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      News & Perspective Drugs & Diseases CME & Education Academy Video Decision Point
      Drugs & Diseases > Pediatrics: Cardiac Disease and Critical Care Medicine

      Chorioamnionitis Workup

      Updated: May 08, 2018
      • Author: Fayez M Bany-Mohammed, MD; Chief Editor: Ted Rosenkrantz, MD  more...
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      Workup

      Laboratory Studies

      During the intrapartum period, diagnosis of chorioamnionitis is usually based on clinical criteria. This is particularly true for pregnancies at term. Chorioamnionitis or intraamniotic infection, as etiologies for preterm labor and preterm premature rupture of the membranes (PPROM), should always be considered. Silent chorioamnionitis is recognized as an important cause of premature labor and PPROM. [5, 158]

      To diagnose silent or obvious amniotic fluid infection or chorioamnionitis, the physician often uses laboratory examinations of the amniotic fluid, maternal blood, maternal urine, or a combination of these.

      Bacteriologic cultures of amniotic fluid and urogenital discharge may be diagnostic for causative pathogens. Investigators suggest that obtaining cervical cultures or performing frequent digital examination increases the risk of initiating amniotic fluid infection in the presence or absence of ruptured membranes.

      Maternal laboratory studies

      Examination of amniotic fluid and urogenital secretions

      Culture of amniotic fluid remains the "gold standard" and most specific test for documentation of intraamniotic infection, but this study is limited by the fact that it may take days to obtain definitive results. More rapid results can be obtained from several other tests, including Gram stain, glucose concentration, white blood cell (WBC) concentration, and leukocyte esterase level. [7] Amniotic fluid, obtained with amniocentesis, may be screened for leukocyte count; Gram stain; pH; glucose concentration; and levels of endotoxin, lactoferrin, and cytokines (eg, interleukin [IL]-6, IL-8, or tumor necrosis factor [TNF]), or a combination of these markers.

      Maternal endotoxin activity appears to show promise as a marker in pregnancies complicated by PPROM; however, more data and larger studies are needed to evaluate its potential in predicting the clinical evolution of preterm birth. [159]  Similarly, findings from a study of 47 women with PPROM suggested that maternal levels of IL-6 in combination with maternal characteristics hold the potential to be good noninvasive predictors of histologic chorioamnionitis. [160]

      Cytokines commonly quantified in either amniotic fluid or blood include IL-6, TNF-alpha, IL-1, and IL-8. [31, 105, 161] No consensus has been reached regarding which cytokine offers the best sensitivity, specificity, and positive versus negative predictive accuracy. However, IL-6, a key mediator of the acute phase response to infection and tissue injury, is one of the most studied markers and a bedside, point-of-care (POC) testing has been developed to test for IL-6 in amniotic fluids and vaginal secretions. [136, 162, 31, 163] Elevated IL-6 levels in cord blood and amniotic fluid have been related to adverse long-term neurologic outcomes in the neonate. [163, 164, 165]  This testing has not become routine yet. However, Chaemsaithong et al reported the potential utility of a rapid IL-6 bedside test (20 minutes) (lateral flow-based immunoassay, or POC test) for measuring IL-6 concentrations in amniotic fluid. Their goal was to identify women with intraamniotic inflammation and/or infection and those who might deliver spontaneously before 34 weeks' gestation among women with preterm labor and intact membranes. [165]

      Data from 136 women with singleton pregnancies who presented with symptoms of preterm labor and underwent amniocentesis showed that the POC test for amniotic fluid IL-6 concentrations had a 93% sensitivity, 91% specificity, and a positive likelihood ratio of 10 for the identification of intraamniotic inflammation by using a threshold of 745 pg/mL. [165] Moreover, the POC test performed similarly to enzyme-linked immunosorbent assay (ELISA) for IL-6 levels and identification of microbial invasion of the amniotic cavity (MIAC), acute inflammatory lesions of the placenta, and patients at risk of impending spontaneous preterm delivery. [165] These investigators found similar results in the setting of PPROM. [163] Other investigators reported similar findings. [162] More recently, matrix metalloproteinase (MMP)-8, a neutrophil collagenase enzyme, has been shown to be a sensitive marker for intraamniotic inflammation that compares well to IL-6 and was developed into rapid POC test as well. [166, 167]

      The rapid development of polymerase chain reaction (PCR) as a diagnostic aid has allowed its use in identifying microbes such as human immunodeficiency virus, cytomegalovirus, herpes simplex, parvovirus, toxoplasmosis, and bacterial DNA in amniotic and other body fluids. PCR has been used for the diagnosis of amniotic fluid infection caused by bacterial pathogens [168] ; however, only university or major academic centers have this relatively expensive technology available to caregivers.

