Clinical chorioamnionitis

INTRODUCTION — Clinical chorioamnionitis is characterized by infection and inflammation of intrauterine structures. It is a common pregnancy complication, especially after prelabor rupture of membranes (PROM). Treatment involves both antibiotic therapy and expeditious delivery. Despite treatment, the disorder is associated with potentially serious maternal, fetal, and neonatal consequences, and offspring may be at increased long-term risk for cerebral palsy and other adverse neurodevelopmental outcomes.

This topic will discuss clinical manifestations, diagnosis, and treatment of clinical chorioamnionitis. Its occurrence and prevention in patients with preterm prelabor rupture of membranes (PPROM) are reviewed separately. (See "Preterm prelabor rupture of membranes: Management and outcome".)

TERMINOLOGY — Historically, the term "clinical chorioamnionitis" referred to infection of the chorion, amnion, or both. Although this term remains in common use, the term intraamniotic infection is also commonly used since infection often involves the amniotic fluid, fetus, and umbilical cord in addition to the membranes. By comparison, the term "histologic chorioamnionitis" has been used by pathologists to describe inflammation without the typical clinical or microbiological findings associated with acute infection; these cases may be the result of sterile inflammation or use of insensitive microbiologic techniques. Adding to the complexity, in 2015, a National Institute of Child Health and Human Development (NICHD) Workshop expert panel recommended use of the term "triple I" to address heterogeneity in terminology [1]. Triple I refers to intrauterine infection or inflammation or both and is defined by strict diagnostic criteria (table 1). These criteria are commonly used to diagnosis clinical chorioamnionitis even though the triple I terminology has not been adopted by most clinicians [2,3].

The terms clinical chorioamnionitis and intraamniotic infection will be used interchangeably in this topic. They are often used interchangeably clinically and in the literature since they are indistinguishable antepartum using standard noninvasive tests. However, we recognize that when amniotic fluid culture and interleukin-6 concentration are available, one-quarter to one-third of chorioamnionitis cases will not have evidence of infection that has extended into the amniotic cavity [4]. We also acknowledge that the two conditions may be associated with different risks for adverse outcome.

PATHOGENESIS

●Migration of cervicovaginal microorganisms through the cervical canal to the decidual-chorionic interface is the most common pathway to chorioamnionitis [5]. The microorganisms can then pass into the amniotic cavity and may eventually infect the fetus. Membrane rupture is not necessary for bacteria to reach the amniotic cavity.

Uncommonly, maternal microorganisms in blood seed the intervillous space, resulting in placental infection and transplacental passage of the microorganisms to the fetus. Microorganisms that invade the placenta by the hematogenous route include Listeria monocytogenes, Zika virus, cytomegalovirus, SARS-CoV-2, Plasmodium species, Campylobacter species and microorganisms causing toxoplasmosis, syphilis, varicella-zoster, parvovirus B19, rubella, and herpes infections [6].

Another uncommon pathway is microbial contamination of the amniotic cavity from a transmyometrial or transcervical procedure. Rarely, microorganisms from a pelvic infection migrate through the fallopian tubes, resulting in chorioamnionitis.

●Local host factors also play roles. Most importantly, intact membranes and the cervical mucus plug are barriers to ascending infection that are impaired by membrane rupture and passage of the plug. Other host barriers to infection may also be impaired. For example, the fetal membranes appear to have antimicrobial activity [7-10] and peroxide-producing lactobacilli in the vagina appear to have favorable immunomodulatory effects that impair the virulence of pathogenic organisms [11].

●Microbial infection activates the maternal/fetal inflammatory response systems and generally leads to labor and/or prelabor rupture of membranes (PROM). Decidual or amniochorial space inflammation is primarily a maternal inflammatory response while intraamniotic inflammation is primarily a fetal inflammatory response [5]. (See 'Histology' below and "Spontaneous preterm birth: Pathogenesis", section on '#2 Inflammation'.)

MICROBIOLOGY — Clinical chorioamnionitis from migration of cervicovaginal microorganisms is typically a polymicrobial infection, often involving enteric flora (table 2). Two-thirds of patients have at least two isolates per specimen of amniotic fluid. By comparison, transplacental infection from microorganisms in the maternal circulation is more likely to be due to a single pathogen, such as L. monocytogenes.

Regardless of gestational age, genital mycoplasmas (Ureaplasma and Mycoplasma species) are the most common isolates and may be detected in the absence of other organisms [12,13]. Because they are highly prevalent (>70 percent) in the lower genital tract, some authorities attribute their isolation from patients with clinical chorioamnionitis to contamination or colonization from the lower genital tract rather than a true infection. However, as data accrue, their pathogenicity is increasingly supported, including induction of a robust inflammatory response with clinical consequences for both mother and neonate [12-15].

Other pathogens frequently associated with clinical chorioamnionitis include anaerobes (eg, Gardnerella vaginalis, Bacteroides spp.), enteric Gram-negative bacilli, and group B Streptococcus. Anaerobes appear to be more frequently involved in preterm than in term chorioamnionitis [16].

