Average and time-specific maternal prenatal inflammatory biomarkers and the risk of labor epidural associated fever

Autoři: Dominique Y. Arce aff001;  Andrea Bellavia aff002;  David E. Cantonwine aff003;  Olivia J. Napoli aff004;  John D. Meeker aff005;  Tamarra James-Todd aff002;  Thomas F. McElrath aff003;  Lawrence C. Tsen aff001
Působiště autorů: Department of Anesthesiology, Perioperative and Pain Medicine, Division of Obstetric Anesthesia, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America aff001;  Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America aff002;  Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America aff003;  Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania, United States of America aff004;  Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan, United States of America aff005
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222958



The use of labor epidural analgesia has been associated with intrapartum fever, known as labor epidural associated fever (LEAF). LEAF is most commonly non-infectious in origin and associated with elevated inflammatory cytokines.


The LIFECODES pregnancy cohort was designed to prospectively collect data to evaluate the association of maternal inflammatory biomarkers with preterm birth in women who delivered between 2007 and 2008 at Brigham and Women’s Hospital. Our secondary analysis of the data from the cohort identified 182 women for whom inflammatory biomarkers (i.e. interleukin-10, interleukin-1β, interleukin-6, tumor necrosis factor-α and C-reactive protein) collected longitudinally over four prenatal visits was available. Maternal temperature and other clinical variables were abstracted from medical records. The primary outcome, the presence of LEAF, was defined as oral temperature ≥ 38°C (≥100.4°F) after epidural analgesia initiation. Multivariable logistic regression estimated the association between inflammatory biomarker concentrations and the odds of developing an intrapartum fever after adjusting for a number of potential confounders.


Women who developed LEAF were more likely to have a longer duration of epidural analgesia, whereas women who did not develop LEAF were more likely to have induced labor and positive or unknown Group B Streptococcus colonization status. However, no differences were seen by nulliparity, mode of delivery, white blood cell count at admission, baseline temperature, length of rupture of membranes and number of cervical exams performed during labor. Unadjusted and multivariable logistic regression models did not provide evidence for or exclude an association between individual maternal inflammatory biomarkers and the odds of developing LEAF, regardless of visit time-period.


The predictive value of maternal inflammatory biomarkers measured during early- and mid-pregnancy for the risk of developing LEAF cannot be excluded.

Klíčová slova:

Analgesia – Biomarkers – Cytokines – Epidural block – Fevers – Inflammation – Labor and delivery – Pregnancy


1. Butwick AJ, Bentley J, Wong CA, Snowden JM, Sun E, Guo N. United States State-Level Variation in the Use of Neuraxial Analgesia During Labor for Pregnant Women. JAMA network open. 2018 Dec 7;1(8):e186567–. doi: 10.1001/jamanetworkopen.2018.6567 30646335

2. Segal S. Labor epidural analgesia and maternal fever. Anesthesia & Analgesia. 2010 Dec 1;111(6):1467–75.

3. 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 Feb 1;129(2):e447–54. doi: 10.1542/peds.2010-2301 22291120

4. Lieberman E, Lang JM, Frigoletto F, Richardson DK, Ringer SA, Cohen A. Epidural analgesia, intrapartum fever, and neonatal sepsis evaluation. Pediatrics. 1997 Mar 1;99(3):415–419. doi: 10.1542/peds.99.3.415 9041298

5. Zaretsky MV, Alexander JM, Byrd W, Bawdon RE. Transfer of inflammatory cytokines across the placenta. Obstetrics & Gynecology. 2004 Mar 1;103(3):546–550.

6. Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. Jama. 1997 Jul 16;278(3):207–211. 9218666

7. Impey L, Greenwood C, MacQuillan K, Reynolds M, Sheil O. Fever in labour and neonatal encephalopathy: a prospective cohort study. British Journal of Obstetrics and Gynaecology. 2001 Jun 1;108(6):594–597. doi: 10.1111/j.1471-0528.2001.00145.x 11426893

8. Blume HK, Li CI, Loch CM, Koepsell TD. Intrapartum fever and chorioamnionitis as risks for encephalopathy in term newborns: a case–control study. Developmental Medicine & Child Neurology. 2008 Jan;50(1):19–24.

9. American College of Obstetricians and Gynecologists. Intrapartum management of intraamniotic infection (Committee Opinion No. 712). Obstetrics and Gynecology. 2017;130(2):e95–101. doi: 10.1097/AOG.0000000000002236 28742677

10. Riley LE, Celi AC, Onderdonk AB, Roberts DJ, Johnson LC, Tsen LC, et. al. Association of epidural-related fever and noninfectious inflammation in term labor. Obstetrics & Gynecology. 2011 Mar 1;117(3):588–595.

