http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–5 ! 2015 Informa UK Ltd. DOI: 10.3109/14767058.2015.1053862
REVIEW ARTICLE
Chorioamnionitis and neonatal outcome in preterm infants: a clinical overview
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Lorenza Pugni1, Carlo Pietrasanta1, Barbara Acaia2, Daniela Merlo3, Andrea Ronchi1, Manuela Wally Ossola2, Silvano Bosari3, and Fabio Mosca1 1
Department of Clinical Sciences and Community Health, NICU, 2Department of Obstetrics and Gynecology, and 3Department of Pathophysiology and Organ Transplantation, Division of Pathology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy Abstract
Keywords
The term chorioamnionitis is used to refer to an intrauterine infection/inflammation occurring between the maternal tissues and the fetal membranes (choriodecidual space) or in the fetal annexes (chorioamniotic membranes, amniotic fluid, umbilical cord). Histological examination of the placenta is the gold standard for diagnosis. However, clinical, biochemical and microbiological criteria are also used to define the disease. The literature contains a large body of evidence showing that chorioamnionitis is the leading cause of very preterm birth and, therefore, contributes significantly to neonatal morbidity and mortality. In recent decades, numerous studies have attempted to establish whether, and to what extent, intrauterine infection/inflammation might negatively affect the short- and long-term outcome of preterm infants. The question is still unanswered. The discrepancy observed across studies can be attributed largely to the use of different inclusion and exclusion criteria, diagnostic criteria and methods, and to whether or not potential confounding factors, such as gestational age were considered. Anyhow, the association between chorioamnionitis and severe prematurity requires serious efforts by researchers to clarify the mechanisms linking intrauterine infection/inflammation with preterm birth, and thus to identify strategies that may guide clinicians’ diagnostic and therapeutic choices, with regard to both mothers and infants.
Brain injury, bronchopulmonary dysplasia, death, funisitis, intrauterine inflammation, prematurity, respiratory distress syndrome, sepsis
Introduction The importance of placental disorders in the diagnosis and treatment of various neonatal clinical conditions has long been recognized. In 1892, Ballantyne, a Scottish obstetrician, wrote: ‘‘During the intrauterine life, the fetus, the membranes, the cord, and the placenta form an organic whole, and disease of any part must react upon and affect the others’’ [1]. The literature now contains a vast body of evidence showing that, of the various disorders of the placenta, infection/inflammation of the fetal membranes or umbilical cord (chorioamnionitis/funisitis) is the cause of preterm birth in a significant percentage of cases (up to 50%) [2–5]. In recent decades, numerous studies attempted to establish whether, and to what extent, intrauterine infection/inflammation might negatively affect the short- and long-term outcome of preterm infants. As the incidence of chorioamnionitis/ funisitis is higher at earlier gestational ages (GAs) [4,6], many authors have attempted to demonstrate a GA-independent
Address for correspondence: Dr Lorenza Pugni, MD, Department of Clinical Sciences and Community Health, NICU, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Via Commenda 12, 20122 Milan, Italy. Tel: +390255032907. Fax: +390255032429. E-mail: [email protected]
History Received 26 February 2015 Revised 19 May 2015 Accepted 19 May 2015 Published online 1 July 2015
negative effect of chorioamnionitis on outcome. However, these studies gave different results, and this is undoubtedly due mainly to the presence of numerous confounding factors, ranging from different study methods to many different postnatal insults occurring frequently after preterm birth.
Intrauterine infection/inflammation: from chorioamnionitis to funisitis, a ‘‘continuum’’ from mother to fetus The term chorioamnionitis is used to refer to an intrauterine status of inflammation, in most cases caused by an infectious agent, occurring between the maternal tissues and the fetal membranes (choriodecidual space) or in the fetal annexes (chorioamniotic membranes, amniotic fluid, umbilical cord). Histological, microbiological, biochemical and clinical criteria are used to define chorioamnionitis [7,8]. Histological examination of the placenta is the gold standard for evaluating antenatal inflammatory processes. In addition to histological criteria, chorioamnionitis can also be diagnosed on the basis of clinical criteria (presence of clinical signs of inflammation in the mother), microbiological findings [positive amniotic fluid culture or polymerase chain reaction (PCR) detection of pathogens], and biochemical criteria [elevated cytokine levels in amniotic fluid, elevated maternal serum C-reactive protein
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(CRP) concentration, presence of fetal fibronectin in cervical and vaginal secretions, etc.] [7,9–12]. Histology is the most sensitive method for diagnosing chorioamnionitis, and clinical examination is the least sensitive one. Edwards [13], in a case series of preterm deliveries, reported a 5–10% prevalence of clinical chorioamnionitis, while the prevalence of histological chorioamnionitis exceeded 50%. Although histological examination of the placenta constitutes the gold standard for diagnosis, this finding is available only after delivery. Amniotic fluid analysis after rupture of membranes, or through amniocentesis, has been widely recognized as a good tool for an early diagnosis of intra-amniotic infection and/or inflammation before delivery [2,3,12]. The amniotic cavity is considered to be sterile; less than 1% of women not in labor at term have bacteria in the