INCIDENCE — Clinical chorioamnionitis occurred in 3.9 percent of births and was the most common peripartum infection in a systematic review evaluating the global incidence of maternal peripartum infection [17]. The incidence in the United States varies widely among individual reports [18]. This variation is due to several factors, including differences in ascertainment (prospective studies report higher rates than retrospective studies), differences in prevalence of risk factors in the populations studied, use of different diagnostic criteria (eg, clinical versus histologic [the incidence of histologic chorioamnionitis is much higher]), and temporal changes in obstetric practice [19-21].

The incidence is higher in preterm pregnancies. Forty to 70 percent of preterm births have been associated with chorioamnionitis [22]. Among term births, clinical chorioamnionitis has been diagnosed in approximately 1 to 3 percent of those with intact membranes [23] and 6 to 10 percent of those with PROM [24].

RISK FACTORS — The most important risk factor for developing clinical chorioamnionitis is longer duration of labor and ruptured membranes. Several other obstetric factors have been associated with an increased risk, including [20,24-35]:

●Prolonged first or second stage of labor

●Prolonged time from rupture of membranes to delivery

●Multiple intrapartum digital vaginal examinations (especially after ruptured membranes)

●Digital rather than speculum examination in patients with preterm prelabor rupture of membranes (PPROM)

●Cervical insufficiency

●Fetal scalp electrode or internal uterine pressure catheter

●Intracervical balloon catheter for cervical ripening/labor induction

●Presence of genital tract pathogens (eg, sexually transmitted infections, group B Streptococcus, bacterial vaginosis)

●Nulliparity

●Meconium-stained amniotic fluid

●Alcohol and tobacco use

●Previous clinical chorioamnionitis

●Epidural analgesia

CLINICAL FINDINGS

Presentation — Clinical chorioamnionitis often occurs in pregnancies with prelabor rupture of membranes (PROM) but can occur with intact membranes, especially in laboring patients. The key clinical findings, which are nonspecific, and their approximate frequencies are as follows [36,37]:

●Fever (100 percent).

●Maternal leukocytosis (white blood cell [WBC] count >15,000/mm³: 70 to 90 percent).

●Maternal tachycardia (>100 beats per minute [bpm]: 50 to 80 percent).

●Fetal tachycardia (>160 bpm: 40 to 70 percent).

●Uterine tenderness (4 to 25 percent).

●Bacteremia (5 to 10 percent). Bacteremia is most common when clinical chorioamnionitis is associated with group B Streptococcus or Escherichia coli infection (bacteremia in 18 and 15 percent of cases, respectively).

●Purulent or malodorous amniotic fluid.

Subclinical cases are not associated with these signs and symptoms, but may lead to labor or PROM and may be associated with reduced fetal heart rate variability [38,39].

Maternal course — Patients with clinical chorioamnionitis are at increased risk for preterm birth, labor abnormalities, sepsis, postpartum infection, and their sequelae.

●Preterm birth – Chorioamnionitis leads to preterm birth via the following pathways: spontaneous preterm labor with intact membranes, preterm prelabor rupture of membranes (PPROM) leading to spontaneous preterm labor, or medically indicated preterm birth [40].

●Dysfunctional labor – Clinical chorioamnionitis is associated with an increased risk of protraction and arrest disorders of labor, which increase the risk for cesarean birth, uterine atony, and postpartum hemorrhage [41-43]. The type of bacteria appears to play a role: Patients with persistent high-virulence organisms (eg, Enterobacteriaceae, Group A and B streptococci, Mycoplasma hominis) in the amniotic fluid have more labor abnormalities than those with low-virulence organisms (Ureaplasma urealyticum, lactobacilli, Staphylococcus epidermidis) [44-48]. The pathophysiologic mechanisms for labor abnormalities related to clinical chorioamnionitis are poorly understood and often complicated by other factors (eg, epidural anesthesia), but the link between clinical chorioamnionitis and both labor abnormalities and postpartum hemorrhage suggests dysfunctional myometrial contractility due to inflammation [41-43,49].

●Sepsis – Population-based studies have reported that chorioamnionitis increased the odds of maternal sepsis 8- to 12-fold and approximately 15 to 20 percent of maternal sepsis was associated with chorioamnionitis [50,51]. In a review of a database including 364 patients with clinical chorioamnionitis, five developed severe sepsis (1.4 percent) and it was difficult to identify these patients upon initial presentation despite use of a modified obstetric early warning scoring system (table 3) [52].

The risk of life-threatening maternal sequelae, such as sepsis, coagulopathy, and adult respiratory distress syndrome related to clinical chorioamnionitis, is low if treatment with broad spectrum antibiotics is initiated upon diagnosis of infection and the pregnancy is delivered. (See 'Maternal management' below.)

●Postpartum infection – Patients with clinical chorioamnionitis who undergo cesarean birth, which is common, are at increased risk for wound infection, endomyometritis, septic pelvic thrombophlebitis, and pelvic abscess [41,53,54]. These complications are uncommon after a vaginal birth.

Histology — The maternal immune response to microbial infection leads to neutrophilic inflammation of the chorioamnion (chorioamnionitis). A fetal immune response may also occur. The fetal immune response leads to neutrophilic inflammation of the fetal vessels in the chorionic plate (chorionic vasculitis) and, less commonly, the umbilical cord (funisitis). Chorioamnionitis is almost always present in cases of funisitis, while funisitis is present in a minority of chorioamnionitis cases (<60 percent, higher in preterm than term gestations) [4,55]. Chorioamnionitis may be staged 1 to 3 based on the anatomic sites infiltrated by neutrophils and graded 1 to 3 based on the intensity of the acute inflammatory process at a particular site. Histologic criteria for chorioamnionitis and funisitis are reviewed separately. (See "The placental pathology report", section on 'Acute chorioamnionitis' and "The placental pathology report", section on 'Inflammation'.)

