Micronutrient Supplementation for Pregnant and Lactating Women to Improve Maternal and Infant Nutritional Status in Low- and Middle-Income Countries: Protocol for a Systematic Review and Meta-analysis
Authors: Shinde Sachin , Wang Dongqing , Yussuf Mashavu H , Mwanyika-Sando Mary , Aboud Said , Fawzi Wafaie W 
Published: July 2022

Background
Two billion people in low- and middle-income countries (LMICs) are deficient in key nutrients. Nutritional deficiencies worsen during pregnancy, causing adverse outcomes for the mother and the fetus, with consequences after pregnancy. These effects may be mitigated by providing micronutrient supplementation to women during pregnancy and lactation. However, the effects of micronutrient supplementation on the nutritional status of pregnant and lactating women and that of their infants remain largely unclear in LMICs.

Objective
The purpose of this systematic review and meta-analysis is to determine the effects of single, double, or multiple micronutrient supplements during pregnancy or lactation on maternal and infant nutritional status in LMICs.

Methods
Randomized controlled trials of single, double, or combinations of micronutrients assessing effects on the maternal (serum, plasma, and breastmilk) and infant (serum and plasma) nutritional status will be included. MEDLINE (through PubMed), EMBASE, CENTRAL (through Cochrane Library), and the World Health Organization (WHO) library database will be used to identify relevant published studies, starting from the inception of each database until February 28, 2022. The Cochrane Risk of Bias Tool will be used to assess the risk of bias in the included studies. The selection of studies, data extraction, and risk of bias assessment will be carried out independently by 2 reviewers. A narrative summary will be provided of all the included studies. Meta-analyses will be performed whenever possible, and the heterogeneity of effects will be evaluated using I2, subgroup analyses, and metaregression. The certainty of the evidence for each outcome will be assessed using the GRADE (Grading of Recommendation, Assessment, Development, and Evaluation) approach.

Results
We will conduct meta-analyses using Stata software (version 16, StataCorp) and present both a narrative and systematic summary of all studies included in this review in text and table form. For continuous outcomes, effect estimates will be expressed as mean differences and standardized mean differences, while for binary outcomes, they will be expressed as risk ratios, rate ratios, hazards ratios, or odds ratios, all with 95% CIs and comparing the intervention group with the control group. When studies for an outcome are adequately consistent with respect to intervention, comparator, and definition of the outcome, a random-effects, inverse variance-weighted meta-analysis will be conducted. We will provide a narrative synthesis for outcomes with insufficient data or extreme heterogeneity.

Conclusions
This review will provide evidence upon which to base policy and programming for women in LMICs to supplement micronutrients in pregnancy and lactation. Detailed results disaggregated by variables such as maternal age, sex of infant, duration, and dose of intervention may also help policy makers, researchers, practitioners, and government agencies to adopt more effective maternal and child health policies and programs in LMICs. The review will also identify any gaps in the existing evidence.

Trial Registration
PROSPERO CRD42022308715; https://tinyurl.com/y33cxekr.

International Registered Report Identifier (IRRID)
PRR1-10.2196/40134