amniotic fluid. The isolation of bacteria in the amniotic fluid is a pathologic finding, defined as microbial invasion of the amniotic cavity (MIAC) [14]. Amniotic fluid can be cultured or processed with molecular technologies to make a diagnosis of MIAC. Several authors have demonstrated that the prevalence of MIAC is higher when molecular techniques are used [15]. Recently, Romero et al. [16] reported that the prevalence of MIAC was 24% by culture, 36% by broad-range PCR coupled with electrospray ionization mass spectrometry, and 41% by both methods combined in 59 women with preterm premature – or prelabor (at least 1 h before the onset of contractions) – rupture of the membranes (PPROM). However, it is well known that preterm delivery and neonatal complications occur also in the presence of an intraamniotic inflammatory status alone, without demonstration of pathogens in the amniotic cavity. An intra-amniotic inflammation can be demonstrated by elevated levels in the amniotic fluid of inflammatory markers, such as interleukin-6 (IL-6), or other pro-inflammatory cytokines. In a study published in 2001, Yoon et al. [17] reported that intra-amniotic inflammation (negative amniotic fluid culture but elevated amniotic fluid IL-6) was more common than intra-amniotic infection (positive amniotic fluid culture regardless of amniotic fluid IL-6 concentration) in patients with preterm labor and intact membranes. The incidence of adverse outcomes (clinical and histologic chorioamnionitis, preterm birth, neonatal morbidity) in patients with intra-amniotic infection was similar to that of patients with intra-amniotic inflammation and a negative amniotic fluid culture. When an infectious/inflammatory state in the mother reaches the fetus, the fetus may react to the insult by mounting its own inflammatory response, the intensity of which is proportional to the maturity of its immune system [3,18]. The ensuing picture, termed fetal inflammatory response syndrome (FIRS) by the authors who first described it in 1998 [19], is characterized by a raised fetal plasma IL-6 level (411 pg/mL) and, histopathologically, by funisitis/chorionic vasculitis and the presence of fetal polymorphonuclear granulocytes in the umbilical cord vessels [20]. In some studies, the prevalence of histological chorioamnionitis has been found to be greater than 50% in women who gave birth prematurely [13] and, among these women, it was significantly higher in those with PPROM than in those who presented with intact membranes (80 versus 33%) [21]. The
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prevalence of histological chorioamnionitis decreases with increasing GA at preterm delivery. In a retrospective study of 4000 preterm infants published in 2004 by Lahra and Jeffery [6], the incidence of histological chorioamnionitis was reported to be 31%, ranging from 66% at 24 weeks of GA to 16% at the end of the 34th week of gestation. The prevalence of funisitis, like that of chorioamnionitis, has been found to be inversely related to GA. In 2005, Lau et al. [22] reported it to be 62% in a population of premature infants with a GA of less than 34 weeks, while Lahra et al. [6], in 2004, reported variable percentages, ranging from 25% in infants with a GA of 30–34 weeks to 65% in those with a GA of less than 25 weeks. The mechanisms through which intrauterine infection leads to preterm labor are the result of activation of the innate immune system. The infectious insult triggers a cascade of events that leads to the release of numerous inflammatory mediators (cytokines, chemokines, prostaglandins, proteases, etc.), resulting in uterine contractions and rupture of the membranes [23]. Bacterial microorganisms are the pathogens most frequently responsible for intrauterine infection. In recent years, several authors have demonstrated, using molecular biology techniques, such as PCR, that the prevalence of MIAC is significantly higher than previously thought based on the results of traditional methods [12,24]. The fact that Ureaplasma spp. (U. urealyticum, U. parvum), genital Mycoplasmas (M. hominis, M. genitalium), Gardnerella vaginalis, and the bacteria belonging to the Bacteroides genus (all organisms of low virulence) are the microorganisms most frequently isolated from the amniotic cavity of women with preterm labor and intact membranes could explain why intrauterine infections are more often chronic than acute conditions [25]. The infection can occur in the early stages of pregnancy, becoming symptomatic more often after the 20th week of gestation [4]. The idea of uterine infection as a chronic condition may initially seem to be at odds with the anatomopathological evidence, according to which most cases of chorioamnionitis are ‘‘acute inflammations’’; in actual fact, a colonization state can exist for considerable time without giving rise to an inflammatory response. However, in some conditions (e.g. a superimposed infection, detachment, even partial, of the placenta, rupture of the membranes), such a response can be triggered, activating the mechanisms that in turn trigger premature labor. The inflammatory cascade described above, which leads to preterm birth following an intrauterine infection, can also be activated by mechanisms that are not primarily infectious, such as hypoxia or changes in the pH of the amniotic fluid. It seems likely that inflammatory states not linked to infections can be responsible for events, such as preterm labor and PPROM. Inflammation can be considered a process through which the organism responds to noxious stimuli. Chorioamnionitis, therefore, is increasingly interpreted as an inflammatory process involving the chorioamniotic membranes, and from this perspective it is clear that the definitive diagnosis must necessarily be a histopathological one, based on microscopic evidence of inflammation of the membranes [21,23].