A histologic diagnosis of chorioamnionitis may be reported in the absence of clinical signs and symptoms of infection or positive cultures from the placenta, membranes, or amniotic fluid. In these cases, the inflammatory changes in the membranes may have resulted from noninfectious insults (hypoxic injury, trauma, meconium, allergens). Negative cultures could also be due to fastidious organisms such as genital mycoplasmas (the most common organisms associated with chorioamnionitis) or antibiotic therapy prior to delivery.

In one study, histologic and bacteriologic results were concordant in approximately 70 percent of the 376 examined placentas [56]. When the diagnosis of chorioamnionitis was based on culture-positive amniotic fluid, sensitivity and specificity of histology were 83 to 100 percent and 23 to 52 percent, respectively [57].

DIAGNOSTIC EVALUATION

All patients

●Complete blood count.

●Diagnostic studies for infections other than chorioamnionitis, such as pyelonephritis or respiratory infection, are performed if the diagnosis of chorioamnionitis versus another cause of fever and leukocytosis is uncertain. The specific studies are guided by the clinical findings (eg, flank pain, cough, dyspnea). (See 'Differential diagnosis' below.)

We do not obtain blood cultures in patients with chorioamnionitis unless we suspect maternal sepsis. (See 'Evaluation for sepsis' below and "Detection of bacteremia: Blood cultures and other diagnostic tests", section on 'Indications for blood cultures'.)

When to perform amniocentesis to test amniotic fluid — In the vast majority of patients, a presumptive diagnosis of clinical chorioamnionitis is adequate for initiating maternal therapy, without the need for amniocentesis (see 'Diagnosis' below). However, when the presumptive diagnosis is uncertain because typical clinical findings (eg, maternal fever) are absent or findings overlap with other disorders, evaluation of amniotic fluid can confirm or exclude intraamniotic infection. Analysis of amniotic fluid is particularly useful in preterm gestations with an uncertain diagnosis because an incorrect diagnosis of chorioamnionitis leading to unnecessary delivery could result in serious morbidity in offspring.

Amniotic fluid culture remains the "gold standard" and the most specific test for documentation of intraamniotic infection but utility is limited because it take days to obtain definitive results, which is too long to be clinically useful. Results from several other tests, including Gram stain, glucose concentration, white blood cell (WBC) concentration, and leukocyte esterase level, can be obtained more rapidly; however, the majority of these tests have relatively low predictive value for a positive amniotic fluid culture (table 4) in patients with preterm prelabor rupture of membranes (PPROM) or preterm labor and even lower ability to predict neonatal sepsis [58,59].

●Gram stain is performed on an unspun specimen of amniotic fluid; centrifugation does not significantly improve test sensitivity. Twenty to 30 high-power fields should be examined. The presence of any bacteria and leukocytes (at least six leukocytes per high-power field) is suspicious for infection since amniotic fluid is sterile in uncomplicated pregnancies with intact membranes [60].

●Glucose concentration is measured with an autoanalyzer. Glucose ≤14 mg/dL suggests infection [61].

●WBC concentration can be determined using a Coulter counter (abnormal result ≥30 cells/mm³) [62].

●Leukocyte esterase activity can be evaluated with a urine dipstick reagent strip (an abnormal result is trace or greater) [63,64].

In patients with preterm labor, the combined result of positive Gram stain, positive leukocyte esterase, low glucose concentration, and elevated WBC concentration has 90 percent sensitivity and 80 percent specificity for predicting positive results of amniotic fluid culture. However, since the prevalence of intraamniotic infection is relatively low in patients with preterm labor (approximately 10 percent), this combination of tests has a false-positive rate of 67 percent; thus, the clinician should use caution in acting prior to obtaining culture results, particularly when the intervention involves a performing a preterm birth. In addition, an elevated WBC concentration is less predictive of infection if the amniocentesis is traumatic (defined as amniotic fluid containing ≥1000 red blood cells/mm³) [62].

Some clinicians perform amniocentesis to exclude subclinical intraamniotic infection in selected patients, such as those with preterm labor that is associated with uterine tenderness, elevated maternal white blood cell count, or fetal tachycardia or patients with physical examination-based cervical insufficiency, before attempts are made to prolong pregnancy (ie, tocolysis, cerclage placement) [65]. The author does not routinely perform amniocentesis in such patients because of the poor predictive value of nonculture-based amniotic fluid testing, the 48-hour delay in obtaining definitive culture results, and the lack of data proving that decision-making based on this information reduces maternal/neonatal morbidity.

Although a small study reported antibiotics eradicated intraamniotic infection (microorganisms identified by culture or polymerase chain reaction) in three of four patients with preterm labor and intact membranes who had a follow-up amniocentesis [66], whether patients with preterm labor or cervical insufficiency should undergo amniocentesis and receive tailored antibiotics and expectant management needs to be investigated in randomized trials looking at short- and long-term outcomes. (See "Cervical insufficiency", section on 'Management of patients with subclinical infection on amniocentesis'.)

