A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition

OBJECTIVE: There is no evidence for the participation of the human fetus in the mechanisms responsible for the onset of preterm labor. We propose that preterm labor in the setting of infection results from the actions of proinflammatory cytokines secreted as part of the fetal and/or maternal host response to microbial invasion. The objective of this study was to determine whether a systemic fetal inflammatory response, defined as an elevation of fetal plasma interleukin-6 concentrations, has a temporal relationship with the commencement of labor. STUDY DESIGN: After informed consent was obtained, amniocentesis and cordocentesis were performed in 41 patients with preterm premature rupture of membranes who were not in labor on admission. Amniotic fluid was cultured for both aerobic and anaerobic bacteria, as well as for mycoplasmas. Fetal plasma interleukin-6 was assayed by a sensitive and specific immunoassay. Statistical analyses included contingency tables and survival analysis with time-dependent Cox regression hazard modeling. RESULTS: Microbial invasion of the amniotic cavity was present in 58.5% (24/41) of patients. Fetuses with fetal plasma interleukin-6 concentrations >11 pg/mL had a higher rate of spontaneous preterm delivery within 48 and 72 hours of the procedure than those with fetal plasma interleukin-6 levels ≤11 pg/mL (88% vs 29% and 88% vs 35%, respectively; P < .05 for all comparisons). Moreover, patients with initiation of labor and delivery within 48 hours of the procedure had a higher proportion of fetuses with plasma interleukin-6 values >11 pg/mL than patients delivered >48 hours (58% [7/12] vs 8% [1/13], respectively; P < .05). Survival analysis indicated that fetuses with elevated fetal plasma interleukin-6 levels had a shorter cordocentesis-to- delivery interval than those without elevated fetal plasma interleukin-6 concentrations (median 0.8 days [range 0.1 to 5] vs median 6 days [range 0.2 to 33.6], respectively; P < .05). Time-dependent Cox regression hazard modeling indicated that fetal plasma interleukin-6 level was the only covariate significantly associated with the duration of pregnancy after we adjusted for gestational age, amniotic fluid interleukin-6 level, and the microbiologic state of the amniotic cavity (P < .01). CONCLUSION: A systemic fetal proinflammatory cytokine response is followed by the onset of spontaneous preterm parturition in patients with preterm premature rupture of membranes.