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

Holger W Unger, Andie Bleicher, Maria Ome-Kaius, Elizabeth H Aitken, Stephen J Rogerson, Holger W Unger, Andie Bleicher, Maria Ome-Kaius, Elizabeth H Aitken, Stephen J Rogerson

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: ClinicalTrials.gov NCT01136850.

Keywords: Iron deficiency; Iron supplementation; Plasmodium falciparum; Plasmodium vivax; Risk.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Participant flow chart. CRP, C-reactive protein; AGP, α-1-acid glycoprotein, LM, light microscopy, qPCR, polymerase chain reaction

References

    1. WHO . World Malaria Report 2019. Geneva: World Health Organization; 2019.
    1. Dellicour S, Tatem AJ, Guerra CA, Snow RW, ter Kuile FO. Quantifying the number of pregnancies at risk of malaria in 2007: a demographic study. PLoS Med. 2010;7:e1000221. doi: 10.1371/journal.pmed.1000221.
    1. Rogerson SJ, Unger HW. Prevention and control of malaria in pregnancy - new threats, new opportunities? Expert Rev Anti Infect Ther. 2017;15:361–375. doi: 10.1080/14787210.2017.1272411.
    1. Barker DJ. The developmental origins of adult disease. Eur J Epidemiol. 2003;18:733–736. doi: 10.1023/A:1025388901248.
    1. Rogerson SJ, Desai M, Mayor A, Sicuri E, Taylor SM, van Eijk AM. Burden, pathology, and costs of malaria in pregnancy: new developments for an old problem. Lancet Infect Dis. 2018;18:e107–e118. doi: 10.1016/S1473-3099(18)30066-5.
    1. Umbers AJ, Unger HW, Rosanas-Urgell A, Wangnapi RA, Kattenberg JH, Jally S, et al. Accuracy of an HRP-2/panLDH rapid diagnostic test to detect peripheral and placental Plasmodium falciparum infection in Papua New Guinean women with anaemia or suspected malaria. Malar J. 2015;14:412. doi: 10.1186/s12936-015-0927-5.
    1. WHO . Policy brief for the implementation of intermittent preventive treatment in malaria in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP) (January 2014) Geneva: World Health Organization; 2014.
    1. Iqbal S, Ekmekcioglu C. Maternal and neonatal outcomes related to iron supplementation or iron status: a summary of meta-analyses. J Matern Fetal Neonatal Med. 2019;32:1528–1540. doi: 10.1080/14767058.2017.1406915.
    1. WHO . Recommendations on antenatal care for a positive pregnancy experience. Geneva: World Health Organization; 2016.
    1. Oppenheimer SJ, Gibson FD, Macfarlane SB, Moody JB, Harrison C, Spencer A, Bunari O. Iron supplementation increases prevalence and effects of malaria: report on clinical studies in Papua New Guinea. Trans R Soc Trop Med Hyg. 1986;80:603–612. doi: 10.1016/0035-9203(86)90154-9.
    1. Oppenheimer SJ, Macfarlane SB, Moody JB, Harrison C. Total dose iron infusion, malaria and pregnancy in Papua New Guinea. Trans R Soc Trop Med Hyg. 1986;80:818–822. doi: 10.1016/0035-9203(86)90393-7.
    1. Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet. 2006;367:133–143. doi: 10.1016/S0140-6736(06)67962-2.
    1. Sangare L, van Eijk AM, Ter Kuile FO, Walson J, Stergachis A. The association between malaria and iron status or supplementation in pregnancy: a systematic review and meta-analysis. PLoS ONE. 2014;9:e87743. doi: 10.1371/journal.pone.0087743.
    1. Georgieff MK, Krebs NF, Cusick SE. The benefits and risks of iron supplementation in pregnancy and childhood. Annu Rev Nutr. 2019;39:121–146. doi: 10.1146/annurev-nutr-082018-124213.
    1. Moya-Alvarez V, Cottrell G, Ouedraogo S, Accrombessi M, Massougbodgi A, Cot M. High iron levels are associated with increased malaria risk in infants during the first year of life in Benin. Am J Trop Med Hyg. 2017;97:497–503. doi: 10.4269/ajtmh.16-0001.
    1. Kabyemela ER, Fried M, Kurtis JD, Mutabingwa TK, Duffy PE. Decreased susceptibility to Plasmodium falciparum infection in pregnant women with iron deficiency. J Infect Dis. 2008;198:163–166. doi: 10.1086/589512.
