The term “clinical chorioamnionitis” refers to an entity diagnosed by the presence of fever (>37.8°C) and at least two of the following criteria: maternal tachycardia (>100 beats/min), maternal leukocytosis [white blood cell (WBC) count >15,000 cells/mm3], uterine tenderness, fetal tachycardia (>160 beats/min), and foul-smelling amniotic fluid (AF) [1–10]. More than 35 years ago, Gibbs recognized the challenges in the diagnosis of intra-amniotic infection (microbial-associated intra-amniotic inflammation) as he indicated that the clinical criteria were neither sensitive nor specific .
The clinical diagnosis of chorioamnionitis is an indication for antimicrobial administration, given that a randomized clinical trial of patients with this condition near term found that the frequency of neonatal bacteremia was significantly greater in patients who were not given antibiotics before delivery than in those who were treated in the neonatal period. This classic trial by Gibbs et al. is the basis for clinical practice today .
Epidural anesthesia and analgesia for labor and delivery have gained wide acceptance, and are used in more than 80% of cases in maternity hospitals [11, 12]. About 10% to 30% of patients who receive epidural analgesia develop a fever [11–29], and the differential diagnosis between clinical chorioamnionitis and an epidural-induced fever is challenging. This has resulted in the increased administration of antibiotics to mothers in labor [17, 18, 21, 30, 31] and their newborns [18, 21, 32, 33], and in the implementation of septic workups in newborns [11, 12, 15, 18, 21, 25, 32, 34, 35]. Recent evidence suggests that the administration of antibiotics has important effects on the microbiome in adults [36–46] and in the neonatal period [37, 40, 43–45, 47–68].
We recently reported, when the AF of patients with clinical chorioamnionitis at term is examined using cultivation and molecular microbiologic techniques, that only 54% of patients have microbial-associated intra-amniotic inflammation in the amniotic cavity . Moreover, 24% of patients have intra-amniotic inflammation without detectable bacteria, and 22% do not have any evidence of intra-amniotic inflammation . Traditionally, one expects that only patients with bacterial infections may benefit from antibiotic administration; however, our observations suggest that relying on the conventional criteria for the diagnosis of clinical chorioamnionitis may result in over-treatment with antimicrobial agents. Therefore, it is timely that the diagnostic performance and accuracy of clinical signs for the diagnosis of clinical chorioamnionitis be revisited using a gold standard for the identification of microbial-associated intra-amniotic inflammation, which represents intra-amniotic infection.
Materials and methods
This retrospective cross-sectional study included women with the diagnosis of clinical chorioamnionitis at term who underwent transabdominal amniocentesis to identify microorganisms in the amniotic cavity. Patients were identified by searching the clinical database and the Bank of Biological Samples of Wayne State University, the Detroit Medical Center, and the Perinatology Research Branch (NICHD/NIH). The criteria for entry were: 1) singleton gestation; 2) gestational age ≥37 weeks; 3) sufficient AF obtained by transabdominal amniocenteses for molecular microbiologic studies; and 4) absence of fetal malformations. A subset of these patients was included in prior studies, which provides a detailed description of sample collection, microbiological studies, and determination of AF IL-6 concentrations [69, 70].
All patients provided written informed consent and the use of biological specimens as well as clinical and ultrasound data for research purposes were approved by the Institutional Review Boards of the NICHD, Wayne State University, and the Sótero del Río Hospital, Santiago, Chile.
Microbial invasion of the amniotic cavity was defined according to the results of AF culture and PCR/ESI-MS (Ibis® Technology – Athogen, Carlsbad, CA, USA) [71–74]. Microbial-associated intra-amniotic inflammation (intra-amniotic infection) was diagnosed when microorganisms were identified in AF using cultivation or molecular techniques and elevated AF IL-6 concentrations (≥2.6 ng/mL) were found, as described in detail elsewhere [69, 75–92].
Clinical chorioamnionitis was diagnosed by the presence of maternal fever (temperature >37.8°C) accompanied by two more of the following criteria: 1) maternal tachycardia (heart rate >100 beats/min); 2) uterine tenderness; 3) foul-smelling AF; 4) fetal tachycardia (heart rate >160 beats/min); and 5) maternal leukocytosis (leukocyte count >15,000 cells/mm3) [1–9, 69, 70, 80]. Acute histologic chorioamnionitis was diagnosed based on the presence of inflammatory cells in the chorionic plate and/or in the chorioamniotic membranes [77, 83, 93–102], and acute funisitis was diagnosed by the presence of neutrophils in the wall of the umbilical vessels and/or in the Wharton’s jelly, also using previously reported criteria [93, 103–108]. Fetal inflammatory response syndrome (FIRS) was diagnosed when umbilical cord blood IL-6 concentrations were ≥11 pg/mL [72, 105, 109–119].