DOI: 10.3109/14767058.2015.1053862
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Chorioamnionitis/funisitis and respiratory outcome The role of infection/inflammation as a stimulus in the development of neonatal pulmonary disease is far from clear [26,27]. Evidence from studies on animal models may explain the reports, by various authors, of reduced incidence of respiratory distress syndrome (RDS) and, conversely, increased incidence of bronchopulmonary dysplasia (BPD) in neonates exposed to chorioamnionitis. In 2009, Kramer et al. [28], in an experimental study in sheep, demonstrated that intra-amniotic administration of endotoxin from Escherichia coli was associated with increased synthesis of surfactant proteins (SP-A, SP-B, SP-C and SP-D), increased synthesis of the lipid component of surfactant (increased saturated phosphatidylcholine), and increased pulmonary compliance compared with controls. At the same time, the authors observed a reduction in the number of alveoli at seven days, reduced expression of different vascular endothelial growth factors at two days, and increased distal arteriolar smooth muscle thickness at seven days after the intraamniotic administration of endotoxin. These results show that intrauterine infection/inflammation, while accelerating lung development, also causes alveolar/microvascular simplification, typical of BPD. Despite experimental evidence from animal models, the results of the many clinical trials conducted in this area have often been conflicting. Been et al. [29], on completion of their meta-analysis, concluded that chorioamnionitis may have a protective effect on RDS, but does not appear to be as strongly associated with BPD as it was thought to be in the past. A meta-analysis published subsequently by Hartling et al. [30] showed an association between chorioamnionitis and BPD, but stressed at the same time the existence of possible publication bias. Certainly, the association between chorioamnionitis and pulmonary disease is difficult to demonstrate due to the presence of numerous confounding factors, such as GA, varying definitions of RDS and BPD, different histopathological classification criteria for inflammation of the fetal annexes, the presence or absence of funisitis in association with the chorioamnionitis, the use or non-use of antenatal steroids, and the range of insults that can damage the lung postnatally. The presence of funisitis in association with chorioamnionitis, for example, appears to have a protective effect on the development of RDS according to some authors [31,32], but not according to others [22]. A reduced response to exogenous surfactant in the presence of funisitis could explain, according to some authors [33], the association between chorioamnionitis, prolonged mechanical ventilation and development of BPD. Among the various confounding factors, it is certainly worth examining closely, on the one hand, the use of antenatal steroids, which exert a protective effect [34], and on the other the various postnatal insults that can damage the lung and favor the development of BPD (mechanical ventilation, oxygen therapy, postnatal infection, patent ductus arteriosus, etc.). Antenatal steroids have long been considered contraindicated in chorioamnionitis due to a fear of adverse effects.
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However, recent evidence suggests that antenatal steroids can be used safely in the presence of chorioamnionitis and that they reduce the incidence of RDS and BPD in infants born to mothers with histological chorioamnionitis; their protective effect on RDS and BPD seems to be lower in the presence of clinical chorioamnionitis [34]. As regards the various insults that can damage the lung after birth, authors are increasingly agreeing that intrauterine inflammation renders the lung more vulnerable to postnatal insults, the suggestion being that the fetal lung, having been exposed to a prolonged proinflammatory stimulus in uterus, displays a more pathological response to postnatal inflammatory stimuli compared with a naı¨ve lung [35]. In view of these findings, every effort must be made to reduce as far as possible iatrogenic insults that can damage the lung.
Chorioamnionitis/funisitis and neurological outcome As seen with respiratory outcome, the results on neurological outcome differ across studies. A recent meta-analysis, published in 2012 by Ylijoki et al. [36], provides a clear overview of the results of numerous studies conducted over the past 20 years exploring the possible association between clinical/ histological chorioamnionitis and brain damage. At the end of their meta-analysis, the authors concluded that most of the articles analyzed did not support the hypothesis that chorioamnionitis is an independent risk factor for impaired neurological development, even though the available evidence was conflicting. They also underlined that the increasingly widespread use of antenatal corticosteroids may have helped to improve outcomes and may therefore explain, in part, the differences across studies. Another important meta-analysis was published in 2010 by Shatrov et al. [37], who analyzed 15 studies (selected from a total of 308) to examine relationships between chorioamnionitis (both clinical and histological) and cerebral palsy (CP). The results showed that either clinical or histological chorioamnionitis were risk factors for the development of CP. Recently, some studies have demonstrated a strong association between funisitis and adverse neurological outcome. In 2013, Soraisham et al. [38], in a study of 384 infants with GA less than 29 weeks evaluated at 30–42 months of corrected age, reported a significantly higher incidence of CP in infants exposed to funisitis compared with infants exposed only to chorioamnionitis and controls. In the same year, Salas et al. [39], in a population of 347 extremely low birth weight infants, showed that the risk of neurological impairment and death was associated with severe funisitis. Very recently, Pappas et al. [40] demonstrated in a large cohort of extremely preterm infants (GA less than 27 weeks) a significant association between histological plus clinical chorioamnionitis and increased risk of cognitive impairment as compared to controls. Most authors attempting to explain the link between intrauterine infection/inflammation and possible brain damage hypothesize a cytokine-mediated mechanism. The release of vasoactive inflammatory mediators brings about blood-brain barrier permeability changes, intravascular cell adhesion, coagulation and thrombosis, leading to endothelial damage which favors intraventricular hemorrhage (IVH).
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Furthermore, pro-inflammatory cytokines can have a direct cytolytic effect on immature oligodendrocytes or cause indirect damage by activation of the microglia. Upon activation, microglia secrete pro-inflammatory cytokines, free radicals and excitatory amino acids, which induce further damage to immature oligodendrocytes and consequently hypomyelination and white matter injury [41–43]. Several studies in animal models have helped to understand the association between systemic fetal inflammatory response and fetal brain injury [41,44]. However, chorioamnionitis may be of varying severity, with fetal involvement in more severe cases. This probably explains why some clinical studies have not shown an association between intrauterine infection/ inflammation and adverse neurological outcome.
