A Randomized Trial of Quadruple Fortified Salt for Anemia and Birth Defects Prevention in Southern India

Women of reproductive age are at increased risk for anemia and micronutrient deficiencies, due in part to social structures and increased nutritional requirements across the conceptional period. Anemia is an important public health problem and has been associated with risk of adverse pregnancy outcomes, including maternal and infant mortality, preterm delivery, and low birth weight. Iron deficiency is the leading cause of anemia worldwide, accounting for 20% to half of the anemia cases. Deficiencies in folate and/or vitamin B12 also result in megaloblastic anemia, and inadequate periconceptional folate and vitamin B12 status have been linked to pregnancy complications, including birth defects.

Neural tube defects are among the most common and debilitating birth defects in the United States and globally. Neural tube defects are structural birth defects that arise when the neural folds fail to fuse entirely during early embryogenesis. It is estimated that there are over 260,000 cases of neural tube defects per year globally, ranging from 1 to 80 per 10,000 births, with higher prevalence in low- and middle-income countries. India has one of the highest burdens of neural tube defects in the world, accounting for over one-third of all neural tube defects globally.

The links between maternal folate status and neural tube defect risk in offspring have been well established. In randomized trials, periconceptional folic acid supplementation reduced the risk of neural tube defects by approximately 70%. Fortification of staple foods with folic acid is one of the most efficacious and cost-effective public health interventions and has been linked to decreased neural tube defects in national folic acid fortification programs. Fortification interventions to date have primarily targeted wheat (and maize) flour, which are not primary staples in some settings with the highest burden of neural tube defects, such as Southern India and China.

There is increasing interest in fortification strategies targeting additional staple foods and micronutrient deficiencies in at-risk populations. Emerging evidence suggests that vitamin B12 deficiency is associated with an increased risk of neural tube defects independent of folate status and may modify red blood cell folate concentrations which are used to predict risk of neural tube defects at the population level. In Southern India, the setting of this randomized trial, rice is the primary staple and folic acid fortification is not currently mandatory. Findings from a recently completed population-based pre-intervention biomarker survey in this setting demonstrated a substantial burden of anemia and micronutrient deficiencies of iron, vitamin B12, and folate in women of reproductive age. Together, these findings underscore the potential benefits of developing additional fortification strategies to deliver folic acid and other micronutrients for prevention of anemia and neural tube defects.

Salt fortification is a promising strategy to prevent multiple micronutrient deficiencies, as it is widely consumed, affordable, and has existing production and distribution systems. In India, salt is one of the most widely consumed and fortifiable foods, and double-fortified salt (i.e., with iron and iodine) is included in the national fortification guidelines and social safety net programs in India for prevention of anemia and iron deficiency. Randomized trials demonstrated that double-fortified salt significantly improved serum ferritin or iron deficiency in women of reproductive age and school children. Findings from meta-analyses suggest that double-fortified salt improves hemoglobin concentrations and decreases risk of anemia; however, findings from double-fortified salt trials in India for anemia have been heterogeneous. For example, in a randomized trial of double-fortified salt among Indian female tea pickers by Haas et al., double-fortified salt improved hemoglobin, serum ferritin, total body iron, and soluble transferrin receptor levels, compared with iodized salt without iron, after adjusting for the respective baseline bio- markers. However, the prevalence of anemia (53%) as well as vitamin B12 (37%) and folate (86%) deficiencies remained high at endpoint. These findings highlight the need to develop additional interventions to target other nutritional causes of anemia and multiple micronutrient deficiencies (i.e., vitamin B12 and folate).