Fetal-placental crosstalk occurs through fetal cytokine synthesis and placental clearance

Background: Cytokines modulate fetal well-being and contribute to parturition. Their origin in fetal blood, whether maternal, placental or fetal, at the time of parturition remains unclear. Objective: To determine fetal and placental contributions to circulating fetal cytokines by measuring umbilical arterial (UmA) and venous (UmV) concentration differences in uncomplicated term pregnancies in the absence and presence of labor. Methods: Term uncomplicated pregnancies were assessed: Group 1 were not in labor and delivered by elective cesarean section (n = 20); Group 2 delivered vaginally following uncomplicated pregnancy and labor (n = 30). UmA and UmV blood was collected before delivery of the placenta to measure circulating cytokines. Placental tissue was collected for histology and to determine cytokine contents and localization. Results: Group 1 UmA and UmV IL-10 concentrations were similar (504 ± 15 and 468 ± 16 pg/ml, respectively; P ≥ 0.1); other cytokines were below level of detection. During labor, IL-10 concentrations increased 15–34%, but placental contents decreased. Group 2 UmA IL-6 and IL-8 concentrations increased (P < 0.001) to 16.7 ± 1.6 and 18.4 ± 4.3 pg/ml, respectively, but were less (P < 0.001) in UmV, 0.29 ± 0.2 and 0.74 ± 0.3 pg/ml, respectively, demonstrating placental clearances ≥97%. This was associated with >6-fold increases in placental IL-6/IL-8 contents (P < 0.001) and chorioamniotic infiltration of activated maternal neutrophils. IL-6 and IL-10 were localized to villous syncytiotrophoblasts. Conclusions: In uncomplicated term pregnancies fetal circulating IL-10 is likely of placental origin, whereas IL-6/IL-8 are derived from the fetus, increase during parturition, and circulating levels are modulated by non-saturable placental clearance, revealing a novel pathway for fetal-placental crosstalk and signaling.