Intraamniotic infection (clinical chorioamnionitis)

INTRODUCTION — Clinical chorioamnionitis or intraamniotic infection (IAI) is a disorder characterized by acute inflammation of the membranes and fetal portion (chorion) of the placenta, typically due to polymicrobial bacterial infection in patients whose membranes have ruptured. It is a common complication of pregnancy associated with potentially serious adverse maternal, fetal, and neonatal effects, as well as increased long-term risks for cerebral palsy and other neurodevelopmental disabilities. Treatment includes both antibiotic therapy and delivery of the infected products of conception.

This topic will discuss clinical manifestations, diagnosis, and treatment of IAI. Prevention of IAI in patients with preterm prelabor rupture of membranes (PPROM) is reviewed separately. (See "Preterm prelabor rupture of membranes: Management and outcome".)

TERMINOLOGY — Historically, infection of the chorion, amnion, or both was termed "chorioamnionitis." Although this term remains in common use, the term "intraamniotic infection" (IAI) is also commonly used since infection often involves the amniotic fluid, fetus, umbilical cord, or placenta in addition to the fetal membranes. Adding to the complexity, 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.

In 2015, a National Institute of Child Health and Human Development Workshop expert panel recommended use of the term "triple I" to address the heterogeneity of this disorder (table 1) [1]. The term triple I refers to intrauterine infection or inflammation or both and is defined by strict diagnostic criteria (see 'Diagnostic criteria' below), but this terminology has not been commonly adopted although the criteria are used [2,3].

PATHOGENESIS

●Migration of flora into the amniotic cavity leads to infection of the fetal membranes, amniotic fluid, placenta, and/or decidua:

•Ascension of cervicovaginal flora through the cervical canal is the most common pathway to IAI.

•Uncommonly, the pathway is hematogenous as a result of maternal bacteremia (eg, Listeria monocytogenes) infecting the intervillous space or from contamination of the amniotic cavity as a result of an invasive procedure (eg, fetoscopy).

•Infection from the peritoneum via the fallopian tubes has also been postulated, but is likely rare [4].

●Local host factors likely play a role in facilitating or preventing infection:

•The cervical mucus plug, membranes, and placenta provide barriers to ascending and transplacental infection

•Rupture of membranes removes barriers.

•In addition to their barrier function, there is evidence that the fetal membranes have antimicrobial activity [5,6]. Cells within fetal membranes appear to mediate innate immune responses through activation of toll-like receptors, key modulators of the innate immune response that recognize components of bacteria and viruses [7,8].

•Peroxide-producing lactobacilli in the vagina may induce changes in the flora that impair the virulence of pathogenic organisms.

●Bacterial infection activates the maternal and fetal inflammatory response systems and generally leads to labor and/or prelabor rupture of membranes. (See "Spontaneous preterm birth: Pathogenesis".)

MICROBIOLOGY — IAI is typically polymicrobial, often involving vaginal or enteric flora (table 2 and table 3). Two-thirds of patients with IAI have at least two isolates per specimen of amniotic fluid. By comparison, transplacental infection from organisms in the maternal circulation (eg, L. monocytogenes, Staphylococcus aureus) are more likely to be due to a single pathogen.

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 [9,10]. Because they are highly prevalent (>70 percent) in the lower genital tract, some authorities attribute their isolation from patients with IAI to contamination or colonization from the lower genital tract rather than a true infection. However, as data accrue, there is increasing support for their pathogenicity, including induction of a robust inflammatory response with clinical consequences for both mother and neonate [9-12].

Other pathogens frequently associated with IAI include anaerobes (including Gardnerella vaginalis, Bacteroides spp), enteric gram-negative bacilli, and group B Streptococcus. Anaerobes appear to be more frequently involved in preterm IAI than in term IAI [13].

INCIDENCE — A systematic review evaluating the global incidence of maternal peripartum infection estimated that clinical chorioamnionitis occurred in 3.9 percent of all patients giving birth and was the most common peripartum infection [14]. The reported incidence of IAI in the United States varies widely among individual studies [15]. 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 [16-18].