Evaluation for sepsis — Most patients with clinical chorioamnionitis are not septic, which is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis should be suspected in patients who meet modified obstetric early warning system criteria (MEWC) (table 3). Other screening tools are available, such as the pregnancy-adjusted sepsis screening tools from the California Maternal Quality Care Collaborative (CMQCC) and the UK Obstetric Surveillance System (UKOSS). In patients with chorioamnionitis/endometritis, the sensitivity for sepsis of the MEWC, CMQCC, and UKOSS systems ranges from 94 to 98 percent, but false-positive rates are higher for MEWC than for the other two systems (92, 60, and 68 percent, respectively, in one study [67]). The CMQCC toolkit for improving diagnosis and treatment of maternal sepsis is available online. The UKOSS system is also available online.

Obtaining a lactate level can be helpful in such patients since an elevated level (eg, >2 mmol/L or greater than the laboratory's upper limit of normal) can be a sign of sepsis, correlates with the severity of sepsis, and can be used to follow the therapeutic response. Evaluation for sepsis is reviewed in detail separately. (See "Evaluation and management of suspected sepsis and septic shock in adults".)

Other tests — Several biomarkers have been studied but none have been proven to be clinically useful. The most commonly performed tests are for amniotic fluid cytokines and C-reactive protein (CRP).

●A point-of-care test for interleukin-6 in amniotic fluid collected transcervically in patients with ruptured membranes is available in some countries, but does not appear to be a good predictor of maternal-fetal infection [68].

●Meta-analyses found no clear evidence to support the use of CRP for the early diagnosis of clinical chorioamnionitis in patients with prelabor rupture of membranes (PROM) [69,70]. Available studies had high heterogeneity, with a wide range for sensitivity and specificity of CRP at various thresholds.

Clinical chorioamnionitis is not associated with specific findings on ultrasound imaging [71].

DIAGNOSIS

Diagnostic criteria — The diagnosis of chorioamnionitis is usually based on clinical findings alone. The key criterion is maternal fever without another identifiable source, which is a manifestation of systemic inflammation; other criteria are insensitive. The following diagnostic criteria are commonly used, with small variations worldwide. They were suggested by a National Institute of Child Health and Human Development (NICHD) Workshop expert panel [1].

●Presumptive diagnosis – A presumptive diagnosis of intraamniotic infection can be made in pregnant patients with:

•Fever – Either an oral temperature ≥39.0°C (102.2°F) once or 38.0°C (100.4°F) to 38.9°C (102.02°F) on ≥2 measurements 30 minutes apart without another clear source PLUS one or more of the following:

-Baseline fetal heart rate >160 bpm for ≥10 minutes, excluding accelerations, decelerations, and periods of marked variability.

-Maternal white cell (WBC) count >15,000/mm³ in the absence of corticosteroids and ideally showing a left shift (bandemia).

-Purulent-appearing fluid coming from the cervical os visualized by speculum examination.

The rationale for these criteria is that the temperature and fetal heart rate thresholds exceed the 90 to 95^th percentile for normal pregnancies and the WBC count exceeds the 80^th percentile. In addition, these thresholds are associated with higher rates of neonatal and maternal morbidity and, in preterm gestations, define a population whose amniotic fluid contains higher concentrations of organisms (>100 colony forming units/mL bacteria) and high-virulence isolates (group B Streptococcus, aerobic Gram-negative rods, anaerobes, and M. hominis). The NICHD criteria do not include maternal tachycardia (heart rate >100 bpm) and fundal tenderness for clinical diagnosis; however, these signs (which are part of the Gibbs criteria [44]) are used by many clinicians in combination with other criteria for presumptive diagnosis.

The American College of Obstetricians and Gynecologists (ACOG) generally endorses the NICHD criteria, except ACOG would make a presumptive diagnosis in patients with isolated fever ≥39.0°C (102.2°F) without another clear source because they are at high risk of an adverse clinical infectious outcome and thus should be managed similar to patients with additional signs of intraamniotic infection [3,72]. The presumptive diagnosis in laboring patients with isolated fever is strengthened in those with risk factors for the disease, especially ruptured membranes, and by excluding other potential sources of fever. (See "Intrapartum fever".)

●Confirmed diagnosis – A confirmed diagnosis of intraamniotic infection can be made in pregnant/postpartum patients with:

•All of the above criteria for suspected intraamniotic infection PLUS one or more of the following objective laboratory findings:

-Positive Gram stain of amniotic fluid.

-Low glucose level (≤14 mg/dL) in amniotic fluid.

-Positive amniotic fluid culture.

-High WBC count (>30 cells/mm³) in amniotic fluid in the absence of a bloody tap.

-Histopathologic evidence of infection or inflammation or both in the placenta, fetal membranes, or the umbilical cord vessels (funisitis).

Laboratory studies should be performed on amniotic fluid obtained by amniocentesis (not collected vaginally) (see 'When to perform amniocentesis to test amniotic fluid' above). Histopathology is obtained after delivery.

