Discussion
infection, enteric dysfunction, anemia, undernutrition
CHRONIC INFECTION, INFLAMMATION, ANEMIA, UNDERNUTRITION, INFECTION
The MISAME-III trial indicates that modest increments in size at birth, attained from prenatal fortified BEP supplementation, are sustained at 6 months of age in terms of improved linear growth and lower prevalence of stunting. However, maternal BEP supplementation during the first 6 months postpartum did not result in a significant effect on infant linear growth at the age of 6 months. Nevertheless, we do find an indication for a lagged benefit of postnatal BEP supplementation, as shown by improved monthly growth trajectories, though this was not confirmed by the cross-sectional analysis of the effect at the age of 12 months in a subsample of infants.The few prior studies that evaluated the impact of maternal LNS supplementation during pregnancy and/or lactation on infant growth found mixed results. Moreover, direct comparisons between our findings on infant growth and those from other LNS trials are difficult, due to heterogeneity in terms of the type and composition of supplements, period and duration of supplementation, and the comparator used as a control group. The most similar RCT, in terms of the type of supplement and study setting, is the MISAME-II trial [Our analysis indicates that LAZ and stunting prevalence at 6 months of age were affected by the prenatal, but not by the postnatal BEP supplementation. Furthermore, there was a modest difference in LAZ growth trajectories between postnatal study arms primarily in late infancy, which, however, did not lead to a significant effect on LAZ at 12 months of age. Other trials evaluated the impact of combined prenatal and postnatal supplementation together with child supplementation. In Ghana [In addition to the lack of BEP effect on anemia prevalence, it was unexpected that two-third of infants at 6 months were anemic. This is despite the fact that mothers in the control and intervention groups received iron and folic acid in the BEP and IFA tablets during pregnancy and lactation. Moreover, we have previously showed that the prenatal BEP and IFA tablets did not have a preventive effect on the 10 pp increase in maternal anemia observed during pregnancy [Our subgroup analysis did not show a differential effect of BEP on infant growth by maternal nutritional status using baseline maternal BMI and MUAC measurements. This might be due to the fact that BMI and MUAC measurements mainly reflect calorie intake and are not sensitive to show maternal status of micronutrients including breastmilk nutrient composition and the probably associated infant linear growth and nutritional status. The plasticity of breastmilk composition in the face of maternal undernutrition or nutritional supplementation is as yet not well established [The current study has several strengths that ensure the reliability of the findings. Supplements compliance was closely verified by a community-based network of village workers that home visited the study participants multiple times per week resulting in high adherence to the study supplements. In addition, supplements were taken under observation of these village workers, which limited the risk of sharing with other household members. The high acceptability of the BEP supplement was achieved by implementing a rigorous two-phase formative study [Key limitations of MISAME-III are the nonblinded administration of BEP and IFA supplements and the lack of information on other prognostic factors of infant growth (e.g., maternal infection, asymptomatic inflammation, stress, or physical activity) to determine the extent to which these might have influenced the effect on nutrient availability (e.g., environmental enteric dysfunction) or nutrient sequestration in the mother. In addition, our trial did not collect data on acute or chronic infection in the child, which could have limited the potential benefits on postnatal LAZ. Furthermore, we are unable to assess the efficacy of BEP supplementation on improved child development outcomes [In conclusion, MISAME-III provides evidence that linear growth benefits from prenatal BEP supplementation at birth are sustained during early infancy. The maternal BEP supplementation during lactation may also lead to a delayed positive effect on infant linear growth. These findings suggest that BEP supplementation during pregnancy can contribute to the efforts to reduce the high burden of child growth faltering in LMICs.