The incidence also varies between preterm and term pregnancies. Among pregnancies that deliver preterm because of preterm labor or preterm prelabor rupture of membranes (PPROM), the incidence ranges from 40 to 70 percent [19]. Among patients at term, clinical chorioamnionitis has been diagnosed in approximately 1 to 3 percent of pregnancies with intact membranes [20] and 6 to 10 percent of those with PROM [21].

RISK FACTORS — Longer length of labor and duration of ruptured membranes appears to be the most important risk factors for IAI. Several other obstetric factors have been associated with an increased risk, including [17,21-31]:

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

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

●Cervical insufficiency

●Internal fetal or uterine contraction monitoring

●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 IAI

CLINICAL FINDINGS

Presentation — IAI 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 frequencies are as follows [32,33]:

●Fever (100 percent).

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

●Maternal tachycardia >100/min (50 to 80 percent).

●Fetal tachycardia >160/min (40 to 70 percent).

●Uterine tenderness (4 to 25 percent).

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

●Purulent or malodorous amniotic fluid.

IAI may be subclinical, which by definition does not present with the above clinical findings. Subclinical infection may manifest as preterm labor with intact membranes or as preterm prelabor rupture of membranes (PPROM). Computerized analysis of the fetal heart rate may show reduced variability [34,35].

Potential maternal sequelae

●Dysfunctional labor – IAI is associated with an increased risk of labor abnormalities, which increase the risk for cesarean birth, uterine atony, postpartum bleeding, and need for blood transfusion [36-38]. 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) [39-43]. The pathophysiologic mechanisms for labor abnormalities related to IAI are poorly understood and often complicated by other factors (eg, epidural anesthesia), but the link between IAI and both labor abnormalities and postpartum bleeding suggests dysfunctional myometrial contractility due to inflammation [36-38,44].

●Localized postpartum infection – Patients with IAI who undergo cesarean birth, which is common, are at increased risk for wound infection, endomyometritis, septic pelvic thrombophlebitis, and pelvic abscess [36,45,46].

●Sepsis – Population-based studies have reported that approximately 15 to 20 percent of maternal sepsis was associated with chorioamnionitis and that chorioamnionitis increased the odds of sepsis 8- to 12-fold [47,48].

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

In a review of a database including 364 patients with IAI, 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 4) [49]. Obtaining a lactate level can be helpful since an elevated level (eg, >2 mmol/L or greater than the laboratory upper limit of normal) can be a sign of sepsis and is associated with an adverse maternal outcome. In septic patients, an elevated serum lactate level correlates with the severity of sepsis and is used to follow the therapeutic response. (See "Evaluation and management of suspected sepsis and septic shock in adults".)

Histology — The maternal immune response to IAI leads to neutrophilic inflammation of the chorioamnion (chorioamnionitis); the fetal immune response leads to neutrophilic inflammation of the umbilical cord (funisitis) and/or fetal vessels in the chorionic plate (chorionic vasculitis). Chorioamnionitis is more common than funisitis: Chorioamnionitis is observed in almost 100 percent of cases of funisitis, while funisitis is observed in up to 60 percent of cases of chorioamnionitis [50]. 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).

Another reason for negative cultures is that cultures for fastidious organisms such as genital mycoplasmas, the most common organisms associated with chorioamnionitis, are not sensitive. Antibiotic therapy prior to delivery could also play a role.

In one study, histologic and bacteriologic results were concordant in approximately 70 percent of the 376 examined placentas [51]. 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 [52].

LABORATORY EVALUATION

All patients — A complete blood count is obtained in all patients.

Testing for infections other than chorioamnionitis, such as pyelonephritis or respiratory infection, is performed if the diagnosis of IAI versus another cause of fever and leukocytosis is uncertain.

We do not obtain blood cultures in patients with IAI except in rare atypical cases, such as maternal sepsis. (See "Detection of bacteremia: Blood cultures and other diagnostic tests", section on 'Indications for blood cultures'.)

Measurement of C-reactive protein (CRP) in maternal serum is not part of the laboratory evaluation. Meta-analyses concluded that an elevated maternal CRP level did not appear to be useful for early diagnosis of IAI or predicting neonatal sepsis but was moderately predictive of histologic chorioamnionitis [53,54]. Available studies were very heterogeneous, with a wide range for sensitivity and specificity of CRP at various thresholds.

