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The Inclusion of Folic Acid in Weekly Iron-Folic Acid Supplements Confers no Additional Benefit on Anemia Reduction in Nonpregnant Women: A Randomized Controlled Trial in Malaysia

Samson KLI, Loh SP, Lee SS, Sulistyoningrum DC, Khor GL, Mohd Shariff ZB, et al.

J Nutr, 2021 Aug 07;151(8):2264-2270.
PMID: 33978167 DOI: 10.1093/jn/nxab115

BACKGROUND: Weekly iron-folic acid (IFA) supplements are recommended for all menstruating women in countries where anemia prevalence is ≥20%; however, it is unknown whether the inclusion of folic acid in weekly IFA supplements reduces anemia.
OBJECTIVES: We examined whether the inclusion of folic acid in weekly IFA supplements conferred any benefit on hemoglobin (Hb) concentration, anemia reduction, or iron status [ferritin and soluble transferrin receptor (sTfR)], over iron alone.
METHODS: In this secondary analysis of a randomized controlled trial in Malaysia, n = 311 nonpregnant women (18-45 y old) received 60 mg Fe with either 0, 0.4, or 2.8 mg folic acid once-weekly for 16 wk. Fasting blood was collected at baseline and 16 wk. A generalized linear model (normal distribution with identity link) was used to assess Hb concentration at 16 wk (primary outcome).
RESULTS: At baseline, 84% of women had low folate status (plasma folate 0.05). Baseline plasma folate concentration did not modify the effect of treatment on Hb concentration at 16 wk. Among all women, the risks of anemia [risk ratio (RR): 0.65; 95% CI: 0.45, 0.96; P = 0.03] and iron deficiency based on ferritin (RR: 0.30; 95% CI: 0.20, 0.44; P
Suboptimal Biochemical Riboflavin Status Is Associated with Lower Hemoglobin and Higher Rates of Anemia in a Sample of Canadian and Malaysian Women of Reproductive Age

Aljaadi AM, How RE, Loh SP, Hunt SE, Karakochuk CD, Barr SI, et al.

J Nutr, 2019 Nov 01;149(11):1952-1959.
PMID: 31318024 DOI: 10.1093/jn/nxz151

BACKGROUND: Riboflavin is required for several redox reactions. Clinical riboflavin deficiency occurs mainly in low-income countries, where it is associated with anemia. The functional significance of suboptimal riboflavin status in different populations and its role in anemia is not well understood.
OBJECTIVES: We assessed the biomarker status of riboflavin and its association with hemoglobin concentration and anemia in women living in Vancouver, Canada, and Kuala Lumpur, Malaysia.
METHODS: Healthy nonpregnant, nonbreastfeeding women (19-45 y) were recruited from Canada ( n = 206) and Malaysia (n = 210) via convenience sampling. Fasting blood was collected to assess riboflavin status [erythrocyte glutathione reductase activity coefficient (EGRac)], hematological indicators, soluble transferrin receptor (sTfR), ferritin, vitamin A, folate, and vitamin B-12 concentrations. Linear and logistic regression models were used to assess the association of riboflavin status with hemoglobin concentration and anemia.
RESULTS: EGRac (mean ± SD) values were higher, indicating poorer riboflavin status, in Malaysian compared with Canadian women (1.49 ± 0.17 compared with 1.38 ± 0.11). Likewise, riboflavin biomarker deficiency (EGRac ≥1.40) was significantly more prevalent among Malaysians than Canadians (71% compared with 40%). More Malaysian than Canadian women were anemic (hemoglobin <120 g/L; 18% compared with 7%). With use of linear regression (pooled sample; n = 416), EGRac values were negatively associated with hemoglobin concentration (r = -0.18; P
Fulltext Effect of once weekly folic acid supplementation on erythrocyte folate concentrations in women to determine potential to prevent neural tube defects: a randomised controlled dose-finding trial in Malaysia

Samson KLI, Loh SP, Khor GL, Mohd Shariff Z, Yelland LN, Leemaqz S, et al.

