Home Clinical chorioamnionitis – an ongoing obstetrical conundrum
Article Publicly Available

Clinical chorioamnionitis – an ongoing obstetrical conundrum

  • Shali Mazaki-Tovi and Edi Vaisbuch EMAIL logo
Published/Copyright: January 12, 2016
Download Article (PDF)
Journal of Perinatal Medicine
From the journal Journal of Perinatal Medicine Volume 44 Issue 1

The clinical entity of intrapartum fever, the hallmark sign of clinical chorioamnionitis, has been known for centuries [1]. As early as the late 18th century it was precisely defined as any fever arising in consequences of pregnancy or delivery [2]. The grave consequences of this condition were well known to the physicians at that time as attested by the comment of John Leake of the New Westminster Lying-in Hospital in 1772: “If those diseases which have been found most dangerous and mortal in their effects ought principally to be considered by physicians, none will more deservedly engage their attention than the Childbed Fever, as there is not, perhaps, any malady…” [3].

The criteria for the diagnosis of clinical chorioamnionitis include fever and two or more of the following: maternal and fetal tachycardia, uterine tenderness, foul smelling amniotic fluid, and maternal leukocytosis [4–13]. These criteria have been used in clinical practice since the early 70s of the previous century. When it comes to management and understanding of the pathophysiology of intrapartum fever and clinical chorioamnionitis, a walk into labor and delivery ward today can be like taking a step back to the 70s. Admittedly, with regard to intrapartum fever, our discipline, which was awarded the wooden spoon by Archie Cochrane for being the least evidence based medical specialty [14], has not done enough yet to restore its reputation.

The association between short- and long-term adverse neonatal outcomes and chorioamnionitis are well established [11, 15–39], with neonatal sepsis and cerebral palsy being the most noteworthy [17, 21]. This issue of the Journal shed new light on the ongoing clinical challenge of diagnosis and management of chorioamnionitis at term. Using state-of-the-art methods and unique study and control population, this set of articles [40–44] provides a wealth of novel and important information and can be viewed as the first genuine and comprehensive attempt to decipher the enigma of clinical chorioamnionitis. These articles challenge the diagnosis, the underlying mechanism of disease and indeed, the very definition of clinical chorioamnionitis at term. Precision in diagnosis and taxonomy, as well as the molecular mechanism(s) responsible for this common and important complication may have preventive, diagnostic and therapeutical implications. Similarly important is to avoid over diagnosis which leads to unnecessary, potentially harmful, treatment and interventions. The urgent need to improve the knowledge in this important subject is evident as the human fetus is probably most vulnerable during labor and delivery and that these complications should be regarded as preventable.

The initial report [45] by Romero’s group recently published in this Journal challenges the clinical diagnosis of chorioamnionitis at term. Using both cultivation and molecular techniques of amniotic fluid, almost 40% of women clinically diagnosed with chorioamnionitis did not have any evidence of bacteria in the amniotic cavity. Notably, nearly 50% did not have evidence of acute inflammatory lesions of the placenta (i.e. histologic chrioamnionitis [46]).

In the first report [40] of the series of articles published in this special issue of the Journal, the authors characterized the intra-amniotic inflammatory response in women with clinical chorioamnionitis at term. Expectably, women with intra-amniotic infection and/or inflammation had significantly higher concentrations of pro- and anti-inflammatory cytokines and chemokines compared to women at term in labor without intra-amniotic inflammation. Yet, although diagnosed with clinical chorioamnionitis, patients without intra-amniotic inflammation had a similar amniotic fluid expression of cytokines/chemokines to normal women in labor at term [40].

The next step was to demonstrate how well the different clinical criteria used for the diagnosis of chorioamnionitis perform in the identification of proven intra-amniotic infection [41]. Not surprisingly, none of the individual clinical signs, or any of their combination, accurately identified patients with intra-amniotic infection or microbial-associated intra-amniotic inflammation. Thus, there is a need for better methods to enhance our precision in the clinical diagnosis of chorioamnionitis at term.

These results lead the authors to focus their interest in the maternal compartment to characterize the plasma cytokine profile [42]. Using cutting edge methods, the authors demonstrate that patients with clinical chorioamnionitis at term have higher maternal plasma concentrations of pyrogenic cytokines than patients in spontaneous labor at term without a fever. However, the absolute concentration of cytokines cannot be used to identify those who have bacteria in the amniotic fluid, suggesting that amniotic fluid assessment is required to identify women with intra-amniotic inflammation.