The Kolmogorov-Smirnov test was used to test whether data were normally distributed. A Chi-square or Fisher’s exact test was used for comparisons of proportions. Kruskal-Wallis and the Mann-Whitney U-tests were used to compare median concentrations of analytes between and among groups. Sensitivity, specificity, accuracy, and likelihood ratios (+/–) were calculated for the identification of microbial-associated intra-amniotic inflammation. Statistical analysis was performed using SPSS 19 (IBM Corp, Armonk, NY, USA). A P value <0.05 was considered statistically significant.
The descriptive characteristics of the study population stratified by the presence or absence of microbial-associated intra-amniotic inflammation or intra-amniotic infection are displayed in Table 1. Fever was a requirement for the diagnosis of clinical chorioamnionitis. The most frequent clinical signs of chorioamnionitis were maternal tachycardia (91.1%; 41/45), followed by fetal tachycardia (75.6%; 34/45) and maternal leukocytosis (WBCs >15,000 cell/mm3) (73.3%; 33/45). Uterine tenderness and foul-smelling AF were found in <10% of the study population (uterine tenderness: 8.9%, 4/45; foul-smelling AF: 6.7%, 3/45) (Table 1). There were no significant differences in the frequency of each clinical sign between clinical chorioamnionitis with and without microbial-associated intra-amniotic inflammation (P>0.05). All patients had an epidural. Amniocenteses were performed before the administration of epidural analgesia in 78% (35/45) of the study participants. All but two of these women received antibiotics, which were administered in most of the cases (88.4%; 38/43) after amniocentesis (Table 1). In three patients, the amniocentesis was performed approximately 5 min after the administration of antibiotics, and in two women, the amniocentesis was performed 45 min after treatment. The information about the microorganisms identified in AF has been published previously . The most frequent microorganisms were Ureaplasma spp. and Gardnerella vaginalis .
Patients with clinical chorioamnionitis at term with microbial-associated intra-amniotic inflammation had a significantly higher median AF WBC count, AF IL-6, and umbilical cord blood IL-6 concentration than those without microbial-associated intra-amniotic inflammation (P<0.001, P<0.001, and P=0.03, respectively). Frequencies of FIRS and acute inflammatory lesions of the placenta were also significantly greater in patients with clinical chorioamnionitis at term with microbial-associated intra-amniotic inflammation than in those without microbial-associated intra-amniotic inflammation (FIRS: 36% vs. 5%; P=0.03, and acute inflammatory lesions of placenta: 70.8% vs. 25%; P=0.02) (Table 1).
The performance of criteria for the diagnosis of clinical chorioamnionitis in the identification of microbial-associated intra-amniotic inflammation is shown in Table 2. The sensitivity of maternal and fetal tachycardia and maternal leukocytosis ranged from 75% to 90%; however, the specificity was poor for these criteria, ranging from 0% to 30%. In contrast, foul-smelling AF and uterine tenderness had a high specificity (95%) but a low sensitivity (8% and 12%, respectively) for the identification of microbial-associated intra-amniotic inflammation. Altogether, the diagnostic accuracy for each clinical criterion ranged between 46.7% and 57.8%. The combination of fever with three or more clinical criteria did not further improve the diagnostic accuracy for the identification of microbial-associated intra-amniotic inflammation (Table 2).
Table 3 shows the diagnostic indices for the identification of intra-amniotic inflammation, regardless of the presence or absence of microorganisms detected by cultivation or molecular microbiologic techniques.
Criteria for the diagnosis of clinical chorioamnionitis have considerable limitations if the goal is to identify the patient with bacterial-associated intra-amniotic inflammation. The standard diagnostic criteria of clinical chorioamnionitis include fever and two or more of the following: maternal and fetal tachycardia, uterine tenderness, foul-smelling AF, and maternal leukocytosis [1–10]. The rationale for the precise cut-off used to define fever and maternal and fetal tachycardia was discussed in detail by Newton , who articulated that the thresholds for maternal and fetal tachycardia are the 90th percentile , and for the WBC count, the 80th percentile .
