Intraamniotic infection (IAI) or chorioamnionitis is described as acute infection and inflammation involving the chorion and amnion layer of the fetal membranes, amniotic fluid, and/or placental decidua.1 New terminology proposed by an expert panel in 2015 replaced IAI or chorioamnionitis with the phrase intrauterine infection, inflammation, or both (triple I) to reflect the heterogeneity of the condition.2,3 However, the American College of Obstetricians and Gynecologists still recommends the use of IAI as the term for this disorder.1 IAI may lead to serious maternal complications such as sepsis, prolonged labor, wound infection, need for hysterectomy, postpartum endometritis, postpartum hemorrhage, adult respiratory distress syndrome, intensive care unit admission, and, in rare instances, maternal death. IAI complicates 40%–70% of preterm births and 1%–13% of term births with preterm premature rupture of membranes or spontaneous labor.4 This article focuses on the clinical diagnosis and management of IAI.
Causes and risk factors
Figure 1 shows the ascending IAI. IAI develops as a result of ascending infections from the lower genital tract, most often in the setting of ruptured membranes. The infection is polymicrobial and involves vaginal or enteric flora, including anaerobes, enteric gram-negative bacilli, and group B streptococcus. The infection is rarely due to hematogenous, transplacental spreading of maternal bacteremia (eg, Listeria monocytogenes) or an invasive diagnostic procedure such as amniocentesis.5 The risk factors include alcohol use; amnioinfusion; bacterial vaginosis; epidural anesthesia; group B streptococcus colonization; high body mass index (obesity); immunocompromised state; long labor hours; long second-stage labor hours; meconium-stained amniotic fluid; high number of cervical examinations; high number of digital vaginal examinations (especially with ruptured membranes); nulliparity; periodontal disease; prolonged membrane rupture; prolonged labor; cigarette smoking; sexually transmitted infections; invasive vaginal procedures such as fetal scalp electrodes or intrauterine pressure catheters; induction with a single-balloon catheter; and twin pregnancies with preterm labor and intact membranes.6 In patients with cervical insufficiency and IAI, administration of antibiotics is followed by resolution of the intraamniotic inflammatory process or IAI in 75% of patients and has been associated with treatment success in approximately 60% of cases.5,7–10
Chorioamnionitis is mainly due to ascending polymicrobial bacterial infections. The organisms frequently found within the amniotic cavity are those normally present in the lower genital tract. We have reviewed and summed up the reported organisms collected by using transabdominal amniocentesis.6,11–23Figure 2 shows the organisms isolated from the amniotic fluid or placenta culture in patients with chorioamnionitis.
Fetal listeriosis has a high mortality rate of 25%–35%, depending on the gestational age at the time of infection. Neonatal listeriosis may present as sepsis or meningitis with severe sequelae and a high case fatality rate of 20%.38 Mylonakis et al. reviewed 160 cases of maternal listeriosis infection and found that 20% of them were placenta or amniotic fluid infections, and 43% of cases were bloodstream infections. 39
The fetal inflammatory response syndrome (FIRS)
Microbial invasion of the amniotic cavity can progress to fetal invasion. Once microorganisms gain access to the fetal mucosa, they are recognized by pattern recognition receptors such as Toll-like receptors, and ligation of such receptors can induce a localized and subsequently systemic inflammatory response, FIRS, which is defined as an elevated fetal plasma concentration of interleukin-6. The major consequences of FIRS include: (1) a short interval-to-delivery; (2) high neonatal morbidity after adjustment for gestational age at birth; (3) multiple organ function involvement that includes the hematopoietic system, immune system, thymus, heart, adrenal glands, skin, lung, brain, kidney, and gut.5,40
Complications and prognosis
The complications of IAI include maternal, fetal and neonatal complications. Maternal complications include: (1) preterm labor or birth; (2) preterm premature rupture of membranes; (3) bacteremia and sepsis; (4) dysfunctional labor resulting in cesarean section delivery; (5) blood transfusion; (6) increased cesarean delivery risk; (7) postpartum hemorrhage; (8) postpartum infection; (9) rare complications, including sepsis, septic shock, disseminated intravascular coagulation, multiple organ dysfunction syndrome, and death. Fetal and neonatal complications include: (1) asphyxia; (2) bronchopulmonary dysplasia; (3) cerebral white matter damage; (4) neurodevelopmental delay; (5) cerebral palsy; (6) neonatal early onset sepsis; (7) FIRS; (8) interventricular hemorrhage; (9) long-term neurodevelopmental delay; (10) late-onset sepsis; (11) morbidity related to preterm birth; (12) necrotizing enterocolitis; (13) peri-intraventricular hemorrhage; (14) periventricular leukomalacia; (15) pneumonia; (16) premature retinopathy; (17) septic shock; (18) perinatal death.5,41–44 Patients with midtrimester cervical insufficiency and bulging fetal membranes have adverse pregnancy outcomes, and placement of a cervical cerclage is an effective therapy in those cases. Preoperative amniocentesis is crucial to exclude IAI and plays a major role in selecting patients who are the best candidates for emergency cervical cerclage.7,18,41,45–50 Amniotic fluid sludge is a marker of IAI and histological chorioamnionitis in cervical insufficiency.51 After clinical examination to rule out uterine activity, or IAI, or both, physical examination-indicated cerclage placement in patients with singleton gestations who have cervical change of the internal os may be beneficial.52Figure 3 shows a patient with histological chorioamnionitis and cervical insufficiency.
