Fetal and early neonatal interleukin-6 response

• Fetal blood IL-6 may identify neonates at risk for adverse neonatal outcome.
• We review IL-6 reference intervals and dynamics during the early postnatal period.
• Stress, systemic injury and infection may affect IL-6 response in the early life.
• According to STARD, accuracy of IL-6 diagnostic studies for neonatal sepsis was sub-optimal.
• White matter injury may arise from postnatal infections through inflammatory IL-6 response.

In 1998, a systemic fetal cytokine response, defined as a plasma interleukin-6 (IL-6) value above 11 pg/mL, was reported to be a major independent risk factor for the subsequent development of neonatal morbid events even after adjustments for gestational age and other confounders. Since then, the body of literature investigating the use of blood concentrations of IL-6 as a hallmark of the fetal inflammatory response syndrome (FIRS), a diagnostic marker of early-onset neonatal sepsis (EONS) and a risk predictor of white matter injury (WMI), has grown rapidly. In this article, we critically review: IL-6 biological functions; current evidence on the association between IL-6, preterm birth, FIRS and EONS; IL-6 reference intervals and dynamics in the early neonatal period; IL-6 response during the immediate postnatal period and perinatal confounders; accuracy and completeness of IL-6 diagnostic studies for EONS (according to the Standards for Reporting of Diagnostic Accuracy statement); and recent breakthroughs in the association between fetal blood IL-6, EONS, and WMI.