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

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)

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

Human neonates elicit a profound hypoferremia which may protect against bacterial sepsis. We examined the transience of this hypoferremia by measuring iron and its chaperone proteins, inflammatory and haematological parameters over the first post-partum week. We prospectively studied term, normal weight Gambian newborns. Umbilical cord vein and artery, and serial venous blood samples up to day 7 were collected. Hepcidin, serum iron, transferrin, transferrin saturation, haptoglobin, c-reactive protein, α1-acid-glycoprotein, soluble transferrin receptor, ferritin, unbound iron-binding capacity and full blood count were assayed. In 278 neonates we confirmed the profound early postnatal decrease in serum iron (22.7 ± 7.0 µmol/L at birth to 7.3 ± 4.6 µmol/L during the first 6–24 h after birth) and transferrin saturation (50.2 ± 16.7% to 14.4 ± 6.1%). Both variables increased steadily to reach 16.5 ± 3.9 µmol/L and 36.6 ± 9.2% at day 7. Hepcidin increased rapidly during the first 24 h of life (19.4 ± 14.4 ng/ml to 38.9 ± 23.9 ng/ml) and then dipped (32.7 ± 18.4 ng/ml) before rising again at one week after birth (45.2 ± 19.1 ng/ml). Inflammatory markers increased during the first week of life. The acute postnatal hypoferremia in human neonates on the first day of life is highly reproducible but transient. The rise in serum iron during the first week of life occurs despite very high hepcidin levels indicating partial hepcidin resistance. Trial Registration: clinicaltrials.gov (NCT03353051). Registration date: November 27, 2017

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

Acknowledgements: We thank Kanifing Municipal Council (KMC) and Kanifing General Hospital (KGH) for their support during the study.Human neonates elicit a profound hypoferremia which may protect against bacterial sepsis. We examined the transience of this hypoferremia by measuring iron and its chaperone proteins, inflammatory and haematological parameters over the first post-partum week. We prospectively studied term, normal weight Gambian newborns. Umbilical cord vein and artery, and serial venous blood samples up to day 7 were collected. Hepcidin, serum iron, transferrin, transferrin saturation, haptoglobin, c-reactive protein, α1-acid-glycoprotein, soluble transferrin receptor, ferritin, unbound iron-binding capacity and full blood count were assayed. In 278 neonates we confirmed the profound early postnatal decrease in serum iron (22.7 ± 7.0 µmol/L at birth to 7.3 ± 4.6 µmol/L during the first 6-24 h after birth) and transferrin saturation (50.2 ± 16.7% to 14.4 ± 6.1%). Both variables increased steadily to reach 16.5 ± 3.9 µmol/L and 36.6 ± 9.2% at day 7. Hepcidin increased rapidly during the first 24 h of life (19.4 ± 14.4 ng/ml to 38.9 ± 23.9 ng/ml) and then dipped (32.7 ± 18.4 ng/ml) before rising again at one week after birth (45.2 ± 19.1 ng/ml). Inflammatory markers increased during the first week of life. The acute postnatal hypoferremia in human neonates on the first day of life is highly reproducible but transient. The rise in serum iron during the first week of life occurs despite very high hepcidin levels indicating partial hepcidin resistance.Trial Registration: clinicaltrials.gov (NCT03353051). Registration date: November 27, 2017

Workflow of screening and inclusion of studies as defined by the PRISMA guidelines.

Workflow of screening and inclusion of studies as defined by the PRISMA guidelines.</p

The search strategy employed to generate the review.

The search strategy employed to generate the review.</p

PRISMA guidelines for full text of review and abstract.

PRISMA guidelines for full text of review and abstract.</p

Data type and definition used to classify 57 compliance papers included in the analysis.

Longitudinal compliance data was reported by both longitudinal studies (cohort, randomised controlled trials) and cross-sectional studies. Abbreviations: CDD–community drug distributor, DOT–directly observed treatment.</p

The complete 89 studies identified as containing compliance data.

The complete 89 studies identified as containing compliance data.</p

Choropleth map of studies published globally from 2016 to 2022 (Papers).

Countries where no papers were published are shown in grey. Four studies are represented as 11 datapoints where studies reported data for more than one country, totalling 96 datapoints from 89 studies. (LF, OV, STH, SCH, Trachoma) Maps showing total population of each country requiring treatment for each of the five (PC)-NTDs. Note: STH map shows total preSAC and SAC population only requiring treatment. All maps have been focused to latitude less than 50 degrees. Data taken from WHO global observatory PCT databank [28]. Abbreviations: LF–lymphatic filariasis, OV–Onchocerciasis, SCH–schistosomiasis, STH–soil-transmitted helminths. Map data acquired from the open source tidyverse package using the map_data() function [29].</p

Summary overview of the 89 studies included in the analysis split by the epidemiological classification of cross-sectional or longitudinal data.

The full data extraction of the 165 studies is provided in S2 Data. Frequency and percentage of studies falling into each category is shown as “n (%)”. Note for ‘Sample Population’, each stratification totals the number of studies, whilst the remaining rows of the table represents a single stratum. Abbreviations: LF–lymphatic filariasis, N–number of studies, OV–onchocerciasis, preSAC–preschool-aged children, SAC–school-aged children, SCH–schistosomiasis, STH–soil-transmitted helminths.</p