Which risk to the fetus is associated with a maternal diagnosis of chorioamnionitis?

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Outcomes

Chorioamnionitis can adversely affect the mother and her unborn infant. In pregnant women, it is associated with a twofold increase in abnormal progression of labor, an increased risk of cesarean section, postpartum hemorrhage, poor cervical dilation, and placental abruption. Surgical complications after cesarean section such as endometritis, pelvic abscess, wound infection, thromboembolism, and bacteremia are also more common in women with chorioamnionitis. The effects of intrauterine infection on the fetus depend on the duration and timing of the inflammatory process. Acute chorioamnionitis is an important risk factor for early-onset neonatal sepsis. Chronic infections, however, are often subclinical and have been associated with a wide variety of organ injury, including the brain (periventricular leukomalacia), lung (bronchopulmonary dysplasia), eye (retinopathy of prematurity), intestine (necrotizing enterocolitis), and thymus (involution and a change in cellular composition).23 Chorioamnionitis, especially with a fetal inflammatory component, has also been associated with hemodynamic instability in the preterm newborn infant.

Chorioamnionitis is considered an important cause of preterm birth; microbiologic data suggest that up to 25% of preterm births are caused by an intrauterine infection. The evidence linking infection and preterm labor is as follows: (1) intrauterine infection (or exposure to microbial products) in experimental animals results in preterm delivery; (2) extrauterine maternal infections (e.g., pyelonephritis) are associated with preterm labor; (3) subclinical intrauterine infections are associated with preterm labor and birth; (4) patients with evidence of intrauterine inflammation (e.g., increased amniotic fluid cytokines or matrix metalloproteinases) in the midtrimester are at increased risk for preterm delivery; (5) in experimental animal models, antibiotic treatment of intrauterine infections can prevent prematurity; (6) treatment of asymptomatic bacteriuria prevents prematurity; (7) administration of antibiotics to women with preterm premature rupture of membranes prolongs gestation; (8) microorganisms can be cultured from the placenta in a high percentage of women presenting with preterm labor; and (9) polymorphonuclear infiltrations in the placenta are associated with spontaneous preterm birth. A possible mechanism for infection-associated preterm birth is shown inFig. 25.6.72

Acute chorioamnionitis is a risk factor for neonatal sepsis.76 That is not surprising given that chorioamnionitis is a key step in the pathway of most ascending infections causing early-onset sepsis. Among infants greater than or equal to 37 weeks’ gestation with proven early-onset sepsis owing toE. coli or group B streptococcus, clinical chorioamnionitis was documented in the medical record about one-third of the time, and histologic chorioamnionitis was documented in 90%.66 Importantly, the risk of EOS in infants born to women with chorioamnionitis is inversely correlated with gestational age. Reported rates of confirmed EOS in infants born at ≥35 weeks’ gestation to mothers with clinical chorioamnionitis range from 0.47%-1.24%.9,33,43 In contrast, rates of EOS in exposed moderate and extremely preterm infants are 5-10 times higher.24,48,65

Chronic Chorioamnionitis

CC has been defined as a subamnionic mononuclear cell infiltrate. While some authors refer to CC as ‘subacute’ chorioamnionitis, the term ‘chronic’ chorioamnionitis is preferred by this author because monocytic chronic inflammatory cells, not polymorphonuclear leukocytes (neutrophils), are involved in this entity. In practice, there is an influx of maternal lymphocytes and macrophages into the fetal chorion that can be identified with appropriate immunostains, if necessary. This lesion can be seen in both the free membranes and the fetal surface of the placenta. A ‘lichenoid’ cellular layer at the base of the fetal surface chorion just above the subchorionic intervillous space can mimic CC but appears to be a hyperplasia of stromal cells (Figure 5). CD3 and vimentin immunostains are helpful in diagnosing CC when such a chorionic cellular population is present. Acute subchorionitis or acute chorioamnionitis can be present concurrently and may mask the chronic inflammatory process. CC is often accompanied by CVUE, which may be patchy throughout the placental parenchyma. The clinical significance of CC is unknown, although one study identified a correlation between subclinical CC seen histologically and intrauterine HIV-1 transmission. Similar to CV and CVUE, the lesion is most often found incidentally upon microscopic examination of placental samples.