Our findings indicate that clinical signs of chorioamnionitis do not accurately identify patients with microbial-associated intra-amniotic inflammation or intra-amniotic infection. Maternal and fetal tachycardia, as well as maternal leukocytosis, had low specificity (5%–30%), whereas foul-smelling AF and uterine tenderness had poor sensitivity (<15%) for the diagnosis of microbial-associated intra-amniotic inflammation. Our observations are consistent with those of a prior study which demonstrated that fever and maternal and fetal tachycardia were not reliable for the identification of acute histologic chorioamnionitis . Several investigators have shown that the majority of women with acute inflammatory placental lesions do not have microorganisms detectable using either cultivation or molecular microbiologic techniques in the chorioamniotic membranes [122–129]. Histologic chorioamnionitis is more sensitive than clinical chorioamnionitis in the identification of patients with a positive AF culture for microorganisms .
The diagnosis of intra-amniotic infection in this study was based on the combination of the presence of microorganisms identified by cultivation or molecular microbiologic methods and intra-amniotic inflammation as a gold standard [71–74, 83–86, 88, 89, 131]. We previously reported that intra-amniotic inflammation with detectable microorganisms was associated with acute histologic chorioamnionitis and funisitis [69, 83–86] and elevated inflammation-related protein concentrations in the AF [70, 83–86].
Efforts to improve the identification of patients with proven intra-amniotic infection are worthwhile because a high rate of false-positive diagnoses has clinical and financial implications. Often, mothers with a fever during labor are given antibiotics [17, 18, 21, 30, 31] – such intervention renders the results of neonatal cultures less reliable, and this frequently results in antibiotic administration in the neonatal period [18, 21, 32, 33], increased septic workups [11, 12, 15, 18, 21, 25, 32, 34, 35], and separation of the neonates from the parents while antibiotic treatment takes place in the nursery [132–135].
We propose that analysis of AF obtained using a transcervical AF collector may facilitate the rapid diagnosis of patients with intra-amniotic inflammation from those who do not have an inflammatory process . Further studies are required to determine if such an approach may reduce the utilization of antibiotics in both patients in labor and in the neonatal period.
The major strength of this study is that both cultivation and molecular microbiologic techniques were used to identify microorganisms in the amniotic cavity collected by transabdominal amniocentesis – therefore, the diagnosis of microbial invasion is based on a gold standard. Most work in clinical chorioamnionitis has been based on a case definition which relies heavily on clinical signs. The shortcomings of such an approach have become clear, now that sterile inflammation has emerged as an important entity in patients at term  as well as those in preterm labor [83, 86], those with preterm prelabor rupture of the membranes , or those with an asymptomatic sonographic short cervix . Non-microbial-associated inflammation appears to account for a sizable segment of patients with clinical chorioamnionitis at term [69, 80].
Criteria used for the diagnosis of clinical chorioamnionitis at term do not accurately identify the subset of patients with intra-amniotic infection or bacterial-associated intra-amniotic inflammation. Further work is required to explore whether such diagnosis is possible by using AF obtained with a transcervical AF collector .
Gibbs RS. Diagnosis of intra-amniotic infection. Semin Perinatol. 1977;1:71–7.Google Scholar
Gibbs RS, Castillo MS, Rodgers PJ. Management of acute chorioamnionitis. Am J Obstet Gynecol. 1980;136:709–13.Google Scholar