11. Sharma SK, Rogers BB, Alexander JM, McIntire DD, Leveno KJ. A randomized trial of the effects of antibiotic prophylaxis on epidural-related fever in labor. Anesthesia & Analgesia. 2014 Mar 1;118(3):604–610.

12. Goetzl L, Rivers J, Evans T, Citron DR, Richardson BE, Lieberman E, Suresh MS. Prophylactic acetaminophen does not prevent epidural fever in nulliparous women: a double-blind placebo-controlled trial. Journal of perinatology. 2004 Aug;24(8):471. doi: 10.1038/sj.jp.7211128 15141263

13. Wang LZ, Hu XX, Liu X, Qian P, Ge JM, Tang BL. Influence of epidural dexamethasone on maternal temperature and serum cytokine concentration after labor epidural analgesia. International Journal of Gynecology & Obstetrics. 2011 Apr 1;113(1):40–43.

14. Segal S, Pancaro C, Bonney I, Marchand JE. Noninfectious fever in the near-term pregnant rat induces fetal brain inflammation: a model for the consequences of epidural-associated maternal fever. Anesthesia & Analgesia. 2017 Dec 1;125(6):2134–2140.

15. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. New England journal of medicine. 1999 Feb 11;340(6):448–454. doi: 10.1056/NEJM199902113400607 9971870

16. Ouyang W, Rutz S, Crellin NK, Valdez PA, Hymowitz SG. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annual review of immunology. 2011 Apr 23;29:71–109. doi: 10.1146/annurev-immunol-031210-101312 21166540

17. Black S, Kushner I, Samols D. C-reactive protein. Journal of Biological Chemistry. 2004 Nov 19;279(47):48487–48490. doi: 10.1074/jbc.R400025200 15337754

18. Ferguson KK, McElrath TF, Meeker JD. Environmental phthalate exposure and preterm birth. JAMA pediatrics. 2014 Jan 1;168(1):61–67. doi: 10.1001/jamapediatrics.2013.3699 24247736

19. Ferguson KK, McElrath TF, Chen YH, Mukherjee B, Meeker JD. Longitudinal profiling of inflammatory cytokines and C‐reactive protein during uncomplicated and preterm pregnancy. American journal of reproductive immunology. 2014 Sep;72(3):326–336. doi: 10.1111/aji.12265 24807462

20. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstetrics & Gynecology. 2009 Dec 1;114(6):1326–1331.

21. Christian LM, Porter K. Longitudinal changes in serum proinflammatory markers across pregnancy and postpartum: effects of maternal body mass index. Cytokine. 2014 Dec 1;70(2):134–140. doi: 10.1016/j.cyto.2014.06.018 25082648

22. Curtin WM, Katzman PJ, Florescue H, Metlay LA, Ural SH. Intrapartum fever, epidural analgesia and histologic chorioamnionitis. Journal of Perinatology. 2015 Jun;35(6):396. doi: 10.1038/jp.2014.235 25675051

23. Maayan-Metzger A, Mazkereth R, Shani A, Kuint J. Risk factors for maternal intrapartum fever and short-term neonatal outcome. Fetal and pediatric pathology. 2006 Jan 1;25(3):169–177. doi: 10.1080/15513810600908461 17060193

24. Marrie RA, Dawson NV, Garland A. Quantile regression and restricted cubic splines are useful for exploring relationships between continuous variables. Journal of clinical epidemiology. 2009 May 1;62(5):511–517 doi: 10.1016/j.jclinepi.2008.05.015 19135859

25. Goetzl L, Evans T, Rivers J, Suresh MS, Lieberman E. Elevated maternal and fetal serum interleukin-6 levels are associated with epidural fever. American journal of obstetrics and gynecology. 2002 Oct 1;187(4):834–838. doi: 10.1067/mob.2002.127135 12388959

26. Dinarello CA. A clinical perspective of IL‐1β as the gatekeeper of inflammation. European journal of immunology. 2011 May;41(5):1203–1217. doi: 10.1002/eji.201141550 21523780

27. Brennan FM, Green P, Amjadi P, Robertshaw HJ, Alvarez‐Iglesias M, Takata M. Interleukin‐10 regulates TNF‐α− converting enzyme (TACE/ADAM‐17) involving a TIMP‐3 dependent and independent mechanism. European journal of immunology. 2008 Apr;38(4):1106–1117. doi: 10.1002/eji.200737821 18383040

