Amniotic Fluid Infection, Cytokines, and Adverse Outcome Among Infants at 34 Weeks’ Gestation or Less Jane Hitti, MD, Peter Tarczy-Hornoch, MD, Janet Murphy, MD, Sharon L. Hillier, PhD, Jan Aura, ARNP, and David A. Eschenbach, MD OBJECTIVE: We examined the hypothesis that amniotic fluid (AF) infection and elevated cytokine concentrations may cause neonatal injury beyond that expected solely from prematurity. METHODS: The effects of exposure to AF infection and elevated cytokine concentrations were measured in 151 infants born to afebrile women in preterm labor with intact membranes at less than or equal to 34 weeks’ gestation. Amniotic fluid was collected by amniocentesis for culture and determination of tumor necrosis factor- and interleu- kin-6. Cytokine concentrations, stratified by AF infection, were compared for three gestational age groups. We then examined the associations between a positive AF culture or elevated AF tumor necrosis factor- concentration and adverse neonatal outcomes, adjusted for birth weight. RESULTS: Amniotic fluid from 45 (30%) of 151 pregnancies had microorganisms, an elevated tumor necrosis factor- concentration, or both. Amniotic fluid cytokine concentra- tions were significantly higher among women in preterm labor at less than or equal to 30 weeks, compared with 31–34 weeks. Nine of 11 infants who died at less than or equal to 24 hours of age had AF infection or elevated AF tumor necrosis factor-. For the 140 surviving infants, AF infection and/or an elevated AF tumor necrosis factor- was associated with respiratory distress syndrome (adjust- ed odds ratio [OR] 1.7), grade 3– 4 intraventricular hemor- rhage (adjusted OR 2.2), necrotizing enterocolitis (adjusted OR 1.8), and multiple organ dysfunction (adjusted OR 3.0). CONCLUSION: Among infants born at less than or equal to 34 weeks to women who have intact membranes and are initially afebrile, those exposed to AF bacteria or cytokines have more adverse neonatal outcomes than unexposed infants of similar birth weight. (Obstet Gynecol 2001;98: 1080 – 8. © 2001 by the American College of Obstetricians and Gynecologists.) Very low birth weight (VLBW) infants (less than 1500 g) have increased morbidity and mortality. 1,2 Most mor- bidity among VLBW infants is attributed to immature organ function. However, a substantial proportion of VLBW infants are exposed to amniotic fluid (AF) infec- tion 3 and its associated proinflammatory response with production of cytokines such as tumor necrosis factor- and interleukin-6 in AF. 4,5 Recent evidence points to the fetus as a major contrib- utor to the inflammatory response caused by AF infec- tion. 6–9 Elevated AF cortisol levels with AF infection also indicate a fetal response to infection. 10 Although a cer- tain amount of neonatal morbidity results from prema- turity, AF infection and the associated fetal and maternal inflammatory responses may further increase neonatal morbidity. Associations are reported between AF infec- tion and respiratory distress syndrome (RDS), 11 bron- chopulmonary dysplasia, 12 periventricular leukomala- cia, 13,14 and cerebral palsy, 14,15 but the effect of AF infection on neonatal morbidity in excess of that expected from prematurity has not been consistently addressed by adjust- ment for birth weight or gestational age. We examined the relationship of AF infection and the concentration of tumor necrosis factor- and interleu- kin-6 in AF with gestational age among afebrile women in preterm labor with intact membranes. A high concen- tration of AF cytokines among pregnancies at an early gestational age would indicate that the fetal immune system is capable of a vigorous response to bacterial antigens by midgestation and could explain a portion of the morbidity sustained by preterm neonates when ex- posed to AF infection. We then examined whether the neonatal outcome was adversely affected by the presence of AF infection or elevated tumor necrosis factor- after adjustment for birth weight. Our hypothesis was that infants exposed to AF bacteria or elevated tumor necro- sis factor- have higher rates of neonatal morbidity than do unexposed infants of similar birth weight. From the Departments of Obstetrics and Gynecology and Pediatrics, University of Washington, Seattle, Washington; and Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania. This work was supported by National Institutes of Health Grant AI-31071. 1080 VOL. 98, NO. 6, DECEMBER 2001 0029-7844/01/$20.00 © 2001 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc. PII S0029-7844(01)01567-8