    1. Bahizire E, D'Alessandro U, Dramaix M, Dauby N, Bahizire F, Mubagwa K, Donnen P. Malaria and iron load at the first antenatal visit in the rural South Kivu, Democratic Republic of the Congo: is iron supplementation safe or could it be harmful? Am J Trop Med Hyg. 2018;98:520–523. doi: 10.4269/ajtmh.17-0585.
    1. Senga EL, Harper G, Koshy G, Kazembe PN, Brabin BJ. Reduced risk for placental malaria in iron deficient women. Malar J. 2011;10:47. doi: 10.1186/1475-2875-10-47.
    1. Penarosas JP, Deregil LM, Garciaasal MN, Dowswell T. Daily oral iron supplementation during pregnancy. Cochrane Database Syst Rev. 2015;7:CD004736.
    1. Mwangi MN, Roth JM, Smit MR, Trijsburg L, Mwangi AM, Demir AY, et al. Effect of daily antenatal iron supplementation on Plasmodium infection in Kenyan women: a randomized clinical trial. JAMA. 2015;314:1009–1020. doi: 10.1001/jama.2015.9496.
    1. Mwangi MN, Echoka E, Knijff M, Kaduka L, Werema BG, Kinya FM, et al. Iron status of Kenyan pregnat women after adjusting for inflammation using BRINDA regression analysis and other correction methods. Nutrients. 2019;11:420. doi: 10.3390/nu11020420.
    1. Etheredge AJ, Premji Z, Gunaratna NS, Abioye AI, Aboud S, Duggan C, et al. Iron supplementation in iron-replete and nonanemic pregnant women in Tanzania: a randomized clinical trial. JAMA Ped. 2015;169:947–955. doi: 10.1001/jamapediatrics.2015.1480.
    1. Fowkes FJI, Moore KA, Opi DH, Simpson JA, Langham F, Stanisic DI, et al. Iron deficiency during pregnancy is associated with a reduced risk of adverse birth outcomes in a malaria-endemic area in a longitudinal cohort study. BMC Med. 2018;16:156. doi: 10.1186/s12916-018-1146-z.
    1. Unger HW, Laurita Longo V, Bleicher A, Ome-Kaius M, Karl S, Simpson JA. The relationship between markers of antenatal iron stores and birth outcomes differs by malaria prevention regimen-a prospective cohort study. BMC Med. 2021;19:236. doi: 10.1186/s12916-021-02114-1.
    1. Unger HW, Ome-Kaius M, Wangnapi RA, Umbers AJ, Hanieh S, Suen CS, et al. Sulphadoxine-pyrimethamine plus azithromycin for the prevention of low birthweight in Papua New Guinea: a randomised controlled trial. BMC Med. 2015;13:9. doi: 10.1186/s12916-014-0258-3.
    1. Keven JB, Katusele M, Vinit R, Rodriguez-Rodriguez D, Hetzel MW, Robinson LJ. Nonrandom selection and multiple blood feeding of human hosts by Anopheles vectors: implications for malaria transmission in Papua New Guinea. Am J Trop Med Hyg. 2021;105:1747–1758. doi: 10.4269/ajtmh.21-0210.
    1. Ome-Kaius M, Unger HW, Singirok D, Wangnapi RA, Hanieh S, Umbers AJ. Determining effects of areca (betel) nut chewing in a prospective cohort of pregnant women in Madang Province, Papua New Guinea. BMC Pregnancy Childbirth. 2015;15:177. doi: 10.1186/s12884-015-0615-z.
    1. Unger HW, Rosanas-Urgell A, Robinson LJ, Ome-Kaius M, Jally S, Umbers AJ. Microscopic and submicroscopic Plasmodium falciparum infection, maternal anaemia and adverse pregnancy outcomes in Papua New Guinea: a cohort study. Malar J. 2019;18:302. doi: 10.1186/s12936-019-2931-7.
    1. Lufele E, Umbers A, Ordi J, Ome-Kaius M, Wangnapi R, Unger H, et al. Risk factors and pregnancy outcomes associated with placental malaria in a prospective cohort of Papua New Guinean women. Malar J. 2017;16:427. doi: 10.1186/s12936-017-2077-4.
    1. Ismail MR, Ordi J, Menendez C, Ventura PJ, Aponte JJ, Kahigwa E, et al. Placental pathology in malaria: a histological, immunohistochemical, and quantitative study. Hum Pathol. 2000;31:85–93. doi: 10.1016/S0046-8177(00)80203-8.
    1. Rogerson SJ, Pollina E, Getachew A, Tadesse E, Lema VM, Molyneux ME. Placental monocyte infiltrates in response to Plasmodium falciparum malaria infection and their association with adverse pregnancy outcomes. Am J Trop Med Hyg. 2003;68:115–119. doi: 10.4269/ajtmh.2003.68.1.0680115.
    1. Bleicher AV, Unger HW, Rogerson SJ, Aitken EH. A sandwich enzyme-linked immunosorbent assay for the quantitation of human plasma ferritin. MethodsX. 2018;5:648–651. doi: 10.1016/j.mex.2018.06.010.
