Advertisement

The fetal inflammatory response syndrome is a risk factor for morbidity in preterm neonates

Published:September 03, 2013DOI:https://doi.org/10.1016/j.ajog.2013.08.030

      Objective

      The aim of this study was to show and discuss an association between fetal inflammatory response syndrome (FIRS) and an adverse neonatal outcome defined as combined severe neonatal morbidity and mortality in preterm neonates hospitalized in our neonatal intensive care unit.

      Study Design

      This was an observational study including all preterm neonates hospitalized in our neonatal intensive care unit over a 21 month period. FIRS was defined as cord blood interleukin (IL)-6 greater than 11 pg/mL. Main outcome parameter was an adverse neonatal outcome defined as hospital mortality and/or the presence of any of 5 prespecified morbidities (bronchopulmonary dysplasia, periventricular leukomalacia, intraventricular hemorrhage, and early- or late-onset sepsis).

      Results

      Fifty-seven of 176 preterm infants hospitalized during the study period (32%) had an adverse neonatal outcome and 62 of these 176 infants (35%) had FIRS with median IL-6 values of 51.8 pg/mL (range, 11.2 to >1000 pg/mL). In a regression analysis, FIRS was significantly associated with adverse neonatal outcome (P < .001) and with the single outcome parameters, intraventricular hemorrhage and early-onset sepsis (P = .006 and P = .018, respectively). In the bivariate analysis, FIRS was associated with death and bronchopulmonary dysplasia (P = .004 and P < .001, respectively). IL-6 correlated with adverse neonatal outcome (r = 0.411, P < .001). When comparing the correlation in neonates less than 32 weeks' gestational age (r = 0.481, P < .001) with neonates 32 weeks or longer (r = 0.233, P = .019), the difference was nearly significant (P = .065).

