Folic acid supplementation in the general population with SCD

• Chronic haemolytic anaemia and increased red blood cell production and turnover in SCD are thought to increase the requirements for folate, a water-soluble family of compounds that is essential for red blood cell production (50, 51). There is, however, limited evidence that folic acid supplementation improves haematological or clinical outcomes in individuals with SCD (50).
• Outside of pregnancy, individuals with SCD commonly take 1 mg of folic acid daily (50). Guidance from the WHO African region is that supplementation of folic acid at 5 mg a day for 10 to 20 days a month be used in the general SCD population to prevent worsening anaemia (23). There are, however, some concerns regarding high folate concentrations in populations with SCD in countries with national programmes of refined-grain folic acid fortification (see section on Folic acid fortification below) (52). Folic acid during pregnancy
• Low folic acid levels during pregnancy are associated with anaemia and fetal neural tube defects (53).
• In the general pregnant population, WHO recommends daily folic acid supplementation of 400 µg or weekly supplements of 2.8 mg (14). Higher-dose folic acid supplementation
• Folic acid is generally considered safe, with an internationally recognized tolerable upper intake level of 1 mg/day and the lowest observed adverse effect level (LOAEL) of 5 mg/day (54, 55). The LOAEL was set by the United States Institute of Medicine at 5 mg/day based on case studies and small observational studies demonstrating that folate doses >5 mg/day from supplemental or fortified foods had been shown to exacerbate or precipitate neuropathy in vitamin B12-deficient individuals (54). Although there are no longterm follow-up studies of offspring exposed to higher doses of folate, there is no evidence of direct toxicity even with folate doses of 15–100 mg/day (56, 57, 58).
• A 2015 systematic review found high-quality evidence that periconception folic acid supplementation prevents neural tube defects compared to no supplementation (relative risk [RR] 0.31, 95% confidence interval [CI] 0.17 to 0.58) but no additional protection was provided with higher doses of folate in the general pregnant population (59). However, the Medical Research Council Vitamin Study, a large randomized controlled trial conducted in seven mostly high-income countries (n=1195), demonstrated that high-dose folic acid (4 mg/day) resulted in a 72% relative risk reduction (95% CI 88% to 29%) for neural tube defects in women with a previously affected pregnancy (60). The 4 mg dose was selected because this was already available as a tablet and was not based on prior dose-finding studies. The authors suggested that the 4 mg dose of folate was responsible for driving the reduction in neural tube defects (60, 61).
• Although some studies have suggested a link between periconceptual high-dose folic acid supplementation and longer-term outcomes, including asthma in the offspring (62, 63) and maternal malignancy, causality has not been established and the consensus is that high-dose folic acid (e.g. 5 mg daily) is generally safe (64).
• The GDG acknowledged that other guidelines have recommended folic acid supplementation at higher doses (5 mg daily) prior to, and during, early pregnancy for women likely to have low folate levels, such as women with diabetes (65), women taking medications for epilepsy (66), and women with obesity (67). Availability of folic acid supplements
• Folic acid supplements at doses of up to 5 mg are readily available, as separate supplements or within prenatal vitamin formulations. Folic acid fortification
• There is substantial heterogeneity in folic acid fortification policies globally (68). Among 193 countries examined up to 31 July 2023, 69 implemented mandatory folic acid fortification, 47 had voluntary fortification, and 77 had no fortification (accounting for 32%, 53% and 15% of the global population, respectively) (68). In areas with a high burden of SCD, fortification was mandatory in most of western, eastern and southern sub-Saharan Africa and the Middle-East; voluntary in India, Saudi Arabia and Sudan; and there was no fortification in northern or central sub-Saharan Africa (68). An Australian study suggests that the introduction of folic acid food fortification increased maternal folate by 63% and reduced the effect of supplementary folic acid (69). Folic acid supplementation and malaria
• Women with SCD living in malaria-endemic regions remain at risk for malaria infection. The WHO Guidelines for malaria recommend antimalarial medicine at predetermined intervals to reduce disease burden in pregnancy, and adverse pregnancy and birth outcomes (70). The only currently available regimen is intermittent prophylaxis with sulfadoxine-pyrimethamine (IpTp-SP).
• The GDG acknowledged that the evidence underlying the recommendation for IpTp-SP did not specify the subpopulation of pregnant women with SCD living in endemic areas (71). However, the GDG also acknowledged the availability of direct moderate-certainty evidence suggesting the reduction of malaria infection at delivery (and the risks of malaria-induced anaemia) and the potential for reduction of low birthweight infants in high-burden areas (low certainty). Therefore, in the absence of direct evidence regarding the use of folic acid supplementation for pregnant women with SCD, the GDG considered the evidence that doses of folic acid of 5 mg or more daily counteract the efficacy of IpTp-SP as an antimalarial (72) and thus reaffirms the existing WHO recommendation that only low-dose formulations of folic acid (i.e. 400 µg daily) be co-administered with sulfadoxine-pyrimethamine (70).