J Korean Med Sci.  2017 Mar;32(3):480-487. 10.3346/jkms.2017.32.3.480.

Amniotic Fluid Infection, Cytokine Levels, and Mortality and Adverse Pulmonary, Intestinal, and Neurologic Outcomes in Infants at 32 Weeks' Gestation or Less

Affiliations
  • 1Departments of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea. pkh0419@snubh.org
  • 2Department of Medicine, Graduate School, Kyung Hee University, Seoul, Korea.
  • 3Department of Pediatrics, Inha University College of Medicine, Inha University Hospital, Incheon, Korea.

Abstract

To what extent the risks of neonatal morbidities are directly related to premature birth or to biological mechanisms of preterm birth remains uncertain. We aimed to examine the effect of exposure to amniotic fluid (AF) infection and elevated cytokine levels on the mortality and pulmonary, intestinal, and neurologic outcomes of preterm infants, and whether these associations persist after adjustment for gestational age at birth. This retrospective cohort study included 152 premature singleton infants who were born at ≤ 32 weeks. AF obtained by amniocentesis was cultured; and interleukin-6 (IL-6) and IL-8 levels in AF were determined. The primary outcome was adverse perinatal outcome defined as the presence of one or more of the followings: stillbirth, neonatal death, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, and periventricular leukomalacia. Logistic regression analysis was adjusted for gestational age at birth and other potential confounders. In bivariate analyses, elevated AF IL-6 and IL-8 levels were significantly associated with adverse perinatal outcome. These results were not changed after adjusting for potential confounders, such as low Apgar scores, mechanical ventilation, and surfactant application. However, the independent effect of elevated cytokine levels in AF disappeared when additionally adjusted for low gestational age at birth; consequently, low gestational age remained strongly associated with the risk of adverse perinatal outcome. In conclusion, elevated levels of pro-inflammatory cytokines in AF are associated with increased risk of adverse perinatal outcomes, but this risk is not independent of low gestational age at birth. Culture-proven AF infection is not associated with this risk.

Keyword

Amniotic Fluid Infection; Cytokines; Gestational Age; Perinatal Outcome; Preterm Birth

MeSH Terms

Amniocentesis
Amniotic Fluid*
Bronchopulmonary Dysplasia
Cohort Studies
Cytokines
Enterocolitis, Necrotizing
Female
Gestational Age
Hemorrhage
Humans
Infant*
Infant, Newborn
Infant, Premature
Interleukin-6
Interleukin-8
Leukomalacia, Periventricular
Logistic Models
Mortality*
Parturition
Perinatal Death
Pregnancy*
Premature Birth
Respiration, Artificial
Retrospective Studies
Stillbirth
Cytokines
Interleukin-6
Interleukin-8

Figure

  • Fig. 1 The presence of composite adverse perinatal outcome, BPD, and IVH according to AF IL-6 and IL-8 levels and GA at birth. (): cut-offs for IL-6 and IL-8 levels; (): cut-off for GA at birth. AF = amniotic fluid, BPD = bronchopulmonary dysplasia, GA = gestational age, IVH = intraventricular hemorrhage, IL = interleukin.


Cited by  1 articles

Maternal Plasma and Amniotic Fluid LBP, Pentraxin 3, Resistin, and IGFBP-3: Biomarkers of Microbial Invasion of Amniotic Cavity and/or Intra-amniotic Inflammation in Women with Preterm Premature Rupture of Membranes
Eunwook Joo, Kyo Hoon Park, Yu Mi Kim, Kwanghee Ahn, Subeen Hong
J Korean Med Sci. 2021;36(44):e279.    doi: 10.3346/jkms.2021.36.e279.