Chorioamnionitis (Intrauterine Inflammation and/or Infection)

In January 2015, an expert panel was convened by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to review the criteria for diagnosis and management of chorioamnionitis.37 They proposed that the phrase “intrauterine inflammation, infection, or both” (abbreviated “Triple I”) be used instead of the term “chorioamnionitis” because of the diverse range of conditions, both infectious and inflammatory, that it was used to describe. Triple I can be diagnosed when fever (diagnosed as maternal temperature greater than or equal to 39.0°C on one reading or greater than or equal to 38.0°C on two occasions separated by 30 minutes) is present with one or more of the following: (1) fetal tachycardia (greater than 160 bpm for 10 minutes or longer), (2) maternal white blood cell count greater than 15,000 × 106 cells/L in the absence of corticosteroids, (3) purulent fluid from the cervical os (cloudy or yellowish thick discharge confirmed visually on speculum examination to be coming from the cervical canal), and (4) biochemical or microbiologic amniotic fluid results consistent with microbial invasion of the amniotic cavity. It is stressed that maternal fever in the absence of other criteria should be categorized as “isolated maternal fever.”37 The new nomenclature of “intrauterine inflammation, infection, or both” (Triple-I) is in the process of being incorporated into practice to replace the term “clinical chorioamnionitis.”

Previously, the diagnosis of chorioamnionitis was made when any combination of the following elements was noted: maternal fever, maternal or fetal tachycardia or both, elevated maternal white blood cell count, uterine tenderness, and purulent fluid or discharge from the cervical os.37 Using this definition, it occurs with variable frequency in the literature with reported event rates ranging from 0.5% to 10%, depending on the means of ascertainment and the demographic and obstetric characteristics of the population. It may be seen in over 90% of deliveries before 24 weeks’ gestation, in almost 40% of women who deliver between 25 and 28 weeks, and in approximately 5% of deliveries at term.38 Independent risk factors include low parity, a history of chorioamnionitis in a prior delivery, the number of vaginal examinations, duration of total labor, duration of ruptured membranes, and use of internal monitors.39,40 Unfortunately, the laboratory diagnosis of chorioamnionitis is neither sensitive nor specific and may not correlate with the clinical presentation.41,42 Moreover, the classic clinical signs of chorioamnionitis are often absent. Goodman et al.41 reviewed the records of 531 women with pathologically proven chorioamnionitis. They found that only 10% of the patients had abdominal tenderness and only 1% had foul-smelling amniotic fluid.

I. EPIDEMIOLOGY

Histologic Chorioamnionitis

A large body of research points toward the choriodecidua as a major site of inflammatory processes linked to PTB.160,623,773,774 In the setting of silent chorioamnionitis, inflammatory cytokines and chemokines, released as a result of engagement of TLRs, lead to recruitment of inflammatory cells such as macrophages, dendritic cells, and neutrophils, with the final purpose of killing the invading pathogens and halting their spread into the amniotic fluid and to the fetus.539,773 The leukocytes invading the chorion and amnion are maternal in origin.775 The process of inflammatory cell migration into the decidual and fetal membrane tissue is tightly controlled and involves chemotactic factors (chemokines) and cell adhesion molecules (e.g., selectins, integrins). The resultant microenvironment is rich in inflammatory mediators that induce tissue damage and result in cytokine and chemokine translocation in the amniotic fluid. Nitric oxide, VEGF, and angiopoietins appear to be involved in the process of cytokine transfer across fetal membranes.773,776

The inflammatory events occurring in the choriodecidua and fetal membranes are important because they could lead to premature activation of myometrial contractility and PTB through synthesis and release of free radicals, prostaglandins, and metalloprotease.594,777,778 Based on these observations, a reasonable assumption is that the development of a maternal inflammatory response (deciduitis) has some diagnostic potential, even if the process at the time of evaluation is subclinical.

Examination of the placenta has been the first step in pathologically classifying the wide range of clinical phenotypes linked to PTB (e.g., infection, abruption, hypoxia) and poor neurodevelopmental outcome of the neonate. A significant focus has been on antenatal inflammatory processes.779–781 The proximity of the placenta to the fetus, and their common embryologic origin, have facilitated a significant number of studies that linked placental inflammatory lesions to short- and long-term neonatal outcomes such as cerebral palsy.782 The major drawback of this approach is that pathologic examination of the placenta is possible only after birth. As a result, histologic biomarkers are irrelevant during the antenatal period, because they do not allow initiation of therapies meant to prevent either PTB or adverse neonatal outcomes. Their overall usefulness is for postnatal counseling and research purposes.

