Background Providing balanced energy–protein (BEP) supplements is a promising intervention to improve birth outcomes in low- and middle-income countries (LMICs); however, evidence is limited. We aimed to assess the efficacy of fortified BEP supplementation during pregnancy to improve birth outcomes, as compared to iron–folic acid (IFA) tablets, the standard of care. Methods and findings We conducted an individually randomized controlled efficacy trial (MIcronutriments pour la SAnté de la Mère et de l’Enfant [MISAME]-III) in 6 health center catchment areas in rural Burkina Faso. Pregnant women, aged 15 to 40 years with gestational age (GA) <21 completed weeks, were randomly assigned to receive either fortified BEP supplements and IFA (intervention) or IFA (control). Supplements were provided during home visits, and intake was supervised on a daily basis by trained village-based project workers. The primary outcome was prevalence of small-for-gestational age (SGA) and secondary outcomes included large-for-gestational age (LGA), low birth weight (LBW), preterm birth (PTB), gestational duration, birth weight, birth length, Rohrer’s ponderal index, head circumference, thoracic circumference, arm circumference, fetal loss, and stillbirth. Statistical analyses followed the intention-to-treat (ITT) principle. From October 2019 to December 2020, 1,897 pregnant women were randomized (960 control and 937 intervention). The last child was born in August 2021, and birth anthropometry was analyzed from 1,708 pregnancies (872 control and 836 intervention). A total of 22 women were lost to follow-up in the control group and 27 women in the intervention group. BEP supplementation led to a mean 3.1 percentage points (pp) reduction in SGA with a 95% confidence interval (CI) of −7.39 to 1.16 (P = 0.151), indicating a wide range of plausible true treatment efficacy. Adjusting for prognostic factors of SGA, and conducting complete cases (1,659/1,708, 97%) and per-protocol analysis among women with an observed BEP adherence ≥75% (1,481/1,708, 87%), did not change the results. The intervention significantly improved the duration of gestation (+0.20 weeks, 95% CI 0.05 to 0.36, P = 0.010), birth weight (50.1 g, 8.11 to 92.0, P = 0.019), birth length (0.20 cm, 0.01 to 0.40, P = 0.044), thoracic circumference (0.20 cm, 0.04 to 0.37, P = 0.016), arm circumference (0.86 mm, 0.11 to 1.62, P = 0.025), and decreased LBW prevalence (−3.95 pp, −6.83 to −1.06, P = 0.007) as secondary outcomes measures. No differences in serious adverse events [SAEs; fetal loss (21 control and 26 intervention) and stillbirth (16 control and 17 intervention)] between the study groups were found. Key limitations are the nonblinded administration of supplements and the lack of information on other prognostic factors (e.g., infection, inflammation, stress, and physical activity) to determine to which extent these might have influenced the effect on nutrient availability and birth outcomes. Conclusions The MISAME-III trial did not provide evidence that fortified BEP supplementation is efficacious in reducing SGA prevalence. However, the intervention had a small positive effect on other birth outcomes. Additional maternal and biochemical outcomes need to be investigated to provide further evidence on the overall clinical relevance of BEP supplementation. Trial registration ClinicalTrials.gov NCT03533712.

Natural abundances of stable nitrogen and carbon isotopes (δ 15 n and δ 13 C) can vary with both dietary intake and metabolic (specifically catabolic) state. In low-income countries, weaning is a period of dietary transition from milk to plant-based foods and a high-risk period for malnutrition. We explored how diet and malnutrition impact hair δ 15 n and δ 13 C in young children by an observational, crosssectional study in Cox's Bazar District, Bangladesh [255 children, 6-59 months with 19.6% wasted (7.1% severely) and 36% stunted (9.8% severely)]. Hair δ 15 n and δ 13 C exhibited exponential decreases with age, with the loss of one trophic level (3.3‰ and 0.8‰, respectively) from 6 to 48 months, which we associate with the shift from exclusive breastfeeding to complete weaning. After adjustment for age and breastfeeding status, hair isotopic values were unaffected by wasting but lower in severe stunting (−0.45‰ to −0.6‰, P < 0.01). In this population of young children, whose isotopic values in hair primarily depended on age, we failed to observe any effect of wasting, likely due to opposite, compensating effects between dietary and metabolic changes involved. In contrast, we evidenced low δ 15 n and δ 13 C values in severely stunted children that likely indicate chronic exposure to diets low in animal products. The natural abundances of stable carbon and nitrogen heavy isotopes (δ 13 C and δ 15 N) in body proteins reflect those of the diet, plus a small discrimination factor, known as the trophic step, which is due to the preferential elimination of light isotopes and is smaller for carbon (+1‰) than for nitrogen (+3-4‰) 1,2. Since δ 13 C and δ 15 N values in the body primarily reflect those of the diet, they have long been used in ecology and archaeology to reconstruct trophic webs and characterize ancient diets 3-6. More recently, they have been used in epidemiology as biomarkers to assess the consumption of fish, animal products, and sugar 7-13. In this regard, measuring isotopic natural abundances in hair has several advantages. Hair is easily and non-invasively sampled and its isotopic values correlate well with those in other body proteins. Moreover, hair keratin is an ideal isotopic archive because it is produced sequentially and is inert after synthesis 14,15 , provided that a sufficient number of follicles is sampled to limit the potential bias due to the presence of a small proportion of hair in the telogen phase, i.e. not growing 15-17. Considering an average hair growth rate of 1 cm per month 17,18 and a one-week delay between hair synthesis and bulb exit 19 , the 5 mm of hair closest to the scalp contains isotopic information for the period between −3 and −1 weeks before sampling.