Reference

1. Callaghan WM, MacDorman MF, Rasmussen SA, Qin C, Lackritz EM. The contribution of preterm birth to infant mortality rates in the United States. Pediatrics. 2006; 118:1566–1573.
2. Robertson PA, Sniderman SH, Laros RK Jr, Cowan R, Heilbron D, Goldenberg RL, Iams JD, Creasy RK. Neonatal morbidity according to gestational age and birth weight from five tertiary care centers in the United States, 1983 through 1986. Am J Obstet Gynecol. 1992; 166:1629–1641.
3. Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF; Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA. 2003; 289:1124–1129.
4. Luig M, Lui K. NSW & ACT NICUS Group. Epidemiology of necrotizing enterocolitis--Part II: risks and susceptibility of premature infants during the surfactant era: a regional study. J Paediatr Child Health. 2005; 41:174–179.
5. Hack M, Wilson-Costello D, Friedman H, Taylor GH, Schluchter M, Fanaroff AA. Neurodevelopment and predictors of outcomes of children with birth weights of less than 1000 g: 1992-1995. Arch Pediatr Adolesc Med. 2000; 154:725–731.
6. Park KH, Kim SN, Oh KJ, Lee SY, Jeong EH, Ryu A. Noninvasive prediction of intra-amniotic infection and/or inflammation in preterm premature rupture of membranes. Reprod Sci. 2012; 19:658–665.
7. Jung HJ, Park KH, Kim SN, Hong JS, Oh KJ, Kim G, Kwon JY. Non-invasive prediction of intra-amniotic inflammation in women with preterm labor. Ultrasound Obstet Gynecol. 2011; 37:82–87.
8. Yoon BH, Romero R, Moon JB, Shim SS, Kim M, Kim G, Jun JK. Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Obstet Gynecol. 2001; 185:1130–1136.
9. 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.
10. Gravett MG, Hitti J, Hess DL, Eschenbach DA. Intrauterine infection and preterm delivery: evidence for activation of the fetal hypothalamic-pituitary-adrenal axis. Am J Obstet Gynecol. 2000; 182:1404–1413.
11. 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.e1–294.e6.
12. Hitti J, Krohn MA, Patton DL, Tarczy-Hornoch P, Hillier SL, Cassen EM, Eschenbach DA. Amniotic fluid tumor necrosis factor-alpha and the risk of respiratory distress syndrome among preterm infants. Am J Obstet Gynecol. 1997; 177:50–56.
13. Ghezzi F, Gomez R, Romero R, Yoon BH, Edwin SS, David C, Janisse J, Mazor M. Elevated interleukin-8 concentrations in amniotic fluid of mothers whose neonates subsequently develop bronchopulmonary dysplasia. Eur J Obstet Gynecol Reprod Biol. 1998; 78:5–10.
14. Yoon BH, Jun JK, Romero R, Park KH, Gomez R, Choi JH, Kim IO. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol. 1997; 177:19–26.
15. Hitti J, Tarczy-Hornoch P, Murphy J, Hillier SL, Aura J, Eschenbach DA. Amniotic fluid infection, cytokines, and adverse outcome among infants at 34 weeks’ gestation or less. Obstet Gynecol. 2001; 98:1080–1088.
16. Yoon BH, Romero R, Jun JK, Park KH, Park JD, Ghezzi F, Kim BI. Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia. Am J Obstet Gynecol. 1997; 177:825–830.
17. Combs CA, Gravett M, Garite TJ, Hickok DE, Lapidus J, Porreco R, Rael J, Grove T, Morgan TK, Clewell W, et al. Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol. 2014; 210:125.e1–125.15.
18. Lee SY, Park KH, Jeong EH, Oh KJ, Ryu A, Kim A. Intra-amniotic infection/inflammation as a risk factor for subsequent ruptured membranes after clinically indicated amniocentesis in preterm labor. J Korean Med Sci. 2013; 28:1226–1232.
19. Ryu A, Park KH, Oh KJ, Lee SY, Jeong EH, Park JW. Predictive value of combined cervicovaginal cytokines and gestational age at sampling for intra-amniotic infection in preterm premature rupture of membranes. Acta Obstet Gynecol Scand. 2013; 92:517–524.
20. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001; 163:1723–1729.
21. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978; 187:1–7.
22. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978; 92:529–534.
23. Section V. Provisions for neonatal care. In : Martin RJ, Fanaroff AA, Walsh MC, editors. Fanaroff and Martin's Neonatal-Perinatal Medicine. 9th ed. St. Louis, MO: Elsevier;2011. p. 553–758.
24. Romero R, Scioscia AL, Edberg SC, Hobbins JC. Use of parenteral antibiotic therapy to eradicate bacterial colonization of amniotic fluid in premature rupture of membranes. Obstet Gynecol. 1986; 67:15S–7S.
25. Mazor M, Chaim W, Hershkowitz R, Wiznitzer A. Eradication of Viridans streptococci from the amniotic cavity with transplacental antibiotic treatment. Arch Gynecol Obstet. 1994; 255:147–151.
26. Lee SE, Romero R, Park CW, Jun JK, Yoon BH. The frequency and significance of intraamniotic inflammation in patients with cervical insufficiency. Am J Obstet Gynecol. 2008; 198:633.e1–633.e8.
27. Kasper DC, Mechtler TP, Böhm J, Petricevic L, Gleiss A, Spergser J, Witt A, Herkner KR, Berger A. In utero exposure to Ureaplasma spp. is associated with increased rate of bronchopulmonary dysplasia and intraventricular hemorrhage in preterm infants. J Perinat Med. 2011; 39:331–336.
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.e1–450.10.
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