Early postnatal hypoferremia in low birthweight and preterm babies: A prospective cohort study in hospital-delivered Gambian neonates

James H Cross, Ousman Jarjou, Nuredin Ibrahim Mohammed, Santiago Rayment Gomez, Bubacarr J B Touray, Andrew M Prentice, Carla Cerami, James H Cross, Ousman Jarjou, Nuredin Ibrahim Mohammed, Santiago Rayment Gomez, Bubacarr J B Touray, Andrew M Prentice, Carla Cerami

Abstract

Background: Neonates, particularly those born preterm (PTB) and with low birthweight (LBW), are especially susceptible to bacterial and fungal infections that cause an estimated 225,000 deaths annually. Iron is a vital nutrient for the most common organisms causing septicaemia. Full-term babies elicit an immediate postnatal hypoferremia assumed to have evolved as an innate defence. We tested whether PTB and LBW babies are capable of the same response.

Methods: We conducted an observational study of 152 babies who were either PTB (born ≥32 to <37 weeks gestational age) and/or LBW (<2500 g) (PTB/LBW) and 278 term, normal-weight babies (FTB/NBW). Blood was sampled from the umbilical cord vein and artery, and matched venous blood samples were taken from all neonates between 6-24 h after delivery. We measured haematological, iron and inflammatory markers.

Findings: In both PTB/LBW and FTB/NBW babies, serum iron decreased 3-fold within 12 h of delivery compared to umbilical blood (7·5 ± 4·5 vs 23·3 ± 7·1 ng/ml, P < 0·001, n = 425). Transferrin saturation showed a similar decline with a consequent increase in unsaturated iron-binding capacity. C-reactive protein levels increased over 10-fold (P < 0·001) and hepcidin levels doubled (P < 0·001). There was no difference in any of these responses between PTB/LBW and FTB/NBW babies.

Interpretation: Premature or low birthweight babies are able to mount a very rapid hypoferremia that is indistinguishable from that in normal term babies. The data suggest that this is a hepcidin-mediated response triggered by acute inflammation at birth, and likely to have evolved as an innate immune response against bacterial and fungal septicaemia.

Trial registration: clinicaltrials.gov (NCT03353051). Registration date: November 27, 2017.

Funding: Bill & Melinda Gates Foundation (OPP1152353).

Keywords: CRP; Hepcidin; Iron; Low birthweight; Neonates; Nutritional immunity; Prematurity; Septicaemia; Sub-Saharan Africa; Transferrin saturation.

Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no competing interests.

Copyright © 2019. Published by Elsevier B.V.

Figures

Fig. 1
Fig. 1
Schematic diagram of all study groupings and the generation of subgroups. PTB = preterm birth, FTB = full-term birth, LBW = low birthweight and NBW = normal birthweight. FTB/NBW neonates are FTB + NBW. PTB/LBW neonates are FTB + LBW, PTB + NBW and PTB + LBW neonates.
Fig. 2
Fig. 2
CONSORT diagram for participant flow. PTB/LBW are displayed in GREEN, and FTB/NBW in ORANGE.
Fig. 3
Fig. 3
Analysis of serum iron (A), TSAT (B) and hepcidin (C) in umbilical cord (BLUE) and postnatal venous blood (RED) based on all study groupings. Horizontal lines represent the arithmetic group means. FTB/NBW are FTB + NBW. PTB/LBW are FTB + LBW, PTB + NBW and PTB + LBW neonates. All group comparisons between cord and venous blood are statistically significant (P < 0·001). Hepcidin displayed as log10.
Fig. 4
Fig. 4
Timecourse of the changes in serum iron (A), TSAT (B), hepcidin (C) and CRP (D) in the first day of life. Means ± 95% CI. PTB/LBW are RED columns and significance lines. FTB/NBW are BLUE columns and significance lines. Columns are plotted according to mean time of bleed for the categories 0, 1–8, 9–16 and 17–24 h. **** = P < 0·0001, *** = P < 0·001, ** = P < 0·01, * = P < 0·05. No significance line = P > 0·05.
Fig. 5
Fig. 5
Comparisions of serum iron (A = cord, B = venous), TSAT (C = cord, D = venous) and hepcidin (E = cord, F = venous) in cord and postnatal venous blood. Means ± 95% CI. FTB/NBW are BLUE columns. PTB/LBW are RED columns. PTB are DARK GREY columns. LBW are LIGHT GREY columns. Significance lines represent the comparision of PTB/LBW , PTB or LBW groups to the FTB/NBW group. ** = P < 0·01, * = P < 0·05. No significance line = P > 0·05.

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