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Placental clearance not synthesis tempers exaggerated pro-inflammatory cytokine response in neonates exposed to chorioamnionitis

Abstract

Background

The source and clearance of cytokines in the fetal circulation in term pregnancies complicated by chorioamnionitis remains unclear as are the contributions of placental transport, synthesis, and clearance. The objectives of the study were to determine (1) fetal and/or placental contributions to synthesis and/or clearance of inflammatory and anti-inflammatory cytokines in term pregnancies complicated by chorioamnionitis and (2) whether this differs in pregnancies further complicated by fetal hypoxia.

Methods

Prospective cohort study of pregnancies >37 weeks gestational age that included: Group 1, uncomplicated cesarean delivery without labor (n = 20); Group 2, uncomplicated vaginal delivery (n = 30); Group 3, pregnancies complicated by chorioamnionitis (n = 10); Group 4, complicated by chorioamnionitis + fetal hypoxia (n = 10). Umbilical arterial (UmA) and venous (UmV) blood were assayed for IL-1β, IL-2, IL-6, IL-8, TNFα, and IL-10.

Results

IL-6 and IL-8 were below assay detection in UmA and UmV blood in Group 1 and increased in Group 2 (P < 0.01), UmA»UmV (P < 0.01). Their concentrations increased further in Groups 3 and 4 (P = 0.003), UmA»UmV. Placental clearance was concentration dependent that approaches saturation in the presence of chorioamnionitis.

Conclusions

Marked increases in fetal synthesis of IL-6 and IL-8 occur in chorioamnionitis. Synthesis increase further when complicated by fetal hypoxia. Cytokine removal occurs via placental concentration-dependent mechanisms, potentially contributing to adverse fetal effects.

Impact

  • The source and role of the placenta in synthesis and/or clearance of inflammatory mediators in term pregnancies complicated by clinical chorioamnionitis are unclear; however, conventional wisdom suggests the placenta is their source.

  • This is the first study demonstrating that circulating concentrations of fetal IL-6 and IL-8 in clinical chorioamnionitis ± birth asphyxia in term pregnancies are of fetal origin.

  • Circulating fetal inflammatory cytokines are cleared by concentration-dependent placental mechanisms that are nearly saturated in chorioamnionitis ± fetal hypoxia.

  • These observations provide additional insight into understanding the fetal immune response in term pregnancies complicated by clinical chorioamnionitis.

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Fig. 1: Proinflammatory cytokines in UmA and UmV in clinical chorioamnionitis with or without fetal hypoxia.
Fig. 2: Comparison of IL-6 and IL-8 concentrations in umbilical arterial (UmA) blood between pregnancies with uncomplicated term cesarean delivery in the absence of labor (Group 1, n = 20), uncomplicated term vaginal delivery (Group 2, n = 30), clinical chorioamnionitis (Group 3, n = 10), and clinical chorioamnionitis with evidence of fetal hypoxia (Group 4, n = 10).
Fig. 3: Comparison of concentration differences for IL-10 in umbilical arterial blood in pregnancies with uncomplicated term delivery by cesarean section without labor (Group 1, n = 10), uncomplicated term vaginal delivery (Group 2, n = 10), clinical chorioamnionitis (Group 3, n = 10), and clinical chorioamnionitis with fetal hypoxia (Group 4, n = 10).

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by MacGregor Professorship awarded to C.R.R.

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Contributions

I.N.M. made substantial contributions to conception and design, acquisition of data, analysis, and interpretation of data. He drafted and submitted the final version of the manuscript after approval from all co-authors. L.F.C. and C.R.R. made substantial contributions to conception and design, analysis, and interpretation of data; revised the article for important intellectual content; and approved the final version of the manuscript. N.U., J.L., L.S.B., R.C.S., and R.L. made substantial contributions to data analysis and interpretation of data. They revised the manuscript critically for important intellectual content and approved its final version to be published.

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Correspondence to Imran N. Mir.

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Mir, I.N., Uddin, N., Liao, J. et al. Placental clearance not synthesis tempers exaggerated pro-inflammatory cytokine response in neonates exposed to chorioamnionitis. Pediatr Res (2022). https://doi.org/10.1038/s41390-022-02147-z

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