      Amniocentesis to obtain amniotic fluid carries the risk of rupturing the fetal membranes and initiating preterm labor. For this reason, screening tests that use cervicovaginal secretions to indicate chorioamnionitis have been reported. Potential markers of cervical or chorionic inflammation include cervical or vaginal concentrations of fetal fibronectin, insulinlike growth factor binding protein-1, and sialidase. Significant association is noted among levels of cervical IL-6, fetal fibronectin, and amnionitis. Conversely, a positive midgestational fetal fibronectin assay was not associated with acute histologic placental inflammation at birth. [169] Proteomic profiling of amniotic fluid detects intrauterine inflammation and/or infection and predicts subsequent neonatal sepsis. [8] Caregivers should follow this research, because in the next 5 to 10 years, proteomic profiling for inflammation or nonculture-based molecular detection of microbes may become routine in obstetric samples.

      Antenatal screening uses rectovaginal specimens to detect the presence of maternal group B streptococcal (GBS) colonization at 35-37 weeks' gestation. Using these specimens, the Centers for Disease Control and Prevention (CDC) recommends selective growth of GBS in broth followed by cultivation using the plate method. [170, 171]  This is the criterion standard assay.​

      The CDC does not recommend direct PCR detection of GBS in rectovaginal samples. Rather, a rectovaginal sample should undergo enhanced growth in selective broth before performing PCR. [170, 171] Maternal colonization with rectovaginal GBS increases the risk of chorioamnionitis, and intrapartum prophylaxis with antibiotics reduces the incidence of neonatal infection from GBS. [172, 173]

      Missed screening and the failure to give intrapartum antibiotics is responsible for the persistence of neonatal GBS infection. [174] Therefore, for mothers that missed GBS screening at 35-37 weeks' gestation, intrapartum testing for GBS using rapid detection methods on vaginal secretions is an option recommended by some authorities. Intrapartum real-time PCR, performed on vaginal swabs, have been shown to be accurate by several investigators, and it performs as well or better than the antepartum culture for identification of GBS vaginal carriers during labor. [175, 176, 177]

      Examinations of maternal blood

      WBC counts or C-reactive protein (CRP) levels in maternal blood have been used to predict acute chorioamnionitis when maternal fever is present. Different studies have supported or refuted the use of CRP to diagnose chorioamnionitis. [178, 179] The CRP level may be a better predictor of the risk of chorioamnionitis than peripheral WBC counts, especially if the mother has received corticosteroids, which may falsely increase the total WBC count.

      Other investigators have suggested that the alpha1-proteinase inhibitor (A1PI) complex in maternal blood is a better predictor of amniotic fluid infection than either CRP levels or WBC count. Analysis of maternal serum for either IL-6 or ferritin content may also be helpful, because elevations in these mediators are associated with maternal or neonatal infection. Serum IL-6 levels may be more predictive of infection than CRP concentrations in maternal blood. Levels of A1PI complex, cytokines, and ferritin in maternal blood have not gained widespread use as markers of acute chorioamnionitis.

      Laboratory studies in newborn infants

      The criterion standard for making a diagnosis of early-onset bacteremia, pneumonia, or meningitis in neonates is the growth of bacteria in an appropriate specimen (ie, blood, tracheal secretions, cerebrospinal fluid [CSF]). Urinary tract infection is an infrequent cause of early-onset bacterial disease in the neonate; thus, bladder catheterization or suprapubic bladder taps are not usually required as part of an evaluation for early-onset sepsis (EOS).