When to perform amniocentesis to test amniotic fluid — In most patients, a presumptive diagnosis of IAI is adequate for initiating maternal therapy (see 'Diagnosis' below). However, when the presumptive diagnosis of IAI is uncertain because of absence of typical clinical findings (eg, maternal fever) or overlap with other disorders (eg, pyelonephritis), evaluation of amniotic fluid can confirm or exclude the diagnosis of IAI. Amniocentesis for amniotic fluid is particularly useful in preterm gestations because an incorrect diagnosis of IAI leading to unnecessary delivery could result in significant morbidity in offspring.

Culture of amniotic fluid remains the "gold standard" and the most specific test for documentation of IAI but is limited by the fact that it may 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 and even lower ability to predict neonatal sepsis [55,56].

●Gram stain is performed on an unspun specimen of amniotic fluid; centrifugation does not significantly improve the sensitivity of the technique. 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 as the amniotic fluid is sterile in uncomplicated pregnancies with intact membranes [57]. In an individual patient-level meta-analysis based on two studies [58,59] with a total of 288 individuals with preterm labor and intact membranes (11.8 percent of whom had culture-confirmed IAI), sensitivity and specificity of positive Gram stain were 65 and 99 percent, respectively [60].

●Glucose concentration is measured with an autoanalyzer. In the individual patient-level meta-analysis discussed above, sensitivity and specificity of glucose ≤14 mg/dL were 85 and 87 percent, respectively [60]. A combination of positive Gram stain or glucose ≤14 mg/dL afforded a sensitivity of 88 percent and specificity of 87 percent; thus this was not much different from a low glucose level alone.

●WBC concentration can be determined using a Coulter counter (abnormal result >30 cells/mm³). In a study of 120 patients with preterm labor and intact membranes, sensitivity was 64 percent and specificity was 95 percent [58].

●Leukocyte esterase activity can be evaluated with a urine dipstick reagent strip (eg, Chemstrip 9 Reagent Strips, an abnormal result is trace or greater). Sensitivity ranges from 85 to 91 percent; specificity ranges from 95 to 100 percent [61,62].

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 IAI is relatively low (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 delivery of an immature fetus. 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) [63].

Some clinicians perform amniocentesis to exclude subclinical IAI 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) [64]. 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 IAI (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 [65], whether patients with preterm labor 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'.)

Tests used in research studies

●Interleukin (IL) 6 – A high level of IL-6 in cervicovaginal fluid appears to be predictive of microbial invasion of the amniotic cavity in patients with preterm labor and intact membranes [66]. Elevated cytokine levels (eg, IL-6, matrix metalloproteinase [67,68]) in amniotic fluid and fetal blood are associated with infection, preterm birth, and systemic fetal inflammatory syndrome [19,55].

Evidence of IAI by elevated IL-6 may be a more important prognostic factor for adverse outcomes than a positive amniotic fluid culture alone, which may represent only colonization. In a study of 305 patients with preterm labor and intact membranes, median latency was similar in pregnancies with and without positive microbial culture [69]. Pregnancies with and without positive microbial culture and IL-6 levels <2.6 ng/mL had longer median latency (23 to 25 days) compared with pregnancies with or without positive microbial culture but IL-6 >11.3 ng/mL (latency <1 to 2 days) [69]. Regardless of microbial culture results, composite perinatal morbidity/mortality rates were lower in pregnancies with IL-6 levels <2.6 ng/mL (morbidity/mortality 21 to 25 percent) than in pregnancies with IL-6 levels >11.3 ng/mL (morbidity/mortality 72 to 81 percent).

The technical complexity of the assays, lack of standards across laboratories, and limited data on test characteristics currently restrict this testing to research settings in the United States. However, a rapid test has become available in some countries and provides results within 20 minutes [70]. Preliminary assessments suggest sensitivity and specificity for intraamniotic inflammation as high as 93 to 97 and 91 to 96 percent, respectively, in preterm pregnancies with ruptured or intact membranes [71,72].