Gibbs RS, Dinsmoor MJ, Newton ER, Ramamurthy RS. A randomized trial of intrapartum vs. immediate postpartum treatment of women with intra-amniotic infection. Obstet Gynecol. 1988;72:823–8.Google Scholar
Gilstrap LC, 3rd, Cox SM. Acute chorioamnionitis. Obstet Gynecol Clin N Am. 1989;16:373–9.Google Scholar
Vinson DC, Thomas R, Kiser T. Association between epidural analgesia during labor and fever. J Fam Pract. 1993;36:617–22.Google Scholar
Sharma SK, Sidawi JE, Ramin SM, Lucas MJ, Leveno KJ, Cunningham FG. Cesarean delivery: a randomized trial of epidural vs. patient-controlled meperidine analgesia during labor. Anesthesiology. 1997;87:487–94.CrossrefGoogle Scholar
Lucas MJ, Sharma SK, McIntire DD, Wiley J, Sidawi JE, Ramin SM, et al. A randomized trial of labor analgesia in women with pregnancy-induced hypertension. Am J Obstet Gynecol. 2001;185:970–5.CrossrefGoogle Scholar
Sharma SK, Alexander JM, Messick G, Bloom SL, McIntire DD, Wiley J, et al. Cesarean delivery: a randomized trial of epidural analgesia vs. intravenous meperidine analgesia during labor in nulliparous women. Anesthesiology. 2002;96:546–51.CrossrefGoogle Scholar
Agakidis C, Agakidou E, Philip Thomas S, Murthy P, John Lloyd D. Labor epidural analgesia is independent risk factor for neonatal pyrexia. J Matern Fetal Neonatal Med. 2011;24:1128–32.Google Scholar
Greenwell EA, Wyshak G, Ringer SA, Johnson LC, Rivkin MJ, Lieberman E. Intrapartum temperature elevation, epidural use, and adverse outcome in term infants. Pediatrics. 2012;129:e447–54.CrossrefGoogle Scholar
Goetzl L, Cohen A, Frigoletto F, Jr., Lang JM, Lieberman E. Maternal epidural analgesia and rates of maternal antibiotic treatment in a low-risk nulliparous population. J Perinatol. 2003;23:457–61.CrossrefGoogle Scholar
Jakobsson HE, Jernberg C, Andersson AF, Sjolund-Karlsson M, Jansson JK, Engstrand L. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS One. 2010;5:e9836.CrossrefGoogle Scholar
Mangin I, Leveque C, Magne F, Suau A, Pochart P. Long-term changes in human colonic Bifidobacterium populations induced by a 5-day oral amoxicillin-clavulanic acid treatment. PloS One. 2012;7:e50257.CrossrefGoogle Scholar
Marild K, Ye W, Lebwohl B, Green PH, Blaser MJ, Card T, et al. Antibiotic exposure and the development of coeliac disease: a nationwide case-control study. BMC Gastroenterol. 2013;13:109.CrossrefGoogle Scholar
Jess T. Microbiota, antibiotics, and obesity. N Engl J Med. 2014;371:2526–8.Google Scholar
Cox LM, Blaser MJ. Antibiotics in early life and obesity. Nat Rev Endocrinol. 2015;11:182–90.Google Scholar
Cox LM, Yamanishi S, Sohn J, Alekseyenko AV, Leung JM, Cho I, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell. 2014;158:705–21.CrossrefGoogle Scholar
Fanaro S, Chierici R, Guerrini P, Vigi V. Intestinal microflora in early infancy: composition and development. Acta Paediatr. 2003;91:48–55.Google Scholar
Schumann A, Nutten S, Donnicola D, Comelli EM, Mansourian R, Cherbut C, et al. Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome. Physiol Genomics. 2005;23:235–45.CrossrefGoogle Scholar
Wall R, Ross RP, Ryan CA, Hussey S, Murphy B, Fitzgerald GF, et al. Role of gut microbiota in early infant development. Clin Med Pediatr. 2009;3:45–54.Google Scholar
Tanaka S, Kobayashi T, Songjinda P, Tateyama A, Tsubouchi M, Kiyohara C, et al. Influence of antibiotic exposure in the early postnatal period on the development of intestinal microbiota. FEMS Immunol Med Microbiol. 2009;56:80–7.CrossrefGoogle Scholar
Marques TM, Wall R, Ross RP, Fitzgerald GF, Ryan CA, Stanton C. Programming infant gut microbiota: influence of dietary and environmental factors. Curr Opin Biotechnol. 2010;21:149–56.CrossrefGoogle Scholar
Mangin I, Suau A, Gotteland M, Brunser O, Pochart P. Amoxicillin treatment modifies the composition of Bifidobacterium species in infant intestinal microbiota. Anaerobe. 2010;16:433–8.CrossrefGoogle Scholar
Ajslev TA, Andersen CS, Gamborg M, Sorensen TI, Jess T. Childhood overweight after establishment of the gut microbiota: the role of delivery mode, pre-pregnancy weight and early administration of antibiotics. Int J Obes. 2011;35:522–9.CrossrefGoogle Scholar