Differential diagnosis — Most of the clinical findings associated with chorioamnionitis are nonspecific. Differential diagnosis includes, but is not limited to:

●Labor – Labor can be associated with fever, maternal and/or fetal tachycardia, leukocytosis, and uterine tenderness. Fever may be related to dehydration, use of prostaglandins for cervical ripening, or neuraxial anesthesia. Maternal leukocytosis occurs with labor and after antenatal corticosteroid therapy, as well as with infections other than chorioamnionitis. Fetal tachycardia may be related to fetal hypoxemia, maternal fever of any etiology, or transplacental passage of some maternal medications. Maternal tachycardia may be physiologic or related to pain, medications, or neuraxial anesthesia.

Diagnosis of clinical chorioamnionitis is difficult in laboring patients with neuraxial anesthesia because fever is common in this setting and may be related to the anesthetic itself. In addition, neuraxial anesthesia masks uterine tenderness and may induce maternal or fetal tachycardia. Lastly, prolonged labor is a risk factor for both requesting neuraxial anesthesia and developing chorioamnionitis. No specific temperature threshold has been found to reliably distinguish chorioamnionitis from neuraxial anesthesia-associated temperature elevation. (See "Intrapartum fever", section on 'Use of neuraxial anesthesia'.)

●Placental abruption – A small abruption can cause uterine tenderness and maternal tachycardia, but is usually associated with vaginal bleeding and absence of fever. (See "Acute placental abruption: Pathophysiology, clinical features, diagnosis, and consequences".)

●Other infections – Extrauterine infections associated with fever (with or without labor) include pyelonephritis, influenza, appendicitis, pneumonia, and COVID-19. These infections can cause maternal tachycardia, leukocytosis, and sometimes abdominal pain; and fetal tachycardia. They can usually be differentiated from chorioamnionitis by the clinical setting (eg, respiratory or gastrointestinal symptoms suggest an extrauterine source of fever) and laboratory tests (pyuria in urine obtained via a catheter suggests pyelonephritis). (See "Intrapartum fever".)

MATERNAL MANAGEMENT

Initiate delivery — Patients with chorioamnionitis should be treated with antibiotics and delivered. Although antimicrobial therapy provides bactericidal concentrations of antibiotics in the fetus and amniotic fluid within one-half to one hour after infusion, which reduces the risk of serious maternal and fetal complications, delivery (ie, evacuation of the products of conception) is required for resolution of the infection. The reason antibiotics alone are ineffective may be because amniotic fluid bacteria can form biofilms, which are resistant to antibiotic treatment [18].

Patients who are not in labor are promptly induced, unless a standard indication for cesarean birth exists. In patients receiving antibiotics, there is no evidence that the duration of labor correlates with adverse neonatal outcome; therefore, cesarean birth is not indicated to shorten labor duration [41,73]. Furthermore, cesarean birth in the setting of intraamniotic infection increases the risks for wound infection, endomyometritis, and venous thrombosis [54].

Histopathologic evaluation of the placenta is recommended. We do not typically obtain placental cultures, but cultures may be obtained by the pathologist in selected cases when specific infections, such as listeriosis or candida, are suspected. (See "Gross examination of the placenta", section on 'Obtaining cultures'.)

Antenatal corticosteroids — Delivery should never be delayed to administer antenatal corticosteroids (ACS). Data are limited and inconclusive regarding ACS administration in patients <34 weeks with preterm intraamniotic infection who are laboring or being induced [74-76]. Some experts do not administer ACS to such patients because many will give birth within hours and the safety of ACS for the mother and newborn in this setting have not been established. A major concern is that its immunosuppressive effects may worsen maternal and/or neonatal outcomes. However, others consider ACS an option since ACS exposure for even a few hours can have newborn benefits, and harm has not been established in patients receiving adequate antibiotic therapy [74,76].

Antibiotic therapy — Broad spectrum parenteral antibiotics for common cervicovaginal pathogens should be administered promptly following a diagnosis of chorioamnionitis, even if neuraxial-related fever cannot be excluded. Early initiation of antibiotics begins treatment of maternal and fetal infection and may reduce the frequency and severity of neonatal infection [77-79].

Intrapartum regimen

Laboring patients — Our preference for patients expected to give birth vaginally is:

●Ampicillin 2 g IV every six hours plus

●Gentamicin 5 mg/kg IV once daily

A single daily gentamicin dose is as, or more, effective and more convenient than thrice-daily dosing and safe when used intrapartum or postpartum [80,81]. It does not result in toxic maternal levels (peak 18.2 micrograms/mL and <2 micrograms/mL by 10 hours) and results in appropriate fetal serum levels (peak 6.9 micrograms/mL); fetal levels are lower with standard dosing (1.5 mg/kg every eight hours: fetal level 2.9 micrograms/mL) [82]. Routine monitoring gentamicin levels is unnecessary for patients who are healthy except for chorioamnionitis. For patients with chronic kidney disease, we adjust the gentamicin dose with the assistance of a clinical pharmacist or other expert; serum levels and creatinine clearance are monitored to guide dosing. (See "Dosing and administration of parenteral aminoglycosides".)

Comparative trials of antibiotic regimens have been few and small, often with design limitations, thus precluding strong recommendations regarding the preferred antibiotic regimen [83]. Some reasonable alternative IV antibiotic regimens are shown in the table (table 5).