●Proteomic biomarkers – Proteomic biomarkers in the amniotic fluid and maternal serum are under investigation in an attempt to identify unique proteins diagnostic of IAI [73-77].

DIAGNOSIS

Diagnostic criteria — The diagnosis of IAI 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 have been suggested by a National Institute of Child Health and Human Development Workshop expert panel (table 1) and endorsed by the American College of Obstetricians and Gynecologists (ACOG) [3].

A presumptive diagnosis of IAI (suspected triple I) 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 two or more measurements 30 minutes apart without another clear source PLUS one or more of the following [1]:

•Baseline fetal heart rate >160 beats/min 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.

For treatment purposes, ACOG suggests that patients with isolated fever ≥39.0°C (102.2°F) without another clear source should be managed as having suspected IAI, as they are at high risk of an adverse clinical infectious outcome [78].

The National Institute of Child Health and Human Development criteria de-emphasized use of maternal tachycardia (heart rate >100 beats per minute) and fundal tenderness for clinical diagnosis, which had been used the past.

The presumptive diagnosis of IAI in febrile laboring patients is strengthened by the presence of risk factors for the disease, especially ruptured membranes, and by excluding other potential sources of fever. (See "Intrapartum fever".)

A confirmed diagnosis of IAI can be made in pregnant/postpartum patients with:

●All of the above criteria for suspected IAI PLUS one or more of the following objective laboratory findings [1] (see 'When to perform amniocentesis to test amniotic fluid' above):

•Positive Gram stain of amniotic fluid.

•Low glucose level in amniotic fluid.

•Positive amniotic fluid culture.

•High WBC count 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. Histopathology is obtained after delivery.

The rationale for these criteria is that the temperature and fetal heart rate criteria 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).

Differential diagnosis — Most of the clinical findings associated with IAI are nonspecific (see 'Presentation' above). For example, isolated intrapartum fever can be related to dehydration, use of prostaglandins for cervical ripening/labor induction, or epidural anesthesia (see "Induction of labor: Techniques for preinduction cervical ripening", section on 'Side effects' and "Intrapartum fever", section on 'Use of neuraxial anesthesia'). Maternal tachycardia during labor may be physiologic or related to pain, epidural anesthesia, or medications. Maternal leukocytosis occurs with both labor and antenatal corticosteroid therapy, as well as infections other than IAI. Fetal tachycardia can be related to fetal hypoxemia, maternal fever of any etiology, or transplacental passage of some maternal medications.

Differential diagnosis of patients who present with clinical findings suggestive of IAI includes, but is not limited to:

●Labor – Labor can be associated with fever (if the patient has an epidural anesthetic), maternal tachycardia, leukocytosis, and uterine tenderness.

Diagnosis of clinical IAI is difficult in laboring patients with epidural anesthesia because fever is common in this setting and may be related to the anesthetic itself. In addition, epidural anesthesia masks uterine tenderness and may induce maternal or fetal tachycardia. Lastly, prolonged labor is a risk factor for both requesting epidural anesthesia and developing IAI. No specific temperature threshold has been found to reliably distinguish IAI from epidural-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 and abdominal pain (with or without labor) include pyelonephritis, influenza, appendicitis, pneumonia, and COVID-19. These infections can cause maternal tachycardia and leukocytosis and fetal tachycardia; however, they can usually be differentiated from IAI 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

Delivery — Patients with IAI (including suspected or confirmed "triple I" (table 1)) should be given antibiotics and delivered. Antimicrobial therapy can provide 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, but IAI can only be cured by delivery of the infected products of conception. The lack of efficacy of antibiotics alone may be because amniotic fluid bacteria can form biofilms, which are resistant to antibiotic treatment [15].

We suggest prompt induction or augmentation of labor, as appropriate, with cesarean birth reserved for standard obstetric indications. In patients receiving antibiotics, there is no evidence that the duration of labor correlates with adverse neonatal outcome [36,79]; therefore, cesarean birth is not indicated to shorten labor duration. Furthermore, cesarean birth in the presence of IAI increases the risk of wound infection, endomyometritis, and venous thrombosis [46].

