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

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 6À24 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).

Iron homeostasis in full-term, normal birthweight Gambian neonates over the first week of life

“…This study reconfirms our previous observation of a rapid and acute hypoferremia in the first day of life 16,17 with serum iron dropping from 23 to7 µmol/L and TSAT falling from 50 to 14%. This may have evolved as an arm of innate immunity designed to protect from neonatal septicemia, a common cause of neonatal death.…”

“…IL-6 also activates the JAK-STAT pathway, leading to the induction of hepcidin synthesis 15 . In previous studies, we 16,17 and others [18][19][20][21] have demonstrated a rapid and profound hypoferremia occurring within the first few hours after delivery. This is assumed to have evolved as a defence against early-onset neonatal sepsis (EONS) and remains robust in premature and low-birthweight babies 17 .…”

“…Our prior analyses 16,17 using data from independent studies, revealed that the early hypoferremia was, at least in part, likely driven by an inflammatory response to the birth process eliciting a rapid IL-6-mediated rise in hepcidin. Hepcidin blocks the release of iron from enterocytes and macrophages 1 and thereby reduces serum iron through the dual actions of preventing iron absorption and recirculation.…”

Folate deficiency in early pregnancy increases the risk of low birth weight: survey of neonates in eastern China

“…In our individuals, serum folate concentrations were generally high, with a mean value of 37.71 nmol/l. Beside the previously known factors (prematurity, preeclampsia) (36,37), the results showed that folate de ciency (< 32.5 nmol/l) before 18 weeks gestation was an independent risk factor for LBW in eastern Chinese pregnant women. This is more accurate than studying the relationship between folic acid supplementation and LBW.…”

Iron supplementation of breastfed Gambian infants from 6 weeks to 6 months of age: protocol for a randomised controlled trial

“…We intend to enrol 100 infants in the trial, which will be sufficient to have 80% probability that, if the true increase in geometric mean serum iron concentration in the iron group increases by 70% or more relative to the control group, the 95% confidence interval for the ratio would exclude zero (with the additional assumptions that the variance of log e serum iron concentration [in µmol/L] is 0.76 for each group 13 ; 10% of infants in the iron group stop taking iron supplements in the course of the intervention period; and the percentage of infants in the control group who stop taking placebo supplements is negligible) ( Figure 3 ). In absolute terms, an increase by 70% corresponds to a change of geometric mean serum iron concentration of 3.0µmol/L, assuming that this concentration is 4.3µmol/L in the placebo group (as observed at Day 0 in Armitage et al 2019 1 ), so that it will have increased 7.3µmol/L in the iron group.…”