Hepcidin, an Iron Regulatory Hormone of Innate Immunity, is Differentially Expressed in Premature Fetuses with Early-Onset Neonatal Sepsis

Objective Hepcidin, a mediator of innate immunity, binds the iron exporter ferroportin, leading to functional hypoferremia through intracellular iron sequestration. We explored hepcidin-ferroportin interactions in neonates clinically diagnosed with early-onset neonatal sepsis (EONS). Study Design Hepcidin and interleukin (IL)-6 were quantified by enzyme-linked immunosorbent assay (ELISA) in 92 paired cord blood-maternal blood samples in the following groups: Yes EONS ( n =41, gestational age [GA] 291 weeks) and No EONS ( n =51, GA 261 weeks). Placental hepcidin and ferroportin expression were evaluated by immunohistochemistry and real-time-polymerase chain reaction (RT-PCR). Liver hepcidin and ferroportin expression patterns were ascertained in autopsy specimens of neonates ( n =8) who died secondary to culture-proven sepsis. Results Cord blood hepcidin was significantly elevated (GA corrected, p =0.018) and was positively correlated with IL-6 ( r =0.379, p =0.001) in EONS. Hepcidin localized at syncytiotrophoblast and fetal vascular endothelium. Placental ferroportin, but not hepcidin mRNA correlated with cord blood hepcidin levels ( r =0.46, p =0.039) and funisitis severity ( r =0.50, p =0.018). Newborns who died from sepsis ( n =4) had higher hepatic hepcidin and iron sequestration, but lower ferroportin staining than those who died of nonsepsis causes ( n =4). Conclusion Premature fetuses with EONS have elevated circulating hepcidin, likely related to lower placenta and liver ferroportin expression. Fetal hepcidin-ferroportin interaction appears to play a role in EONS pathophysiology independent of maternal response to intrauterine inflammation.