Cesarean birth — In patients with chorioamnionitis who will undergo a cesarean birth, we suggest adding anaerobic coverage to the intrapartum regimen because anaerobes play a major role in postsurgical infections. The addition of anaerobic coverage may reduce the risk of developing such infections [74,83,84] and has been proven to reduce treatment failure in patients with endometritis [81].

Our preference is:

●Ampicillin 2 g IV every six hours plus

●Gentamicin 5 mg/kg IV once daily plus

●Either metronidazole 500 mg IV or clindamycin 900 mg IV every eight hours

The author also administers a single dose of azithromycin 500 mg IV, as this is part of his routine antibiotic prophylaxis for cesarean birth to provide broad spectrum coverage that includes ureaplasmas [85,86]. Although azithromycin is commonly used for antibiotic prophylaxis in patients undergoing cesarean birth during labor or after membrane rupture (table 6), evidence of effectiveness in the setting of patients with chorioamnionitis who are receiving other antibiotics remains to be established and requires study.

Penicillin allergy — Evidence-based data to guide the treatment of chorioamnionitis in patients with a penicillin allergy are lacking.

●At the author's institution, ampicillin is replaced with vancomycin:

•Gentamicin 5 mg/kg once daily plus vancomycin, typically 15 to 20 mg/kg IV every 8 to 12 hours for most patients with normal kidney function based on actual body weight, rounded to the nearest 250 mg increment. Dosing and monitoring for patients who require therapy for more than two to three days are described separately. (See "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults", section on 'Subsequent maintenance dose/interval'.)

●An acceptable alternative is:

•Gentamicin 5 mg/kg once daily plus clindamycin 900 mg IV every eight hours, except when group B Streptococcus coverage is needed. In these cases, clindamycin should only be used if clindamycin-inducible resistance testing is negative. (See "Prevention of early-onset group B streptococcal disease in neonates", section on 'Patients with penicillin allergy'.)

Fetal monitoring during labor — Continuous electronic fetal monitoring is the usual approach. Fetal compromise may develop due to sequelae of chorioamnionitis (villous edema, hyperthermic stress, fetal infection) or other factors. Fetal infection is not associated with a specific pattern of periodic fetal heart rate changes, except mild baseline tachycardia in some cases, which is a category II tracing. Management of category II tracings is reviewed separately. (See "Intrapartum category I, II, and III fetal heart rate tracings: Management".)

While there is no evidence suggesting that use of a scalp electrode increases the risk of neonatal sepsis in the setting of chorioamnionitis, it is prudent to limit its use to pregnancies in which an external device does not provide adequate information.

Antipyretics — Acetaminophen is typically administered to reduce fever. The combination of maternal fever and fetal acidosis conferred a 12.5 percent risk of neonatal encephalopathy (odds ratio [OR] 94, 95% CI 29-307) in one study, and each of these factors also appeared to have an independent effect (fever OR 8.1, 95% CI 3.5-18.6; neonatal acidosis OR 11.5, 95% CI 5.0-26.5) [87].

Antipyretic therapy may also avoid fever-related fetal tachycardia, which is useful since an abnormal fetal heart rate is a factor in decision-making regarding need for cesarean birth.

Postpartum care — Postpartum care is routine, except for additional doses of antibiotic therapy.

Duration of antibiotic therapy — The optimal duration of postpartum parenteral antibiotic therapy has not been determined conclusively. There is no evidence that oral antibiotics are beneficial after discontinuation of parenteral therapy [88].

●After a vaginal birth – Practice varies regarding use of postpartum antibiotics after vaginal birth. The author of this topic administers one additional dose of antibiotics (ampicillin plus gentamicin) after vaginal birth, whereas other experts (including the section editor of this topic) do not. The American College of Obstetricians and Gynecologists (ACOG) committee opinion on intraamniotic infection states that additional antibiotic doses are not required after vaginal birth [3]. The available clinical trials have not demonstrated a clear benefit of postpartum antibiotic therapy for patients with chorioamnionitis [83]. However, the trials had important limitations (small size, incomplete follow-up) and may have been underpowered to detect a meaningful difference. Thus, the author of the topic continues to provide a dose of postpartum antibiotic therapy to ensure adequate treatment of the infection.

●After a cesarean birth, the author of this topic administers additional postpartum doses of the intrapartum antibiotic regimen until the patient is afebrile and asymptomatic for at least 48 hours. However, administering only one additional dose of this regimen or continuing the regimen until the patient is afebrile and asymptomatic for at least 24 hours are reasonable alternatives (particularly for patients without obesity), given the low quality of available evidence. The author's approach is based on limited data that persistent fever in patients with chorioamnionitis is more common after cesarean birth (15 versus 1 percent after vaginal birth) and serious complications in patients with chorioamnionitis primarily occur after cesarean birth [89].

Maternal course — Chorioamnionitis usually resolves rapidly after delivery, particularly after vaginal birth. Patients with persistent fever and/or pelvic pain should be evaluated for endometritis, wound infection, and, rarely, septic pelvic thrombophlebitis. (See "Postpartum endometritis" and "Cesarean birth: Postoperative care, complications, and long-term sequelae", section on 'Wound complications' and "Septic pelvic thrombophlebitis".)

PERINATAL OUTCOME — Variations among studies in the criteria used for diagnosis of chorioamnionitis and assessment of perinatal outcome make it difficult to compare data across studies and draw conclusions.