    1. Daru J, Colman K, Stanworth SJ, De La Salle B, Wood EM, Pasricha SR. Serum ferritin as an indicator of iron status: what do we need to know? Am J Clin Nutr. 2017;106(Suppl 6):1634S–1639S. doi: 10.3945/ajcn.117.155960.
    1. WHO . Assessing the iron status of populations. Geneva: World Health Organization; 2007.
    1. WHO . Serum ferritin concentations for the assessment of iron status and iron deficiency in populations. Geneva: World Health Organization; 2011.
    1. Namaste SM, Rohner F, Huang J, Bhushan NL, Flores-Ayala R, Kupka R, et al. Adjusting ferritin concentrations for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. Am J Clin Nutr. 2017;106(Suppl 1):359S–371S.
    1. Diallo S, Roberts SA, Gies S, Rouamba T, Swinkels DW, Geurts-Moespot AJ, et al. Malaria early in the first pregnancy: potential impact of iron status. Clin Nutr. 2020;39:204–214. doi: 10.1016/j.clnu.2019.01.016.
    1. Moya-Alvarez V, Cottrell G, Ouedraogo S, Accrombessi M, Massougbodgi A, Cot M. Does iron increase the risk of malaria in pregnancy. Open Forum Infect Dis. 2015;2:ofv038. doi: 10.1093/ofid/ofv038.
    1. Goheen MM, Bah A, Wegmuller R, Verhoef H, Darboe B, Danso E, et al. Host iron status and erythropoietic response to iron supplementation determines susceptibility to the RBC stage of falciparum malaria during pregnancy. Sci Rep. 2017;7:17674. doi: 10.1038/s41598-017-16896-z.
    1. Clark MA, Goheen MM, Fulford A, Prentice AM, Elnagheeb MA, Patel J, et al. Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum. Nat Commun. 2014;5:4446. doi: 10.1038/ncomms5446.
    1. Stoffel NU, Uyoga MA, Mutuku FM, Frost JN, Mwasi E, Paganini D, et al. Iron deficiency anemia at time of vaccination predicts decreased vaccine response and iron supplementation at time of vaccination increases humoral vaccine response: a birth cohort study and a randomized trial follow-up study in Kenyan Infants. Front Immunol. 2020;11:1313. doi: 10.3389/fimmu.2020.01313.
    1. Jiang Y, Li C, Wu Q, An P, Huang L, Wang J, et al. Iron-dependent histone 3 lysine 9 demethylation controls B cell proliferation and humoral immune responses. Nat Commun. 2019;10:2935. doi: 10.1038/s41467-019-11002-5.
    1. Bundi CK, Nalwoga A, Lubyayi L, Muriuki JM, Mogire RM, Opi H, et al. Iron deficiency is associated with reduced levels of Plasmodium falciparum-specific antibodies in African children. Clin Infect Dis. 2021;73:43–49. doi: 10.1093/cid/ciaa728.
    1. Aitken EH, Damelang T, Ortega-Pajares A, Alemu A, Hasang W, Dini S, et al. Developing a multivariate prediction model of antibody features associated with protection of malaria-infected pregnant women from placental malaria. Elife. 2021;10:e65776. doi: 10.7554/eLife.65776.
    1. Ndam NT, Denoeud-Ndam L, Doritchamou J, Viwami F, Salanti A, Nielsen MA, et al. Protective antibodies against placental malaria and poor outcomes during pregnancy. Benin Emerg Infect Dis. 2015;21:813–823. doi: 10.3201/eid2105.141626.
    1. Nacher M, McGready R, Stepniewska K, Cho T, Looareesuwan S, White NJ, Nosten F. Haematinic treatment of anaemia increases the risk of Plasmodium vivax malaria in pregnancy. Trans R Soc Trop Med Hyg. 2003;97:273–276. doi: 10.1016/S0035-9203(03)90140-4.
    1. Barffour MA, Schulze KJ, Coles CL, Chileshe J, Kalungwana N, Siamusantu W, et al. Malaria exacerbates inflammation-associated elevation in ferritin and soluble transferrin receptor with only modest effects on iron deficiency and iron deficiency anaemia among rural Zambian children. Trop Med Int Health. 2018;23:53–62. doi: 10.1111/tmi.13004.
    1. Anchang-Kimbi JK, Achidi EA, Nkegoum B, Sverremark-Ekstrom E, Troye-Blomberg M. Diagnostic comparison of malaria infection in peripheral blood, placental blood and placental biopsies in Cameroonian parturient women. Malar J. 2009;8:126. doi: 10.1186/1475-2875-8-126.
    1. Muriuki JM, Mentzer AJ, Kimita W, Ndungu FM, Macharia AW, Webb EL, et al. Iron status and associated malaria risk among African children. Clin Infect Dis. 2019;68:1807–1814. doi: 10.1093/cid/ciy791.

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