      Controversy has arisen regarding the inclusion of the lumbar puncture as part of the evaluation for EOS. Some clinicians have argued that meningitis is rarely seen as a manifestation of EOS, the neonate with meningitis has obvious manifestations, and the asymptomatic term neonate does not require a lumbar puncture as part of the evaluation for EOS. Furthermore, other caregivers argue that a lumbar puncture can only be performed safely when life-threatening pulmonary dysfunction or hypertension resolves. Alternatively, other investigators have stressed that cases of meningitis are missed with this approach. [180]

      The medical literature contains good evidence that meningitis may occur in association with sterile blood cultures. Because meningitis is a devastating neonatal infection, no lumbar puncture may result in inadequate antibiotic therapy. Thus, we recommend that a lumbar puncture be performed selectively; when the newborn is symptomatic, especially with central nervous system (CNS) symptoms/signs such as lethargy, irritability, apneas, and seizures; when inflammatory markers are severely deranged, and also when the blood culture is positive.

      Studies that are also considered specific for infection include positive findings on Gram stains of tracheal secretions or CSF. [181] The tracheal secretions must be obtained shortly after birth (< 4-6 hours). The reason is that colonization of the airways may occur from the neonatal intensive care unit (NICU) environment during this time frame. Both tracheal fluids and CSF should be sterile at birth. The presence of bacteria on microscopic analysis (ie, Gram stain) indicates that more than 10,000 colony-forming units (CFUs) of bacteria are present per milliliter of specimen (body fluid). However, the absence of bacteria in either CSF or tracheal secretions does not exclude infection. A final diagnosis should be based on culture results; this testing takes 24-48 hours.

      An absence of neutrophils in CSF or tracheal secretions is expected. The presence of neutrophils in tracheal aspirates obtained after birth indicates that the fetus has mounted an inflammatory response to infection in the environment. Studies by the original author and separate studies by pathologists indicate that neutrophils present in tracheal secretions shortly after birth originate from the fetus or neonate and do not represent aspirated maternal neutrophils found in infected amniotic fluid. This conclusion is based on examining Y-body fluorescence in neutrophils present in the tracheal secretions of infected male neonates. In some studies, 50% of the neutrophils present in tracheal secretions of infants with suspected congenital pneumonia had Y-chromosome fluorescence, indicating a fetal origin. Maternal neutrophils can gain access to the fetal lung only when gasping occurs during fetal asphyxia.

      Bacterial antigen detection in CSF (especially for GBS) may be a useful indicator of bacterial infection; however, false-positive tests have been reported and the test is rarely done in the present day. Bacterial antigen detection in the urine should not be used in a neonate's evaluation for sepsis.

      All other tests used to diagnose early-onset bacterial infection in the neonate should be considered screening tests. The most common laboratory studies used to screen for neonatal sepsis are WBC profiles and CRP determinations. These tests, at best, are presumptive indicators of infection.

      WBC profiles (leukopenia [< 5000/µL], leukocytosis [>30,000/µL], a markedly diminished absolute neutrophil count [ANC] [< 500-1500/µL], an immature-to-total neutrophil ratio [>0.3-0.4]) are commonly used screening tests for the septic neonate. Note that the immature-to-total neutrophil ratio of 0.3-0.4 is higher than the previous value of 0.2 reported in the classic studies of Manroe (1977 and 1979). [182, 183] Clinical pathologists have been less accepting of the immature-to-total neutrophil ratio as a diagnostic aid in neonatal sepsis, [184]  and studies have reexamined the WBC counts and the leukocyte profiles present in extremely preterm infants [185] and at high altitude. [186] Other diagnostic tests (eg, inflammatory factors, adhesion molecules, cytokines, neutrophil surface antigens, even bacterial DNA) may be superior alternatives to this test. To date, these markers of neonatal inflammation/infection have not replaced leukocyte counts as diagnostic methods.

      WBC profiles and kinetics are influenced by the genetic make-up of the patient, the gestational age, maternal noninfectious disorders such as pregnancy-induced hypertension (PIH), medications administered to the mother, fetal disease, and other factors. Reference range WBC counts in the neonate do not exclude infection, and serial studies of WBC indices at approximately 6- to 12-hour intervals may be more useful in detecting sepsis. [187] A continued assessment of WBC kinetics offers more information regarding decision making. For example, a physician should be particularly concerned with a falling total WBC count, a declining absolute mature neutrophil count, and a rising immature-to-total neutrophil ratio. These findings, taken together, indicate depletion in the bone marrow–related storage pool of neutrophils. [188]

