Review question
Does taking folic acid (folate) supplements affect the risk or severity of malaria infection amongst people who are taking (antifolate) medications to prevent or treat malaria, in areas where malaria is common?
Key messages
° People who received folic acid supplementation (alone or with iron) and antifolate antimalarial treatment were less likely to eliminate malaria parasites and had increased treatment failure.
° There were not enough studies to examine whether taking folic acid supplementation at a lower dose, like 400 μg, might affect the risk of malaria infection or health outcomes if infected. This low dose is currently recommended before and during early pregnancy for the prevention of neural tube defects.
Malaria and the importance of folate
Malaria is a disease spread by the bite of certain types of female mosquitoes and is found in over 80 countries. The malaria parasite needs folate to grow and survive, and some medicines used to prevent and treat malaria target folate. Folic acid (the synthetic form of folate) is recommended at a dose of 400 μg daily to prevent neural tube defects. There are some concerns that folic acid (particularly higher doses) may affect malaria and how well some medicines work to prevent and treat malaria.
What did we want to find out?
This review was done to see how folic acid affects malaria risk and severity amongst people taking antifolate antimalarial medications and living in areas where malaria is common.
Specifically, we aimed to answer the following questions:
Prevention: For people who do not have malaria and are taking antimalarial drugs to prevent malaria, do folic acid supplements increase their risk of getting malaria or having worse outcomes?
Treatment: For people who have malaria and are being treated with antifolate antimalarial medications, does taking folic acid supplements affect how well the drugs work to treat malaria?
What did we do?
We searched for trials that looked at folic acid supplementation in people taking antifolate antimalarial medications to prevent or treat malaria. We compared and summarised the results of the trials and rated our confidence in the information based on how the study was done.
What did we find?
We included eight trials (3486 people); three were prevention trials and five were treatment trials. Most trials used higher folic acid doses (> 1.0 mg) and included the medication sulfadoxine-pyrimethamine (SP). The prevention studies did not include the main outcomes we were trying to assess. In the treatment studies, people who took folic acid and antifolate antimalarial drugs were less likely to clear malaria parasites from their bodies (day 3) and were more likely to have treatment failure (up to 28 days after treatment) compared to the same treatment but without folic acid. Most of the included trials provided the antimalarial SP and folic acid with doses above the tolerable upper intake level (upper limit; > 1.0 mg). Only one trial included folic acid at a dose of 400 μg per day (the recommended daily dose of folic acid for prevention of neural tube defects); there were no differences in parasite clearance or treatment failure between the arm with 400 μg per day of folic acid and the arm with no folic acid.
What are the limitations of the evidence?
The small number of trials and the size of the studies were limitations of this review, and no prevention studies reported main outcomes.
How up to date is this evidence?
The evidence is up-to-date as of September 13, 2024.
Baca abstrak penuh
Malaria is an infectious disease transmitted by female Anopheles mosquitoes, with ongoing transmission in over 80 countries. The malaria parasite requires folate for survival and growth; antifolate antimalarial medications used for prevention and treatment target enzymes in folate metabolism as their mechanism of action. Periconceptional folic acid (synthetic form of folate) supplementation (400 μg/day) is the standard of care for neural tube defect prevention. Concerns have been raised about the potential effects of folic acid (including above the tolerable upper intake level (UL) > 1.0 mg/day) in the context of malaria prevention and treatment, including the efficacy of antimalarial medications. Examining the potential impact of folic acid on malaria risk and severity amongst people taking antifolate antimalarial medications may inform public health programmes in malaria-endemic areas.
Matlamat
To examine the effects of folic acid supplementation on the risk and severity of malaria infection amongst people taking antifolate antimalarials and living in areas with malaria endemicity.
Prevention: Amongst uninfected people taking antifolate antimalarial medications for malaria prevention, does folic acid supplementation increase susceptibility or severity of malaria infection?
Treatment: Amongst people with malaria infection who are being treated with antifolate antimalarial drugs, does folic acid supplementation reduce parasite clearance or increase the risk of treatment failure?
Kaedah Pencarian
We searched databases including CENTRAL, MEDLINE, Embase, CINAHL, Scopus, and trial registries (September 13, 2024), grey literature, and reference searches to identify additional studies.
Kriteria Pemilihan
Randomised trials evaluating the effects of folic acid supplementation (alone or in combination with iron or other vitamins and minerals) amongst individuals taking antifolate antimalarial medications in malaria-endemic areas.
