The onset of spontaneous preterm parturition is preceded by an intense pro-inflammatory cytokine response in the human fetus

OBJECTIVE: Strong evidence supports that the fetus plays a central role in the initiation of parturition. Preterm labor in the setting of infection is thought to result from the participation of pro-inflammatory cytokines secreted as part of the host response (fetal and/or maternal) to microbial invasion. A missing link in support of this hypothesis is whether or not these cytokines increase in the human fetus prior to the onset of preterm labor. The objective of this study was to determine if the onset of preterm parturition is associated with a change in fetal plasma concentrations of pro-inflammatory cytokines in patients with preterm PROM. STUDY DESIGN: Amniocenteses and cordocenteses were performed in 41 patients with preterm PROM who were not in labor upon admission to the hospital. This study had multi-institutional IRB approval and written informed consents were obtained from all patients. Amniotic fluid (AF) was cultured for bacteria and Mycoplasmas. Fetal plasma (FP) Interleukin-6 (IL6) was assayed by a sensitive and specific immunoassay. Statistical analysis included survival analysis with Cox proportional hazard modeling and contingency tables. RESULTS: 1) Microbial invasion of the amniotic cavity was present in 56% (23/41); 2) fetuses with FP IL-6 concentrations >6 pg/ml (as derived from ROC analysis) had a higher rate of spontaneous delivery within 24, 48, and 72 hours than those with FP IL-6 ≤ 6 pg/ml (44% vs. 19%, 89% vs 25% and 89% vs. 31%, respectively, p < 0.05 for 48 and 72 hours); 3) survival analysis indicated that fetuses with elevated FP IL-6 had a shorter cordocentesis to delivery interval than those with normal fetal IL-6 concentrations (median 20.5 h, [1-120] vs. median 168 h [5-806]. respectively, p = 0.01); and 4) Cox proportional hazards model indicated that FP IL-6 was the only significant covariate determining duration of pregnancy after adjusting for gestational age, AF Gram stain and AF white blood cell count (p<0.0.05). CONCLUSION: This study provides strong support for a role of the human fetal cytokine system in the onset of spontaneous preterm parturition.