Malaria early in the first pregnancy: Potential impact of iron status

Abstract

Background & aims: Low iron stores may protect from malaria infection, therefore improving iron stores in early pregnancy in line with current recommendations could increase malaria susceptibility. To test this hypothesis we compared iron biomarkers and red cell indices in nulliparae and primigravidae who participated in a randomized controlled trial of long-term weekly iron supplementation.

Methods: Cross-sectional and longitudinal data analysis from a randomized controlled trial of long-term weekly iron supplementation in rural Burkina Faso. Malaria parasitaemia was monitored and biomarkers and red cell indices measured at study end-points: plasma ferritin, transferrin receptor (sTfR), zinc protoporphyrin, hepcidin, sTfR/log10 ferritin ratio, body iron, haemoglobin, red cell distribution width; mean corpuscular haemoglobin concentration/volume, and C-reactive protein. Correlation coefficients between biomarkers and red cell indices were determined. A regression correction approach based on ferritin was used to estimate iron body stores, allowing for inflammation. Body iron differences were compared between nulliparae and primigravidae, and the association determined of iron biomarkers and body iron stores with malaria.

Results: Iron and haematological indices of 972 nulliparae (mean age 16.5 years) and 314 primigravidae (median gestation 18 weeks) were available. Malaria prevalence was 54.0% in primigravidae and 41.8% in nulliparae (relative risk 1.28, 95% CI 1.13-1.45, P < 0.001), anaemia prevalence 69.7% and 43.4% (P < 0.001), and iron deficient erythropoiesis (low body iron) 8.0% and 11.7% (P = 0.088) respectively. Unlike other biomarkers the sTfR/log10 ferritin ratio showed no correlation with inflammation as measured by CRP. Most biomarkers indicated reduced iron deficiency in early pregnancy, with the exception of haemoglobin. Body iron increased by 0.6-1.2 mg/kg in early gestation, did not differ by malaria status in nulliparae, but was higher in primigravidae with malaria (6.5 mg/kg versus 5.0 mg/kg; relative risk 1.53, 95% CI 0.67-2.38, P < 0.001).

Conclusion: In primigravidae, early pregnancy haemoglobin was not a good indicator of requirement for iron supplementation, which could be detrimental given the association of better iron status with increased malaria infection.

Trial registration: clinicaltrials.gov:NCT01210040. Until placed in a public repository, data relating to the current study can be requested from the corresponding author and will be made available following an end user data agreement and sponsor approval.

Keywords: Inflammation; Iron biomarkers; Malaria; Non-pregnant; Pregnant.

Conflict of interest statement

Conflict of interest

Dorine Swinkels is Medical Director of the “Hepcidinanalysis.com” initiative, which aims to serve the scientific, medical and pharmaceutical communities with high-quality hepcidin measurements (www.hepcidinanalysis.com). The remaining authors disclose they do not have any conflict of interest.

Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1.. Participant Flow diagram

46 (iron) and 27 (control) women were identified as in early pregnancy at end assessment (FIN), or became pregnant within a few months following this assessment, and were then also screened at ANC1. These are totalled in the pregnant cohort in the Figure. 57 were subsequently screened at ANC1 and are considered in the separate longitudinal analysis. LTFU indicates loss to follow-up.

Figure 2.. Correlations for unadjusted and adjusted serum ferritin, sTfR/log10ferritin ratio, and adjusted body iron stores with haemoglobin in pregnant and non-pregnant women

Panel key. For primigravidae, A: Unadjusted ferritin; B: adjusted ferritin; C: sTfR/log10ferritin; D: Body iron stores. For nulliparae, E Unadjusted ferritin; F: adjusted ferritin; G: sTfR/log10ferritin; H: Body iron stores. Difference in the relationships between pregnant and non-pregnant women were highly significant (P<0.0001) (supplementary file) and remained in the malaria (P<0.0001) and non-malaria (P<0.0001) sub-groups for each comparison. Open circles represent non-malaria cases; closed circles malaria blood slide positive cases.

Figure 3. Cumulative body iron distributions by CRP cut-off or presence of malaria

Cumulative frequency of body iron distribution in women in presence or absence of P.falciparum parasitaemia. Body iron distributions are shown using adjusted ferritin estimations. Distributions are compared to those of US women in the first trimester (n=189) (12–49 years) in the National Health and Nutrition Examination Survey (NHANES) in the US population from 1999–2006 [reference 33], and for non-pregnant women (n= 409) (20– 45 years) in the NHANES III study in the US population from 1988 −1994 as reported by Cook et al [reference 21]. Malaria sub-group indicates blood slide negative and positive cases. Panels A and B use a combined (pregnant and non-pregnant) regression slope correction estimate for log ferritin against log CRP. Panels C and D [adj2] use a specific correction, based on separate regression slope correction estimates for primigravidae, or nulliparae, for log ferritin against log CRP.