OBJECTIVE: The aim of this study was to determine whether fetal exposure to intra-amniotic inflammation and a systemic fetal inflammatory response (funisitis) are associated with the development of cerebral palsy at the age of 3 years. STUDY DESIGN: This cohort study included 123 preterm singleton newborns (gestational age at birth, </=35 weeks) born to mothers who underwent amniocentesis and were followed up for >/=3 years. The presence of intra-amniotic inflammation was determined by elevated amniotic fluid concentrations of proinflammatory cytokines such as interleukins 6 and 8 and by amniotic fluid white blood cell count. Cytokine concentrations were measured with sensitive and specific immunoassays. Funisitis was diagnosed in the presence of neutrophil infiltration into the umbilical vessel walls or Wharton jelly. Cerebral palsy was diagnosed by neurologic examination at the age of 3 years. RESULTS: Newborns with subsequent development of cerebral palsy had a higher rate of funisitis and were born to mothers with higher median concentrations of interleukins 6 and 8 and higher white blood cell counts in the amniotic fluid compared with newborns without subsequent development of cerebral palsy (funisitis: 75\% 9/12 vs 23\% 24/105; interleukin 6: median, 18.9 ng/mL; range, 0. 02-92.5 ng/mL; vs median, 1.0 ng/mL; range, 0.01-115.2 ng/mL; interleukin 8: median, 13.0 ng/mL; range, 0.1-294.5 ng/mL; vs median, 1.2 ng/mL; range, 0.05-285.0 ng/mL; white blood cell count: median, 198 cells/mm(3); range, 0->1000 cells/mm(3); vs median, 3 cells/mm(3); range, 0-19,764 cells/mm(3); P <.01 for each). After adjustment for the gestational age at birth, the presence of funisitis and elevated concentrations of interleukins 6 and 8 in amniotic fluid significantly increased the odds of development of cerebral palsy (funisitis: odds ratio, 5.5; 95\% confidence interval, 1.2-24.5; interleukin 6: odds ratio, 6.4; 95\% confidence interval, 1. 3-33.0; interleukin 8: odds ratio, 5.9; 95\% confidence interval, 1. 1-30.7; P <.05 for each). CONCLUSION: Antenatal exposure to intra-amniotic inflammation and evidence of a systemic fetal inflammatory response (funisitis) are strong and independent risk factors for the subsequent development of cerebral palsy at the age of 3 years.