Chorioamnionitis/funisitis and sepsis Intrauterine infection is very closely related to sepsis occurring within the first 72 h of life (early-onset sepsis ¼ EOS). EOS may represent the last stage of an intrauterine infection that has been transmitted from the mother to the fetus; alternatively, the underlying mechanism may be that of rupture of membranes, as a result of which the amniotic cavity ceases to be a protected environment for the fetus. If we consider that Streptococcus agalactiae and Escherichia coli are the pathogens most frequently responsible for EOS (i.e. pathogens that colonize the lower genital tract but are not usually involved in intrauterine infection), then the second etiopathogenetic mechanism appears to be the most likely [22]. The pathogens that cause EOS are therefore different from the ones that caused the chorioamnionitis. Some studies, however, have shown that EOS can be caused by Ureaplasma spp. and Mycoplasma spp., which are the etiological agents most frequently responsible for chorioamnionitis [45]. Some authors therefore feel that the incidence of EOS may be underestimated, not only because the antibiotics given to a mother with suspected clinical chorioamnionitis and/or PPROM can affect the results of blood cultures in the newborn, but also because the presence of a mycoplasma as the causative agent can be confirmed only by using specific culture media that are not routinely used, or molecular biology techniques. Many studies have linked histological chorioamnionitis, funisits and even more clinical chorioamnionitis with EOS [22,40,46,47]. Contrary to what is seen with RDS, IVH and, albeit to a lesser extent, with BPD, antenatal steroids do not seem to have a protective effect on EOS, in the presence of either clinical or histological chorioamnionitis [34]. A study recently published by Strunk et al. [48] reported, for the first time, a decreased incidence of late-onset sepsis (LOS) in infants exposed to histological chorioamnionitis. The authors retrospectively studied 838 infants with a GA of less than 30 weeks, born to women whose placenta was histologically examined. The presence of histological chorioamnionitis significantly increased the risk of EOS, but reduced the risk of LOS even after multivariate analysis. Since chorioamnionitis is usually caused by pathogens of low virulence, the authors hypothesized that chorioamnionitis, leading only to inflammation, may actually promote maturation of the fetal immune system through mechanisms that are
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as yet unknown but that possibly involve transplacental transfer of microbial ligands and/or maternal immune mediators. This hypothesis awaits further confirmation.
Chorioamnionitis/funisitis and perinatal/neonatal mortality Some studies demonstrated an association between placental inflammation and perinatal or early neonatal mortality. In 1987, Quinn et al. [49] found that perinatal mortality rate in infants exposed to chorioamnionitis was significantly higher than that in non-exposed infants; the exposed infants also showed a significantly higher incidence of death with no defined cause. Most of the studies conducted subsequently failed to confirm these data, including studies of subjects exposed to chorioamnionitis associated with funisitis [6] and clinical chorioamnionitis [46]. However, Lau et al. [22], in a study published in 2005, reported an increased incidence of death in infants exposed to chorioamnionitis associated with funisitis. An higher incidence of death has also been reported by Salas et al. [39] in infants exposed to severe FIRS. Recently, some authors hypothesized that there may be a stepwise increase in neonatal morbidities and mortality according to histological stage (or grade) of chorioamnionitis and funisitis [50]. Certainly, the increasingly widespread use of antenatal steroids can probably explain why some recent studies have failed to demonstrate an association between chorioamnionitis and perinatal or early neonatal death. A meta-analysis published in 2011 [34] highlighted an association between antenatal corticosteroid administration and reduced mortality in infants exposed to chorioamnionitis, both histological and clinical.
Final remarks Given the conflicting results of the various studies exploring this issue, the possibility that preterm infants exposed to infectious/inflammatory states in uterus are at an increased risk of a severe outcome cannot be excluded. This possibility deserves to be closely examined and justifies the efforts of researchers to clarify the mechanisms linking intrauterine infection/inflammation with preterm birth, and thus to identify strategies that may guide clinicians’ diagnostic and therapeutic choices, with regard to both mothers (e.g. identifying women at risk and the most appropriate ‘‘timing’’ of delivery) and infants, and ensure approaches that take into account the increased risk of adverse outcomes in this population of infants.
Declaration of interest All authors declare that they have no conflicts of interests.
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29. Been JV, Zimmermann LJ. Histological chorioamnionitis and respiratory outcome in preterm infants. Arch Dis Child Fetal Neonatal Ed 2009;94:18–25. 30. 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: 8–17. 31. Lahra MM, Beeby PJ, Jeffery HE. Maternal versus fetal inflammation and respiratory distress syndrome: a 10-year hospital cohort study. Arch Dis Child Fetal Neonatal Ed 2009;94:13–16. 32. Lee J, Oh KJ, Park CW, et al. The presence of funisitis is associated with a decreased risk for the development of neonatal respiratory distress syndrome. Placenta 2011;32:235–40. 33. Been JV, Rours IG, Kornelisse RF, et al. Chorioamnionitis alters the response to surfactant in preterm infants. J Pediatr 2010;156:10–15. 34. Been JV, Degraeuwe PL, Kramer BW, Zimmermann LJ. Antenatal steroids and neonatal outcome after chorioamnionitis: a metaanalysis. BJOG 2011;118:113–22. 35. Jobe AH. Antenatal associations with lung maturation and infection. J Perinatol 2005;25:31–5. 36. Ylijoki M, Ekholm E, Haataja L, Lehtonen L. Is chorioamnionitis harmful for the brain of preterm infants? A clinical overview. Acta Obstet Gynecol Scand 2012;91:403–19. 