Pathologic examination of the placenta has a further limitation: the relatively large subjectivity in interpretation of histologic findings. First, the inflammatory lesions responsible for similar outcomes are characterized by a high degree of heterogeneity and poor to moderate intraoperator and interoperator variability.783 Second, the intricacy and redundancy of biologic processes responsible for cellular and tissue injury might lead to identical pathologic footprints in the context of distinctive triggers. Third, a mild degree of histologic chorioamnionitis may occur after normal labor at term, without pathologic consequences for the newborn.781,784

Diagnosis of Chorioamnionitis

Chorioamnionitis can be either a clinical syndrome or a silent, indolent process. The clinical diagnosis of chorioamnionitis is made when a pregnant woman has a constellation of findings that include fever, a tender uterus, an elevated blood granulocyte count, and bacteria and/or inflammatory cells in amniotic fluid and often preterm or prolonged rupture of membranes.66 Clinical chorioamnionitis is an imprecise diagnosis that has little prognostic or treatment value.67 The diagnosis of clinical chorioamnionitis is frequently made for near-term or term labors, and occasionally infection can be caused by highly virulent organisms. Before 30 weeks of gestation, clinical chorioamnionitis is most often diagnosed after attempts to delay preterm delivery or with preterm prolonged rupture of membranes. Another method to diagnose chorioamnionitis is by histopathology of the chorioamnion with inflammation, indicating histologic chorioamnionitis. The amount of infiltration of the chorioamnion by inflammatory cells and the intensity of secondary changes are used to grade the severity of the fetal exposure to inflammation.68 Inflammation of the cord, called funisitis, is generally considered to indicate a more advanced inflammatory process that involves the fetus.69 Another diagnostic approach is to culture amniotic fluid or fetal membranes for organisms or to assay amniotic fluid for proinflammatory inflammatory mediators such as tumor necrosis factor α (TNF-α) and interleukin-1 (IL-1) and IL-6.70 With the recognition that only a minority of organisms in the human biome can be cultured, polymerase chain reaction (PCR) and DNA sequencing techniques are being used to demonstrate that chorioamnionitis is often polymicrobial with organisms that cannot be cultured.71 Technologies to identify multiple proteins in biologic fluids also are being adapted to develop proteomic biomarkers for chorioamnionitis in amniotic fluid.72 These technologies have the potential to rapidly diagnose inflammation and to identify specific organisms. Such approaches will change the understanding of fetal exposures to inflammation and pathology related to specific organisms.

The chorioamnion is fetal tissue, and the amniotic fluid surrounding the fetus is in direct contact with the fetal gut, skin, and lung.69 Therefore the fetus will be exposed to inflammation if there is histologic chorioamnionitis or if the amniotic fluid contains mediators of inflammation. The Venn diagram in Fig. 2.6 illustrates the diagnostic conundrum. Clinical chorioamnionitis does not correlate well with the subsequent diagnosis of histologic chorioamnionitis, and an amniotic fluid diagnosis of infection may or may not predict chorioamnionitis associated with preterm delivery. PCR-based analyses of amniotic fluid call into question the assumption that fetal colonization with organisms is abnormal and will cause preterm delivery. Gerber and associates73 demonstrated that 11% of 254 presumably normal amniotic fluid samples collected at 15 to 19 weeks of gestation for genetic analysis were PCR-positive for Ureaplasma urealyticum. Although 17 of the 29 Ureaplasma-positive pregnancies had preterm labor, only 2 fetuses were delivered before 34 weeks of gestation. Perni and colleagues74 analyzed 179 amniotic fluid samples and found that 13% were positive for Ureaplasma and 6% were positive for Mycoplasma hominis, and in 28 of the 33 pregnancies with positive amniotic fluid samples infants were not delivered preterm. Deep sequencing of the microbial genome reveals “colonization” of the amniotic fluid in some women without apparent adverse effects, suggesting the presence of an amniotic biome.75,76 Attempts to extensively culture the placenta/chorioamnion have recovered multiple organisms of low virulence that include vaginal flora.77 The severity of the chorioamnionitis does not correlate well with the organisms but tends to be more severe with Ureaplasma and Mycoplasma species.78–80 Furthermore, in many preterm deliveries, polymicrobial organisms are recovered by culture or PCR from the amniotic fluid. The unknowns are the association of organisms with pregnancies that are not delivered preterm and the variety of organisms that can be identified by PCR. For example, Steel and coworkers81 used a fluorescent probe for a common 16S ribosomal RNA bacterial sequence and identified organisms deep within the membranes of all preterm deliveries and many term deliveries. These results suggest that the human pregnancy can tolerate colonization/infection with low-pathogenicity organisms. The provocative question is: Does the fetus need exposure to a biome for normal development?