Next, the authors focused their attention to the fetus [43] and placenta [44]. Characterization of inflammatory status in dyads of maternal-fetal samples revealed that neonates born to mothers with clinical chorioamnionitis at term had higher concentrations of umbilical cord plasma cytokines than those born to mothers without clinical chorioamnionitis. This inflammatory “mirror syndrome” was anticipated. However, less predictable is the finding that even neonates exposed to clinical chorioamnionitis without intra-amniotic inflammation had elevated concentrations of inflammatory cytokines. This suggests that intrapartum fever, per se, is associated with an altered fetal immune response. Thus, antibiotics administration, which is the mainstay of treatment in patients with intrapartum fever [9, 47–50], may be too little and too late. The role of other therapeutic strategies such as anti-inflammatory agents should be investigated in this clinical set-up [51, 52].

The conventional wisdom is that histology is the “gold standard” for the diagnosis of chorioamnionitis. Nevertheless, despite the association between histologic chorioamnionitis/funisitis and intra-amniotic infection/fetal inflammatory response syndrome [53–55], the performance indices of histology were surprisingly low [44]. The practical conclusion is that the current pathologic methods have limitations in the identification of the fetus exposed to amniotic cavity infection. One way to look at the placenta is as the “black-box” of the pregnancy. However, in contrast to chorioamnionitis in preterm gestations, in the context of term deliveries, the time interval between the occurrence of clinical chorioamnionitis and the delivery of the placenta may be too short for the placenta to “record” the insult.

The term “clinical chorioamnionitis” is an oxymoron. As the name implies, diagnosis of chorioamnionitis is based on histological evaluation of the placenta. However, the prefix “clinical” means that the diagnosis should be made well before the delivery of the placenta. The articles in this special issue of the Journal bridge the gap and attempt to ease the inherent tension between the “clinical” and the “chorioamnionitis”.

Corresponding author: Prof. Edi Vaisbuch, Department of Obstetrics and Gynecology, Kaplan Medical Center, Rehovot, and The Hebrew University and Hadassah School of Medicine, Jerusalem, Israel, Tel.: +972-8-9441-225, Fax: +972-8-9411-944, E-mail:

References

[1] DeLacy M. Puerperal fever in eighteenth-century Britain. Bull Hist Med. 1989;63:521–56.Search in Google Scholar

[2] Kirkland T. A treatise on childbed fevers and the methods of preventing them. FC 1774:283.Search in Google Scholar

[3] Leake J. Practical observations on the Childbed fever. FC 1772:117.Search in Google Scholar

[4] MacVicar J. Chorioamnionitis. Clin Obstet Gynecol. 1970;13:272–90.10.1097/00003081-197006000-00005Search in Google Scholar

[5] Gibbs RS. Diagnosis of intra-amniotic infection. Semin Perinatol. 1977;1:71–7.Search in Google Scholar

[6] Gibbs RS, Castillo MS, Rodgers PJ. Management of acute chorioamnionitis. Am J Obstet Gynecol. 1980;136:709–13.10.1016/0002-9378(80)90445-7Search in Google Scholar

[7] Gibbs RS, Blanco JD, St Clair PJ, Castaneda YS. Quantitative bacteriology of amniotic fluid from women with clinical intraamniotic infection at term. J Infect Dis. 1982;145:1–8.10.1093/infdis/145.1.1Search in Google Scholar

[8] Hollander D. Diagnosis of chorioamnionitis. Clin Obstet Gynecol. 1986;29:816–25.10.1097/00003081-198612000-00008Search in Google Scholar

[9] Gibbs RS, Dinsmoor MJ, Newton ER, Ramamurthy RS. A randomized trial of intrapartum versus immediate postpartum treatment of women with intra-amniotic infection. Obstet Gynecol. 1988;72:823–8.10.1097/00006250-198812000-00001Search in Google Scholar

[10] Gilstrap LC, 3rd, Cox SM. Acute chorioamnionitis. Obstet Gynecol Clin North Am. 1989;16:373–9.10.1016/S0889-8545(21)00165-0Search in Google Scholar

[11] Newton ER. Chorioamnionitis and intraamniotic infection. Clin Obstet Gynecol. 1993;36:795–808.10.1097/00003081-199312000-00004Search in Google Scholar PubMed

[12] Tita AT, Andrews WW. Diagnosis and management of clinical chorioamnionitis. Clin Perinatol. 2010;37:339–54.10.1016/j.clp.2010.02.003Search in Google Scholar PubMed PubMed Central

[13] Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science 2014;345:760–5.10.1126/science.1251816Search in Google Scholar PubMed PubMed Central

