Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years

OBJECTIVE: The aim of this study was to determine whether fetal exposure to intra-amniotic inflammation and a systemic fetal inflammatory response (fu nisitis) are associated with the development of cerebral palsy at the age o f 3 years. STUDY DESIGN: This cohort study included 123 preterm singleton newborns (ge stational age at birth, less than or equal to 35 weeks) born to mothers who underwent amniocentesis and were followed up for greater than or equal to 3 years. The presence of intra-amniotic inflammation was determined by elev ated amniotic fluid concentrations of proinflammatory cytokines such as int erleukins 6 and 8 and by amniotic fluid white blood cell count. Cytokine co ncentrations were measured with sensitive and specific immunoassays. Funisi tis was diagnosed in the presence of neutrophil infiltration into the umbil ical vessel walls or Wharton jelly. Cerebral palsy was diagnosed by neurolo gic examination at the age of 3 years. RESULTS: Newborns with subsequent development of cerebral palsy had a highe r rate of funisitis and were born to mothers with higher median concentrati ons of interleukins 6 and 8 and higher white blood cell counts in the amnio tic 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/m L; 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, 0-19,7 64 cells/mm(3); P < .01 for each). After adjustment for the gestational age at birth, the presence of funisitis and elevated concentrations of interle ukins 6 and 8 in amniotic fluid significantly increased the odds of develop ment 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 indepe ndent risk factors for the subsequent development of cerebral palsy at the age of 3 years.