Madan JC, Salari RC, Saxena D, Davidson L, O’Toole GA, Moore JH, et al. Gut microbial colonisation in premature neonates predicts neonatal sepsis. Arch Dis Child Fetal Neonatal Ed. 2012;97:F456–62.Google Scholar
Russell SL, Gold MJ, Hartmann M, Willing BP, Thorson L, Wlodarska M, et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep. 2012;13:440–7.CrossrefGoogle Scholar
Fouhy F, Guinane CM, Hussey S, Wall R, Ryan CA, Dempsey EM, et al. High-throughput sequencing reveals the incomplete, short-term recovery of infant gut microbiota following parenteral antibiotic treatment with ampicillin and gentamicin. Antimicrob Agents Chemotherapy. 2012;56:5811–20.Google Scholar
Romero R, Korzeniewski SJ. Are infants born by elective cesarean delivery without labor at risk for developing immune disorders later in life? Am J Obstet Gynecol. 2013;208:243–6.CrossrefGoogle Scholar
Mai V, Torrazza RM, Ukhanova M, Wang X, Sun Y, Li N, et al. Distortions in development of intestinal microbiota associated with late onset sepsis in preterm infants. PLoS One. 2013;8:e52876.CrossrefGoogle Scholar
Berrington JE, Stewart CJ, Embleton ND, Cummings SP. Gut microbiota in preterm infants: assessment and relevance to health and disease. Arch Dis Child Fetal Neonatal Ed. 2013;98:F286–90.CrossrefGoogle Scholar
Mueller NT, Whyatt R, Hoepner L, Oberfield S, Dominguez-Bello MG, Widen EM, et al. Prenatal exposure to antibiotics, cesarean section and risk of childhood obesity. Int J Obes. 2014. [Epub ahead of print].Google Scholar
Murphy R, Stewart AW, Braithwaite I, Beasley R, Hancox RJ, Mitchell EA, et al. Antibiotic treatment during infancy and increased body mass index in boys: an international cross-sectional study. Int J Obes. 2014;38:1115–9.CrossrefGoogle Scholar
Romero R, Miranda J, Kusanovic JP, Chaiworapongsa T, Chaemsaithong P, Martinez A, et al. Clinical chorioamnionitis at term I: microbiology of the amniotic cavity using cultivation and molecular techniques. J Perinat Med. 2015;43:19–36.Google Scholar
Romero R, Chaemsaithong P, Korzeniewski SJ, Tarca AL, Bhatti G, Xu Z, et al. Clinical chorioamnionitis at term II: the intra-amniotic inflammatory response. J Perinat Med. 2016;44:5–22.Google Scholar
DiGiulio DB, Romero R, Amogan HP, Kusanovic JP, Bik EM, Gotsch F, et al. Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation. PLoS One. 2008;3:e3056.CrossrefGoogle Scholar
DiGiulio DB, Romero R, Kusanovic JP, Gomez R, Kim CJ, Seok KS, et al. Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J Reprod Immunol. 2010;64:38–57.Google Scholar
DiGiulio DB, Gervasi M, Romero R, Mazaki-Tovi S, Vaisbuch E, Kusanovic JP, et al. Microbial invasion of the amniotic cavity in pre-eclampsia as assessed by cultivation and sequence-based methods. J Perinat Med. 2010;38:503–13.Google Scholar
DiGiulio DB, Gervasi MT, Romero R, Vaisbuch E, Mazaki-Tovi S, Kusanovic JP, et al. Microbial invasion of the amniotic cavity in pregnancies with small-for-gestational-age fetuses. J Perinat Med. 2010;38:495–502.Google Scholar
Jun JK, Yoon BH, Romero R, Kim M, Moon JB, Ki SH, et al. Interleukin 6 determinations in cervical fluid have diagnostic and prognostic value in preterm premature rupture of membranes. Am J Obstet Gynecol. 2000;183:868–73.CrossrefGoogle Scholar
Yoon BH, Romero R, Moon JB, Shim SS, Kim M, Kim G, et al. Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Obstet Gynecol. 2001;185:1130–6.CrossrefGoogle Scholar
Madan I, Romero R, Kusanovic JP, Mittal P, Chaiworapongsa T, Dong Z, et al. The frequency and clinical significance of intra-amniotic infection and/or inflammation in women with placenta previa and vaginal bleeding: an unexpected observation. J Perinat Med. 2010;38:275–9.Google Scholar
Cruciani L, Romero R, Vaisbuch E, Kusanovic JP, Chaiworapongsa T, Mazaki-Tovi S, et al. Pentraxin 3 in amniotic fluid: a novel association with intra-amniotic infection and inflammation. J Perinat Med. 2010;38:161–71.Google Scholar
