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

Presented at the Sixteenth Annual Meeting of the Society of Perinatal Obstetricians, Kamuela, Hawaii, February 4-10, 1996.
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Abstract

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.)

Section snippets

Study design

A retrospective cohort study was carried out to examine the relationship between the amniotic fluid concentrations of TNF-α, IL-1β, IL-6, and IL-1 receptor antagonist and the risk for development of brain white matter lesions. The cohort consisted of women who were admitted to Seoul National University Hospital between January 1993 and May 1995 with preterm labor, preterm premature rupture of membranes, or pregnancy-induced hypertension and who met the following criteria: (1) preterm singleton

Clinical characteristics of patients with white matter lesions

Ninety-six women met the study criteria, and 23 (24%) of their newborns had brain white matter lesions. Cystic lesions were present in 15 cases and periventricular white matter tissue loss was present in eight cases. Two cases were excluded from further analysis because the volume of amniotic fluid was insufficient to assay all the cytokines under study. Neither of these newborns had white matter lesions.

The clinical characteristics of the study population stratified according to the presence

Comment

Strong evidence supports a causal relationship between ascending intrauterine infection, the production of inflammatory cytokines by intrauterine tissues, and preterm labor and delivery.3 Recently Leviton11 has proposed that the inflammatory cytokines released during the course of intrauterine infection (i.e. IL-1, TNF-α) are also responsible for the brain white matter damage observed in preterm infants in whom cerebral palsy subsequently develops. The results of the current study support this

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  • Cited by (0)

    From the Departments of Obstetrics and Gynecology,a Pediatrics,b and Radiology,c College of Medicine, Seoul National University, and the Perinatology Research Branch, National Institute of Child Health and Human Development.d

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    Supported by grant No. 03-95-010 from the Seoul National University Research Fund and grant No. HMP-96-M-2-0020 from the '96 Good Health R & D Project, Ministry of Health and Welfare, Republic of Korea.

    Reprint requests: Bo Hyun Yoon, MD, PhD, Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, 110-744, Korea.

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