080 Wu¨rzburg, Germany
EDUCATIONAL AIMS To illustrate a gestation-dependent effect of chorioamnionitis on BPD as major risk factor for spontaneous early preterm birth To demonstrate evidence for a direct gestation-independent effect of chorioamnionitis for BPD To highlight the role of chorioamnionitis as a postnatal risk factor for BPD
A R T I C L E I N F O
S U M M A R Y
Keywords: Chronic lung disease of infancy Prematurity Fetal inflammatory response syndrome
Bronchopulmonary dysplasia (BPD) is a major sequel of extremely premature birth. Multiple ante- and postnatal factors act in concert to injure the immature lung in the pathogenesis of the disease. Among them, chorioamnionitis - according to current evidence – plays a pivotal role. Pulmonary inflammatory processes seen in animal models of chorioamnionitis resemble those seen in premature infants who developed BPD. Chorioamnionitis can doubtlessly induce extremely preterm birth, thus contributing to a gestation-dependent risk of BPD. A gestation-independent association of chorioamnionitis with an increased risk of developing BPD has been demonstrated by a recent systematic review of clinical observational studies. Antenatal inflammation with signs of a systemic fetal response reduces the response to exogenous surfactant in infants with respiratory distress syndrome, leading to a longer need for mechanical ventilation. Moreover, chorioamnionitis increases the risk of early onset sepsis. Both mechanical ventilation and sepsis are, however, major postnatal risk factors for BPD. ß 2013 Elsevier Ltd. All rights reserved.
INTRODUCTION The pathogenetic role of chorioamnionitis in the development of bronchopulmonary dysplasia (BPD) has been addressed in a number of prospective observational clinical studies or retrospective case-control studies, which have been partially summarised in systematic reviews. These meta-analyses are suitable to generate hypotheses concerning the role of chorioamnionitis in the evolution of BPD but they do not prove a causal relationship between the two items. Animal studies have been applied as proof of concept that chorioamnionitis can cause pulmonary changes resembling human BPD. Nevertheless, it remains unclear if the results of these models can be transferred to extremely premature human infants. However, there is no clinically feasible way of
* Corresponding author. Tel.: +49 931 20127831; fax: +49 931 20127833. E-mail addresses: [email protected] (W. Thomas), [email protected] (C.P. Speer). * Tel.: +49 651 9472654. 1526-0542/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.prrv.2013.09.004
generating a higher level of evidence than currently available to demonstrate that chorioamnionitis is an important risk factor for the development of BPD. CHORIOAMNIONITIS AND EXTREMELY PREMATURE BIRTH ‘Chorioamnionitis’ is not a unique diagnosis but rather describes various manifestations of inflammatory processes affecting tissues of either mixed fetal-maternal or fetal origin [1]. Histological, microbiological and biochemical criteria have been used to define chorioamnionitis [2–4]. The term ‘fetal inflammatory response syndrome’ (FIRS) denotes the activation of the innate immune system of the fetus by infection/inflammation in utero, reflected by increased cord blood concentrations of proinflammatory cytokines and/or histological signs of funisitis/ chorionic vasculitis [4,5]. Both microbial colonization of placental tissue and histological evidence for placental and umbilical cord vessel inflammation have been shown to be associated with spontaneous early preterm birth [6,7]. In many of these cases pathogens of low virulence, such
50
W. Thomas, C.P. Speer / Paediatric Respiratory Reviews 15 (2014) 49–52
Figure 1. Simplified illustration of the role of chorioamnionitis for the development of bronchopulmonary dysplasia (BPD). Chorioamnionitis induces early preterm birth which leads to the immaturity of the lung as major prerequisite for BPD. It also induces a local pulmonary inflammatory process making the lung susceptible for further postnatal injuries. Among these postnatal risk factors, chorioamnionitis with systemic fetal inflammatory response (FIRS) has been shown to increase the likelihood of early onset sepsis and to deteriorate the response to exogenuous surfactant administration, which leads to a longer need for mechanical ventilation (MV) and supplemental oxygen (O2).
as Ureaplasma urealyticum and Mycoplasma hominis are isolated from the maternal urogenital tract [8]. Clinical signs of inflammation/infection, like maternal fever, tachycardia, leukocytosis or elevated C-reactive protein, uterine tenderness, foul-smelling vaginal discharge or fetal tachycardia, can only be found in a minority of these cases. As a major risk factor for spontaneous preterm birth, chorioamnionitis unequivocally contributes to the gestation-dependent morbidity of extremely premature infants, including BPD (Figure 1) [1,9]. The assessment of chorioamnionitis as a gestation-independent risk factor for adverse respiratory outcome of these infants is hampered by methodological shortcomings of many studies addressing these issues [10]. Moreover, mainly two major pregnancy disorders lead to preterm birth: (1) inflammation and (2) placental dysfunction resulting from vascular malfunction [6]. Since both entities are closely associated with adverse neonatal outcome, the assessment of either of them as gestation-independent risk factor in very premature infants is impeded by the lack of a ‘normal’ control group. CHORIOAMNIONITIS AND BPD To date, BPD still represents the most common respiratory disease complicating the neonatal clinical course after very preterm birth [11,12]. It has clearly been shown that BPD is an inflammatory disease, at least in the initial phase of the disease [13,14]. Several proinflammatory mediators have been found increased in airway secretions of very low birth weight (VLBW) infants developing BPD. These mediators induce a pulmonary microvascular leakage leading to an influx of plasma proteins into the airspace, which is able to inactivate surfactant and perpetuate bronchoalveolar inflammation [15]. Such a prolonged inflammatory response in the fetal lung has been shown in an ovine model of chorioamnionitis, induced by the intraamniotic injection of lipopolysaccharide (LPS) [16,17]. In this model the pulmonary inflammation was accompanied by a disturbed vascularization and alveolarization, leading to a histological picture which very closely resembles the pattern seen in infants who have died with BPD [18].
