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

Holger W Unger, Valentina Laurita Longo, Andie Bleicher, Maria Ome-Kaius, Stephan Karl, Julie A Simpson, Amalia Karahalios, Elizabeth H Aitken, Stephen J Rogerson, Holger W Unger, Valentina Laurita Longo, Andie Bleicher, Maria Ome-Kaius, Stephan Karl, Julie A Simpson, Amalia Karahalios, Elizabeth H Aitken, Stephen J Rogerson

Abstract

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 .

Keywords: Adverse birth outcomes; Infection; Intermittent preventive treatment; Iron deficiency; Iron stores; Iron supplementation; Plasmodium falciparum.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Participant flow chart. Of 2793 women enrolled in the parent trial, 1892 had plasma available for ferritin, alpha-1-acid glycoprotein, and C-reactive protein and were included in the present analyses. Reasons for exclusion are indicated in the diagram. Abbreviations: AGP, α-1-acid glycoprotein; CRP, C-reactive protein; IPTp, intermittent preventive treatment in pregnancy
Fig. 2
Fig. 2
Conceptual directed acyclic graph of mediation iron deficiency (ferritin P. falciparum and/or P. vivax infections on light microscopy and/or polymerase chain reaction, and placental malaria as active or past infection on histology

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