Associations of maternal iron deficiency with malaria infection in a cohort of pregnant Papua New Guinean women

Abstract

Background Iron deficiency (ID) is common in malaria-endemic settings. Intermittent preventative treatment of malaria in pregnancy (IPTp) and iron supplementation are core components of antenatal care in endemic regions to prevent adverse pregnancy outcomes. ID has been associated with reduced risk of malaria infection, and correspondingly, iron supplementation with increased risk of malaria infection, in some studies. Methods A secondary analysis was conducted amongst 1888 pregnant women enrolled in a malaria prevention trial in Papua New Guinea. Maternal ID was defined as inflammation-corrected plasma ferritin levels < 15 μg/L at antenatal enrolment. Malaria burden (Plasmodium falciparum, Plasmodium vivax) was determined by light microscopy, polymerase chain reaction, and placental histology. Multiple logistic and linear regression analyses explored the relationship of ID or ferritin levels with indicators of malaria infection. Models were fitted with interaction terms to assess for modification of iron-malaria relationships by gravidity or treatment arm. Results Two-thirds (n = 1226) and 13.7% (n = 258) of women had ID and peripheral parasitaemia, respectively, at antenatal enrolment (median gestational age: 22 weeks), and 18.7% (120/1,356) had evidence of malaria infection on placental histology. Overall, ID was associated with reduced odds of peripheral parasitaemia at enrolment (adjusted odds ratio [aOR] 0.50; 95% confidence interval [95% CI] 0.38, 0.66, P < 0.001); peripheral parasitaemia at delivery (aOR 0.68, 95% CI 0.46, 1.00; P = 0.050); and past placental infection (aOR 0.35, 95% CI 0.24, 0.50; P < 0.001). Corresponding increases in the odds of infection were observed with two-fold increases in ferritin levels. There was effect modification of iron-malaria relationships by gravidity. At delivery, ID was associated with reduced odds of peripheral parasitaemia amongst primigravid (AOR 0.44, 95% CI 0.25, 0.76; P = 0.003), but not multigravid women (AOR 1.12, 95% CI 0.61, 2.05; P = 0.720). A two-fold increase in ferritin associated with increased odds of placental blood infection (1.44, 95% CI 1.06, 1.96; P = 0.019) and active placental infection on histology amongst primigravid women only (1.24, 95% CI 1.00, 1.54; P = 0.052). Conclusions Low maternal ferritin at first antenatal visit was associated with a lower risk of malaria infection during pregnancy, most notably in primigravid women. The mechanisms by which maternal iron stores influence susceptibility to infection with Plasmodium species require further investigation. Trial registration

Role of iron in the reduction of anemia among women of reproductive age in low-middle income countries: insights from systematic review and meta-analysis

“…In addition to the dietary resources, one needs to be aware of the geographical regions before providing iron. For example, health professionals may need to treat malaria in areas with endemic malaria while providing iron therapy to women [ 67 ]. Similarly, iron may also be affected by worm infestation.…”

Iron deficiency, pregnancy, and neonatal development

“…It is worthwhile noting that ID, defined by any other marker, was not associated with an increased risk of malaria infection 82 . A secondary analysis of a large randomized controlled trial of malaria treatment during pregnancy, using serum ferritin levels less than 15 mg/L to classify women as iron deficient before week 27 of gestation (after adjustment for the markers of inflammation CRP and alpha‐1‐acid glycoprotein (AGP), and parasitemia), confirmed a reduced odds of concurrent malaria parasitemia in iron‐deficient women (adjusted odds ratio 0.50; 95% CI, 0.38–0.66, P < 0.001) 27 . This association was still true at delivery, with low ferritin levels before week 27 showing an association with decreased odds of peripheral infection (adjusted odds ratio 0.68; 95% CI, 0.46–1.00, P < 0.050) 27 .…”

“…A secondary analysis of a large randomized controlled trial of malaria treatment during pregnancy, using serum ferritin levels less than 15 mg/L to classify women as iron deficient before week 27 of gestation (after adjustment for the markers of inflammation CRP and alpha‐1‐acid glycoprotein (AGP), and parasitemia), confirmed a reduced odds of concurrent malaria parasitemia in iron‐deficient women (adjusted odds ratio 0.50; 95% CI, 0.38–0.66, P < 0.001) 27 . This association was still true at delivery, with low ferritin levels before week 27 showing an association with decreased odds of peripheral infection (adjusted odds ratio 0.68; 95% CI, 0.46–1.00, P < 0.050) 27 . Interestingly, these associations were only seen in primigravidae (who, in areas of high transmission, and due to their lack of previous exposure to parasite antigens that specifically bind to the placenta, are more susceptible to infection 83 ).…”

“…We did not address the impacts of iron on neurodevelopment since this is the subject of another review in this Supplement 24 ; (3) Maternal and infant susceptibility to infections: infections may influence iron metabolism, for example, via upregulation of hepcidin, via direct effects on ferroportin expression, and upregulation of ferritin expression. However, the impact of ID on infection is less often studied 25–30 …”

“…Interestingly, these associations were only seen in primigravidae (who, in areas of high transmission, and due to their lack of previous exposure to parasite antigens that specifically bind to the placenta, are more susceptible to infection 83 ). 27 …”