Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-l[3, and tumor necrosis factor-s), neonatal brain white matter lesions, and cerebral palsy Bo Hyun Yoon, MD, PhD," Jong Kwan Jun, MD," Roberto Romero, MD, a Kyo Hoon Park, MD," Ricardo Gomez, MI), a Jung-Hwan Choi, MD, PhD, b and In-One Kim, MD, PhD c Seoul, Korea, and Bethesda, Maryland 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-s, interleukin-l~B, 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-c~, interleukin-l~, 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-l~8 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-1 [3: 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 chodoamnionitis 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-1 [3 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.) Key words: Brain, white matter lesions, cytokines, cerebral palsy, prematurity, periventricular leukomalacia, amniotic fluid, chorioamnionitis Clinical and epidemiologic evidence indicates that brain white matter lesions detected with neurosonogra- phy during the neonatal period are the most accurate predictor of cerebral palsy in low-birth-weight infants? These lesions include echodensities and echolucencies 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 Supported by grant No. 03-95-010 firm the Seoul National University Research Fund and grant No. HMP-96-M-2-O020 from the '96 Good Health R&D h'oject, Ministry of Health and Welfare, Republic of Korea. Presented at the Sixteenth Annual Meeting of the Society of Perinatal Obstetridans, Kamuela, Hawaii, February 4-10, 1996. Received for publication October 10, 1996; revised February 5, 1997; accepted February 20, 199Z and have been described as the ultrasonographic ante- cedent or counterpart of white matter tissue injury. Cavitating lesions, representing necrotic loci, have been reported in 7% to 26% of babies with birth weights <1500 gm2; 62% to 100% of these infants had cerebral palsy.1 Strong evidence supports a role for infection in the pathogenesis of preterm labor s and neonatal brain white matter lesions.4-7 Newborns with sepsis 4 or those born to mothers with documented infection5-7 are at increased Reprint requests: Bo Hyun Yoon, MD, PIzD, Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, 110-744, Korea. 6/1/81377 19