Clinical chorioamnionitis at term: definition, pathogenesis, microbiology, diagnosis, and treatment

Abstract

Clinical chorioamnionitis, the most common infection-related diagnosis in labor and delivery units, is an antecedent of puerperal infection and neonatal sepsis. The condition is suspected when intrapartum fever is associated with two other maternal and fetal signs of local or systemic inflammation (eg, maternal tachycardia, uterine tenderness, maternal leukocytosis, malodorous vaginal discharge or amniotic fluid, and fetal tachycardia). Clinical chorioamnionitis is a syndrome caused by intraamniotic infection, sterile intraamniotic inflammation (inflammation without bacteria), or systemic maternal inflammation induced by epidural analgesia. In cases of uncertainty, a definitive diagnosis can be made by analyzing amniotic fluid with methods to detect bacteria (Gram stain, culture, or microbial nucleic acid) and inflammation (white blood cell count, glucose concentration, interleukin-6, interleukin-8, matrix metalloproteinase-8). The most common microorganisms are Ureaplasma species, and polymicrobial infections occur in 70% of cases. The fetal attack rate is low, and the rate of positive neonatal blood cultures ranges between 0.2% and 4%. Intrapartum antibiotic administration is the standard treatment to reduce neonatal sepsis. Treatment with ampicillin and gentamicin have been recommended by professional societies, although other antibiotic regimens, eg, cephalosporins, have been used. Given the importance of Ureaplasma species as a cause of intraamniotic infection, consideration needs to be given to the administration of antimicrobial agents effective against these microorganisms such as azithromycin or clarithromycin. We have used the combination of ceftriaxone, clarithromycin, and metronidazole, which has been shown to eradicate intraamniotic infection with microbiologic studies. Routine testing of neonates born to affected mothers for genital mycoplasmas could improve the detection of neonatal sepsis. Clinical chorioamnionitis is associated with decreased uterine activity, failure to progress in labor, and postpartum hemorrhage; however, clinical chorioamnionitis by itself is not an indication for cesarean delivery. Oxytocin is often administered for labor augmentation, and it is prudent to have uterotonic agents at hand to manage postpartum hemorrhage. Infants born to mothers with clinical chorioamnionitis near term are at risk for early-onset neonatal sepsis and for long-term disability such as cerebral palsy. A frontier is the noninvasive assessment of amniotic fluid to diagnose intraamniotic inflammation with a transcervical amniotic fluid collector and a rapid bedside test for IL-8 for patients with ruptured membranes. This approach promises to improve diagnostic accuracy and to provide a basis for antimicrobial administration.

Keywords: Batson's plexus; Gardnerella vaginalis; NLRP3 inflammasome; Ureaplasma species; abnormal fetal heart rate pattern; adverse maternal outcome; adverse neonatal outcome; amniocentesis; amniotic fluid; ampicillin; antibiotics; antipyretics; azithromycin; biomarker; carbapenem; cerebral palsy; chemokine; clarithromycin; clavulanic acid; cytokine; epidural; fetal heart rate tracing; fetal inflammatory response syndrome; fetal tachycardia; fever; funisitis; genital mycoplasma; gentamycin; histologic chorioamnionitis; infection; inflammasome; interleukin-6 (IL-6); interleukin-8 (IL-8); intraamniotic infection; intraamniotic inflammation; intrapartum fever; maternal N-acetylcysteine (NAC); maternal leukocytosis; matrix metalloproteinase-8 (MMP-8); neonatal bacteremia; neonatal sepsis; overshoot; piperacillin; postpartum hemorrhage; pyrogenic; sterile intraamniotic inflammation; tazobactam, ticarcillin.

Figure 1. Definitions of chorioamnionitis: clinical, histologic, and microbiologic

Chorioamnionitis can be defined as a clinical or a histopathologic identity or from a microbiologic point of view: (1) the clinical diagnosis of chorioamnionitis is based on clinical signs, eg, maternal fever, uterine tenderness, malodorous discharge, and maternal and fetal tachycardia, and on laboratory abnormalities, ie, leukocytosis; (2) histologic chorioamnionitis is diagnosed by histopathologic examination of the placenta; the characteristic morphologic feature of acute histologic chorioamnionitis is diffuse infiltration of neutrophils into the chorioamniotic membranes; and (3) microbiologic chorioamnionitis, or intraamniotic infection, refers to the presence of microorganisms in the amniotic fluid, retrieved by amniocentesis. These terms are not synonymous, and confusion is caused when they are used interchangeably.