IAI has been documented in patients with preterm labor with intact membranes, preterm prelabor rupture of membranes, cervical insufficiency, asymptomatic short cervix, idiopathic vaginal bleeding, placenta previa, stillbirth, fetal growth restriction, pregnancy with an intrauterine device, and clinical chorioamnionitis at term.5 IAI categories include suspected IAIs, confirmed IAIs and isolated maternal fever.1 The features of IAI and isolated maternal fever are described as follows.
Suspected IAI, fever without a clear source plus any of the following: (1) baseline fetal tachycardia fetal heart rate greater than 160 beats per min for 10 minutes or longer, excluding accelerations, decelerations, and periods of marked variability; (2) maternal white blood cell count greater than 15 000 per mm3 in the absence of corticosteroids; (3) definite purulent fluid from the cervical os. Confirmed IAI: all of the above plus (1) amniocentesis-proven infection through a positive Gram stain; (2) low glucose or positive amniotic fluid culture; (3) placental pathology revealing diagnostic features of infection. Isolated maternal fever: maternal oral temperature of 39.0°C or greater on any one occasion is documented fever. If the oral temperature is between 38.0°C and 39.0°C, repeat the measurement in 30 minutes; if the repeat value remains at least 38.0°C, fever is documented.1,2
Presumptive diagnosis is based on clinical and laboratory findings, the presence of risk factors, and the absence of other causes of maternal fever. Diagnosis can be confirmed based on objective laboratory evidence of infection in amniotic fluid obtained by amniocentesis or cesarean section. Positive amniotic fluid culture is the gold standard for diagnosis, but it is of limited clinical use because results may not be available for up to 3 days. Other amniotic fluid tests findings include positive Gram stains, low glucose levels, and elevated white blood cell counts.17,20,53 Tests for maternal blood C-reactive protein level and leukocytosis have a low sensitivity and specificity.54 Kurakazu et al. found that the combination of maternal blood and amniotic fluid biomarkers could improve the predictive accuracy of histologic chorioamnionitis.55 The sonographic evaluation of the fetal thymus is also more sensitive than the fetal biophysical profile for the diagnosis of histologic chorioamnionitis.54Table 1 shows the maternal serum and amniotic fluid diagnostic tests for chorioamnionitis.4,20,56
Standardizing gross examination and histologic sampling of the placenta is important to find placental abnormal. At least 4–5 microscopic slides including sections of the umbilical cord, membrane roll, and three sections of the placental parenchyma, are examined for routine placentas. The placentas may be selected for pathologic examination or stored in a refrigerator at 4°C for approximately 1 week to submit pathologic examination if required. Freezing distorts histologic detail and should be avoided.
Histopathologic evidence of infection or inflammation in the placenta, fetal membranes, or umbilical cord vessels (funisitis) confirms the diagnosis. The histologic grading and staging of acute chorioamnionitis are described as follows.
Grade: Grade 1 (mild-moderate), individual or small clusters of maternal neutrophils diffusely infiltrating the amnion, chorionic plate, chorion laeve, and/or subchorionic fibrin. Grade 2 (severe), three or more chorionic microabscesses (microabscess: confluent neutrophils measuring at least 10–20 cells in extent) between the chorion and decidua in the membranes and/or under the chorionic plate or a continuous band of confluent chorionic polymorphonuclear leukocytes more than 10 cells in width occupying more than half of the subchorionic fibrin or one revolution of the membrane role.
Chronic (or subacute) chorioamnionitis: more than occasional maternally derived mononuclear cells (usually macrophages) in the chorionic plate (most frequently below the amnion) in cases without exogenous pigment deposition (ie, meconium, haemosiderin). Neutrophils may be rare or abundant, but coexistent acute chorioamnionitis should be present in at least one section.