Histopathologic evaluation of the placenta is recommended in the setting of IAI. We do not typically obtain cultures of the placenta, but cultures may be obtained by the pathologist in selected cases when specific infections, such as listeriosis or candida, are suspected.

Antibiotic therapy — Broad spectrum antibiotics should be administered promptly following a diagnosis of IAI to initiate treatment of both the mother and fetus. We administer antibiotics to patients with a presumptive diagnosis of IAI even if epidural-related fever cannot be excluded, as early initiation of antibiotic therapy may reduce the frequency and severity of neonatal infection [80-82].

Intrapartum regimen — Administration of broad spectrum parenteral antibiotics with coverage for common pathogens (eg, cervicovaginal flora) is the preferred therapy of both IAI and postpartum endometritis. Our preference is:

●Ampicillin 2 g intravenously every six hours plus

●Gentamicin 5 mg/kg intravenously once daily

A single daily gentamicin dose is equally or more effective and more convenient than thrice-daily dosing and safe when used intrapartum or postpartum [83,84]. 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) [85]. Routine monitoring of gentamicin levels is unnecessary for patients who are healthy except for IAI. For patients with renal insufficiency, 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".)

Penicillin-allergic patients are discussed below. (See 'Penicillin-allergic patients' below.)

Alternatives — Some reasonable alternative intravenous antibiotic regimens include:

●Ampicillin 2 g every six hours plus gentamicin 1.5 mg/kg every eight hours for patients with normal renal function. Some centers use a gentamicin load (eg, 2 mg/kg) with thrice-daily dosing, but objective data to support its superiority are lacking.

●Ampicillin-sulbactam 3 g every six hours.

●Ticarcillin-clavulanate 3.1 g every four hours (limited availability).

●Cefoxitin 2 g every 8 hours.

●Cefotetan 2 g every 12 hours.

●Piperacillin-tazobactam 3.375 g every 6 hours or 4.5 g every 8 hours.

●Ertapenem 1 g every 24 hours.

Comparative trials of antibiotic regimens have been few and small, often with design limitations, thus precluding strong recommendations regarding the preferred antibiotic regimen [86].

Cesarean birth — In patients with IAI undergoing cesarean birth, anaerobic coverage should be added to the intrapartum regimen because anaerobes play a major role in complications associated with postcesarean endometritis. The addition of anaerobic coverage has reduced failure rates of postcesarean endometritis. Our preference is [84]:

●Ampicillin 2 g intravenously every six hours plus

●Gentamicin 5 mg/kg intravenously once daily plus

●Either metronidazole 500 mg orally or intravenously or clindamycin 900 mg intravenously every eight hours

The author also administers a single dose of azithromycin 500 mg intravenously, as this is part of his routine antibiotic prophylaxis for cesarean birth [87,88]. Although azithromycin is commonly used for antibiotic prophylaxis in patients undergoing cesarean birth during labor or after membrane rupture (table 5), evidence of effectiveness in the setting of IAI remains to be established.

Penicillin-allergic patients are discussed below. (See 'Penicillin-allergic patients' below.)

Postpartum treatment — The optimal duration of antibiotic therapy after delivery has not been determined conclusively.

●Vaginal birth – The author administers one additional dose of antibiotics after vaginal birth, but discontinuing antibiotics is a reasonable alternative, given the low quality of available evidence.

●Cesarean birth – The author administers additional postpartum doses of the antibiotic regimen that was described above for patients undergoing cesarean birth (ampicillin, gentamicin, plus either clindamycin or metronidazole) 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.

These approaches are based on data from a few small randomized trials and observational studies of patients treated for chorioamnionitis before birth that compared the outcomes of those treated with no or one postpartum dose of antibiotics with the outcomes of those who received multiple postpartum antibiotic doses [80,89]. In these trials, administration of multiple doses of antibiotics was not associated with a significant reduction in treatment failure (usually defined as persistent fever) compared with less intensive therapy.

