Definitions and Epidemiology

Chorioamnionitis (or intra-amniotic infection) is a major cause of fetal, neonatal, and maternal morbidity and mortality.10,44,49,57,59,69 There are strong associations between chorioamnionitis and maternal morbidity,⁵⁹ preterm birth,^46,52 early-onset neonatal sepsis,⁶⁷ bronchopulmonary dysplasia,³³ retinopathy of prematurity,^17,63 and periventricular leukomalacia.⁴⁵ The literature supporting these associations has been inconsistent, largely because of lack of precision in the diagnosis of chorioamnionitis. Potential sites of microbial invasion include the choriodecidual space (between maternal tissues and the fetal membranes), the fetal membranes, the placenta, the amniotic fluid, the umbilical cord, and the fetus (Figure 26-1).³⁰ When characteristic clinical signs are present, the condition is usually termed clinical chorioamnionitis. However, histologic chorioamnionitis (inflammation of the chorion and amnion) is three times as common as clinical chorioamnionitis confirmed by amniotic fluid culture.²⁰ Two main varieties of chorioamnionitis can be identified, acute chorioamnionitis and subclinical chorioamnionitis.³⁰ They differ in their clinical manifestations, microbiology, and risk to the fetus (Figure 26-2). Although acute chorioamnionitis is strongly associated with early-onset sepsis, the subclinical variety may contribute to the risk of chronic lung disease and brain injury.^33,45

Chorioamnionitis complicates 1% to 5% of all pregnancies.⁵⁹ The prevalence of histologic chorioamnionitis ranges from 50% to 70% in very low birth weight infants to 10% to 15% for infants born at term gestation. Approximately 30% of women with preterm labor and intact membranes exhibit histologic chorioamnionitis, as do 80% of women with preterm, premature rupture of membranes (PPROM). Histologic chorioamnionitis almost always represents an ascending infection of organisms colonizing the maternal birth canal. Histologic acute chorioamnionitis represents the inflammatory response of the mother and fetus to the presence of microorganisms (usually bacterial or fungal) in the amniotic cavity. Acute chorioamnionitis cannot occur before the fusion of the amnion and chorion (≈11 weeks’ gestation) and is rare before 20 weeks of gestation. Before that time, a chronic choriodeciduitis can develop, which is subclinical and has been linked to an increased incidence of preterm birth, chronic lung disease, and periventricular leukomalacia. It is controversial whether the choriodeciduitis represents an infectious process or a maternal immune response to fetal antigens.⁵⁴

As noted, histologic chorioamnionitis is three times as common as clinical chorioamnionitis and only about two thirds of women with suspected clinical chorioamnionitis have evidence of placental inflammation. Part of the difficulty of identifying women with chorioamnionitis is that microbial invasion of the amniotic cavity (MIAC) can be chronic and clinically silent.³⁰ Furthermore, histologic chorioamnionitis can occur with negative cultures from amniotic fluid. Some of these “negative cultures” can be explained by the fastidiousness of the microorganisms found in amniotic fluid and the difficulty in recovering them using standard culture techniques. Histologic chorioamnionitis has been associated with intra-amniotic infection in 72% of cases of preterm birth. However, the likelihood of neonatal sepsis in women with histologic or clinical chorioamnionitis varies dramatically with gestational age (Table 26-1).⁶⁶

Risk Factors

Epidemiologic investigations have demonstrated several factors associated with the development of clinical chorioamnionitis, including maternal colonization with group B streptococcus (GBS), GBS bacteriuria, nulliparity, the use of internal monitoring devices, meconium-stained amniotic fluid, serial vaginal digital examinations, duration of active labor, and duration of membrane rupture.3,60,64 Importantly, meconium-stained amniotic fluid is not only a risk factor for chorioamnionitis, but also may be a consequence of fetal stress secondary to intra-amniotic infection. There are some data to suggest that women diagnosed with chorioamnionitis during their first pregnancy are at increased risk for developing chorioamnionitis in subsequent pregnancies,^18,43 indicating a persistent predisposing condition or particular underlying host susceptibility. The presence of abnormal vaginal flora (e.g., bacterial vaginosis, aerobic vaginitis) during the first trimester is associated with adverse pregnancy outcomes, including early preterm birth and miscarriage,²³ although discrete evidence linking the presence of abnormal flora of the lower genital tract with the development of acute clinical chorioamnionitis is lacking. Rather, it is hypothesized that these vaginal microbes ascend into the intrauterine cavity and induce a subclinical, chronic inflammatory response that in turn predisposes to preterm rupture of membranes and/or the onset of preterm labor. Finally, recent case-control gene association studies have identified single nucleotide polymorphisms in maternal immunoregulatory genes (IL-10, IL-6) that may influence susceptibility to chorioamnionitis.^7,55