Romero R, Chaiworapongsa T, Alpay Savasan Z, Xu Y, Hussein Y, Dong Z, et al. Damage-associated molecular patterns (DAMPs) in preterm labor with intact membranes and preterm PROM: a study of the alarmin HMGB1. J Matern Fetal Neonatal Med. 2011;24:1444–55.Google Scholar
Romero R, Chaiworapongsa T, Savasan ZA, Hussein Y, Dong Z, Kusanovic JP, et al. Clinical chorioamnionitis is characterized by changes in the expression of the alarmin HMGB1 and one of its receptors, sRAGE. J Matern Fetal Neonatal Med. 2012;25:558–67.Google Scholar
Gervasi MT, Romero R, Bracalente G, Erez O, Dong Z, Hassan SS, et al. Midtrimester amniotic fluid concentrations of interleukin-6 and interferon-gamma-inducible protein-10: evidence for heterogeneity of intra-amniotic inflammation and associations with spontaneous early (<32 weeks) and late (>32 weeks) preterm delivery. J Perinat Med. 2012;40:329–43.Google Scholar
Kim SK, Romero R, Savasan ZA, Xu Y, Dong Z, Lee DC, et al. Endoglin in amniotic fluid as a risk factor for the subsequent development of bronchopulmonary dysplasia. Am J Reprod Immunol. 2013;69:105–23.CrossrefGoogle Scholar
Romero R, Miranda J, Chaiworapongsa T, Chaemsaithong P, Gotsch F, Dong Z, et al. A novel molecular microbiologic technique for the rapid diagnosis of microbial invasion of the amniotic cavity and intra-amniotic infection in preterm labor with intact membranes. Am J Reprod Immunol. 2014;71:330–58.CrossrefGoogle Scholar
Romero R, Miranda J, Chaemsaithong P, Chaiworapongsa T, Kusanovic JP, Dong Z, et al. Sterile and microbial-associated intra-amniotic inflammation in preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2014:1–16.Google Scholar
Romero R, Miranda J, Chaiworapongsa T, Chaemsaithong P, Gotsch F, Dong Z, et al. Sterile intra-amniotic inflammation in asymptomatic patients with a sonographic short cervix: prevalence and clinical significance. J Matern Fetal Neonatal Med. 2014:1–17.Google Scholar
Romero R, Miranda J, Chaiworapongsa T, Korzeniewski SJ, Chaemsaithong P, Gotsch F, et al. Prevalence and clinical significance of sterile intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Reprod Immunol. 2014;72:458–74.CrossrefGoogle Scholar
Chaemsaithong P, Romero R, Korzeniewski SJ, Dong Z, Yeo L, Hassan SS, et al. A point of care test for the determination of amniotic fluid interleukin-6 and the chemokine CXCL-10/IP-10. J Matern Fetal Neonatal Med. 2014:1–10.Google Scholar
Kacerovsky M, Musilova I, Andrys C, Hornychova H, Pliskova L, Kostal M, et al. Prelabor rupture of membranes between 34 and 37 weeks: the intraamniotic inflammatory response and neonatal outcomes. Am J Obstet Gynecol. 2014;210:325.e1–10.Google Scholar
Combs CA, Gravett M, Garite TJ, Hickok DE, Lapidus J, Porreco R, et al. Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol. 2014;210:125.e1–15.Google Scholar
Chaemsaithong P, Romero R, Korzeniewski SJ, Dong Z, Martinez-Varea A, Yoon BH, et al. A rapid interleukin-6 bedside test for the identification of intra-amniotic inflammation in preterm labor with intact membranes. J Matern Fetal Neonatal Med. 2015. [Epub ahead of print].Google Scholar
Chaemsaithong P, Romero R, Korzeniewski SJ, Dong Z, Martinez-Varea A, Yoon BH, et al. A point of care test for interleukin-6 in amniotic fluid in preterm prelabor rupture of membrances: a step toward the early treatment of acute intra-amniotic inflammation/infection. J Matern Fetal Neonatal Med. 2015. [Epub ahead of print].Google Scholar
Chaiworapongsa T, Erez O, Kusanovic JP, Vaisbuch E, Mazaki-Tovi S, Gotsch F, et al. Amniotic fluid heat shock protein 70 concentration in histologic chorioamnionitis, term and preterm parturition. J Matern Fetal Neonatal Med. 2008;21:449–61.Google Scholar
Seong HS, Lee SE, Kang JH, Romero R, Yoon BH. The frequency of microbial invasion of the amniotic cavity and histologic chorioamnionitis in women at term with intact membranes in the presence or absence of labor. Am J Obstet Gynecol. 2008;199:375.e1–5.Google Scholar