37. Shatrov JG, Birch SC, Lam LT, et al. Chorioamnionitis and cerebral palsy. Obstet Gynecol 2010;116:387–92. 38. Soraisham AS, Trevenen C, Wood S, et al. Histological chorioamnionitis and neurodevelopmental outcome in preterm infants. J Perinatol 2013;33:70–5. 39. Salas AA, Faye-Petersen OM, Sims B, et al. Histological characteristics of the fetal inflammatory response asssociated with neurodevelopmental impairment and death in extremely preterm infants. J Pediatr 2013;163:652–7. 40. Pappas A, Kendrick DE, Shankaran S, et al. Chorioamnionitis and early childhood outcomes among extremely low-gestational-age neonates. JAMA Pediatr 2014;168:137–47. 41. Kuypers E, Ophelders D, Jellema RK, Kunzmann S. White matter injury following fetal inflammatory response syndrome induced by chorioamnionitis and fetal sepsis: lessons from experimental ovine models. Early Hum Dev 2012;88:931–6. 42. Volpe JJ, Kinney HC, Jensen FE, Rosenberg PA. Reprint of ‘‘The developing oligodendrocyte: key cellular target in brain injury in the premature infant’’. Int J Dev Neurosci 2011;29:565–82. 43. Gavilanes AWD, Strackx E, Kramer BW, et al. Chorioamnionitis induced by intraamniotic lipopolysaccharide resulted in an intervaldependent increase in central nervous system injury in the fetal sheep. Am J Obstet Gynecol 2009;200:437.e1–8. 44. Burd I, Bentz AI, Chai J, et al. Inflammation-induced preterm birth alters neuronal morphology in the mouse fetal brain. J Neurosci Res 2010;88:1872–81. 45. Goldenberg RL, Andrews WW, Goepfert AR, et al. 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. 46. Soraisham AS, Singhal N, McMillan DD, et al. A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol 2009;200:372.e1–6. 47. Lee SY, Leung CW. Histological chorioamnionitis – implication for bacterial colonization, laboratory markers of infection, and early onset sepsis in very-low-birth-weight neonates. J Matern Fetal Neonatal Med 2012;25:364–8. 48. Strunk T, Doherty D, Jacques A, et al. Histologic chorioamnionitis is associated with reduced risk of late-onset sepsis in preterm infants. Pediatrics 2012;129:134–41. 49. Quinn PA, Butany J, Taylor J, Hannah W. Chorioamnionitis: its association with pregnancy outcome and microbial infection. Am J Obstet Gynecol 1987;156:379–87. 50. Lee Y, Kim HJ, Choi SJ, et al. Is there a stepwise increase in neonatal morbidities according to histological stage (or grade) of acute chorioamnionitis and funisitis? Effect of gestational age at delivery. J Perinat Med 2015;43:259–67.
REVIEW ARTICLE
Chorioamnionitis and neonatal outcome in preterm infants: a clinical overview
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Lorenza Pugni1, Carlo Pietrasanta1, Barbara Acaia2, Daniela Merlo3, Andrea Ronchi1, Manuela Wally Ossola2, Silvano Bosari3, and Fabio Mosca1 1
Department of Clinical Sciences and Community Health, NICU, 2Department of Obstetrics and Gynecology, and 3Department of Pathophysiology and Organ Transplantation, Division of Pathology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy Abstract
Keywords
The term chorioamnionitis is used to refer to an intrauterine infection/inflammation occurring between the maternal tissues and the fetal membranes (choriodecidual space) or in the fetal annexes (chorioamniotic membranes, amniotic fluid, umbilical cord). Histological examination of the placenta is the gold standard for diagnosis. However, clinical, biochemical and microbiological criteria are also used to define the disease. The literature contains a large body of evidence showing that chorioamnionitis is the leading cause of very preterm birth and, therefore, contributes significantly to neonatal morbidity and mortality. In recent decades, numerous studies have attempted to establish whether, and to what extent, intrauterine infection/inflammation might negatively affect the short- and long-term outcome of preterm infants. The question is still unanswered. The discrepancy observed across studies can be attributed largely to the use of different inclusion and exclusion criteria, diagnostic criteria and methods, and to whether or not potential confounding factors, such as gestational age were considered. Anyhow, the association between chorioamnionitis and severe prematurity requires serious efforts by researchers to clarify the mechanisms linking intrauterine infection/inflammation with preterm birth, and thus to identify strategies that may guide clinicians’ diagnostic and therapeutic choices, with regard to both mothers and infants.
Brain injury, bronchopulmonary dysplasia, death, funisitis, intrauterine inflammation, prematurity, respiratory distress syndrome, sepsis
Introduction The importance of placental disorders in the diagnosis and treatment of various neonatal clinical conditions has long been recognized. In 1892, Ballantyne, a Scottish obstetrician, wrote: ‘‘During the intrauterine life, the fetus, the membranes, the cord, and the placenta form an organic whole, and disease of any part must react upon and affect the others’’ [1]. The literature now contains a vast body of evidence showing that, of the various disorders of the placenta, infection/inflammation of the fetal membranes or umbilical cord (chorioamnionitis/funisitis) is the cause of preterm birth in a significant percentage of cases (up to 50%) [2–5]. In recent decades, numerous studies attempted to establish whether, and to what extent, intrauterine infection/inflammation might negatively affect the short- and long-term outcome of preterm infants. As the incidence of chorioamnionitis/ funisitis is higher at earlier gestational ages (GAs) [4,6], many authors have attempted to demonstrate a GA-independent
Address for correspondence: Dr Lorenza Pugni, MD, Department of Clinical Sciences and Community Health, NICU, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Via Commenda 12, 20122 Milan, Italy. Tel: +390255032907. Fax: +390255032429. E-mail: [email protected]
History Received 26 February 2015 Revised 19 May 2015 Accepted 19 May 2015 Published online 1 July 2015
negative effect of chorioamnionitis on outcome. However, these studies gave different results, and this is undoubtedly due mainly to the presence of numerous confounding factors, ranging from different study methods to many different postnatal insults occurring frequently after preterm birth.
