Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1β, and tumor necrosis factor-α), neonatal brain white matter lesions, and cerebral palsy


      OBJECTIVE: Ultrasonographically detectable neonatal brain white matter lesions are the most important identifiable risk factor for cerebral palsy. Inflammatory cytokines released during the course of intrauterine infections have been implicated in the genesis of brain white matter lesions and subsequent cerebral palsy. This study was undertaken to determine whether fetuses who subsequently were diagnosed to have periventricular brain white matter lesions could be identified by determining the concentrations of inflammatory cytokines in the amniotic fluid. STUDY DESIGN: Women with complicated preterm gestations underwent amniocentesis for clinical indications. Amniotic fluid concentrations of tumor necrosis factor-α, interleukin-1β, interleukin-6, and the natural interleukin-1 receptor antagonist were determined by immunoassay. Periventricular white matter lesions of the neonate were diagnosed by neurosonography. Univariate and multivariate analyses were conducted. RESULTS: Ninety-four women and their neonates were included in the study; white matter lesions were diagnosed in 24% (23/94) of the newborns. The mothers of newborns with brain white matter lesions had higher median concentrations of tumor necrosis factor-α, interleukin-1β, and interleukin-6 (but not interleukin-1 receptor antagonist) in amniotic fluid than did those who were delivered of newborns without white matter lesions (p < 0.01 for each). Acute histologic chorioaminionitis was more common in the placentas of neonate with white matter lesions than in those without these lesions (82% [18/22] vs 42% [30/71], p < 0.005). Neonates with white matter lesions were delivered at a lower mean gestational age and birth weight and had a higher rate of significant complications (including respiratory distress syndrome, intraventricular hemorrhage, and infection-related complications) than did those without white matter lesions. The differences in median interleukin-1β and interleukin-6 levels between these two groups remained significant after adjustment for gestational age and birth weight (interleukin-6: odds ratio 5.7, 95% confidence interval 1.3 to 24.4; interleukin-1β: odds ratio 4.4, 95% confidence interval 1.1 to 17.0). Of the 94 newborns included in this study, 11 died before age 6 months and eight had cerebral palsy; all eight had white matter lesions and elevated cytokine levels in amniotic fluid. Histologic chorioamnionitis was more common in the placentas of neonates with cerebral palsy than in those without cerebral palsy (86% [6/7] vs 44% [33/75], p < 0.05). CONCLUSIONS: Infants at risk for development of brain white matter lesions can be identified by the concentrations of interleukin-6 and interleukin-1β in amniotic fluid. Our findings support the hypothesis that inflammatory cytokines released during the course of intrauterine infection play a role in the genesis of brain white matter lesions.(Am J Obstet Gynecol 1997;177:19-26.)


      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 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