28. Brennan FM, Green P, Amjadi P, Robertshaw HJ, Alvarez‐Iglesias M, Takata M. Interleukin‐10 regulates TNF‐α− converting enzyme (TACE/ADAM‐17) involving a TIMP‐3 dependent and independent mechanism. European journal of immunology. 2008 Apr;38(4):1106–1117. doi: 10.1002/eji.200737821 18383040

29. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harbor perspectives in biology. 2014 Oct 1;6(10):a016295. doi: 10.1101/cshperspect.a016295 25190079

30. Keelan JA, Blumenstein M, Helliwell RJ, Sato TA, Marvin KW, Mitchell MD. Cytokines, prostaglandins and parturition—a review. Placenta. 2003 Apr 1;24:S33–46. doi: 10.1053/plac.2002.0948 12842412

31. Cartmell T, Poole S, Turnbull AV, Rothwell NJ, Luheshi GN. Circulating interleukin‐6 mediates the febrile response to localised inflammation in rats. The Journal of physiology. 2000 Aug;526(3):653–661.

32. Chai Z, Gatti S, Toniatti C, Poli V, Bartfai T. Interleukin (IL)-6 gene expression in the central nervous system is necessary for fever response to lipopolysaccharide or IL-1 beta: a study on IL-6-deficient mice. Journal of Experimental Medicine. 1996 Jan 1;183(1):311–316. doi: 10.1084/jem.183.1.311 8551238

33. LeMay LG, Otterness IG, Vander AJ, Kluger MJ. In vivo evidence that the rise in plasma IL 6 following injection of a fever-inducing dose of LPS is mediated by IL 1β. Cytokine. 1990 May 1;2(3):199–204. doi: 10.1016/1043-4666(90)90016-m 2104223

34. Wang J, Ando T, Dunn AJ. Effect of Homologous lnterleukin-1, lnterleukin-6 and Tumor Necrosis Factor-α on the Core Body Temperature of Mice. Neuroimmunomodulation. 1997;4(5–6):230–236. doi: 10.1159/000097341 9650815

35. Zheng H, Fletcher D, Kozak W, Jiang M, Hofmann KJ, Corn CA, et. al. Resistance to fever induction and impaired acute-phase response in interleukin-1β-deficient mice. Immunity. 1995 Jul 1;3(1):9–19. doi: 10.1016/1074-7613(95)90154-x 7621081

36. Del Arroyo AG, Sanchez J, Patel S, Phillips S, Reyes A, Cubillos C, Fernando R, David AL, Reeve A, Sodha S, Ciechanowicz S. Role of leucocyte caspase-1 activity in epidural-related maternal fever: a single-centre, observational, mechanistic cohort study. British journal of anaesthesia. 2019 Jan 1;122(1):92–102. doi: 10.1016/j.bja.2018.09.024 30579413

37. Sun X, Guo JH, Zhang D, Chen JJ, Lin WY, Huang Y, et. al. Activation of the epithelial sodium channel (ENaC) leads to cytokine profile shift to pro‐inflammatory in labor. EMBO molecular medicine. 2018 Oct 1;10(10):e8868. doi: 10.15252/emmm.201808868 30154237

38. Bergeron J, Gerges N, Guiraut C, Grbic D, Allard MJ, Fortier LC, et. al. Activation of the IL-1β/CXCL1/MMP-10 axis in chorioamnionitis induced by inactivated Group B Streptococcus. Placenta. 2016 Nov 1;47:116–123. doi: 10.1016/j.placenta.2016.09.016 27780533

39. Clodi M, Vila G, Geyeregger R, Riedl M, Stulnig TM, Struck J, et. al. Oxytocin alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men. American Journal of Physiology-Endocrinology and Metabolism. 2008 Sep;295(3):E686–91. doi: 10.1152/ajpendo.90263.2008 18593851

40. Cahill AG, Duffy CR, Odibo AO, Roehl KA, Zhao Q, Macones GA. Number of cervical examinations and risk of intrapartum maternal fever. Obstetrics & Gynecology. 2012 Jun 1;119(6):1096–1101.

41. Christian LM. Effects of stress and depression on inflammatory immune parameters in pregnancy. American journal of obstetrics and gynecology. 2014 Sep 1;211(3):275–277. doi: 10.1016/j.ajog.2014.06.042 24956551

Článek vyšel v časopise


2019 Číslo 11