Study protocol: prospectively planned individual patient data (IPD) meta-analysis testing the effect of balanced energy-protein (BEP) supplementation provided to lactating women on maternal and infant outcomes

Undernourished pregnant and lactating women from food insecure settings, most commonly found in low- and middle-income countries, are at risk of adverse maternal and infant health outcomes. Often, undernourishment is characterized by low body mass index (BMI), low mid upper arm circumference (MUAC), short stature, and/or micronutrient deficiencies, which put pregnant women at risk for complications such intrauterine growth restriction and preterm birth (Kozuki et al. 2015). The World Health Organization recommends balanced energy-protein (BEP) supplementation in populations at risk of undernourishment (defined as more than 20% of women with a BMI less than 18.5 kg/m2) to reduce the risk of stillbirth and small for gestational age neonates (World Health Organization 2016). The consequences of undernourishment among lactating mothers have commonly been overlooked. Lactating mothers require additional calories to produce quality and quantity milk, which in turn confers health and development benefits to the infant (Nommsen et al. 1991; Dewey et al. 1991; American College of Obstetricians and Gynecologists 2016). There is a high prevalence of malnutrition in mothers and children from low- and middle-income countries, and research from randomized controlled trials is needed to clarify if BEP could be a valuable intervention during lactation. BEP supplementation products are ready-to-eat or prepared foods that provide protein (accounts for less than 25% of the total energy content) and energy. When given during pregnancy, BEP products are fortified with micronutrients or an additional micronutrient supplement is given (typically multiple micronutrients or iron-folic acid). The current evidence coming from systematic reviews and meta-analyses has focused on studies where BEP is given during pregnancy (Imdad and Bhutta 2012; Ota et al. 2015; Stevens et al. 2015; Lassi et al. 2020; Perumal et al. 2021) but not lactation. This evidence is difficult to disentangle because there is significant heterogeneity in the populations, comparison/control groups, study design, and BEP product formulations (i.e., energy and protein content). Given these limitations, in 2017, an expert panel organized by the Bill and Melinda Gates Foundation (BMGF) created guidelines for the macro- and micronutrient content of BEP supplements (Report of an Expert Consultation held at the Bill & Melinda Gates Foundation 2017). This group also suggested that these BEP products should be developed and tested on pregnant and lactating women in low-resource settings. A number of studies (all randomized interventions) were subsequently funded by BMGF. As these studies’ investigators were developing protocols independently, in 2020 BMGF convened the Maternal Nutrition Harmonization Workshop to harmonize key variables across these trials. This effort was expanded, and the Maternal BEP Studies Harmonization Initiative was formed to examine the pooled effect of BEP across pregnancy and lactation. The current protocol describes our prospective individual participant data (IPD) meta-analysis that focuses on BEP given during lactation. Subsequent work will examine BEP given during pregnancy. Given the high prevalence of infant stunting in low- and middle-income countries (World Health Organization 2018b; Local Burden of Disease Child Growth Failure Collaborators 2020), and the importance of supporting the nutrient intake of mothers providing breastmilk to infants, this IPD meta-analysis will focus on assessing the effect of BEP given to mothers during lactation on infant length-for-age z scores (LAZ) at 6 months of age. We will also examine additional infant and maternal anthropometric and health outcomes.