Adverse effects — Chorioamnionitis is associated with a 2- to 3.5-fold increase in risk of adverse perinatal outcome [90]. Adverse outcomes include perinatal death, asphyxia, early-onset neonatal sepsis, septic shock, respiratory distress syndrome, pneumonia, meningitis, intraventricular hemorrhage (IVH), cerebral white matter damage, necrotizing enterocolitis, and bronchopulmonary dysplasia [90-93]. Among pregnancies with clinical chorioamnionitis, 6 percent of neonates have been diagnosed with early-onset neonatal sepsis [93]. Among newborns with early-onset neonatal sepsis, up to 40 percent have been associated with clinical chorioamnionitis [37].

A substantial proportion of adverse perinatal outcome is mediated by preterm birth. In one study, the comparative rates of complications for preterm versus term cases of chorioamnionitis were: perinatal death (25 versus 6 percent), neonatal sepsis (28 versus 6 percent), respiratory distress (62 versus 35 percent), pneumonia (20 versus 3 percent), and grade 3 or 4 IVH (24 versus 8 percent) [94].

Neurodevelopmental impairment — Some studies, but not all, report that chorioamnionitis is associated with potential long-term disabilities, such as neurodevelopmental delay and cerebral palsy. Although the relationship is largely mediated by preterm birth, these adverse outcomes have also been observed at or near term [95].

In a meta-analysis of the relationship between chorioamnionitis and cerebral palsy, significant associations were observed between cerebral palsy and both clinical chorioamnionitis (pooled odds ratio [OR] 2.42, 95% CI 1.52-3.84) and histologic chorioamnionitis (pooled OR 1.83, 95% CI 1.17-2.89) [95]. However, the analysis was limited by potential biases, such as differences in definitions and diagnostic criteria across studies, extent of blinding in determining exposure status, and whether the study controlled for potential confounders. A subsequent secondary analysis of data from 1574 newborns of patients at high risk for preterm birth <32 weeks enrolled in one clinical trial reported an association between neurocognitive deficits at two years of age and proven neonatal sepsis but not with clinical chorioamnionitis [96]. The mean gestational age of these infants at birth was 29 weeks. In a population-based cohort study of children born at 24 to 34 weeks of gestation after preterm labor or PPROM that included 124 children exposed to clinical chorioamnionitis and 2803 who were not exposed, chorioamnionitis was not associated with an increased risk for moderate to severe neurodevelopmental disorders (including cerebral palsy) at five years of age (8.2 versus 9.6 percent; adjusted OR [aOR] 0.9, 95% CI 0.5-1.8) [97]. The study was limited by the 40 percent loss to follow-up even though the authors assessed its impact statistically.

Fetal infection/inflammation is likely a more important predictor of neonatal outcome than isolated maternal, amniotic fluid, or amniochorion infection/inflammation [98]. The term systemic fetal inflammatory syndrome (also known as fetal inflammatory response syndrome) refers to the fetal immune response to intrauterine infection and the potential consequences of this response: preterm labor, fetal growth restriction, severe neonatal morbidity, brain injury, and development of chronic lung disease in the child [99-109]. Funisitis and chorionic vasculitis appear to be the placental histologic manifestations of fetal inflammatory response syndrome and markers for adverse outcome [108,110-112]. Laboratory findings include fetal plasma interleukin-6 concentration >11 pg/mL [99,113].

Neuroinflammation during the perinatal period can increase the risk of long-term neurologic and neuropsychiatric disease [114]. High fetal/neonatal levels of cytokines and chemokines, especially tumor necrosis factor [106], appear to mediate fetal/neonatal brain injury [101,104,106,115-117]. These inflammatory substances can cause cerebral ischemia and damage, ultimately leading to IVH and periventricular leukomalacia. Intervention, such as maternal treatment with an anti-inflammatory cytokine, to prevent these outcomes is one area of investigation [107,118].

Newborn evaluation and care — (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Evaluation and initial management'.)

PREVENTION — One strategy to prevent chorioamnionitis is administration of prophylactic antibiotics to patients with preterm prelabor rupture of membranes (PPROM), which reduces the incidence of clinical chorioamnionitis, prolongs latency, and improves neonatal outcomes. The evidence for this approach is reviewed separately (see "Preterm prelabor rupture of membranes: Management and outcome", section on 'Administer prophylactic antibiotic therapy'). For patients with term prelabor rupture of membranes (PROM), we prefer delivery, rather than expectant management plus antibiotic prophylaxis. (See "Prelabor rupture of membranes at term: Management", section on 'Antibiotic prophylaxis'.)

Attention to modifiable risk factors may also reduce the incidence of chorioamnionitis. Modifiable risk factors that pertain to the health care provider include use of a speculum rather than digital examinations in patients with PPROM, conduct of labor (eg, minimizing the number of vaginal examinations), and use of prophylactic antibiotics in patients with group B Streptococcus colonization (see 'Risk factors' above and "Prevention of early-onset group B streptococcal disease in neonates"). Modifiable risk factors that the patient can control include avoidance of tobacco and alcohol. (See 'Risk factors' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Group B streptococcal infection in pregnant women and neonates" and "Society guideline links: Labor".)