[14] Godlee F. Obstetrics and the wooden spoon. Br Med J. 2012;345:e7017.10.1136/bmj.e7017Search in Google Scholar

[15] Yoder PR, Gibbs RS, Blanco JD, Castaneda YS, St Clair PJ. A prospective, controlled study of maternal and perinatal outcome after intra-amniotic infection at term. Am J Obstet Gynecol. 1983;145:695–701.10.1016/0002-9378(83)90575-6Search in Google Scholar

[16] Nelson KB, Ellenberg JH. Antecedents of cerebral palsy. I. Univariate analysis of risks. Am J Dis Child. 1985;139:1031–8.10.1001/archpedi.1985.02140120077032Search in Google Scholar

[17] Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. J Am Med Assoc. 1997;278:207–11.10.1001/jama.1997.03550030047032Search in Google Scholar

[18] Alexander JM, McIntire DM, Leveno KJ. Chorioamnionitis and the prognosis for term infants. Obstet Gynecol. 1999;94:274–8.Search in Google Scholar

[19] Yoon BH, Romero R, Kim KS, Park JS, Ki SH, Kim BI, et al. A systemic fetal inflammatory response and the development of bronchopulmonary dysplasia. Am J Obstet Gynecol. 1999;181:773–9.10.1016/S0002-9378(99)70299-1Search in Google Scholar

[20] Yoon BH, Romero R, Park JS, Kim CJ, Kim SH, Choi JH, et al. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol. 2000;182:675–81.10.1067/mob.2000.104207Search in Google Scholar PubMed

[21] Wu YW, Colford, JM Jr. Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis. J Am Med Assoc. 2000;284:1417–24.10.1001/jama.284.11.1417Search in Google Scholar PubMed

[22] Wu YW, Escobar GJ, Grether JK, Croen LA, Greene JD, Newman TB. Chorioamnionitis and cerebral palsy in term and near-term infants. J Am Med Assoc. 2003;290:2677–84.10.1001/jama.290.20.2677Search in Google Scholar PubMed

[23] Mittendorf R, Covert R, Montag AG, elMasri W, Muraskas J, Lee KS, et al. Special relationships between fetal inflammatory response syndrome and bronchopulmonary dysplasia in neonates. J Perinat Med. 2005;33:428–34.10.1515/JPM.2005.076Search in Google Scholar PubMed

[24] Bashiri A, Burstein E, Mazor M. Cerebral palsy and fetal inflammatory response syndrome: a review. J Perinat Med. 2006;34:5–12.10.1515/JPM.2006.001Search in Google Scholar PubMed

[25] Lee SE, Romero R, Jung H, Park CW, Park JS, Yoon BH. The intensity of the fetal inflammatory response in intraamniotic inflammation with and without microbial invasion of the amniotic cavity. Am J Obstet Gynecol. 2007;197:294 e1–6.10.1016/j.ajog.2007.07.006Search in Google Scholar PubMed

[26] 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;42:731–43.10.1515/jpm-2014-0250Search in Google Scholar PubMed PubMed Central

[27] Horvath B, Lakatos F, Tóth C, Bödecs T, Bódis J. Silent chorioamnionitis and associated pregnancy outcomes: a review of clinical data gathered over a 16-year period. J Perinat Med. 2014;42:441–7.10.1515/jpm-2013-0186Search in Google Scholar PubMed

[28] Bastek JA, Weber AL, McShea MA, Ryan ME, Elovitz MA. Prenatal inflammation is associated with adverse neonatal outcomes. Am J Obstet Gynecol. 2014;210:450 e1–10.10.1016/j.ajog.2013.12.024Search in Google Scholar PubMed

[29] 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 e1–125 e15.10.1016/j.ajog.2013.11.032Search in Google Scholar PubMed

[30] 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 e1–325 e10.10.1016/j.ajog.2013.10.882Search in Google Scholar PubMed

[31] Boyer A, Cameron L, Munoz-Maldonado Y, Bronsteen R, Comstock CH, Lee W, Goncalves LF. Clinical significance of amniotic fluid sludge in twin pregnancies with a short cervical length. Am J Obstet Gynecol. 2014;211:506 e1–9.10.1016/j.ajog.2014.05.044Search in Google Scholar PubMed

[32] Cobo T, Kacerovsky M, Jacobsson B. Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol. 2014;211:708.10.1016/j.ajog.2014.06.060Search in Google Scholar PubMed

[33] Stanek J, Biesiada J. Relation of placental diagnosis in stillbirth to fetal maceration and gestational age at delivery. J Perinat Med. 2014;42:457–71.10.1515/jpm-2013-0219Search in Google Scholar PubMed