      Conclusion

      FIRS is a risk factor for adverse neonatal outcome in preterm infants. In particular, the combination of IL-6 greater than 11 pg/mL and low gestational age increased the risk for severe neonatal morbidity or death.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Callaghan W.M.
        • MacDorman M.F.
        • Rasmussen S.A.
        • Qin C.
        • Lackritz E.M.
        The contribution of preterm birth to infant mortality rates in the United States.
        Pediatrics. 2006; 118: 1566-1573
        • Black R.E.
        • Cousens S.
        • Johnson H.L.
        • et al.
        Global, regional, and national causes of child mortality in 2008: a systematic analysis.
        Lancet. 2010; 375: 1969-1987
        • Mathews T.J.
        • MacDorman M.F.
        Infant mortality statistics from the 2007 period linked birth/infant death data set. National vital statistics reports: from the Centers for Disease Control and Prevention, National Center for Health Statistics.
        Natl Vital Stat Rep. 2011; 59: 1-30
        • Larroque B.
        • Bréart G.
        • Kaminski M.
        • et al.
        Survival of very preterm infants: epipage, a population based cohort study.
        Arch Dis Child Fetal Neonatal Ed. 2004; 89: F139-F144
        • Horbar J.D.
        • Carpenter J.H.
        • Badger G.J.
        • et al.
        Mortality and neonatal morbidity among infants 501 to 1500 grams from 2000 to 2009.
        Pediatrics. 2012; 129: 1019-1026
        • Fanaroff A.A.
        • Stoll B.J.
        • Wright L.L.
        • et al.
        Trends in neonatal morbidity and mortality for very low birthweight infants.
        Am J Obstet Gynecol. 2007; 196: 147.e1-147.e8
        • Romero R.
        • Gomez R.
        • Ghezzi F.
        • et al.
        A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition.
        Am J Obstet Gynecol. 1998; 179: 186-193
        • Goldenberg R.L.
        • Culhane J.F.
        • Iams J.D.
        • Romero R.
        Epidemiology and causes of preterm birth.
        Lancet. 2008; 371: 75-84
        • Trivedi S.
        • Joachim M.
        • McElrath T.
        • et al.
        Fetal-placental inflammation, but not adrenal activation, is associated with extreme preterm delivery.
        Am J Obstet Gynecol. 2012; 206: 236.e1-236.e8
        • Gotsch F.
        • Romero R.
        • Kusanovic J.P.
        • et al.
        The fetal inflammatory response syndrome.
        Clin Obstet Gynecol. 2007; 50: 652-683
        • Lee S.E.
        • Romero R.
        • Jung H.
        • Park C.W.
        • Park J.S.
        • Yoon B.H.
        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
        • Romero R.
        • Gómez R.
        • Chaiworapongsa T.
        • Conoscenti G.
        • Kim J.C.
        • Kim Y.M.
        The role of infection in preterm labour and delivery.
        Pediatr Perinat Epidemiol. 2001; 15: 41-56
        • Goepfert A.R.
        • Andrews W.W.
        • Carlo W.
        • et al.
        Umbilical cord plasma interleukin-6 concentrations in preterm infants and risk of neonatal morbidity.
        Am J Obstet Gynecol. 2004; 191: 1375-1381
        • Watts D.H.
        • Krohn M.A.
        • Hillier S.L.
        • Eschenbach D.A.
        The association of occult amniotic fluid infection with gestational age and neonatal outcome among women in preterm labor.
        Obstet Gynecol. 1992; 79: 351-357
        • Andrews W.W.
        • Hauth J.C.
        • Goldenberg R.L.
        • Gomez R.
        • Romero R.
        • Cassell G.H.
        Amniotic fluid interleukin-6: correlation with upper genital tract microbial colonization and gestational age in women delivered after spontaneous labor versus indicated delivery.
        Am J Obstet Gynecol. 1995; 173: 606-612
        • Yoon B.H.
        • Romero R.
        • Moon J.
        • et al.
        Differences in the fetal interleukin-6 response to microbial invasion of the amniotic cavity between term and preterm gestation.
        J Matern Fetal Neonat Med. 2003; 13: 32-38
        • Gomez R.
        • Romero R.
        • Ghezzi F.
        • Yoon B.H.
        • Mazor M.
        • Berry S.M.
        The fetal inflammatory response syndrome.
        Am J Obstet Gynecol. 1998; 179: 194-202
        • Bashiri A.
        • Burstein E.
        • Mazor M.
        Cerebral palsy and fetal inflammatory response syndrome: a review.
        J Perinat Med. 2006; 34: 5-12
        • Jobe A.H.
        • Bancalari E.
        Bronchopulmonary dysplasia.
        Am J Respir Crit Care Med. 2001; 163: 1723-1729
        • de Vries L.S.
        • Eken P.
        • Dubowitz L.M.
        The spectrum of leukomalacia using cranial ultrasound.
        Behav Brain Res. 1992; 49: 1-6
        • Papile L.A.
        • 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
        • Letsky E.A.
        Haematological values in the newborn.
        in: Rennie J.M. Roberton N.R.C. Textbook of neonatology. Churchill Livingstone, Edinburgh, UK1999: 1399
        • Hofer N.
        • Müller W.
        • Resch B.
        Non-infectious conditions and gestational age influence C-reactive protein values in newborns during the first 3 days of life.
        Clin Chem Lab Med. 2011; 49: 297-302
        • Rooth G.
        • Huch A.
        • Huch R.
        Guidelines for the use of fetal monitoring.
        Int J Gynecol Obstet. 1987; 25: 9
        • Altman D.G.
        • Bland J.M.
        Interaction revisited: the difference between two estimates.
        BMJ. 2003; 326: 219
        • Yoon B.H.
        • Romero R.
        • Park J.S.
        • 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: 1124-1129
        • Ambalavanan N.
        • Carlo W.A.
        • D'Angio C.T.
        • et al.
        Cytokines associated with bronchopulmonary dysplasia or death in extremely low birth weight infants.
        Pediatrics. 2009; 123: 1132-1141
        • Kotecha S.
        • Chan B.
        • Azam N.
        • Silverman M.
        • Shaw R.J.
        Increase in interleukin-8 and soluble intercellular adhesion molecule-1 in bronchoalveolar lavage fluid from premature infants who develop chronic lung disease.
        Arch Dis Child Fetal Neonat Ed. 1995; 72: F90-F96
        • Kotecha S.
        • Wilson L.
        • Wangoo A.
        • Silverman M.
        • Shaw R.J.