There is no clear answer to the question “What is chorioamnionitis?” The multiple ways to make the diagnosis are not necessarily congruent. Furthermore, if one accepts that chorioamnionitis results from colonization/infection, then the diagnosis is imprecise in the extreme in relation to how infectious diseases are generally diagnosed. The diagnosis of an infection includes the identity of the organism, an estimate of the duration of infection, its intensity, and specific sites of involvement. The diagnosis of chorioamnionitis contains none of these elements. Research is now linking genetically determined inflammatory response characteristics of the mother and fetus with prematurity.82 The chronic indolent chorioamnionitis associated with prematurity may result from the interaction of the environment and the genetically determined immunomodulatory characteristics of the mother and fetus. Challenges for the future are how to better diagnose and to understand what makes patients susceptible to chorioamnionitis, and how to quantify the severity potential for fetal injury from the chorioamnionitis.67

Histologic Chorioamnionitis and Pulmonary Outcomes

Chorioamnionitis has been defined by histologic criteria (presence of polymorphonuclear cells in choriodecidual space, fetal membranes, and/or cord), microbiologic criteria (positive results of culture or molecular detection methods), and/or biochemical criteria (elevated amniotic fluid cytokine and chemokine levels) as evidence of infection/inflammation in the intrauterine compartment.14 Clinical chorioamnionitis defined by maternal fever, maternal and fetal tachycardia, uterine tenderness, foul-smelling vaginal discharge, and leukocytosis is present in less than 40% of cases of histologic chorioamnionitis,5 indicating that the majority of intrauterine infections are subclinical.15

Standardization of placental pathology review has provided a framework for characterizing the stage or extent of polymorphonuclear cell infiltration and grading for severity.16 In response to microbial invasion, maternal polymorphonuclear cells progress from infiltration of the subchorionic plate fibrin and/or membranous chorionic trophoblast layer (stage 1) to infiltration of the chorionic plate or chorionic connective tissue and/or amnion (stage 2) to necrotizing chorioamnionitis with degenerated neutrophils, thickened eosinophilic membrane, and amnionic epithelial degeneration (stage 3). A grade of inflammation is assigned to describe the number of neutrophils or presence of microabcesses.16 It has been proposed that the presence of advanced maternal stage of necrotizing amnionitis is indicative of prolonged infection/inflammation.16-18

The fetal inflammatory response syndrome (FIRS) has been defined biochemically by elevated umbilical cord concentrations of cytokines (interleukin-1β [IL-1β], IL-6, and tumor necrosis factor-α [TNFα]).5,19 However, this response also involves a broader inflammatory response, including upregulation of chemokines (IL-8, macrophage inflammatory protein-1β [MIP-1β], and RANTES [regulated upon activation, normal T cell expressed and secreted]), adhesion molecules (intracellular adhesion molecule-1 [ICAM-1], ICAM-3, and E-selectin), matrix metalloproteinases (MMP-1 and MMP-9), an angiogenic factor (vascular endothelial growth factor [VEGF]), and an acute-phase protein (C-reactive protein [CRP]), in venous blood in the first few days of life.18 Histologically, the response is defined by fetal vasculitis/funisitis characterized by polymorphonuclear infiltration of the chorionic vessels or umbilical cord.14 Stages of fetal vasculitis describe the progression from neutrophils in the wall of chorionic plate vessels or umbilical vein (stage 1) to one or both umbilical arteries (stage 2) to concentric bands around one or more umbilical vessel accompanied by cellular debris, or eosinophilic precipitate (stage 3, necrotizing funisitis).16 Intensity of the inflammation is graded according to the number of neutrophils present.