Some clinicians continue the administration of antibiotics after birth in all patients until they are afebrile and asymptomatic for at least 24 hours. This is a reasonable alternative approach, given the small number of subjects and postpartum febrile events in the available studies and differences among the studies in patient characteristics and treatment regimens. In one retrospective study, patients most likely to benefit from this approach were those who underwent cesarean birth since they had a higher prevalence of persistent fever after delivery (15 versus 1 percent after vaginal birth) [89].

The American College of Obstetricians and Gynecologists (ACOG) committee opinion on IAI states that additional antibiotic doses are not required after vaginal birth and at least one additional dose is indicated after cesarean birth [3].

There is no evidence that oral antibiotics are beneficial after discontinuation of parenteral therapy [90].

Treatment of patients with postpartum endometritis is discussed separately. (See "Postpartum endometritis".)

Group B Streptococcus-positive patients — Patients receiving intrapartum penicillin G for group B Streptococcus (GBS) prophylaxis need broader antibiotic coverage if they develop IAI. An appropriate option is ampicillin and gentamicin.

Penicillin-allergic patients — Evidence-based data to guide the treatment of IAI in penicillin-allergic patients are lacking (see "Penicillin allergy: Immediate reactions"). At our institution, we substitute vancomycin for ampicillin (ie, gentamicin 5 mg/kg once daily plus vancomycin, typically 15 to 20 mg/kg every 8 to 12 hours for most patients with normal renal 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'.)

Gentamicin 5 mg/kg once daily plus clindamycin 900 mg intravenously every 8 hours is an acceptable alternative, unless GBS coverage is indicated. 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 — Use of continuous electronic fetal monitoring is appropriate in these patients to detect development of fetal compromise due to sequelae of IAI (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 IAI, it is prudent to limit use of an internal device 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) [91].

This observation supports the use of antipyretics in patients with IAI. Reduction of intrapartum fever with antipyretics may also reduce fetal tachycardia, thereby avoiding the tendency to perform a cesarean birth because of an abnormal fetal heart rate pattern.

Postpartum care — Postpartum care is routine as IAI resolves rapidly after delivery in most patients, particularly after vaginal birth. Patients with persistent fever and/or pelvic pain should be evaluated for postpartum 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".)

FETAL AND NEONATAL OUTCOME

Adverse effects of intraamniotic infection — Exposure to IAI increases the risk of adverse outcome by 2- to 3.5-fold, independent of the duration of infection [92]. Adverse fetal/neonatal outcomes include perinatal death, asphyxia, early-onset neonatal sepsis, septic shock, pneumonia, meningitis, intraventricular hemorrhage (IVH), cerebral white matter damage, and long-term disability including cerebral palsy, as well as morbidity related to preterm birth [93-98]. Among pregnancies with clinical chorioamnionitis, 6 percent of neonates have been diagnosed with early-onset neonatal sepsis [99]. Among newborns with early-onset neonatal sepsis, up to 40 percent have been associated with clinical chorioamnionitis [33].

Preterm infants appear to have a higher rate of short-term complications from IAI than term infants; in one study the comparative rates of complications were: perinatal death (25 versus 6 percent in preterm and term infants), neonatal sepsis (28 versus 6 percent), pneumonia (20 versus 3 percent), grade 3 or 4 IVH (24 versus 8 percent), and respiratory distress (62 versus 35 percent) [95].

There is some evidence that fetal exposure to inflammation can induce interleukin (IL) 1 production, which enhances surfactant protein and lipid synthesis thereby promoting lung maturation; however, adverse effects on fetal lung development and outcome can also occur [100-102]. These adverse effects include structural changes and alterations in growth factor expression and the immune system and possibly an increased risk for bronchopulmonary dysplasia.

Neurodevelopmental impairment — Neurodevelopmental impairment associated with IAI may involve multiple factors, including asphyxia and toxic injury by bacterial products. Most studies have found that neurodevelopmental delay and cerebral palsy are potential long-term disabilities resulting from IAI, and the relationship is mediated in large part by preterm birth [103-106]. However, the relationship is also observed at or near term [107]. In a meta-analysis of the relationship between chorioamnionitis and cerebral palsy, there were significant associations 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) [107]. However, this analysis was limited by many potential biases, such as differences in the definitions 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 [108]. The mean gestational age of these infants at birth was 29+3 weeks.