        • Leviton A
        • Paneth N.
        White matter damage in preterm newborns—an epidemiologic perspective.
        Early Hum Dev. 1990; 24: 1-22
        • Trounce JQ
        • Rutter N
        • Levene MI.
        Periventricular leukomalacia and intraventricular hemorrhage in the preterm neonate.
        Arch Dis Child. 1986; 61: 1196-1202
        • Gomez R
        • Ghezzi F
        • Romero R
        • Munoz H
        • Tolosa JE
        • Rojas I.
        Premature labor and intraamniotic infection.
        Clin Perinatol. 1995; 22: 281-342
        • Leviton A
        • Gilles FH
        • Neff R
        • Yaney P.
        Multivariate analysis of risk of perinatal telencephalic leukoencephalopathy.
        Am J Epidemiol. 1976; 104: 621-626
        • Verma U
        • Tejani N
        • Klein S
        • Reale MR
        • Beneck D
        • Figueroa R
        • et al.
        Obstetrical antecedents of intraventricular hemorrhage and periventricular leukomalacia.
        Am J Obstet Gynecol. 1997; 176: 275-281
        • Bejar R
        • Wozniak P
        • Allard M
        • Benirschke K
        • Vaucher Y
        • Coen R
        • et al.
        Antenatal origin of neurologic damage in newborn infants, I: preterm infants.
        Am J Obstet Gynecol. 1988; 159: 357-363
        • Mays J
        • Verma U
        • Klein S
        • Tejani N.
        Acute appendicitis in pregnancy and the occurrence of major intraventricular hemorrhage and periventricular leukomalacia.
        Obstet Gynecol. 1995; 86: 650-652
        • Nelson KB
        • Ellenberg JH.
        Predictors of very low birth weight and the relation of these to cerebral palsy.
        JAMA. 1985; 254: 1473-1479
        • Murphy DJ
        • Sellers S
        • Mackenzie IZ
        • Yudkin PL
        • Johnson AM.
        Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies.
        Lancet. 1995; 346: 1449-1454
        • Gilles FH
        • Averill D
        • Kerr CS.
        Neonatal endotoxin encephalopathy.
        Ann Neurol. 1977; 2: 49-56
        • Leviton A.
        Preterm birth and cerebral palsy: is tumor necrosis factor the missing link?.
        Dev Med Child Neurol. 1993; 35: 553-558
        • Yoon BH
        • Romero R
        • Kim CJ
        • Jun JK
        • Gomez R
        • Choi J-H
        • et al.
        Amniotic fluid interleukin-6: a sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity.
        Am J Obstet Gynecol. 1995; 172: 960-970
        • Yoon BH
        • Romero R
        • Yang SH
        • Jun JK
        • Kim I-O
        • Choi J-H
        • et al.
        Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with periventricular white matter lesions associated with periventricular leukomalacia.
        Am J Obstet Gynecol. 1996; 174: 1433-1440
        • McMenamin JB
        • Shackelford GD
        • Volpe JJ.
        Outcome of neonatal intraventricular hemorrhage with periventricular echodense lesions.
        Ann Neurol. 1984; 15: 285-290
        • Creasy AA
        • Stevens P
        • Kenney J
        • Allison AC
        • Warren K
        • Catlett R
        • et al.
        Endotoxin and cytokine profile in plasma of baboons challenged with lethal and sublethal Escherichia coli.
        Circ Shock. 1991; 33: 84-91
        • Van Deventer SJH
        • Bhller HR
        • Ten Cate JW
        • Aarden LA
        • Hack CE
        • Stork A.
        Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways.
        Blood. 1990; 76: 2520-2526
        • Baggia S
        • Gravett MG
        • Witkin SS
        • Haluska GJ
        • Novy MJ.
        Interleukin-1β intra-amniotic infusion induces tumor necrosis factor-α, prostaglandin production, and preterm contractions in pregnant rhesus monkeys.
        J Soc Gynecol Invest. 1996; 3: 121-126
        • Weatherstone KB
        • Rich EA.
        Tumor necrosis factor/cachectin and interleukin-1 secretion by cord blood monocytes from premature and term neonates.
        Pediatr Res. 1989; 25: 342-346
        • Sharief MK
        • Thompson FJ.
        In vivo relationship of tumor necrosis factor-α on blood-brain barrier damage to patients with active multiple sclerosis.
        J Neuroimmunol. 1992; 38: 27-34
        • Lee SC
        • Liu W
        • Dickson DW
        • Brosnan CF
        • Berman JW.
        Cytokine production by human fetal microglia and astrocytes: differential induction by lipopolysaccharide and IL-1β.
        J Immunol. 1993; 150: 2659-2667
        • Selmaj K
        • Raine CS
        • Path FRC
        • Cross AH.
        Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro.
        Ann Neurol. 1988; 23: 339-346
        • Yoon BH
        • Romero R
        • Kim CJ
        • Koo JN
        • Choe G
        • Syn HC
        • et al.
        High expression of tumor necrosis factor-α and interleukin-6 in periventricular leukomalacia.
        Am J Obstet Gynecol. 1997; (In press)
        • Deguchi K
        • Mizuguchi M
        • Takashima S.
        Immunohistochemical expression of tumor necrosis factor-α in neonatal leukomalacia.
        Pediatr Neurol. 1996; 14: 13-16
        • Yoon BH
        • Kim CJ
        • Romero R
        • Jun JK
        • Park KH
        • Choi ST
        • et al.
        Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits.
        Am J Obstet Gynecol. 1997; (In press)
        • Leviton A
        • Gilles FH.
        Etiologic relationships among the perinatal telencephalic leukoencephalopathies.
        in: The developing human brain: growth and epidemiologic neuropathy. John Wright PSG, Boston1983: 304-315
        • Hauth JC
        • Goldenberg RL
        • Andrews WW
        • Dubard MB
        • Copper RL.
        Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis.
        N Engl J Med. 1995; 333: 1732-1736