Microbiology

Chorioamnionitis is almost always polymicrobial. Using culture-based techniques, Ureaplasma urealyticum and Mycoplasma hominis are the most common organisms recovered (47% and 30%, respectively) in culture-proved chorioamnionitis.⁷⁰ Other cultivable organisms include anaerobes, such as Gardnerella vaginalis (25%) and bacteroides (30%), and aerobes, including GBS (15%) and Escherichia coli (8%).⁷⁰ Interestingly, anaerobes are more frequently involved in preterm deliveries rather than intra-amniotic infection at term gestation.⁶⁵

Broad-range PCR has been used to identify the kinds of microorganisms found in the amniotic fluid of women with preterm labor or PPROM.²² Several conclusions are evident: (1) PCR-based techniques identify 30% to 50% more organisms than culture-based methods; (2) five phyla are commonly represented (Figure 26-3); and (3) the patterns of microorganisms in amniotic fluid in women with preterm labor and intact membranes are different from those found in amniotic fluid samples from women with PPROM (Figures 26-4 and 26-5).²¹ However, given the high sensitivity of PCR, the increased likelihood of detecting DNA from nonviable or environmental contaminants makes the clinical significance of this microbial diversity somewhat uncertain. Studies of the association of MIAC (using PCR-based techniques) with fetal inflammation or perinatal outcomes noted statistically significant associations with elevated concentrations of inflammatory mediators in amniotic fluid and increased rates of histologic chorioamnionitis, preterm delivery and adverse neurological outcomes. In addition, there are strong correlations between (1) MIAC (diagnosed by PCR) and the mean or median time from amniocentesis until delivery, and (2) the microbial abundance and gestational age at delivery.

Diagnosis

The clinical diagnosis of chorioamnionitis is problematic. Strictly defined, the diagnosis requires maternal fever (≥100.4° F) plus two other findings, including maternal leukocytosis, maternal and fetal tachycardia, uterine tenderness, and foul-smelling or purulent amniotic fluid.⁶⁹ In everyday clinical practice, however, the diagnosis is suspected/diagnosed when fever is the sole manifestation. More importantly, once the diagnosis of chorioamnionitis is made, current recommendations from the Centers for Disease Control and Committee on Fetus and Newborn suggest a full sepsis evaluation and initiation of antimicrobial therapy, even in healthy-appearing infants.^19,53 Fever is present in 95% to 100% of patients with chorioamnionitis.⁷⁰ Individual clinical criteria have variable sensitivity and generally low specificity for chorioamnionitis (Table 26-2). Epidural anesthesia is associated with an increased risk of fever during labor with a relative risk of 3.34 (CI 2.63-4.23).^6,61 The general belief is that the fever associated with an epidural is noninfectious in origin; however, fever may be more likely to occur when placental inflammation is present. Fever following placement of an epidural can occur within 1 hour, but almost always within 4 to 6 hours. It is noteworthy that fever induces an inflammatory response in the mother, manifested by increased interleukin-6 levels. Epidural anesthesia also affects the body’s thermoregulatory mechanisms by decreasing heat dissipation via sweating.

Laboratory testing may be helpful in confirming or excluding the diagnosis of chorioamnionitis, particularly when the diagnosis is uncertain. Leukocytosis has been described in 70% to 90% of patients with clinical chorioamnionitis. In the absence of other signs and symptoms, isolated leukocytosis is of limited value. Measurements of acute phase reactants such as C-reactive protein have not been helpful in establishing the diagnosis.27,51 A number of amniotic fluid markers have been used for the diagnosis of chorioamnionitis. These include culture, Gram stain, glucose levels, white blood cell counts, leukocyte esterase, DAMPs (damage-associated molecular patterns), soluble Toll-like receptors, matrix metalloproteinase, cytokines (e.g., TNF-α, interleukins-6 and -8), and qualitative assessment of amniotic proteins (proteomics).¹³ Proteomics is the characterization of the patterns of proteins and peptides in complex biologic samples (e.g., amniotic fluid). Using a newly developed technology (SELDI-TOF mass spectrometry), Buhimschi et al. demonstrated that the severity of chorioamnionitis and funisitis were significantly associated with the degree of intra-amniotic inflammation and time to delivery.^13,14,15 The degree of inflammation was expressed as a mass-restricted score based on the absence or presence of four proteins, which are members of the innate immunity arm of antimicrobial defenses (neutrophil defensin-2, neutrophil defensin-1, calgranulin-A and calgranulin-C) (Figure 26-6).

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