Fetal infection/inflammation is likely a more important predictor of neonatal outcome than isolated maternal, amniotic fluid, or amniochorion infection/inflammation [103]. 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 [109-119]. Funisitis and chorionic vasculitis appear to be the placental histologic manifestations of fetal inflammatory response syndrome and markers for adverse outcome [118,120-122]. Laboratory findings include fetal plasma IL-6 concentration IL-6 >11 pg/mL [109,123].

Neuroinflammation during the perinatal period can increase the risk of long-term neurologic and neuropsychiatric disease [124]. High fetal/neonatal levels of cytokines and chemokines, especially tumor necrosis factor [116], appear to mediate fetal/neonatal brain injury [111,114,116,125-127]. These inflammatory substances can cause cerebral ischemia and damage, ultimately leading to intraventricular hemorrhage and periventricular leukomalacia. Intervention to prevent these outcomes is an active area of investigation. As an example, in a pilot study in rodents, intrapartum maternal treatment with an anti-inflammatory cytokine (eg, IL-10) prevented severe white matter damage in the pups of mothers with intrauterine infection [117,128].

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

PREVENTION — The main strategy to prevent IAI 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 term PROM, we prefer delivery to expectant management with 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 IAI. 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 – Intraamniotic infection (IAI; also called chorioamnionitis) refers to infection of the amniotic fluid, membranes, placenta, and/or umbilical cord. It may be subgrouped as clinical (overt) or subclinical infection, or as histologic chorioamnionitis (which may be noninfectious). (See 'Introduction' above and 'Histology' above.)

●Microbiology and pathogenesis – IAI is typically polymicrobial (table 3 and table 2) and usually results from migration of cervicovaginal flora through the cervical canal in patients with ruptured membranes. Other causes include transplacental infection associated with bacteremia and bacterial contamination during invasive procedures. (See 'Microbiology' above and 'Pathogenesis' above.)

●Clinical manifestations and diagnosis – Criteria for maternal fever, a presumptive diagnosis of IAI (suspected IAI), and a confirmed diagnosis of IAI are shown in the table (table 1). (See 'Diagnosis' above.)

The use of maternal tachycardia and fundal tenderness for clinical diagnosis is deemphasized because these findings are nonspecific and tenderness can be masked by neuraxial anesthesia.

●Treatment

•IAI cannot be cured medically without delivery. We suggest prompt induction or augmentation of labor, as appropriate, with cesarean birth reserved for standard obstetric indications (Grade 2C). Immediate (cesarean) birth in the presence of reassuring intrapartum fetal testing and adequate progress of labor does not improve neonatal or maternal outcome provided that antibiotics are being administered. (See 'Delivery' above.)

•Broad spectrum antibiotics should be started as soon as a presumed diagnosis is made and continued through delivery to minimize maternal and fetal morbidity. Our preference is ampicillin 2 g intravenously every six hours plus gentamicin 5 mg/kg once daily. In patients undergoing cesarean birth, clindamycin 900 mg or metronidazole 500 mg intravenously is added to this regimen preoperatively to reduce postsurgical infections related to anaerobes. (See 'Intrapartum regimen' above.)

-After vaginal birth, the author administers one additional dose of antibiotics, but discontinuing antibiotics is a reasonable alternative. (See 'Postpartum treatment' above.)

-After cesarean birth, the author administers the antibiotic regimen until the patient is afebrile and asymptomatic for at least 48 hours; a minimum of at least one additional dose postpartum is a reasonable alternative (particularly for nonobese patients). (See 'Postpartum treatment' above.)

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

●Sequelae

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

•Neonatal – Adverse neonatal outcomes associated with IAI include perinatal death, asphyxia, early-onset neonatal sepsis, septic shock, pneumonia, meningitis, intraventricular hemorrhage, cerebral white matter damage, and long-term neurodevelopmental disability including cerebral palsy, as well as morbidity related to preterm birth. (See 'Fetal and neonatal outcome' above.)

●Prevention – The main strategy to prevent IAI 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.)