Intrauterine infection/inflammation: from chorioamnionitis to funisitis, a ‘‘continuum’’ from mother to fetus The term chorioamnionitis is used to refer to an intrauterine status of inflammation, in most cases caused by an infectious agent, occurring between the maternal tissues and the fetal membranes (choriodecidual space) or in the fetal annexes (chorioamniotic membranes, amniotic fluid, umbilical cord). Histological, microbiological, biochemical and clinical criteria are used to define chorioamnionitis [7,8]. Histological examination of the placenta is the gold standard for evaluating antenatal inflammatory processes. In addition to histological criteria, chorioamnionitis can also be diagnosed on the basis of clinical criteria (presence of clinical signs of inflammation in the mother), microbiological findings [positive amniotic fluid culture or polymerase chain reaction (PCR) detection of pathogens], and biochemical criteria [elevated cytokine levels in amniotic fluid, elevated maternal serum C-reactive protein
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(CRP) concentration, presence of fetal fibronectin in cervical and vaginal secretions, etc.] [7,9–12]. Histology is the most sensitive method for diagnosing chorioamnionitis, and clinical examination is the least sensitive one. Edwards [13], in a case series of preterm deliveries, reported a 5–10% prevalence of clinical chorioamnionitis, while the prevalence of histological chorioamnionitis exceeded 50%. Although histological examination of the placenta constitutes the gold standard for diagnosis, this finding is available only after delivery. Amniotic fluid analysis after rupture of membranes, or through amniocentesis, has been widely recognized as a good tool for an early diagnosis of intra-amniotic infection and/or inflammation before delivery [2,3,12]. The amniotic cavity is considered to be sterile; less than 1% of women not in labor at term have bacteria in the amniotic fluid. The isolation of bacteria in the amniotic fluid is a pathologic finding, defined as microbial invasion of the amniotic cavity (MIAC) [14]. Amniotic fluid can be cultured or processed with molecular technologies to make a diagnosis of MIAC. Several authors have demonstrated that the prevalence of MIAC is higher when molecular techniques are used [15]. Recently, Romero et al. [16] reported that the prevalence of MIAC was 24% by culture, 36% by broad-range PCR coupled with electrospray ionization mass spectrometry, and 41% by both methods combined in 59 women with preterm premature – or prelabor (at least 1 h before the onset of contractions) – rupture of the membranes (PPROM). However, it is well known that preterm delivery and neonatal complications occur also in the presence of an intraamniotic inflammatory status alone, without demonstration of pathogens in the amniotic cavity. An intra-amniotic inflammation can be demonstrated by elevated levels in the amniotic fluid of inflammatory markers, such as interleukin-6 (IL-6), or other pro-inflammatory cytokines. In a study published in 2001, Yoon et al. [17] reported that intra-amniotic inflammation (negative amniotic fluid culture but elevated amniotic fluid IL-6) was more common than intra-amniotic infection (positive amniotic fluid culture regardless of amniotic fluid IL-6 concentration) in patients with preterm labor and intact membranes. The incidence of adverse outcomes (clinical and histologic chorioamnionitis, preterm birth, neonatal morbidity) in patients with intra-amniotic infection was similar to that of patients with intra-amniotic inflammation and a negative amniotic fluid culture. When an infectious/inflammatory state in the mother reaches the fetus, the fetus may react to the insult by mounting its own inflammatory response, the intensity of which is proportional to the maturity of its immune system [3,18]. The ensuing picture, termed fetal inflammatory response syndrome (FIRS) by the authors who first described it in 1998 [19], is characterized by a raised fetal plasma IL-6 level (411 pg/mL) and, histopathologically, by funisitis/chorionic vasculitis and the presence of fetal polymorphonuclear granulocytes in the umbilical cord vessels [20]. In some studies, the prevalence of histological chorioamnionitis has been found to be greater than 50% in women who gave birth prematurely [13] and, among these women, it was significantly higher in those with PPROM than in those who presented with intact membranes (80 versus 33%) [21]. The
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prevalence of histological chorioamnionitis decreases with increasing GA at preterm delivery. In a retrospective study of 4000 preterm infants published in 2004 by Lahra and Jeffery [6], the incidence of histological chorioamnionitis was reported to be 31%, ranging from 66% at 24 weeks of GA to 16% at the end of the 34th week of gestation. The prevalence of funisitis, like that of chorioamnionitis, has been found to be inversely related to GA. In 2005, Lau et al. [22] reported it to be 62% in a population of premature infants with a GA of less than 34 weeks, while Lahra et al. [6], in 2004, reported variable percentages, ranging from 25% in infants with a GA of 30–34 weeks to 65% in those with a GA of less than 25 weeks. The mechanisms through which intrauterine infection leads to preterm labor are the result of activation of the innate immune system. The infectious insult triggers a cascade of events that leads to the release of numerous inflammatory mediators (cytokines, chemokines, prostaglandins, proteases, etc.), resulting in uterine contractions and rupture of the membranes [23]. Bacterial microorganisms are the pathogens most frequently responsible for intrauterine infection. In recent years, several authors have demonstrated, using molecular biology techniques, such as PCR, that the prevalence of MIAC is significantly higher than previously thought based on the results of traditional methods [12,24]. The fact that Ureaplasma spp. (U. urealyticum, U. parvum), genital Mycoplasmas (M. hominis, M. genitalium), Gardnerella vaginalis, and the bacteria belonging to the Bacteroides genus (all organisms of low virulence) are the microorganisms most frequently isolated from the amniotic cavity of women with preterm labor and intact membranes could explain why intrauterine infections are more often chronic than acute conditions [25]. The infection can occur in the early stages of pregnancy, becoming symptomatic more often after the 20th week of gestation [4]. The idea of uterine infection as a chronic condition may initially seem to be at odds with the anatomopathological evidence, according to which most cases of chorioamnionitis are ‘‘acute inflammations’’; in actual fact, a colonization state can exist for considerable time without giving rise to an inflammatory response. However, in some conditions (e.g. a superimposed infection, detachment, even partial, of the placenta, rupture of the membranes), such a response can be triggered, activating the mechanisms that in turn trigger premature labor. The inflammatory cascade described above, which leads to preterm birth following an intrauterine infection, can also be activated by mechanisms that are not primarily infectious, such as hypoxia or changes in the pH of the amniotic fluid. It seems likely that inflammatory states not linked to infections can be responsible for events, such as preterm labor and PPROM. Inflammation can be considered a process through which the organism responds to noxious stimuli. Chorioamnionitis, therefore, is increasingly interpreted as an inflammatory process involving the chorioamniotic membranes, and from this perspective it is clear that the definitive diagnosis must necessarily be a histopathological one, based on microscopic evidence of inflammation of the membranes [21,23].