Figure 2. Nomenclature of states related to intraamniotic inflammation and intraamniotic infection

Microorganisms in amniotic fluid can be detected by cultivation methods and/or by molecular microbiologic techniques. Intraamniotic inflammation is defined by the presence of inflammatory cells (white blood cell count ≥ 50 cells/mm³) or by an elevated concentration of a biomarker of inflammation, eg, an interleukin-6 concentration ≥2.6 ng/mL or a matrix metalloproteinase-8 concentration >23 ng/mL. On the basis of the results of the presence of microorganisms in amniotic fluid and intraamniotic inflammation, patients can be classified into four subgroups; (1) no intraamniotic infection (negative amniotic fluid by culture and PCR and the absence of intra-amniotic inflammation); (2) microorganisms in amniotic fluid without intraamniotic inflammation (positive amniotic fluid by either culture or PCR but the absence of intraamniotic inflammation); (3) sterile intraamniotic inflammation (negative amniotic fluid by culture and PCR but the presence of intraamniotic inflammation); and (4) intraamniotic infection (positive amniotic fluid by either culture or PCR and the presence of intraamniotic inflammation). PCR: polymerase chain reaction.

Figure 3. Anatomy of the placental disc and chorioamniotic membranes and acute inflammatory lesions of the placenta: chorioamnionitis, chorionic vasculitis, and funisitis

A. The placenta is composed of 3 major structures: the chorioamniotic membranes, the placental disc, and the umbilical cord. Acute inflammatory lesions of the placenta are characterized by the infiltration of neutrophils in any of these structures. Specifically, when the inflammatory process affects the chorion and amnion, the term is acute chorioamnionitis. If the inflammatory process involves the umbilical cord (umbilical vein, umbilical artery, and the Wharton’s jelly), this is referred to as acute funisitis, the histologic counterpart of the fetal inflammatory response syndrome. B. Acute chorioamnionitis (stage 2 acute inflammation of the chorioamniotic membranes): neutrophilic migration into the amniotic connective tissue is shown (asterisk). C. Chorionic vasculitis is inflammation on the surface of the fetal vessels within the chorionic plate. Acute chorionic vasculitis (asterisk) is a stage 1 fetal inflammatory response. D. Funisitis: its characteristic feature is concentric, perivascular distribution of degenerated neutrophils (asterisk). Modified from Kim CJ et al. Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance. Am J Obstet Gynecol. 2015;213(4 Suppl):S29–52.

Figure 4. The syndrome of chorioamnionitis at term: intraamniotic infection and sterile intraamniotic inflammation

Patients with clinical chorioamnionitis at term, when studied with molecular microbiologic techniques and assessed for intraamniotic inflammation, are grouped into 3 categories: (1) intraamniotic infection (presence of microorganisms and intraamniotic inflammation); (2) sterile intraamniotic inflammation; and (3) maternal signs or symptoms of systemic inflammation without evidence of intraamniotic infection. The relative frequencies of these 3 conditions were calculated as 65% (58/89) in intraamniotic infection; 15% (13/89) in intraamniotic inflammation; and 20% (18/89) for no evidence of intraamniotic infection.

Figure 5. Frequency of microorganisms in the amniotic cavity of patients at term without labor, patients in labor with intact membranes, and those with prelabor rupture of membranes at term

In the presence of ruptured membranes, 34% of patients at term have microorganisms in amniotic fluid, which is higher compared to those without labor (1%) and to those with spontaneous labor with intact membranes (19%). Patients at term, not in labor, and with intact membranes rarely have bacteria detected in the amniotic cavity (left side of the figure, with a frequency of 1%). Patients in labor at term with intact membranes have a higher frequency of bacteria in the amniotic cavity even if the membranes are intact (middle part of the figure, with a frequency of 19%). Rupture of the chorioamniotic membranes at term prior to the onset of labor has a higher frequency of bacteria in the amniotic cavity (right side of the figure and table, with a frequency of approximately 34%). This frequency is similar to that observed in patients with preterm PROM. PROM: premature rupture of the membranes.