SUMMARY AND RECOMMENDATIONS

●Terminology – Clinical chorioamnionitis and intraamniotic infection are commonly used terms to describe infection of the fetal membranes. The infection also may involve the amniotic fluid, fetus, umbilical cord, decidua, and placenta. (See 'Terminology' above.)

●Microbiology and pathogenesis – Clinical chorioamnionitis is typically polymicrobial (table 2) and usually results from ascending migration of cervicovaginal flora. Other sources include transplacental infection from microorganisms in maternal blood in the intervillous space and microbial contamination from transmyometrial or transcervical procedures. (See 'Microbiology' above and 'Pathogenesis' above.)

●Clinical manifestations – Clinical chorioamnionitis usually occurs in pregnancies with prelabor rupture of membranes (PROM) or preterm labor with intact membranes. The key clinical findings and their approximate frequencies are:

•Fever (100 percent)

•Maternal leukocytosis (white blood cell [WBC] count >15,000/mm³: 70 to 90 percent)

•Maternal tachycardia (>100 beats per minute [bpm]: 50 to 80 percent)

•Fetal tachycardia (>160 bpm: 40 to 70 percent)

•Uterine tenderness (4 to 25 percent)

•Bacteremia (5 to 10 percent)

•Purulent or malodorous amniotic fluid

●Diagnosis – Criteria for presumptive and confirmed diagnosis of chorioamnionitis are shown in the table (table 1). (See 'Diagnosis' above.)

●Role of amniocentesis – In the vast majority of patients, a presumptive diagnosis of clinical chorioamnionitis is adequate for initiating maternal therapy, without the need for amniocentesis. However, when the presumptive diagnosis is uncertain because typical clinical findings (eg, maternal fever) are absent or findings overlap with other disorders, evaluation of amniotic fluid can confirm or exclude intraamniotic infection. Amniotic fluid culture is the "gold standard" and the most specific test for documentation of intraamniotic infection but utility is limited because it take days to obtain definitive results. Results from Gram stain, glucose concentration, WBC concentration, and leukocyte esterase level can be used but have relatively low sensitivity and specificity for a positive amniotic fluid culture (table 4). (See 'When to perform amniocentesis to test amniotic fluid' above.)

●Treatment

•Initiate delivery – Clinical chorioamnionitis cannot be cured medically without delivery; therefore, patients who are not in labor are promptly induced, unless a standard indication for cesarean birth exists. In patients receiving antibiotics, there is no evidence that the duration of labor correlates with adverse neonatal outcome; therefore, cesarean birth is not indicated to shorten labor duration. (See 'Initiate delivery' above.)

•Intrapartum antibiotic regimen – Broad spectrum antibiotics should be started as soon as a presumptive diagnosis is made and continued through delivery to minimize maternal and fetal morbidity (table 5). We suggest ampicillin plus gentamicin rather than other regimens (Grade 2C). For patients undergoing cesarean birth, we suggest adding clindamycin or metronidazole to this regimen preoperatively (Grade 2C), given the increased risk of postsurgical anaerobic infection in this setting. Some experts (including the author of this topic) also provide a single dose of azithromycin before a cesarean birth, whereas other experts (including the section editor) do not. (See 'Intrapartum regimen' above.)

Substitutions are needed for penicillin-allergic patients. (See 'Penicillin allergy' above.)

•Duration of antibiotic therapy

-After vaginal birth, practice varies regarding use of postpartum antibiotics. Acceptable options are to either discontinue antibiotics or provide one additional dose of antibiotics (ampicillin plus gentamicin). (See 'Postpartum care' above.)

-After cesarean birth, postpartum antibiotics (ampicillin plus gentamicin plus clindamycin or metronidazole but not azithromycin) are usually continued for 24 to 48 hours. Some experts (including the author of this topic) continue antibiotic therapy until the patient is afebrile and asymptomatic for at least 48 hours; other experts (including the section editor) discontinue antibiotics after 24 hours if the patient is afebrile. (See 'Postpartum care' above.)

●Sequelae

•Maternal – In addition to maternal infectious complications (eg, postpartum endometritis, sepsis), clinical chorioamnionitis may impair myometrial contractility, which can result in labor abnormalities, need for cesarean birth, uterine atony, and postpartum hemorrhage. Cesarean birth in the presence of clinical chorioamnionitis increases the risk of wound infection, endomyometritis, septic pelvic thrombophlebitis, and pelvic abscess. (See 'Maternal course' above.)

•Neonatal – Adverse neonatal outcomes associated with clinical chorioamnionitis include perinatal death, asphyxia, early-onset neonatal sepsis, septic shock, respiratory distress syndrome, pneumonia, meningitis, intraventricular hemorrhage (IVH), necrotizing enterocolitis, and bronchopulmonary dysplasia. Potential long-term disabilities include neurodevelopmental delay and cerebral palsy. Preterm birth mediates a substantial proportion of these outcomes. (See 'Perinatal outcome' above.)

●Prevention – The main strategy to prevent clinical chorioamnionitis is administration of prophylactic antibiotics to patients with preterm prelabor rupture of membranes (PPROM). Other strategies include use of a speculum rather than digital examinations in patients with PPROM, minimizing the number of intrapartum vaginal examinations (particularly after membrane rupture), and use of prophylactic intrapartum antibiotics in patients with group B Streptococcus colonization. (See 'Prevention' above.)