DOI: 10.3109/14767058.2015.1053862
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Chorioamnionitis/funisitis and respiratory outcome The role of infection/inflammation as a stimulus in the development of neonatal pulmonary disease is far from clear [26,27]. Evidence from studies on animal models may explain the reports, by various authors, of reduced incidence of respiratory distress syndrome (RDS) and, conversely, increased incidence of bronchopulmonary dysplasia (BPD) in neonates exposed to chorioamnionitis. In 2009, Kramer et al. [28], in an experimental study in sheep, demonstrated that intra-amniotic administration of endotoxin from Escherichia coli was associated with increased synthesis of surfactant proteins (SP-A, SP-B, SP-C and SP-D), increased synthesis of the lipid component of surfactant (increased saturated phosphatidylcholine), and increased pulmonary compliance compared with controls. At the same time, the authors observed a reduction in the number of alveoli at seven days, reduced expression of different vascular endothelial growth factors at two days, and increased distal arteriolar smooth muscle thickness at seven days after the intraamniotic administration of endotoxin. These results show that intrauterine infection/inflammation, while accelerating lung development, also causes alveolar/microvascular simplification, typical of BPD. Despite experimental evidence from animal models, the results of the many clinical trials conducted in this area have often been conflicting. Been et al. [29], on completion of their meta-analysis, concluded that chorioamnionitis may have a protective effect on RDS, but does not appear to be as strongly associated with BPD as it was thought to be in the past. A meta-analysis published subsequently by Hartling et al. [30] showed an association between chorioamnionitis and BPD, but stressed at the same time the existence of possible publication bias. Certainly, the association between chorioamnionitis and pulmonary disease is difficult to demonstrate due to the presence of numerous confounding factors, such as GA, varying definitions of RDS and BPD, different histopathological classification criteria for inflammation of the fetal annexes, the presence or absence of funisitis in association with the chorioamnionitis, the use or non-use of antenatal steroids, and the range of insults that can damage the lung postnatally. The presence of funisitis in association with chorioamnionitis, for example, appears to have a protective effect on the development of RDS according to some authors [31,32], but not according to others [22]. A reduced response to exogenous surfactant in the presence of funisitis could explain, according to some authors [33], the association between chorioamnionitis, prolonged mechanical ventilation and development of BPD. Among the various confounding factors, it is certainly worth examining closely, on the one hand, the use of antenatal steroids, which exert a protective effect [34], and on the other the various postnatal insults that can damage the lung and favor the development of BPD (mechanical ventilation, oxygen therapy, postnatal infection, patent ductus arteriosus, etc.). Antenatal steroids have long been considered contraindicated in chorioamnionitis due to a fear of adverse effects.
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However, recent evidence suggests that antenatal steroids can be used safely in the presence of chorioamnionitis and that they reduce the incidence of RDS and BPD in infants born to mothers with histological chorioamnionitis; their protective effect on RDS and BPD seems to be lower in the presence of clinical chorioamnionitis [34]. As regards the various insults that can damage the lung after birth, authors are increasingly agreeing that intrauterine inflammation renders the lung more vulnerable to postnatal insults, the suggestion being that the fetal lung, having been exposed to a prolonged proinflammatory stimulus in uterus, displays a more pathological response to postnatal inflammatory stimuli compared with a naı¨ve lung [35]. In view of these findings, every effort must be made to reduce as far as possible iatrogenic insults that can damage the lung.
Chorioamnionitis/funisitis and neurological outcome As seen with respiratory outcome, the results on neurological outcome differ across studies. A recent meta-analysis, published in 2012 by Ylijoki et al. [36], provides a clear overview of the results of numerous studies conducted over the past 20 years exploring the possible association between clinical/ histological chorioamnionitis and brain damage. At the end of their meta-analysis, the authors concluded that most of the articles analyzed did not support the hypothesis that chorioamnionitis is an independent risk factor for impaired neurological development, even though the available evidence was conflicting. They also underlined that the increasingly widespread use of antenatal corticosteroids may have helped to improve outcomes and may therefore explain, in part, the differences across studies. Another important meta-analysis was published in 2010 by Shatrov et al. [37], who analyzed 15 studies (selected from a total of 308) to examine relationships between chorioamnionitis (both clinical and histological) and cerebral palsy (CP). The results showed that either clinical or histological chorioamnionitis were risk factors for the development of CP. Recently, some studies have demonstrated a strong association between funisitis and adverse neurological outcome. In 2013, Soraisham et al. [38], in a study of 384 infants with GA less than 29 weeks evaluated at 30–42 months of corrected age, reported a significantly higher incidence of CP in infants exposed to funisitis compared with infants exposed only to chorioamnionitis and controls. In the same year, Salas et al. [39], in a population of 347 extremely low birth weight infants, showed that the risk of neurological impairment and death was associated with severe funisitis. Very recently, Pappas et al. [40] demonstrated in a large cohort of extremely preterm infants (GA less than 27 weeks) a significant association between histological plus clinical chorioamnionitis and increased risk of cognitive impairment as compared to controls. Most authors attempting to explain the link between intrauterine infection/inflammation and possible brain damage hypothesize a cytokine-mediated mechanism. The release of vasoactive inflammatory mediators brings about blood-brain barrier permeability changes, intravascular cell adhesion, coagulation and thrombosis, leading to endothelial damage which favors intraventricular hemorrhage (IVH).