[34] Armstrong-Wells J, Donnelly M, Post MD, Manco-Johnson MJ, Winn VD, Sébire G. Inflammatory predictors of neurologic disability after preterm premature rupture of membranes. Am J Obstet Gynecol. 2015;212:212 e1–9.10.1016/j.ajog.2014.09.016Search in Google Scholar PubMed PubMed Central

[35] Kim CJ, Romero R, Chaemsaithong P, Kim JS. Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance. Am J Obstet Gynecol. 2015;213(4 Suppl):S53–69.10.1016/j.ajog.2015.08.041Search in Google Scholar PubMed PubMed Central

[36] Mir IN, Johnson-Welch SF, Nelson DB, Brown LS, Rosenfeld CR, Chalak LF. Placental pathology is associated with severity of neonatal encephalopathy and adverse developmental outcomes following hypothermia. Am J Obstet Gynecol. 2015. doi: 10.1016/j.ajog.2015.09.072.10.1016/j.ajog.2015.09.072Search in Google Scholar

[37] Wong LF, Holmgren CM, Silver RM, Varner MW, Manuck TA. Outcomes of expectantly managed pregnancies with multiple gestations and preterm premature rupture of membranes prior to 26 weeks. Am J Obstet Gynecol. 2015;212:215 e1–9.10.1016/j.ajog.2014.09.005Search in Google Scholar

[38] Lee Y, Kim HJ, Choi SJ, Oh SY, Kim JS, Roh CR, et al. Is there a stepwise increase in neonatal morbidities according to histological stage (or grade) of acute chorioamnionitis and funisitis?: effect of gestational age at delivery. J Perinat Med. 2015;43:259–67.10.1515/jpm-2014-0035Search in Google Scholar

[39] Romero R, Grivel JC, Tarca AL, Chaemsaithong P, Xu Z, Fitzgerald W, et al. Evidence of perturbations of the cytokine network in preterm labor. Am J Obstet Gynecol. 2015. doi: 10.1016/j.ajog.2015.07.037.10.1016/j.ajog.2015.07.037Search in Google Scholar

[40] 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.Search in Google Scholar

[41] Romero R, Chaemsaithong P, Korzeniewski SJ, Kusanovic JP, Docheva N, Martinez-Varea A, et al. Clinical chorioamnionitis at term III: how well do clinical criteria perform in the identification of proven intra-amniotic infection? J Perinat Med. 2016;44:23–32.10.1515/jpm-2015-0044Search in Google Scholar

[42] Romero R, Chaemsaithong P, Docheva N, Korzeniewski SJ, Tarca AL, Bhatti G, et al. Clinical chorioamnionitis at term IV: the maternal plasma cytokine profile. J Perinat Med. 2016;44:77–98.Search in Google Scholar

[43] Romero R, Chaemsaithong P, Docheva N, Korzeniewski SJ, Tarca AL, Bhatti G, 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;44:53–76.Search in Google Scholar

[44] Romero R, Chaemsaithong P, Docheva N, Korzeniewski SJ, Kusanovic JP, Yoon BH, et al. Clinical chorioamnionitis at term VI: acute chorioamnionitis and funisitis according to the presence or absence of microorganisms and inflammation in the amniotic cavity. J Perinat Med. 2016;44:33–51.Search in Google Scholar

[45] 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;43:19–36.10.1515/jpm-2014-0249Search in Google Scholar

[46] Kim CJ, Romero R, Chaemsaithong P, Chaiyasit N, Yoon BH, Kim YM. Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance. Am J Obstet Gynecol. 2015;213(4 Suppl):S29–52.10.1016/j.ajog.2015.08.040Search in Google Scholar

[47] Gilstrap LC, 3rd, Leveno KJ, Cox SM, Burris JS, Mashburn M, Rosenfeld CR. Intrapartum treatment of acute chorioamnionitis: impact on neonatal sepsis. Am J Obstet Gynecol. 1988;159:579–83.10.1016/S0002-9378(88)80012-7Search in Google Scholar

[48] Maberry MC, Gilstrap 3rd, LC. Intrapartum antibiotic therapy for suspected intraamniotic infection: impact on the fetus and neonate. Clin Obstet Gynecol. 1991;34:345–51.10.1097/00003081-199106000-00016Search in Google Scholar PubMed

