In this study, we found a 31% reduction in childhood mortality due to maternal antenatal/postnatal supplementation with iron-folic acid plus vitamin A as compared with vitamin A alone, in a setting where maternal iron deficiency and anemia are common. To our knowledge, this is the first time that the long-term effect of maternal iron-folic acid supplementation, normally a global policy for pregnant women, on childhood survival has been observed. The randomized, controlled design of the study provided statistical strength for making causal inferences regarding this effect. The study also achieved a high rate of follow-up of children.
Intermittent administration of large doses of vitamin A to preschool children has been shown to reduce mortality among children under age 5 years by 30% (20
). However, beyond this intervention, few trials have been undertaken to examine the impact of direct supplementation with micronutrients on childhood mortality. Iron-folic acid or zinc supplementation to children from ages 1 month to 36 months in the same population in Nepal had no impact on survival (15
). A reduction in mortality resulting from an intervention such as antenatal/postnatal iron-folic acid supplementation, as currently exists in many malnutrition settings, provides a new and previously unreported benefit to offspring during childhood.
While the combination of iron-folic acid also contained vitamin A, the impact on mortality is probably due to iron-folic acid alone, since the control group receiving vitamin A alone had a higher mortality rate. However, a positive interaction between the nutrients cannot be ruled out.
Previously, multiple micronutrients have shown no effect or modest effects on birth weight (12
), and based on results from 2 South Asian trials that were not independently powered to find an impact on mortality, administration of multiple micronutrients may elevate risks of neonatal and perinatal mortality relative to iron-folic acid (14
). One trial conducted in Indonesia, however, showed a significant 18% reduction in early infant mortality (<3 months) that was attributed to antenatal/postnatal micronutrient supplementation, as compared with iron-folic acid (23
). In the present analysis, the hazard ratio for mortality from birth to age 7.5 years was 0.93 for multiple micronutrients versus controls, suggesting that no long-term adverse effect on mortality occurred. Similarly, the combination of folic acid-iron-zinc had a hazard ratio of 0.80, suggesting potential inhibition of iron with zinc, which was also seen with the birth-weight outcome in the original trial (4
). Iron was present at the same dosage in all 3 preparations. We have previously suggested a potential role of negative nutrient-nutrient interactions in causing this (14
). The hazard ratio for folic acid alone was 0.89.
Plausible mechanisms for iron supplementation's reducing mortality risk are not known at present, although they may include its effect on birth outcomes such as decreased low birth weight (4
) and preterm birth (6
), as well as increases in infant iron stores (24
), all of which may have an impact on long-term survival. Whether maternal iron status plays a role in the development of fetal immunity or early programming is not well established, but the plausibility of such a mechanism cannot be overruled. Given that in this setting of high iron deficiency, where direct supplementation to these children from ages 1 month to 36 months had no impact on childhood mortality (15
), it is likely that there exists a critical window of time in the fetal period when iron nutriture can influence future health and survival—a window that may close during the postnatal period. As such, the intervention effect on long-term survival is probably due to supplementation mostly during pregnancy, not the postpartum period.
Our study suffered from our being unable to obtain medical diagnoses for causes of death. A medical determination of cause of death is rare in this environment, where most deaths occur at home and are unattended by physicians. Relying on parental recall for verbal autopsies has been considered valid, and we used these data for deaths when available. However, since many deaths had occurred several years prior to follow-up, we were able to use only crudely categorized causes of death as reported by the parents. However, the available data seemed to indicate that fewer infectious and severe acute deaths occurred in the folic acid-iron group than in the control group; the proportionate mortality ratios for these deaths were 55 and 74, respectively. We also did not collect data on iron status among children, although we did not expect iron supplementation during pregnancy to affect the status of children at school ages. It is also unlikely that the impact on survival was related to the 3 months of postnatal supplementation in women, since breast milk is a poor source of iron for infants. Overall, despite the significant findings, the sample size we had was still limited for observation of mortality outcomes, and we had 50% power to detect a difference of 30% or more with α
0.05, assuming a mortality rate of 100 per 1,000 livebirths. In addition, comparison between treatment groups could not be done because of the overlapping and wide confidence intervals. For more efficiency, one could increase the size of the control arm; however, we did not do this in the original study, which limited our ability to examine between-group differences for a rarer outcome such as mortality.
We undertook sensitivity analyses to examine the impact of losses to follow-up on the study findings, applying 3 different assumptions regarding the survival of those lost to follow-up: that all survived, that all died, or that half died. We had 161 children who were lost to follow-up. The relative risks for iron + folic acid ranged from 0.71 (all lost survived) to 0.73 (all lost died), and the 95% confidence interval around 0.73 was (0.50, 0.99), after adjustment for clustering using generalized estimating equations Poisson regression analysis with exchangeable correlation. This analysis suggests that the approximately 30% reduction in mortality we observed in the iron-folic acid group was a robust estimate and not vulnerable to the uncertain vital experience among children lost to follow-up.
We know of 1 other study which involved follow-up of the offspring (at age 2 years) of women who participated in a multiple micronutrient supplementation trial (25
). In that study, Vaidya et al. (25
) found small but significant increases in body size and weight among children whose mothers had received multiple micronutrients during pregnancy as compared with iron-folic acid alone. More such follow-ups will be required to examine the long-term effects of maternal nutrient interventions on a range of outcomes. These studies would contribute to our understanding of the role of nutrition in the developmental origins of health and disease.
The findings of this study may be generalizable to a large swath of the South Asian population living on the Indian subcontinent, including northern India and Bangladesh, where similar burdens of maternal malnutrition, low birth weight, and childhood infectious morbidity and mortality exist.
In conclusion, these high-compliance follow-up data from a randomized, placebo-controlled trial cohort provide strong evidence for a beneficial effect of antenatal/postnatal iron-folic acid supplementation on childhood survival through early school age, extending previously observed beneficial effects on birth size, anemia, infant iron status, and early infant survival. Currently, use of antenatal iron and folic acid supplement is low, despite existing policies and persistent maternal iron deficiency and anemia, in many regions of the world. The findings reported here provide new impetus for programs to extend and improve coverage with iron and folic acid supplementation as part of routine antenatal care in undernourished and underserved populations in rural South Asia.