Figure 6. Frequency of intraamniotic infection and sterile intraamniotic inflammation in patients with clinical chorioamnionitis at term according to membrane status

Prevalence of intraamniotic infection and sterile intraamniotic inflammation in patients with clinical chorioamnionitis at term according to the status of the membranes at the time of amniocentesis. Modified from Romero R et al. Clinical chorioamnionitis at term X: microbiology, clinical signs, placental pathology, and neonatal bacteremia—implications for clinical care. J Perinat Med. 2021;49(3):275–98.²

Figure 7. Probability of clinical chorioamnionitis by the number of digital cervical examinations and by the number of hours after rupture of membranes

Each additional cervical examination confers an incremental risk of clinical chorioamnionitis. A greater length of time from rupture to delivery is associated with an increased risk of clinical chorioamnionitis. Modified from Gomez Slagle HB et al. Incremental risk of clinical chorioamnionitis associated with cervical examination. Am J Obstet Gynecol MFM. 2022;4(1):100524.

Figure 8. Amniotic fluid neutrophils and monocytes in patients with clinical chorioamnionitis at term

Hematoxylin and eosin staining shows the typical morphology of neutrophils (red arrow) and monocytes (green arrow) in the amniotic fluid of patients with clinical chorioamnionitis. Magnification 400X. Scale bars: 50 μm. Modified from Martinez-Varea A. et al. Clinical chorioamnionitis at term VII: the amniotic fluid cellular immune response. J Perinat Med. 2017;45(5):523–38.

Figure 9. The amniotic, maternal, and fetal inflammatory responses in patients with clinical chorioamnionitis at term

(A) Amniotic fluid concentrations of inflammatory cytokines (IL-1β, IFN-γ, TNF-α, and TNF-β) are higher in patients with clinical chorioamnionitis at term than in those with spontaneous labor at term. Modified from Romero R et al. Clinical chorioamnionitis at term II: the intra-amniotic inflammatory response. J Perinat Med. 2016;44(1):5–22. (B) Maternal plasma concentrations of pyrogenic cytokines (IL-2, IL-6, IL-1β, and IL-17α) are higher in patients with clinical chorioamnionitis at term than in those with spontaneous labor at term. Modified from Romero R et al. Clinical chorioamnionitis at term IV: the maternal plasma cytokine profile. J Perinat Med. 2016;44(1):77–98. (C) Umbilical cord plasma concentrations of inflammatory cytokines and chemokines (IL-12p70, IL-6, IL-16, and IL-8) are higher in fetuses with clinical chorioamnionitis at term than in those delivered by women with spontaneous labor at term. Modified from Romero R et al. Clinical chorioamnionitis at term V: umbilical cord plasma cytokine profile in the context of a systemic maternal inflammatory response. J Perinat Med. 2016;44(1):53–76. * p < 0.05 IFN: interferon; IL: interleukin; TNF: tumor necrosis factor

Figure 10. Fetal inflammatory response syndrome in clinical chorioamnionitis

A. Fetal inflammatory response syndrome can be diagnosed by an increased concentration of umbilical cord plasma IL-6 ( ≥ 11pg/mL). B. The median concentration of umbilical cord plasma IL-6 is higher in fetuses with clinical chorioamnionitis than in those delivered by patients with near-term labor without clinical chorioamnionitis [27.46 pg/mL vs. 2.13 pg/mL; p<0.001]. Sixty-two percent of fetuses (16/26) with clinical chorioamnionitis have a fetal plasma concentration of IL-6 >11 pg/mL. Modified from Chaiworapongsa T et al. Evidence for fetal involvement in the pathologic process of clinical chorioamnionitis. Am J Obstet Gynecol. 2002;186(6):1178–82. IL: interleukin.