[49] Edwards SE, Grobman WA, Lappen JR, Winter C, Fox R, Lenguerrand E, et al. Modified obstetric early warning scoring systems (MOEWS): validating the diagnostic performance for severe sepsis in women with chorioamnionitis. Am J Obstet Gynecol. 2015;212:536 e1–8.10.1016/j.ajog.2014.11.007Search in Google Scholar PubMed

[50] Saccone G, Berghella V. Antibiotic prophylaxis for term or near-term premature rupture of membranes: metaanalysis of randomized trials. Am J Obstet Gynecol. 2015;212:627 e1–9.10.1016/j.ajog.2014.12.034Search in Google Scholar

[51] Wang B, Navath RS, Menjoge AR, Balakrishnan B, Bellair R, Dai H, et al., Inhibition of bacterial growth and intramniotic infection in a guinea pig model of chorioamnionitis using PAMAM dendrimers. Int J Pharm. 2010;395:298–308.10.1016/j.ijpharm.2010.05.030Search in Google Scholar

[52] Kannan S, Dai H, Navath RS, Balakrishnan B, Jyoti A, Janisse J, et al., Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model. Sci Transl Med. 2012;4:130ra46.10.1126/scitranslmed.3003162Search in Google Scholar

[53] Gomez R, Romero R, Kusanovic JP, Mazaki-Tovi S, Pineles BL, Erez O, et al. The fetal inflammatory response syndrome. Am J Obstet Gynecol. 1998;179:194–202.10.1016/S0002-9378(98)70272-8Search in Google Scholar

[54] 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;11:18–25.10.1080/jmf.11.1.18.25Search in Google Scholar PubMed

[55] Gotsch F, Romero R, Kusanovic JP, Mazaki-Tovi S, Pineles BL, Erez O, et al. The fetal inflammatory response syndrome. Clin Obstet Gynecol. 2007;50:652–83.10.1097/GRF.0b013e31811ebef6Search in Google Scholar PubMed

Published Online: 2016-1-12
Published in Print: 2016-1-1

©2016 by De Gruyter

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Clinical chorioamnionitis – an ongoing obstetrical conundrum
  4. Original articles
  5. Clinical chorioamnionitis at term II: the intra-amniotic inflammatory response
  6. Clinical chorioamnionitis at term III: how well do clinical criteria perform in the identification of proven intra-amniotic infection?
  7. Clinical chorioamnionitis at term VI: acute chorioamnionitis and funisitis according to the presence or absence of microorganisms and inflammation in the amniotic cavity
  8. Clinical chorioamnionitis at term V: umbilical cord plasma cytokine profile in the context of a systemic maternal inflammatory response
  9. Clinical chorioamnionitis at term IV: the maternal plasma cytokine profile
  10. Screening of lysyl oxidase (LOX) and lysyl oxidase like (LOXL) enzyme expression and activity in preterm prelabor rupture of fetal membranes
  11. Letter to the Editor
  12. GPR120 local regulation might explain the contradictory pro/anti-inflammatory effects of ω-3 PUFA observed in gestational tissue
  13. Letter Reply
  14. Reply to: GPR120 local regulation might explain the contradictory pro/anti-inflammatory effects of ω-3 PUFA observed in gestational tissues
  15. Congress Calendar
  16. Congress Calendar
https://doi.org/10.1515/jpm-2015-0366

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Clinical chorioamnionitis – an ongoing obstetrical conundrum
  4. Original articles
  5. Clinical chorioamnionitis at term II: the intra-amniotic inflammatory response
  6. Clinical chorioamnionitis at term III: how well do clinical criteria perform in the identification of proven intra-amniotic infection?
  7. Clinical chorioamnionitis at term VI: acute chorioamnionitis and funisitis according to the presence or absence of microorganisms and inflammation in the amniotic cavity
  8. Clinical chorioamnionitis at term V: umbilical cord plasma cytokine profile in the context of a systemic maternal inflammatory response
  9. Clinical chorioamnionitis at term IV: the maternal plasma cytokine profile
  10. Screening of lysyl oxidase (LOX) and lysyl oxidase like (LOXL) enzyme expression and activity in preterm prelabor rupture of fetal membranes
  11. Letter to the Editor
  12. GPR120 local regulation might explain the contradictory pro/anti-inflammatory effects of ω-3 PUFA observed in gestational tissue
  13. Letter Reply
  14. Reply to: GPR120 local regulation might explain the contradictory pro/anti-inflammatory effects of ω-3 PUFA observed in gestational tissues
  15. Congress Calendar
  16. Congress Calendar
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 12.10.2025 from https://www.degruyterbrill.com/document/doi/10.1515/jpm-2015-0366/html
Scroll to top button