Abstract
ABSTRACT.In malaria endemic countries, anemia in pregnant women occurs as a result of erythrocyte destruction by Plasmodium infections and other causes including malnutrition. Iron supplementation is recommended as treatment of iron-deficiency anemia. Erythrocyte destruction results in increased release of cytotoxic free heme that is scavenged by haptoglobin (Hp), hemopexin (Hx) and heme oxygenase-1 (HO-1). Paradoxically, iron supplementation in pregnant women has been reported to enhance parasitemia and increase levels of free heme. The relationship between free heme, heme scavengers, and birth outcomes has not been investigated, especially in women who are on iron supplementation. We hypothesized that parasite-infected pregnant women on routine iron supplementation have elevated heme and altered expression of heme scavengers. A cross-sectional study was conducted to determine the association between plasma levels of free heme, HO-1, Hp, Hx, and malaria status in pregnant women who received routine iron supplementation and their birth outcomes. Heme was quantified by colorimetric assay and scavenger protein concentration by ELISA. We demonstrated that iron-supplemented women with asymptomatic parasitemia had increased free heme (mean 75.6 µM; interquartile range [IQR] 38.8–96.5) compared with nonmalaria iron-supplemented women (mean 34.9 µM; IQR 17.4–43.8, P < 0.0001). Women with preterm delivery had lower levels of Hx (mean 656.0 µg/mL; IQR 410.9–861.3) compared with women with full-term delivery (mean: 860.9 µg/mL; IQR 715.2–1055.8, P = 0.0388). Our results indicate that iron supplementation without assessment of circulating levels of free heme and heme scavengers may increase the risk for adverse pregnancy outcomes.
Highlights
In 2019, there were an estimated 229 million cases of malaria worldwide and an estimated 409,000 malaria deaths
We have previously reported that iron supplementation elevates circulating free heme levels in the blood of pregnant women in malaria endemic regions and that elevated levels of free heme were associated with adverse birth outcomes.[24]
There is much evidence that plasmodial infection during pregnancy is associated with adverse birth outcomes such as low birth weight (LBW) and preterm delivery (PTD)
Summary
In 2019, there were an estimated 229 million cases of malaria worldwide and an estimated 409,000 malaria deaths. Children less than 5 years of age, pregnant women, and patients with HIV/AIDS, as well as nonimmune migrants, mobile populations, and travelers are at considerably higher risk of contracting malaria, and developing severe disease, than others.[1] Clinically, asymptomatic plasmodial infection refers to parasitemia of any density in the absence of fever or other acute symptoms, in individuals who have not recently received treatment. Malaria patients can develop severe complications if left untreated, involving central nervous system (cerebral malaria), pulmonary system (respiratory failure), renal system (acute renal failure) and hematopoietic system (severe malaria anemia).[2,3,4] During pregnancy, placental malaria (PM) is characterized by the accumulation of parasitized red blood cells (pRBC) in the placental intervillous space and subsequent prominent infiltration of maternal monocytes/macrophages.[5] Previous studies in Ghana reported that many pregnant women attending antenatal care were asymptomatically infected with Plasmodium falciparum.[6] The pathogenesis of PM is not completely understood but many studies have associated PM with adverse birth outcomes including high rates of miscarriage, low birth weight (LBW), preterm delivery (PTD), intrauterine growth retardation (IUGR), and neonatal and maternal mortality. A major complication of PM is maternal anemia, which can be attributed to direct destruction of pRBC in symptomatic and asymptomatic individuals.[7,8,9]
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