Iron Homeostasis in Full Term, Normal Birthweight Gambian Neonates Over the First Week of Life

Abstract

Background: Human neonates elicit a profound hypoferremia to protect against bacterial and fungal sepsis on their first day of life. We examined the transience of this effect by measuring iron and its chaperone proteins, inflammatory and hematological parameters over the first post-partum week. Methods: We prospectively studied term (>37 completed gestational weeks), normal weight (>2500g) newborns at Kanifing General Hospital, The Gambia. Blood was sampled from the umbilical cord vein (CDV) and artery (CDA). Neonatal venous blood was sampled at 6-24h (V1) in all babies who were then randomized to a second blood draw at 25-80h (V2), 81-136h (V3) or 137-192h (V4). Hepcidin, serum iron, transferrin saturation, transferrin, haptoglobin, CRP, AGP, sTfR, ferritin, TIBC, UIBC and full blood count were assayed. Findings: 278 neonates (54.3% males, gestational age 39.4±1.3wk, birth weight 3299±368g) were enrolled. We confirmed the profound early post-natal decrease in serum iron (CDV=22.7±7.0µmol/L to V1=7.3±4.3µmol/L, P<0.0001) and TSAT (50.2±16.7% to 14.4±6.1%, P<0.0001). Both variables increased steadily to reach 16.5±3.9µmol/L and 36.7±9.2% at V4 (P for trend <0.0001 for each). Hepcidin increased rapidly after birth (CDV=19.4±14.4ng/ml to V1=38.9±23.9ng/ml, P<0.0001) then dipped before rising again by V4. Inflammatory markers increased from V1 onwards. Network analysis revealed a disconnect between the correlations observed in CDV and V2-V4 and those in V1. Surprisingly, serum iron and TSAT were only weakly influenced by hepcidin. Interpretations: This data shows that the rapid anti-infective post-natal hypoferremia in human neonates is transient. The later rise in serum iron despite very high hepcidin indicates hepcidin resistance possibly caused by macrophage saturation with iron released from degradation of fetal erythrocytes. Pharmacological prolongation of hypoferremia might offer an ancillary tool in the armoury against antimicrobial resistance, but would need to overcome or circumvent the hepcidin. Funding: Bill & Melinda Gates Foundation (OPP1152353). Trial Registration: clinicaltrials.gov (NCT03353051). Registration date: November 27, 2017. Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: The trial was approved by the Medical Research Council Unit The Gambia at London School of Hygiene and Tropical Medicine (MRCG at LSHTM) Scientific Coordinating Committee, the Joint Gambia Government/MRC Ethics Committee (SCC1525) and the London School of Hygiene and Tropical Medicine Ethics Committee (Ref:14316) and conducted according to Good Clinical Practice (GCP) standards. All participants gave written, informed consent.