Unger, Holger W

Laurita Longo, Valentina

Bleicher, Andie

Ome-Kaius, Maria

Karl, Stephan

Simpson, Julie A

Karahalios, Amalia

Aitken, Elizabeth H

Rogerson, Stephen J

2021-10-05

BACKGROUND: Iron deficiency (ID) has been associated with adverse pregnancy outcomes, maternal anaemia, and altered susceptibility to infection. In Papua New Guinea (PNG), monthly treatment with sulphadoxine-pyrimethamine plus azithromycin (SPAZ) prevented low birthweight (LBW; <2500 g) through a combination of anti-malarial and non-malarial effects when compared to a single treatment with SP plus chloroquine (SPCQ) at first antenatal visit. We assessed the relationship between ID and adverse birth outcomes in women receiving SPAZ or SPCQ, and the mediating effects of malaria infection and haemoglobin levels during pregnancy. METHODS: Plasma ferritin levels measured at antenatal enrolment in a cohort of 1892 women were adjusted for concomitant inflammation using C-reactive protein and α-1-acid glycoprotein. Associations of ID (defined as ferritin <15 μg/L) or ferritin levels with birth outcomes (birthweight, LBW, preterm birth, small-for-gestational-age birthweight [SGA]) were determined using linear or logistic regression analysis, as appropriate. Mediation analysis assessed the degree of mediation of ID-birth outcome relationships by malaria infection or haemoglobin levels. RESULTS: At first antenatal visit (median gestational age, 22 weeks), 1256 women (66.4%) had ID. Overall, ID or ferritin levels at first antenatal visit were not associated with birth outcomes. There was effect modification by treatment arm. Amongst SPCQ recipients, ID was associated with a 81-g higher mean birthweight (95% confidence interval [CI] 10, 152; P = 0.025), and a twofold increase in ferritin levels was associated with increased odds of SGA (adjusted odds ratio [aOR] 1.25; 95% CI 1.06, 1.46; P = 0.007). By contrast, amongst SPAZ recipients, a twofold increase in ferritin was associated with reduced odds of LBW (aOR 0.80; 95% CI 0.67, 0.94; P = 0.009). Mediation analyses suggested that malaria infection or haemoglobin levels during pregnancy do not substantially mediate the association of ID with birth outcomes amongst SPCQ recipients. CONCLUSIONS: Improved antenatal iron stores do not confer a benefit for the prevention of adverse birth outcomes in the context of malaria chemoprevention strategies that lack the non-malarial properties of monthly SPAZ. Research to determine the mechanisms by which ID protects from suboptimal foetal growth is needed to guide the design of new malaria prevention strategies and to inform iron supplementation policy in malaria-endemic settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT01136850 .

Department of Obstetrics and Gynaecology, Royal Darwin Hospital, Darwin, Northern Territory, Australia.

Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.

Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK.

Catholic University of Sacred Heart, Rome, Italy.

Department of Obstetrics and Gynaecology, San Pietro-Fatebenefratelli Hospital, Rome, Italy.

Department of Medicine (RMH), Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia.

Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea.

Australian Institute of Tropical Health & Medicine, James Cook University, Cairns, Australia.

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

Department of Infectious Diseases, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia.

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia.

Department of Medicine (RMH), Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia. sroger@unimelb.edu.au.

Department of Infectious Diseases, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia. sroger@unimelb.edu.au.

© 2021. The Author(s).

BMC Med. 2021 Oct 5;19(1):236. doi: 10.1186/s12916-021-02114-1.

0000-0003-4287-1982

https://pubmed.ncbi.nlm.nih.gov/34607575/?otool=iaurydwlib

https://hdl.handle.net/10137/11926

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The relationship between markers of antenatal iron stores and birth outcomes differs by malaria prevention regimen-a prospective cohort study.

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