In human stillborns, histological chorioamnionitis has also been shown associated with a higher pulmonary expression of proinflammatory cytokines, accompanied by an influx of neutrophils and an increased apoptosis of airway epithelial cells [19,20]. Watterberg and colleagues first described a decreased incidence of RDS but an increased rate of BPD after histological chorioamnionitis in a prospective observational study [21]. The authors concluded that the prenatal inflammatory process accelerates lung maturation but promotes pulmonary inflammation leading to lung injury in the long run; a hypothesis which has been confirmed by a number of in vitro and in vivo experiments as well as clinical studies [14]. However, the infants included in Watterberg’s study were rather mature infants and they were neither treated with prenatal steroids nor with exogenous surfactant. Both therapeutic strategies have dramatically ameliorated adverse neonatal outcomes after extremely premature birth and most likely mitigate the association between prenatal inflammation and neonatal respiratory disease [22,23]. That might at least partially explain the inconsistent findings of subsequent clinical studies addressing the association of histological chorioamnionitis with BPD [10,24–27]. However, one very recent pathway analysis in a single center, including 189 infants with a gestational age of less than 32 weeks, identified histological chorioamnionitis with evidence of FIRS as a major direct risk factor for BPD. The association between FIRS and the development of BPD could only partially be explained by lower gestational age or longer and more intensive mechanical ventilation in this study [28]. Interestingly, histological chorioamnionitis along with funisitis, reflecting FIRS, has been shown to reduce the response to exogenous surfactant in infants with RDS. In a prospectively enrolled cohort of 301 patients with a gestational age < 32 weeks, infants with histological signs of FIRS, who received surfactant, needed more supplemental oxygen and had a longer time to extubation than those without histological signs of fetal involvement. The reduced response to exogenous surfactant was associated with a higher risk of developing BPD [29]. Elevated concentrations of proinflammatory cytokines in the amniotic fluid of premature infants have been associated with the
W. Thomas, C.P. Speer / Paediatric Respiratory Reviews 15 (2014) 49–52
development of BPD [30,31]. More recently, concentrations of matrix metalloproteinase 8 and white blood cell counts in amniotic fluid were shown to be higher in premature infants who developed BPD without RDS compared to infants with BPD after RDS [32]. These data suggest that intraamniotic inflammation has an impact on chronic respiratory disease in these patients. The finding that elevated cord blood concentrations of the proinflammatory interleukin-6 (IL-6) predicted BPD in infants born < 34 weeks of gestation better than elevated intraamniotic IL-6 allows the conclusion that FIRS contains an even more pronounced risk for BPD than local intraamniotic inflammation [33]. The role of infection of the maternal urogenital tract with microorganisms of low virulence, such as Ureaplasma, for spontanteous preterm birth has already been highlighted earlier. As a consequence, airways of many extremely premature infants are colonized with Ureaplasma urealyticum or parvum, which can induce a relevant pulmonary inflammation [34]. This colonization has clearly been associated with an increased risk for BPD, as outlined in a recent systematic review [35]. In addition, a considerable number of very preterm infants which has been identified with positive cord blood cultures of Ureaplasma urealyticum or Mycoplasma hominis were more likely to develop BPD [36,37]. Very recently, data from 59 observational and case-control studies including more than 15,000 patients have been summarised in a comprehensive systematic review [38]. This metaanalysis confirmed that chorioamnionitis represents a risk factor for the development of BPD. The diagnostic criteria for chorioamnionitis (histological, clinical, microbiological or combinations) varied substantially between the studies. The association with BPD was obvious for histological chorioamnionitis, which was assessed in the majority of studies included. A sub-analysis of 17 studies, which adjusted results for gestational age and birth weight, yielded a less accentuated, but still significant, interrelationship between chorioamnionitis and BPD [38]. The single most important risk factor for BPD is immaturity of the lung. However, according to the ‘‘multiple hit’’ hypothesis, the imminent risk for the disease associated with extremely low gestational age can be increased by a bunch of antenatal and postnatal factors [39]. In accordance with this hypothesis, a nested case control study demonstrated that histological chorioamnionitis in combination with mechanical ventilation and postnatal sepsis increased the risk of BPD [40]. A recent population-based study from Israel including almost 16,000 very low birth weight infants born in a period of eleven years identified early onset sepsis as one major postnatal risk factor for BPD [41]. Both histological and clinical chorioamnionitis have been associated with an increased risk of early onset sepsis in extremely premature infants [2,42,43]. These findings support the notion that exposure to infection/inflammation in utero plays a pathogenetic role for BPD also by increasing the risk of early postnatal systemic infection. In conclusion, chorioamnionitis is essential for the development of BPD as it clearly increases the likelihood of very premature birth as the single most important risk factor for the disease. It is able to induce a chronic inflammatory process of the immature lung making it more prone to postnatal injuries. Moreover, antenatal inflammation reduces the infant’s response to surfactant in RDS leading to higher supplemental oxygen requirements and a longer duration of mechanical ventilation. It is also associated with early onset sepsis in premature infants which is an additional postnatal factor contributing to an increased risk of BPD.
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