Figure 11. Laboratory diagnosis of intraamniotic inflammation and intraamniotic infection

Definitive diagnoses of intraamniotic inflammation and intraamniotic infection require a transabdominal amniocentesis to collect amniotic fluid. Amniotic fluid should be assessed by (1) a WBC count and differential; (2) a glucose concentration; (3) a Gram stain and a bacterial culture that include aerobic/anaerobic bacteria and genital mycoplasmas; (4) MMP-8; (5) cytokines, eg, IL-6; and (6) other tests (eg, rapid tests, PCR). Intraamniotic inflammation is the presence of an inflammatory response in the amniotic cavity, which can be diagnosed by a WBC count ≥ 50 cells/mm³, an amniotic fluid glucose concentration <14 mg/dL, an IL-6 concentration ≥ 2.6 ng/mL, or an MMP-8 concentration >23 ng/mL. Rapid tests for amniotic fluid MMP-8 (Yoon’s MMP-8 Check®; OBMed Co., Ltd., Seoul, Republic of Korea) and IL-6 (Milenia QuickLine®; Milenia Biotec, Bad Nauheim, Germany) are available to be performed at the bedside. Microorganisms in amniotic fluid can be identified by Gram stain, cultivation methods, or molecular microbiologic techniques. IL: interleukin; MMP: matrix metalloproteinase; PCR: polymerase chain reaction; rRNA: ribosomal RNA; WBC: white blood cell.

Figure 12.. Amniotic fluid collector and rapid test to assess the presence of intraamniotic inflammation by determining interleukin-8 at the bedside

A. A transcervical collector allows sampling of amniotic fluid after rupture of the membranes. B. Rapid analysis of an interleukin-8 concentration at the bedside can be used to diagnose intraamniotic inflammation.

Figure 13.. Relationship between maternal fever and uterine contractility

Uterine contractility significantly and steadily declined 2 hours after the onset of maternal fever. Modified from Zackler A et al. Suspected Chorioamnionitis and Myometrial Contractility: Mechanisms for Increased Risk of Cesarean Delivery and Postpartum Hemorrhage. Reprod Sci. 2019;26(2):178–83.

Figure 14.. Fetal tachycardia in a case of clinical chorioamnionitis at 40 weeks of gestation

A. Fetal heart rate of 190 beats per minute (bpm). The associated loss of variability is also noteworthy. B. Tachycardia is associated with decelerations. The amniotic fluid culture was positive for Ureaplasma urealyticum and Staphylococcus aureus. The concentration of interleukin-6 in amniotic fluid was 37.49 ng/mL (cut-off 2.6 ng/mL), which is consistent with intraamniotic inflammation. The fetus presented fetal systemic inflammation, as demonstrated by the presence of funisitis. The newborn was septic, and the neonatal blood culture was positive for Staphylococcus aureus, the same bacterium identified in the amniotic fluid.

Figure 15.. Epidural analgesia, maternal temperature, and serum interleukin-6 concentrations

A. Mean vaginal temperature (°C) of patients during labor according to intrapartum pain control. Pregnant women who received epidural analgesia (red) had an increased mean temperature after the administration of anesthetic agents. By contrast, the temperature of women receiving pethidine (non-epidural, blue) remained constant. Modified from Fusi L et al. Maternal pyrexia associated with the use of epidural analgesia in labour. Lancet. 1989 Jun 3;1(8649):1250–2. B. Maternal serum interleukin-6 (IL-6) concentrations significantly increase with the duration of epidural analgesia. Modified Goetzl et al. Elevated maternal and fetal serum interleukin-6 levels are associated with epidural fever. Am J Obstet Gynecol. 2002 Oct;187(4):834–8.

Figure 16.. A needle in the epidural space, optical imaging, and the mechanisms of fever

A. Fiberscope of the epidural space. During pregnancy, the density of the epidural vessels is higher than that of non-pregnant subjects. It has been proposed that during pregnancy the inferior vena cava becomes compressed by the pregnant uterus and that this causes the epidural veins to engorge and the volume of the epidural space (*, blue) to decrease. Thus, a similar volume of local anesthetic agents can spread more extensively in the pregnant state than in the non-pregnant state. Modified from Eltzschig HK et al. Regional anesthesia and analgesia for labor and delivery. N Engl J Med. 2003 Jan 23;348(4):319–32 and from Igarashi T et al. The fiberscopic findings of the epidural space in pregnant women. Anesthesiology. 2000 Jun;92(6):1631–6. B. Local anesthetics such as ropivacaine used during epidural analgesia can induce maternal systemic inflammation. Ropivacaine can directly cause endothelial cell apoptosis, and this induces the release of damage-associated molecular patterns (DAMP), also known as alarmins, that trigger the production of pyrogenic cytokines (eg, interleukin (IL)-1β, IL-6, IL-8), which may be responsible for fever in pregnant women following epidural analgesia.