Multiple epidemiologic studies have addressed the association of histologic chorioamnionitis with and without cord involvement with gestation-independent effects on neonatal pulmonary outcomes (summarized in a 2010 review14). In 1996,Watterberg and colleagues20 observed that histologic chorioamnionitis was associated with a reduced risk for respiratory distress syndrome (RDS), but an increased risk for bronchopulmonary dysplasia (BPD) in a small cohort of mechanically ventilated preterm infants with birth weight less than 2000 g who were not exposed to antenatal steroids or exogenous surfactant. Subsequent studies over the past 15 years have found an association of chorioamnionitis with a reduced effect21-24 or no effect25-27 on RDS risk and an increased effect,5,25,27 a decreased effect,28 or no effect22,26,29,30 on BPD risk.

Limitations of many of the studies include single-center cohorts with varying gestational age ranges, racial/ethnic distributions, and inclusion criteria, and sample sizes inadequately powered to analyze possible confounding or risk modification of gestational age and other important variables. For instance, Redline and associates29 observed in a retrospective study that histologic chorioamnionitis tended to be higher in white infants and lower in African-American infants with BPD at 36 weeks postmenstrual age, suggesting that racial differences in response to chorioamnionitis may explain, in part, differences in study outcomes. Interpretation of these studies is also complicated by the potential selection bias of center-specific placental review criteria and nonstandardized criteria for chorioamnionitis diagnosis. A major challenge is the lack of a true “normal” comparison group, because many preterm placentas without chorioamnionitis have other lesions that may affect outcomes.14

It has been proposed that the timing, duration of exposure, and severity of chorioamnionitis affects neonatal pulmonary outcomes. In a cohort of 276 preterm infants born before 33 weeks of gestation at our institution, histologic chorioamnionitis was associated with 3.6-fold higher risk for BPD in infants born at 28 weeks gestation or earlier, but not in infants of 29 to 32 weeks gestation. Maternal stage of chorioamnionitis was significantly correlated with BPD severity5 as defined by National Institutes of Health (NIH) consensus criteria.3 Forty percent of the infants in whom moderate or severe BPD developed were exposed to longstanding or necrotizing amnionitis (stage 3) compared with 34% of infants in whom mild BPD developed and 19% infants without BPD (Fig. 6-2). Fetal vasculitis was not associated with BPD in this study. Subacute chorioamnionitis, a pathologic diagnosis distinct from acute chorioamnionitis, is characterized by mixed degenerative polymorphonuclear neutrophils/leukocytes (PMNs) and mononuclear cells in the chorionic plate with greatest severity involving the amnion.31 In a study comparing 90 singleton placentas with stage 3 acute and subacute chorioamnionitis at 23 to32 weeks of gestation with gestational age– and birth weight–matched controls without chorioamnionitis, the presence of amniotic necrosis was independently associated with BPD,31 suggesting that longstanding or chronic inflammation contributes to lung injury in utero.

Although histologic chorioamnionitis may decrease the risk for RDS because of maturational effects in the fetal lung, it may also contribute to an increase in susceptibility to augmented postnatal lung injury. In a case-control study, Van Marter and coworkers32 observed that histologic chorioamnionitis was associated with a decreased rate of BPD in infants undergoing ventilation for less than 1 week but an increased rate of BPD in infants undergoing prolonged ventilation or with postnatal sepsis. Furthermore, infants exposed to histologic chorioamnionitis with fetal vasculitis in another study had impaired responses to exogenous administration of surfactant, which contributed to both prolonged mechanical ventilation after surfactant administration and the development of BPD.33 Peripheral blood leukocytosis (leukocyte count > 30,000/mm3) in the first 2 days of life in chorioamnionitis-exposed infants has been found to increase the risk for BPD 4.6-fold but to decrease the risk for death.34 Antenatal exposure to histologic chorioamnionitis may be an important response modifier of other postnatal interventions. Although there was no overall benefit of low-dose prophylactic hydrocortisone therapy in preterm infants in a randomized trial, the subgroup of chorioamnionitis-exposed infants in the treatment arm experienced significantly decreased mortality and improved survival without BPD in comparison with placebo-treated infants.35