BMJ Open, 2020 02 05;10(2):e034598.
PMID: 32029499 DOI: 10.1136/bmjopen-2019-034598

INTRODUCTION: Folic acid (0.4 mg) taken prior to and during early pregnancy reduces the risk of neural tube defects (NTDs). Because these birth defects occur early in pregnancy, before women may know they are pregnant, many countries have mandated the addition of folic acid to food staples. In countries where fortification is not possible, and weekly iron folic acid programmes exist to reduce anaemia, the WHO recommends that 2.8 mg (7×0.4 mg) folic acid be given instead of the current weekly practice of 0.4 mg. Currently, there is a lack of evidence to support if the 2.8 mg folic acid per week dose is sufficient to raise erythrocyte folate concentrations to a level associated with a reduced risk of a NTD-affected pregnancy. We aim to conduct a three-arm randomised controlled trial to determine the effect of weekly folic acid with iron on erythrocyte folate, a biomarker of NTD risk.
METHODS AND ANALYSIS: We will recruit non-pregnant women (n=300; 18-45 years) from Selangor, Malaysia. Women will be randomised to receive either 2.8, 0.4 or 0.0 (placebo) mg folic acid with 60 mg iron weekly for 16 weeks, followed by a 4-week washout period. The primary outcome will be erythrocyte folate concentration at 16 weeks and the mean concentration will be compared between randomised treatment groups (intention-to-treat) using a linear regression model adjusting for the baseline measure.
ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of British Columbia (H18-00768) and Universiti Putra Malaysia (JKEUPM-2018-255). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals.
TRIAL REGISTRATION NUMBERS: ACTRN12619000818134 and NMRR-19-119-45736.
Fulltext Weekly iron-folic acid supplements containing 2.8 mg folic acid are associated with a lower risk of neural tube defects than the current practice of 0.4 mg: a randomised controlled trial in Malaysia

Samson KLI, Loh SP, Lee SS, Sulistyoningrum DC, Khor GL, Shariff ZBM, et al.

BMJ Glob Health, 2020 12;5(12).
PMID: 33272946 DOI: 10.1136/bmjgh-2020-003897

INTRODUCTION: Weekly iron-folic acid (IFA) supplements are recommended for all menstruating women in countries where anaemia prevalence is >20%. Anaemia caused by folate deficiency is low worldwide, and the need to include folic acid is in question. Including folic acid might reduce the risk of a neural tube defect (NTD) should a woman become pregnant. Most weekly supplements contain 0.4 mg folic acid; however, WHO recommends 2.8 mg because it is seven times the daily dose effective in reducing NTDs. There is a reluctance to switch to supplements containing 2.8 mg of folic acid because of a lack of evidence that this dose would prevent NTDs. Our aim was to investigate the effect of two doses of folic acid, compared with placebo, on red blood cell (RBC) folate, a biomarker of NTD risk.
METHODS: We conducted a three-arm double-blind efficacy trial in Malaysia. Non-pregnant women (n=331) were randomised to receive 60 mg iron and either 0, 0.4, or 2.8 mg folic acid once weekly for 16 weeks.
RESULTS: At 16 weeks, women receiving 0.4 mg and 2.8 mg folic acid per week had a higher mean RBC folate than those receiving 0 mg (mean difference (95% CI) 84 (54 to 113) and 355 (316 to 394) nmol/L, respectively). Women receiving 2.8 mg folic acid had a 271 (234 to 309) nmol/L greater mean RBC folate than those receiving 0.4 mg. Moreover, women in the 2.8 mg group were seven times (RR 7.3, 95% CI 3.9 to 13.7; p<0.0001) more likely to achieve an RBC folate >748 nmol/L, a concentration associated with a low risk of NTD, compared with the 0.4 mg group.
CONCLUSION: Weekly IFA supplements containing 2.8 mg folic acid increases RBC folate more than those containing 0.4 mg. Increased availability and access to the 2.8 mg formulation is needed.
TRAIL REGISTRATION NUMBER: This trial is registered with the Australian New Zealand Clinical Trial Registry (ACTRN12619000818134).
Fulltext Malaria is a cause of iron deficiency in African children

Muriuki JM, Mentzer AJ, Mitchell R, Webb EL, Etyang AO, Kyobutungi C, et al.

Nat Med, 2021 Apr;27(4):653-658.
PMID: 33619371 DOI: 10.1038/s41591-021-01238-4

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.