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Furthermore, pro-inflammatory cytokines can have a direct cytolytic effect on immature oligodendrocytes or cause indirect damage by activation of the microglia. Upon activation, microglia secrete pro-inflammatory cytokines, free radicals and excitatory amino acids, which induce further damage to immature oligodendrocytes and consequently hypomyelination and white matter injury [41–43]. Several studies in animal models have helped to understand the association between systemic fetal inflammatory response and fetal brain injury [41,44]. However, chorioamnionitis may be of varying severity, with fetal involvement in more severe cases. This probably explains why some clinical studies have not shown an association between intrauterine infection/ inflammation and adverse neurological outcome.
Chorioamnionitis/funisitis and sepsis Intrauterine infection is very closely related to sepsis occurring within the first 72 h of life (early-onset sepsis ¼ EOS). EOS may represent the last stage of an intrauterine infection that has been transmitted from the mother to the fetus; alternatively, the underlying mechanism may be that of rupture of membranes, as a result of which the amniotic cavity ceases to be a protected environment for the fetus. If we consider that Streptococcus agalactiae and Escherichia coli are the pathogens most frequently responsible for EOS (i.e. pathogens that colonize the lower genital tract but are not usually involved in intrauterine infection), then the second etiopathogenetic mechanism appears to be the most likely [22]. The pathogens that cause EOS are therefore different from the ones that caused the chorioamnionitis. Some studies, however, have shown that EOS can be caused by Ureaplasma spp. and Mycoplasma spp., which are the etiological agents most frequently responsible for chorioamnionitis [45]. Some authors therefore feel that the incidence of EOS may be underestimated, not only because the antibiotics given to a mother with suspected clinical chorioamnionitis and/or PPROM can affect the results of blood cultures in the newborn, but also because the presence of a mycoplasma as the causative agent can be confirmed only by using specific culture media that are not routinely used, or molecular biology techniques. Many studies have linked histological chorioamnionitis, funisits and even more clinical chorioamnionitis with EOS [22,40,46,47]. Contrary to what is seen with RDS, IVH and, albeit to a lesser extent, with BPD, antenatal steroids do not seem to have a protective effect on EOS, in the presence of either clinical or histological chorioamnionitis [34]. A study recently published by Strunk et al. [48] reported, for the first time, a decreased incidence of late-onset sepsis (LOS) in infants exposed to histological chorioamnionitis. The authors retrospectively studied 838 infants with a GA of less than 30 weeks, born to women whose placenta was histologically examined. The presence of histological chorioamnionitis significantly increased the risk of EOS, but reduced the risk of LOS even after multivariate analysis. Since chorioamnionitis is usually caused by pathogens of low virulence, the authors hypothesized that chorioamnionitis, leading only to inflammation, may actually promote maturation of the fetal immune system through mechanisms that are
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as yet unknown but that possibly involve transplacental transfer of microbial ligands and/or maternal immune mediators. This hypothesis awaits further confirmation.
Chorioamnionitis/funisitis and perinatal/neonatal mortality Some studies demonstrated an association between placental inflammation and perinatal or early neonatal mortality. In 1987, Quinn et al. [49] found that perinatal mortality rate in infants exposed to chorioamnionitis was significantly higher than that in non-exposed infants; the exposed infants also showed a significantly higher incidence of death with no defined cause. Most of the studies conducted subsequently failed to confirm these data, including studies of subjects exposed to chorioamnionitis associated with funisitis [6] and clinical chorioamnionitis [46]. However, Lau et al. [22], in a study published in 2005, reported an increased incidence of death in infants exposed to chorioamnionitis associated with funisitis. An higher incidence of death has also been reported by Salas et al. [39] in infants exposed to severe FIRS. Recently, some authors hypothesized that there may be a stepwise increase in neonatal morbidities and mortality according to histological stage (or grade) of chorioamnionitis and funisitis [50]. Certainly, the increasingly widespread use of antenatal steroids can probably explain why some recent studies have failed to demonstrate an association between chorioamnionitis and perinatal or early neonatal death. A meta-analysis published in 2011 [34] highlighted an association between antenatal corticosteroid administration and reduced mortality in infants exposed to chorioamnionitis, both histological and clinical.
Final remarks Given the conflicting results of the various studies exploring this issue, the possibility that preterm infants exposed to infectious/inflammatory states in uterus are at an increased risk of a severe outcome cannot be excluded. This possibility deserves to be closely examined and justifies the efforts of researchers to clarify the mechanisms linking intrauterine infection/inflammation with preterm birth, and thus to identify strategies that may guide clinicians’ diagnostic and therapeutic choices, with regard to both mothers (e.g. identifying women at risk and the most appropriate ‘‘timing’’ of delivery) and infants, and ensure approaches that take into account the increased risk of adverse outcomes in this population of infants.
Declaration of interest All authors declare that they have no conflicts of interests.
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