Pengumpulan Data dan Analisis
Primary outcomes included uncomplicated malaria or severe malaria, parasite clearance, and treatment failure. Cochrane RoB 2 was used to evaluate the risk of bias. Certainty of evidence was assessed using GRADE for primary outcomes. We performed meta‐analyses using random‐effects models for all outcomes.
Keputusan Utama
Eight trials with 3486 participants were included: three malaria prevention trials and five malaria treatment trials. Most treatment trials included folic acid doses above the UL (> 1.0 mg/d); one trial included 400 μg per day. Antifolate antimalarials included sulfadoxine-pyrimethamine (SP; five trials), sulfisoxazole plus pyrimethamine (one trial), atovaquone-proguanil (one trial), and proguanil (one trial). Some studies had unclear or high risk of bias due to missing outcome data.
Malaria prevention
Comparison 1: Folic acid (alone or in combination with other vitamins and minerals) + antifolate antimalarials versus placebo/no folic acid + antifolate antimalarial medications.
Data for primary outcomes, uncomplicated and severe malaria, were not reported. One trial reported laboratory parasitaemia; there was little to no difference in malaria parasitaemia amongst pregnant women receiving folic acid (with iron) and antifolate antimalarials compared to iron and antifolate antimalarials (Risk Ratio (RR) 1.21; 95% CI 0.56 to 2.62; P = 0.63; 1 trial, 643 individuals).
Comparisons 2–4: No studies reported data for Comparisons 2–4.
Malaria treatment
Comparison 1: Folic acid (alone or in combination with other vitamins and minerals) + antifolate antimalarial medications versus placebo/no folic acid with antifolate antimalarials. People receiving folic acid (alone or with iron) and antifolate antimalarials were less likely to clear malaria parasites (day 3) compared to individuals who did not receive folic acid (RR 0.89; 95% CI 0.84 to 0.95, 4 trials, 929 individuals, moderate-certainty evidence); and had increased risk of treatment failure on day 7 (RR 2.12; 95% CI 1.41 to 3.19, 4 trials, 1062 individuals, moderate-certainty evidence), day 14 (RR 1.97; 95% CI 1.44 to 2.70, 3 trials; 891 individuals; moderate-certainty evidence), and day 28 (RR 1.35; 95% CI 1.21 to 1.51; 4 trials; 1012 individuals, moderate-certainty evidence).
Comparison 2: Folic acid alone + antifolate antimalarials versus placebo/no folic acid + antifolate antimalarial medication. Folic acid supplementation with antifolate antimalarials likely had lower parasite clearance (day 3) (RR 0.87; 95% CI 0.79 to 0.96, 2 trials, 229 individuals, moderate certainty of the evidence), and increased treatment failure (day 7: RR 2.58; 95% CI 0.89 to 7.45; P = 0.08; 2 trials; 344 individuals, moderate-certainty evidence; day 14: RR 4.15; 95% CI 0.92 to 18.65; P = 0.06; 1 trial; 173 individuals, moderate-certainty evidence; and day 28: RR 1.47; 95% CI 0.86 to 2.49; P = 0.16; 2 trials; 294 individuals, moderate-certainty evidence), compared to no folic acid and antifolate antimalarials.
Comparison 3: Folic acid with iron + antifolate antimalarial medication versus placebo/no folic acid with iron + antifolate antimalarial medication. People receiving folic acid with iron and antifolate antimalarials were less likely to clear malaria parasites (day 3: RR 0.90; 95% CI 0.83 to 0.98; P = 0.02; 2 trials; 700 individuals, moderate-certainty evidence), and had increased treatment failure (day 7: RR 1.96; 95% CI 1.05 to 3.65; P = 0.03; 2 trials; 718 individuals; day 14: RR 1.90; 95% CI 1.35 to 2.67; 2 trials; 718 individuals; day 28: RR 1.17; 95% CI 0.79 to 1.74; 2 trials; 578 individuals; all moderate-certainty evidence), compared to iron and antifolate antimalarials.
Comparison 4: No studies reported data.
Kesimpulan Pengarang
Malaria prevention: None of the included trials reported primary outcomes.
Malaria treatment: People who received folic acid supplementation (alone or with iron) and antifolate antimalarial treatment were less likely to clear malaria parasitaemia (day 3), and had increased treatment failure (days 7, 14, 28). Most of the included trials provided folic acid with doses above the tolerable UL (> 1.0 mg). One trial included folic acid at a dose of 400 μg/d (recommended dose for preventing neural tube defects) and showed little to no difference in parasite clearance or treatment failure.
