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Journal of Perinatal Medicine

Official Journal of the World Association of Perinatal Medicine

Editor-in-Chief: Dudenhausen, Joachim W.

Editorial Board Member: / Bancalari, Eduardo / Greenough, Anne / Genc, Mehmet R. / Chervenak, Frank A. / Chappelle, Joseph / Bergmann, Renate L. / Bernardes, J.F. / Bevilacqua, G. / Blickstein, Isaac / Cabero Roura, Luis / Carbonell-Estrany, Xavier / Carrera, Jose M. / D`Addario, Vincenzo / D'Alton, MD, Mary E. / Dimitrou, G. / Grunebaum, Amos / Hentschel, Roland / Köpcke, W. / Kawabata, Ichiro / Keirse, M.J.M.C. / Kurjak M.D., Asim / Lee, Ben H. / Levene, Malcolm / Lockwood, Charles J. / Marsal, Karel / Makatsariya, Alexander / Nishida, Hiroshi / Papp, Zoltán / Pejaver, Ranjan Kumar / Pooh, Ritsuko K. / Romero, Roberto / Saugstad, Ola D. / Schenker, Joseph G. / Sen, Cihat / Seri, Istvan / Vetter, Klaus / Winn, Hung N. / Young, Bruce K. / Zimmermann, Roland

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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

Maria-Teresa Gervasi1 / 2 / Gabriella Bracalente4 / Offer Erez5 / Zhong Dong2 / Sonia S. Hassan2, 3 / Lami Yeo2, 3 / Bo Hyun Yoon6 / Tinnakorn Chaiworapongsa2, 3

1Ob/Gyn Unit, Department for Health of Mothers and Children, Azienda Ospedaliera, Padova, Italy

2Perinatology Research Branch, NICHD/NIH/DHHS, Detroit, MI, and Bethesda, MD, USA

3Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA

4Ob/Gyn Unit, Department for Health of Mothers and Children, ASL 9 Treviso, Italy

5Department of Obstetrics and Gynecology, Soroka University Medical Center, School of Medicine, Faculty of Health Sciences, Ben Gurion University of The Negev, Beer Sheva, Israel

6Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea

Corresponding author: Roberto Romero, MD Perinatology Research Branch, NICHD, NIH, DHHS Wayne State University/Hutzel Women’s Hospital 3990 John R, Box 4 Detroit, MI 48201 USA Tel.: +1 (313) 993-2700 Fax: +1 (313) 993-2694

©2012 by Walter de Gruyter Berlin Boston. This content is open access.

Citation Information: . Volume 40, Issue 4, Pages 329–343, ISSN (Online) 1619-3997, ISSN (Print) 0300-5577, DOI: 10.1515/jpm-2012-0034, June 2012

Publication History

Received:
2012-02-21
Revised:
2012-03-09
Accepted:
2012-03-19

Abstract

Introduction: Intra-amniotic inflammation is traditionally defined as an elevation of amniotic fluid interleukin (IL)-6. Previous case control studies have suggested an association between an elevated midtrimester amniotic fluid IL-6 and preterm delivery, although such an association has been recently challenged. Intra-amniotic inflammation can also be defined by an elevation of the T-cell chemokine, Interferon-gamma-inducible protein (IP)-10. An elevation in amniotic fluid IP-10 has been associated with chronic chorioamnionitis, a lesion frequently found in late spontaneous preterm birth and fetal death. In contrast, an elevation in amniotic fluid IL-6 is typically associated with acute chorioamnionitis and funisitis. This study was conducted to examine the relationship between an elevation in amniotic fluid IL-6 in the midtrimester and preterm delivery at or before 32 weeks of gestation, and the amniotic fluid concentration of IP-10 and preterm delivery after 32 weeks of gestation.

Materials and methods: This cohort study included 847 consecutive women undergoing genetic midtrimester amniocentesis; in 796 cases, amniotic fluid and pregnancy outcome was available for study after exclusion of abnormal karyotype and/or fetal congenital anomalies. Spontaneous preterm delivery was defined as early (≤32 weeks) or late (after 32 completed weeks of pregnancy). The amniotic fluid and maternal blood concentrations of IL-6 and IP-10 were measured by specific immunoassays.

Results: 1) The prevalence of preterm delivery was 8.3% (66/796), while those of early and late spontaneous preterm delivery were 1.5% (n=12), and 4.5% (n=36), respectively; 2) patients who had a spontaneous preterm delivery after 32 weeks of gestation had a higher median amniotic fluid IP-10 concentration than those who delivered at term [median 713 pg/mL, inter-quartile range (IQR) 509–1427 pg/mL vs. median 589 pg/mL, IQR 402–953 pg/mL; P=0.006] and an elevation of amniotic fluid IP-10 concentration above 502 pg/mL (derived from an ROC curve) was associated with late spontaneous preterm delivery [odds ratio 3.9 (95% CI 1.6–9.9)]; 3) patients who had a spontaneous preterm delivery ≤32 weeks of gestation had a higher median amniotic fluid IL-6 concentration than those who delivered at term [median 2052 pg/mL, IQR 435–3015 pg/mL vs. median 414 pg/mL, IQR 209–930 pg/mL; P=0.006], and an elevated amniotic fluid IL-6 concentration above 1740 pg/mL (derived from an ROC curve) was associated with early spontaneous preterm delivery [odds ratio 9.5 (95% CI 2.9–31.1)]; 4) subclinical intra-amniotic inflammation, defined as an elevation of IL-6 (≥2.9 ng/mL) or IP-10 (≥2.2 ng/mL) concentration above the 95th percentile of patients who had uncomplicated term delivery (n=652 for IL-6 and n=633 for IP-10), was observed in 6.3% (50/796) and 5.8% (45/770) of cases, respectively. Although each type of inflammation is a risk factor for spontaneous preterm delivery, many patients had a term delivery without complication; 5) the amniotic fluid in the midtrimester did not contain microorganisms detectable with cultivation techniques.

Conclusions: Intra-amniotic inflammation is heterogeneous. Some patients have elevated amniotic fluid concentrations of IL-6, and are at risk for spontaneous preterm delivery before 32 weeks of gestation, while others have an elevated IP-10 (a chemotactic T-cell chemokine) and such patients are at risk for spontaneous preterm delivery after 32 weeks of gestation. A fraction of patients have subclinical intra-amniotic inflammation and deliver at term. The clinical significance of this condition remains to be determined.

Keywords: Chemokines; chorioamnionitis; chronic chorioamnionitis; cytokines; early preterm labor; late preterm labor; maternal anti-fetal rejection; midtrimester amniocentesis; pregnancy

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