Park CW, Moon KC, Park JS, Jun JK, Romero R, Yoon BH. The involvement of human amnion in histologic chorioamnionitis is an indicator that a fetal and an intra-amniotic inflammatory response is more likely and severe: clinical implications. Placenta. 2009;30:56–61.CrossrefGoogle Scholar
Kacerovsky M, Pliskova L, Bolehovska R, Musilova I, Hornychova H, Tambor V, et al. The microbial load with genital mycoplasmas correlates with the degree of histologic chorioamnionitis in preterm PROM. Am J Obstet Gynecol. 2011;205:213.e1–7.Google Scholar
Mi Lee S, Romero R, Lee KA, Jin Yang H, Joon Oh K, Park CW, et al. The frequency and risk factors of funisitis and histologic chorioamnionitis in pregnant women at term who delivered after the spontaneous onset of labor. J Matern Fetal Neonatal Med. 2011;24:37–42.Google Scholar
Tsiartas P, Kacerovsky M, Musilova I, Hornychova H, Cobo T, Savman K, et al. The association between histological chorioamnionitis, funisitis and neonatal outcome in women with preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2013;26:1332–6.Google Scholar
Korzeniewski SJ, Romero R, Cortez J, Pappas A, Schwartz AG, Kim CJ, et al. A “multi-hit” model of neonatal white matter injury: cumulative contributions of chronic placental inflammation, acute fetal inflammation and postnatal inflammatory events. J Perinat Med. 2014;42:731–43.Google Scholar
Kim SM, Romero R, Park JW, Oh KJ, Jun JK, Yoon BH. The relationship between the intensity of intra-amniotic inflammation and the presence and severity of acute histologic chorioamnionitis in preterm gestation. J Matern Fetal Neonatal Med. 2014:1–10.Google Scholar
Yoon BH, Romero R, Park JS, Kim M, Oh SY, Kim CJ, et al. The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical cord plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis. Am J Obstet Gynecol. 2000;183:1124–9.CrossrefGoogle Scholar
Park JS, Romero R, Yoon BH, Moon JB, Oh SY, Han SY, et al. The relationship between amniotic fluid matrix metalloproteinase-8 and funisitis. Am J Obstet Gynecol. 2001;185:1156–61.CrossrefGoogle Scholar
Pacora P, Chaiworapongsa T, Maymon E, Kim YM, Gomez R, Yoon BH, et al. Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome. J Matern Fetal Neonatal Med. 2002;11:18–25.Google Scholar
Yoon BH, Romero R, Shim JY, Shim SS, Kim CJ, Jun JK. C-reactive protein in umbilical cord blood: a simple and widely available clinical method to assess the risk of amniotic fluid infection and funisitis. J Matern Fetal Neonatal Med. 2003;14:85–90.Google Scholar
Lee SE, Romero R, Kim CJ, Shim SS, Yoon BH. Funisitis in term pregnancy is associated with microbial invasion of the amniotic cavity and intra-amniotic inflammation. J Matern Fetal Neonatal Med. 2006;19:693–7.Google Scholar
Park CW, Lee SM, Park JS, Jun JK, Romero R, Yoon BH. The antenatal identification of funisitis with a rapid MMP-8 bedside test. J Perinat Med. 2008;36:497–502.Google Scholar
Chaiworapongsa T, Romero R, Kim JC, Kim YM, Blackwell SC, Yoon BH, et al. Evidence for fetal involvement in the pathologic process of clinical chorioamnionitis. Am J Obstet Gynecol. 2002;186:1178–82.CrossrefGoogle Scholar
Kim SK, Romero R, Chaiworapongsa T, Kusanovic JP, Mazaki-Tovi S, Mittal P, et al. Evidence of changes in the immunophenotype and metabolic characteristics (intracellular reactive oxygen radicals) of fetal, but not maternal, monocytes and granulocytes in the fetal inflammatory response syndrome. J Perinat Med. 2009;37:543–52.Google Scholar
Madsen-Bouterse SA, Romero R, Tarca AL, Kusanovic JP, Espinoza J, Kim CJ, et al. The transcriptome of the fetal inflammatory response syndrome. Am J Reprod Immunol. 2010;63:73–92.Google Scholar
Romero R, Savasan ZA, Chaiworapongsa T, Berry SM, Kusanovic JP, Hassan SS, et al. Hematologic profile of the fetus with systemic inflammatory response syndrome. J Perinat Med. 2011;40:19–32.Google Scholar