        Increase in interleukin (IL)-1 beta and IL-6 in bronchoalveolar lavage fluid obtained from infants with chronic lung disease of prematurity.
        Pediatr Res. 1996; 40: 250-256
        • Vento G.
        • Capoluongo E.
        • Matassa P.G.
        • et al.
        Serum levels of seven cytokines in premature ventilated newborns: correlations with old and new forms of bronchopulmonary dysplasia.
        Intensive Care Med. 2006; 32: 723-730
        • Viscardi R.M.
        • Muhumuza C.K.
        • Rodriguez A.
        • et al.
        Inflammatory markers in intrauterine and fetal blood and cerebrospinal fluid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants.
        Pediatr Res. 2004; 55: 1009-1017
        • Goodman R.B.
        • Pugin J.
        • Lee J.S.
        • Matthay M.A.
        Cytokine-mediated inflammation in acute lung injury.
        Cytokine Growth Factor Rev. 2003; 14: 523-535
        • Belperio J.A.
        • Keane M.P.
        • Lynch 3rd, J.P.
        • Strieter R.M.
        The role of cytokines during the pathogenesis of ventilator-associated and ventilator-induced lung injury.
        Semin Respir Crit Care Med. 2006; 27: 350-364
        • Gurkan O.U.
        • He C.
        • Zielinski R.
        • et al.
        Interleukin-6 mediates pulmonary vascular permeability in a two-hit model of ventilator-associated lung injury.
        Exp Lung Res. 2011; 37: 575-584
        • Strieter R.M.
        • Belperio J.A.
        • Keane M.P.
        Cytokines in innate host defense in the lung.
        J Clin Invest. 2002; 109: 699-705
        • Yoon B.H.
        • Romero R.
        • Kim K.S.
        • et al.
        A systemic fetal inflammatory response and the development of bronchopulmonary dysplasia.
        Am J Obstet Gynecol. 1999; 181: 773-779
        • Rojas M.A.
        • Gonzalez A.
        • Bancalari E.
        • Claure N.
        • Poole C.
        • Silva-Neto G.
        Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease.
        J Pediatr. 1995; 126: 605-610
        • Bauer M.
        • Fast C.
        • Haas J.
        • Resch B.
        • Lang U.
        • Pertl B.
        Cystic periventricular leukomalacia in preterm infants: an analysis of obstetric risk factors.
        Early Hum Dev. 2009; 85: 163-169
        • Dean J.M.
        • Farrag D.
        • Zahkouk S.A.M.
        • et al.
        Cerebellar white matter injury following systemic endotoxemia in preterm fetal sheep.
        Neuroscience. 2009; 160: 606-615
        • Perlman J.M.
        • Risser R.
        • Broyles R.S.
        Bilateral cystic periventricular leukomalacia in the premature infant: associated risk factors.
        Pediatrics. 1996; 97: 822-827
        • Resch B.
        • Neubauer K.
        • Hofer N.
        • et al.
        Episodes of hypocarbia and early-onset sepsis are risk factors for cystic periventricular leukomalacia in the preterm infant.
        Early Hum Dev. 2012; 88: 27-31
        • Zupan V.
        • Gonzalez P.
        • Lacaze-Masmonteil T.
        • et al.
        Periventricular leukomalacia: risk factors revisited.
        Dev Med Child Neurol. 1996; 38: 1061-1067
        • Hofer N.
        • Müller W.
        • Resch B.
        White matter damage and neonatal sepsis.
        Acta Paediatr. 2011; 100 (author reply e1-2): e1
        • Yoon B.H.
        • Romero R.
        • Yang S.H.
        • et al.
        Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia.
        Am J Obstet Gynecol. 1996; 174: 1433-1440
        • Larsen J.W.
        • Sever J.L.
        Group B Streptococcus and pregnancy: a review.
        Am J Obstet Gynecol. 2008; 198 (discussion 448-50): 440-448
        • Regan J.A.
        • Klebanoff M.A.
        • Nugent R.P.
        • et al.
        Colonization with group B streptococci in pregnancy and adverse outcome. VIP Study Group.
        Am J Obstet Gynecol. 1996; 174: 1354-1360
        • Puopolo K.M.
        • Draper D.
        • Wi S.
        • et al.
        Estimating the probability of neonatal early-onset infection on the basis of maternal risk factors.
        Pediatrics. 2011; 128: e1155-e1163
        • Dutta S.
        • Reddy R.
        • Sheikh S.
        • Kalra J.
        • Ray P.
        • Narang A.
        Intrapartum antibiotics and risk factors for early onset sepsis.
        Arch Dis Child Fetal Neonatal Ed. 2010; 95: F99-F103
        • Chaiworapongsa T.
        • Romero R.
        • Kim J.C.
        • et al.
        Evidence for fetal involvement in the pathologic process of clinical chorioamnionitis.
        Am J Obstet Gynecol. 2002; 186: 1178-1182
        • Pacora P.
        • Chaiworapongsa T.
        • Maymon E.
        • et al.
        Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome.
        J Matern Fetal Neonat Med. 2002; 11: 18-25
        • Strunk T.
        • Doherty D.
        • Jacques A.
        • et al.
        Histologic chorioamnionitis is associated with reduced risk of late-onset sepsis in preterm infants.
        Pediatrics. 2012; 129: e134-e141
        • Schlapbach L.J.
        • Aebischer M.
        • Adams M.
        • et al.
        Impact of sepsis on neurodevelopmental outcome in a Swiss National Cohort of extremely premature infants.
        Pediatrics. 2011; 128: e348-e357
        • Stoll B.J.
        • Hansen N.I.
        • Adams-Chapman I.
        • et al.
        Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection.
        JAMA. 2004; 292: 2357-2365
        • Yoon B.H.
        • Romero R.
        • Park J.S.
        • 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: 675-681
        • Wu Y.W.
        • Colford Jr., J.M.
        Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis.
        JAMA. 2000; 284: 1417-1424
        • Hatfield T.
        • Wing D.A.
        • Buss C.
        • Head K.
        • Muftuler L.T.
        • Davis E.P.
        Magnetic resonance imaging demonstrates long-term changes in brain structure in children born preterm and exposed to chorioamnionitis.
        Am J Obstet Gynecol. 2011; 205: 384.e1-384.e8
        • Mittendorf R.
        • Montag A.G.
        • MacMillan W.
        • et al.
        Components of the systemic fetal inflammatory response syndrome as predictors of impaired neurologic outcomes in children.
        Am J Obstet Gynecol. 2003; 188 (discussion 1444-6): 1438-1444