- (1) Maternal inflammatory response: Stage 1, early acute subchorionitis/chorionitis. Stage 2, acute chorioamnionitis. Stage 3, necrotizing chorioamnionitis.
- (2) Fetal inflammatory response: Stage 1, umbilical phlebitis/chorionic vasculitis. Stage 2, umbilical arteritis. Stage 3, concentric periphlebitis/necrotizing funisitis.
- (3) Specific patterns: Acute villitis/fetal capillaritis: neutrophils in the villous stroma and/or the adjacent subtrophoblastic space, that is, Gram-negative bacilli. Acute intervillositis/intervillous abscesses: neutrophils within perivillous fibrin or the intervillous space, that is, streptococci, Listeria monocytogenes, and other rare bacteria. Decidual plasma cells: unequivocal plasma cells in either the decidua basalis or capsularis. Peripheral funisitis: small punctate microabscesses with neutrophils on the outer surface of the cord, that is, Candida spp infection.5,57–58Figure 4 shows the histologic changes of acute chorioamnionitis.
The management of chorioamnionitis mainly includes antibiotic therapy and delivery. Women with previable preterm premature rupture of membranes (PPROM) should be offered realistic counseling from a multidisciplinary approach. The separation of the mother and the fetus to preserve the life of the mother should prioritize delivery methods that result in a living fetus if possible, with appropriate neonatal resuscitation available. In cases where delivery of a living fetus is not possible, priority should be given to delivery methods that result in an intact fetal corpus. IAI alone is rarely an indication for cesarean delivery.1 Mifepristone/misoprostol can be used to induce labor in the midtrimester for dilation and evacuation.59 Administration of intrapartum antibiotics is recommended whenever an IAI is suspected or confirmed.60 Antibiotics should be considered in the setting of isolated maternal fever unless a source other than IAI is identified and documented. There are no randomized trials comparing the efficacy of various antibiotic regimens. The recommended antibiotic regimens for the treatment of IAI are included in Table 2.
Eradication of IAI after treatment with antibiotics was confirmed in 79% of patients with preterm labor, intact membranes, and IAI who had a follow-up amniocentesis. Treatment success occurred in 84% of patients who underwent follow-up amniocentesis.64 Lee et al. found that the administration of ceftriaxone, metronidazole, and clarithromycin was associated with a more successful eradication of intraamniotic inflammation/infection and prevented secondary intraamniotic inflammation/infection more frequently than an antibiotic regimen that included ampicillin and/or cephalosporins in patients with preterm PROM.16 Pustotina et al. found that intravenous antibiotic therapy at 15–24 weeks of gestation in women with amniotic fluid “sludge” can protect from infection-related complications, and demonstrated high beneficial effects of adding antibiotics to anti-inflamatory drug (indomethacin) and/or vaginal progesterone in women with a short cervix.65 Several studies have demonstrated the safe use of gentamicin during pregnancy.66–68 Gentamicin was recommended to treat IAI by the American College of Obstetricians and Gynecologists, but rarely be used in some countries such as China for safety issue.1 For about one-third of positive Ureaplasma species or Mycoplasma hominis in amniotic fluid or placenta by culture or polymerase chain reaction from patients with chorioamnionitis, a lot of studies should be done to evaluate its influence.
Communication between obstetric and neonatal teams is essential for appropriate neonatal treatment. Clinical management is different for term and late preterm neonates compared with preterm neonates with a gestational age <34 weeks. When IAI is suspected or confirmed, neonates with a gestational age <34 weeks should be given antibiotic treatment as soon as cultures are performed. The duration of neonatal antimicrobial therapy is more than 5 days. The negative blood cultures of neonates are generally not reliable when their mother received broad-spectrum antibiotics before delivery. Cord blood procalcitonin is a marker significantly associated with early-onset sepsis and adverse neonatal and infantile outcomes related to in utero inflammatory status.69–70
Expectant management of PPROM is a major cause of clinical chorioamnionitis. The main preventative strategy is the administration of antibiotics to women with PPROM, which reduces the incidence of clinical chorioamnionitis, prolongs the time to delivery, and improves neonatal outcomes.59 Some other prevention methods include treatment of periodontal disease, treatment of genitourinary tract infection, and group B streptococcus intrapartum chemoprophylaxis and minimizing invasive vaginal procedures such as the use of intrauterine pressure catheters, electronic fetal scalp electrodes, and intracervical foley bulbs.4,71
Figure 1 was drawn by Shengmenart with modification.
This research was supported by the Shenzhen Science and Technology Innovation Commission (JCYJ20180228162311024).
Conflicts of Interest
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