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 (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, 535 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/mm3; range, 0-,1000 cells/mm3; vs median, 3 cells/mm3; range, 0-19,764 cells/mm3; 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). Conclusions: 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.