PERINATAL INFLAMMATION, CORD BLOOD CYTOKINES, AND POSTNATAL HEMODYNAMIC VARIABLES

Chorioamnionitis is the most common cause of SIRS in the preterm newborn. Cord blood IL-6 concentration is the most sensitive and specific plasma marker of chorioamnionitis and it is the strongest predictor of blood pressure immediately after delivery (21). IL-6 concentration correlates inversely with systolic, mean, and diastolic blood pressure in the neonate. The findings of decreased blood pressure and increased cardiac output in infants with placental inflammation and fetal vessel inflammation (funisitis) suggest that systemic vascular resistance decreases in infants born after chorioamnionitis. In addition, infants born after chorioamnionitis and presenting with funisitis have higher IL-6 and IL-1β concentrations and right ventricular cardiac output compared to their counterparts without funisitis. Clinically these preterm neonates present with increased heart rate and decreased mean and diastolic blood pressures (22–25). These hypotensive neonates also have an impaired cerebral blood flow (CBF) autoregulation (pressure passive cerebral circulation) (26) predisposing them to decreased CBF while hypotensive potentially contributing to their white matter injury (27,29). With correction of hypotension and improvement of cerebral perfusion these infants may develop periventricular–intraventricular hemorrhage during the reperfusion phase of the hemodynamic compromise. Indeed in this patient population, there is an association between wide blood pressure swings and brain injury (28,29). Finally, chorioamnionitis with fetal inflammatory response has been associated with premature birth and an increased risk for postnatal mortality and morbidity including white matter injury and cerebral palsy, periventricular intraventricular hemorrhage, and chronic lung disease (30–35).

Microbial Invasion of the Amniotic Cavity in Clinical Chorioamnionitis at Term

Clinical chorioamnionitis is the most common infection-related pregnancy complication at term65,66 and is associated with adverse maternal159,160 and neonatal outcomes.83,161-174 Neonates born to mothers with clinical chorioamnionitis at term are at an increased risk for cerebral palsy (odds ratio [OR] 9.3, 95% confidence interval [CI] 2.7 to 3.1).163 The microbiology of clinical chorioamnionitis was originally described in 1982 by means of cultivation of amniotic fluid obtained with a transcervical catheter. However, such a method of amniotic fluid collection is associated with high rates of contamination.61 We recently reported that clinical chorioamnionitis is a heterogeneous condition by describing the microbiology of the amniotic fluid in patients with clinical chorioamnionitis at term using cultivation methods and molecular microbiologic techniques.51 The most common organisms detected are G. vaginalis and U. urealyticum. Overall, 54% of patients with a diagnosis of clinical chorioamnionitis at term have intraamniotic infection, whereas 24% have sterile intraamniotic inflammation and 22% have no evidence of an inflammatory response in the amniotic cavity.51,175 The cause of such a systemic inflammatory response in the mother without an intraamniotic inflammatory response176 has been attributed to maternal neuroinflammation associated with the administration of epidural anesthesia.177-191

Even neonates born to mothers exposed to clinical chorioamnionitis at term but without intraamniotic inflammation have systemic intravascular inflammation, suggesting that intrapartum fever (maternal systemic inflammation) alters the fetal immune response.192 Accumulating evidence demonstrates that maternal systemic inflammation can predispose the fetus to impaired brain development.193-201 Clinical chorioamnionitis at term is a unique model to examine the effect of maternal systemic inflammation in the presence or absence of intraamniotic inflammation with or without bacteria. Recently, an animal model for chorioamnionitis at term was developed.202

Clinical Lung Maturation

Although chorioamnionitis is generally considered to have adverse effects on the fetus, some reports indicate a clinical benefit. Watterberg and colleagues18 reported that histologic chorioamnionitis and high IL-1β levels in airway samples determined on the first postnatal day predicted a decreased incidence of RDS but an increased incidence of BPD. Infants in whom blood cultures were positive for Ureaplasma urealyticum also had a lower incidence of RDS but a higher incidence of BPD than infants with negative blood cultures.19 Higher cord plasma levels of IL-6 predicted a lower incidence of RDS in another report.20 Although these small clinical series may reflect a reporting bias, chorioamnionitis was associated with improved survival for 881 infants born at less than 26 weeks' gestation in the United Kingdom and Ireland in 1995.21 Histologic chorioamnionitis also was associated with less RDS in 446 consecutive singleton births before 32 weeks' gestation (Table 77-1).

The associations of chorioamnionitis with outcomes such as RDS and BPD are quite complex. In a large epidemiologic report, histologic chorioamnionitis predicted a decreased incidence of BPD unless the infant received mechanical ventilation or developed postnatal sepsis, which in combination with histologic chorioamnionitis increased the risk for BPD.22 This study suggests that fetal exposure to inflammation can induce clinically apparent maturation of the lung, but that subsequent injury (as from ventilation or sepsis) may increase the injury response, thereby resulting in BPD.