Chaiworapongsa T, Romero R, Berry SM, Hassan SS, Yoon BH, Edwin S, et al. The role of granulocyte colony-stimulating factor in the neutrophilia observed in the fetal inflammatory response syndrome. J Perinat Med. 2011;39:653–66.Google Scholar
Vaisbuch E, Romero R, Gomez R, Kusanovic JP, Mazaki-Tovi S, Chaiworapongsa T, et al. An elevated fetal interleukin-6 concentration can be observed in fetuses with anemia due to Rh alloimmunization: implications for the understanding of the fetal inflammatory response syndrome. J Matern Fetal Neonatal Med. 2011;24:391–6.Google Scholar
Romero R, Soto E, Berry SM, Hassan SS, Kusanovic JP, Yoon BH, et al. Blood pH and gases in fetuses in preterm labor with and without systemic inflammatory response syndrome. J Matern Fetal Neonatal Med. 2012;25:1160–70.Google Scholar
Savasan ZA, Chaiworapongsa T, Romero R, Hussein Y, Kusanovic JP, Xu Y, et al. Interleukin-19 in fetal systemic inflammation. J Matern Fetal Neonatal Med. 2012;25: 995–1005.Google Scholar
Stampalija T, Romero R, Korzeniewski SJ, Chaemsaithong P, Miranda J, Yeo L, et al. Soluble ST2 in the fetal inflammatory response syndrome: in vivo evidence of activation of the anti-inflammatory limb of the immune response. J Matern Fetal Neonatal Med. 2013;26:1384–93.Google Scholar
Olding L. Value of placentitis as a sign of intrauterine infection in human subjects. Acta Pathol Microbiol Scand A, Pathol. 1970;78:256–64.Google Scholar
Pankuch GA, Appelbaum PC, Lorenz RP, Botti JJ, Schachter J, Naeye RL. Placental microbiology and histology and the pathogenesis of chorioamnionitis. Obstet Gynecol. 1984;64:802–6.Google Scholar
Dong Y, St Clair PJ, Ramzy I, Kagan-Hallet KS, Gibbs RS. A microbiologic and clinical study of placental inflammation at term. Obstet Gynecol. 1987;70:175–82.Google Scholar
Hillier SL, Martius J, Krohn M, Kiviat N, Holmes KK, Eschenbach DA. A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med. 1988;319:972–8.CrossrefGoogle Scholar
Hillier SL, Witkin SS, Krohn MA, Watts DH, Kiviat NB, Eschenbach DA. The relationship of amniotic fluid cytokines and preterm delivery, amniotic fluid infection, histologic chorioamnionitis, and chorioamnion infection. Obstet Gynecol. 1993;81:941–8.Google Scholar
Torricelli M, Voltolini C, Conti N, Vellucci FL, Orlandini C, Bocchi C, et al. Histologic chorioamnionitis at term: implications for the progress of labor and neonatal wellbeing. J Matern Fetal Neonatal Med. 2013;26:188–92.Google Scholar
Romero R, Sirtori M, Oyarzun E, Avila C, Mazor M, Callahan R, et al. Infection and labor. V. Prevalence, microbiology, and clinical significance of intraamniotic infection in women with preterm labor and intact membranes. Am J Obstet Gynecol. 1989;161:817–24.CrossrefGoogle Scholar
Cobo T, Kacerovsky M, Holst RM, Hougaard DM, Skogstrand K, Wennerholm UB, et al. Intra-amniotic inflammation predicts microbial invasion of the amniotic cavity but not spontaneous preterm delivery in preterm prelabor membrane rupture. Acta Obstet Gynecol Scand. 2012;91:930–5.CrossrefGoogle Scholar
Klaus MH, Kennell JH. Mothers separated from their newborn infants. Pediatr Clin N Am. 1970;17:1015–37.Google Scholar
Kratochvil MS, Robertson CM, Kyle JM. Parents’ view of parent-child relationship eight years after neonatal intensive care. Social Work in Health Care. 1991;16:95–118.Google Scholar
Lee SM, Romero R, Park JS, Chaemsaithong P, Jun JK, Yoon BH. A transcervical amniotic fluid collector: a new medical device for the assessment of amniotic fluid in patients with ruptured membranes. J Perinat Med. 2015;43:381–9.Google Scholar
Gotsch F, Romero R, Chaiworapongsa T, Erez O, Vaisbuch E, Espinoza J, et al. Evidence of the involvement of caspase-1 under physiologic and pathologic cellular stress during human pregnancy: a link between the inflammasome and parturition. J Matern Fetal Neonatal Med. 2008; 21:605–16.Google Scholar
The authors stated that there are no conflicts of interest regarding the publication of this article.