      The predictive accuracy of WBC indices for the diagnosis of the EOS is poor. Likewise, the accuracy of CRP determinations to predict neonatal infections shortly after birth is low. However, a negative CRP (especially if done serially, 12-24 hours apart) is a reason to stop antibiotic therapy after 48 hours. [189, 10]

      Akin to maternal diagnostic studies for infection, levels of A1PI complex and cytokines (eg, IL-1 and IL-6; in particular, IL-1 receptor antagonist), as well as the detection of bacterial products in neonatal blood, have not gained widespread use as markers of neonatal sepsis. However, these effectors of inflammation may prove to have better predictive accuracy than WBC tests or the CRP level. Procalcitonin level may have better sensitivity, specificity, and positive and negative predictive value than CRP in the diagnosis of early-onset neonatal sepsis and is increasingly being used. [9, 10] Cell-surface markers of inflammation on leukocytes remain under investigation as potential markers to detect EOS. [190, 191, 192]  Serum amyloid A levels appear to be have high sensitivity at the onset of symptoms and 2 days after, although existing data show a variable positive predictive value with a high negative predictive value. [10]

      Molecular methods that use real-time PCR and DNA sequencing for amplification and detection of 16S rRNA of pathogenic bacteria in neonatal blood have created enormous interest because a rapid diagnosis is possible. [193, 194, 195]  However, despite showing that 16S rRNA PCR increased the sensitivity in detecting bacterial DNA in newborns with signs of sepsis and allowing shortening of antibiotic courses, a report concluded that uncertainty about the bacterial cause of sepsis was not reduced by this test, and that blood culture remains currently irreplaceable. [196] As technology advances, caregivers should pay close attention to this rapidly advancing field.

      Next:

      Imaging Studies

      Ultrasonography may be used to ascertain fetal well-being. A biophysical profile (BPP) provides information about the status of the fetus. A low BPP score, and especially the loss of fetal breathing movements, has been associated with fetal bacterial infection after premature rupture of membranes (PROM). [139, 140] Other investigations have not confirmed the importance of a low BPP score. Specifically, the absence of fetal breathing, may not be a reliable test for amnionitis prior to 32 weeks' gestation. [197, 198]

      Before the fetus is viable, vaginal ultrasonography can be used to identify women with a shortened cervical canal, which is associated with a higher risk of preterm delivery. [11, 12, 13] Researchers suggest a shortened cervical canal or cervical insufficiency are linked to ascending urogenital infection that initiates premature labor, PROM, or both.

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      Procedures

      Needle aspiration and analysis of amniotic fluid (amniocentesis) is the only invasive procedure used to confirm the diagnosis of acute chorioamnionitis. This procedure can be risky with intact fetal membranes, because the fetal membranes can rupture during or after the procedure. Bleeding or placental abruption can also be a consequence of amniocentesis. The procedure should be performed using ultrasonographic guidance to avoid fetal injury. For these reasons, amniocentesis to diagnose maternal chorioamnionitis has had limited application in obstetric practice.

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      Histologic Findings and Staging

      Histologic findings

      Gross and microscopic examinations of the placenta, fetal membranes, and umbilical cord for evidence of inflammation and infection are crucial to make a definitive diagnosis of chorioamnionitis. [14]  Histologic chorioamnionitis is a reliable indicator of infection whether or not it is clinically apparent. [199]  Nevertheless, anatomic studies should be correlated with a culture aseptically obtained from the fetal surface of the placenta.

      The microbiologic cultures should include an attempt to isolate aerobic and anaerobic bacteria. Special microbiologic techniques may be required for certain microorganisms such as Listeria monocytogenes. Only with these methods can the pathologist help the bedside clinician delineate the cause of maternal chorioamnionitis and neonatal sepsis. Clinicians are encouraged to ask pathologists for help in their search for infections causing disease in the pregnant woman, fetus, and newborn. Obstetricians must also obtain the placenta, fetal membranes, and umbilical cord samples for analytical studies when suspicious clinical circumstances are noted.

      Staging

      Redline and colleagues proposed a scoring system for placental examination that promotes consistency when pathologists judge the severity of chorioamnionitis. [200]

      Several physiologic scores have also been proposed for neonates who have life-threatening illness, but a report by Lim et al could not conclude that these scores accurately predicted neonatal morbidity and mortality during infection. [201]

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      Staging

       

       

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