Effect of balanced energy-protein supplementation during pregnancy and lactation on birth outcomes and infant growth in rural Burkina Faso: study protocol for a randomised controlled trial

Introduction Adequate nutrition during pregnancy is crucial to both mother and child. Maternal malnutrition can be the cause of stillbirth or lead to poor birth outcomes such as preterm delivery and small-for-gestational-age newborns. There is a probable positive effect of providing pregnant women a balanced energy-protein (BEP) food supplement, but more evidence is needed. The MIcronutriments pour la SAnté de la Mère et de l’Enfant (MISAME) III project aims to improve birth outcomes and infant growth by testing a BEP supplement during pregnancy and lactation in rural Burkina Faso. This paper describes the study protocol. Methods and analysis MISAME-III is a four-arm individually randomised efficacy trial implemented in six rural health centre catchments areas in the district of Houndé. Eligible pregnant women, aged between 15 and 40 years old and living in the study areas, will be enrolled. Women will be randomly assigned to one of the four study groups: (1) prenatal intervention only, (2) postnatal intervention only, (3) prenatal and postnatal intervention or (4) no prenatal or postnatal intervention. The intervention group will receive the BEP supplement and iron/folic acid (IFA) tablets, while the control group will only receive the IFA tablets following the national health protocol. Consumption will be supervised by trained village women on a daily basis by means of home visits. The primary outcomes are small-for-gestational age at birth and length-for-age z-score at 6 months of age. Secondary outcomes will be measured at birth and during the first 6 months of the infants’ life. Women will be enrolled from October 2019 until the total sample size is reached. Ethics and dissemination MISAME-III has been reviewed and approved by the University Hospital of Ghent and the ethics committee of Centre Muraz, Burkina Faso. Informed consent will be obtained. Results will be published in relevant journals and shared with other researchers and public health institutions. Trial registration number NCT03533712.


GENERAL COMMENTS
This study protocol is well written and well thought out. The introduction provides some global and LMIC-specific interventions, but given that many nutrition interventions are context-specific, it would be nice to include some information on the previous studies done in Burkina Faso. There have been a number of recent studies on nutrient interventions during pregnancy in Burkina Faso, including multiple micronutrient supplements and lipid-based supplements. In this overview, I would also incorporate how the MISAME III study fits into the previous MISAME projects.

Leila Nikniaz
Tabriz health services management research center. Tabriz. University of Medical Sciences, Tabriz, Iran REVIEW RETURNED 25-Jul-2020

GENERAL COMMENTS
I think this is a complete protocol for evaluating the effect of the supplement on birth outcomes. The question that arises is that do all the enrolled women have the same gestational age? Given that the energy supplementation affects pregnancy outcomes over time, the same duration of supplementation is essential for all women. professional language editing is needed. Considering the time effect on the association between nutrients during pregnancy and birth outcomes, it is necessary to intervene at the same pregnant stage. So, the intervention will start at which gestational week and end at which gestational week in this protocol? 3.The article mentioned that blinding of participants and community-based project workers will not be possible since the supplements are identifiable (page 10 line 46-47) and The FA will inform women on the supplement's function(page 8 line 60 and page 9 line3). Will this operation cause a placebo effect? 4.What's the percent of total energy from protein of the fortified BEP supplements and what is your basis? 5.How to calculate dietary diversity score? 6.Sample size: Do you know the exclusive breastfeeding rate of the study population? It is recommended to consider the population's exclusive breastfeeding rate when determining the sample size of the postnatal intervention group.

VERSION 1 -AUTHOR RESPONSE
Reviewer: 1 Megan Bourassa New York Academy of Sciences, USA Please state any competing interests or state 'None declared': None declared Comments to the Author Question 4: This study protocol is well written and well thought out. The introduction provides some global and LMIC-specific interventions, but given that many nutrition interventions are context-specific, it would be nice to include some information on the previous studies done in Burkina Faso. There have been a number of recent studies on nutrient interventions during pregnancy in Burkina Faso, including multiple micronutrient supplements and lipid-based supplements. In this overview, I would also incorporate how the MISAME III study fits into the previous MISAME projects. Answer from the Authors: Added on page 4 and 5 of the Manuscript. I think this is a complete protocol for evaluating the effect of the supplement on birth outcomes. The question that arises is that do all the enrolled women have the same gestational age? Given that the energy supplementation affects pregnancy outcomes over time, the same duration of supplementation is essential for all women. Answer : The study aims at including pregnant women as early as possible. The initial screening relies on selfreported amenorrhea to a study community worker who visits every woman once every four weeks. Because of the RCT the main concern is to treat pregnant women in the intervention and control arm in a similar way. The study only includes women with a gestational age below 20 weeks to reduce the heterogeneity in gestational age at inclusion and to allow for sufficient time for the supplement to support pregnancy. Question 8 : 2.Considering the time effect on the association between nutrients during pregnancy and birth outcomes, it is necessary to intervene at the same pregnant stage. So, the intervention will start at which gestational week and end at which gestational week in this protocol? Answer : We aimed to include women as early as possible in pregnancy by announcing the start of our study in the villages, by visiting all eligible women in the area once a month and by adding the exclusion criterion of 20 weeks or more of gestational age for inclusion. The trial is an individually randomized controlled trial so gestational age at enrolment should be equally balanced between intervention and control. The intervention will start as soon as possible (once a pregnancy is confirmed by a pregnancy test) and lasts up to delivery. All women randomised in the postnatal intervention group continue supplementation up to 6 months after birth.
Question 9 : 3.The article mentioned that blinding of participants and community-based project workers will not be possible since the supplements are identifiable (page 10 line 46-47) and The FA will inform women on the supplement's function(page 8 line 60 and page 9 line3). Will this operation cause a placebo effect?
Answer from the Authors: A placebo effect would appear if a group gets a supplement/medicine without an active compound which in this study, is not the case. Women belonging to the intervention group receive daily BEP supplement and iron folic acid tablets, while the control/comparison group receives iron and folic acid (standard of care). Iron and folic acid is expected to influence the main study outcome as well and can thus be seen as an active comparator. It is recommended to consider the population's exclusive breastfeeding rate when determining the sample size of the postnatal intervention group. Answer from the Authors: It is not possible to find specific data on exclusive breastfeeding in that part of the country since there is a lot of variety across the country. According to data from the National Nutrition Survey in 2013, early and exclusive breastfeeding rates ranges from 20.5 percent to 74.1 percent. The primary study outcome for the postnatal intervention is child growth. Exclusive breastfeeding is a secondary auxiliary study outcome for this study. We collect data on exclusive breastfeeding to verify if maternal BEP supplement is not associated with breastfeeding practices, but there is no study hypothesis ex ante. As such, we do not present a formal sample size calculation.