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Multiple Micronutrient Supplements in Pregnancy

Following the release of the 2016 WHO Guidelines for Antenatal Care, The New York Academy of Sciences assembled a scientific task force comprised of international experts in micronutrient deficiencies, public health, nutrition, pediatrics and health economics to:

  • Compile the evidence on the prevalence of micronutrient deficiencies in pregnant women or women of reproductive age
  • Review the evidence on the benefits and risks of multiple micronutrient supplements on maternal and perinatal outcomes
  • Create a roadmap to guide decisions in countries considering the implementation of such programs.

The findings from the first phase of this initiative show that substantial benefits may be expected, in terms of mortality reduction and poor birth outcome, by shifting from IFA to MMS in Antenatal Care programs.

Promoting MMS in Low and Middle-Income Countries

The Multiple Micronutrient Supplementation Technical Advisory Group (TAG) assists countries considering the use of multiple micronutrient supplements in their antenatal care programs. The New York Academy of Sciences and the TAG have collaborated with UNICEF, with funding from the Bill & Melinda Gates Foundation, to promote the uptake of MMS by pregnant women in a number of pilot low and middle-income countries (LMICs). These promotional efforts encompass the following activities:

  • Recruitment and coordination of a Technical Advisory Group (TAG) to provide evidence and materials to governments in LMICs so that they can tailor the use of MMS to their specific conditions
  • Facilitation of global MMS efforts, via the creation of a communications hub to advise and document the pilot phase throughout the planned implementation
  • Provision of technical support to UNICEF as it rolls out MMS in four pilot countries (Bangladesh, Madagascar, Burkina Faso and Tanzania), as well as other locations considering making the switch from iron and folic acid to MMS

For this initiative, UNICEF assisted with the rollout and implementation of MMS in pilot LMIC countries. Vitamin Angels supplied the product and provision of MMS. The Healthy Mother’s Healthy Babies Consortium brought together stakeholders, including country representatives, research and knowledge institutions, non-governmental organization (NGOs), technical organizations, UN agencies, private sector stakeholders, and funders to work together to raise awareness, trigger policy change and accelerate adoption of MMS.

Review of Evidence

Why MMS?

Multiple-micronutrient deficiencies often coexist among women of reproductive age (WRA) in low- and middle-income countries (LMICs). This may put their health and that of their offspring at risk, especially during pregnancy when micronutrients requirements increase. Multiple micronutrient supplements (MMS) may fill those gaps but in 2016 the WHO Guidelines for Antenatal Care reaffirmed their recommendation of IFA for routine use in pregnancy. WHO’s recommendation was based on “…some evidence of risk, and some important gaps in the evidence”. The WHO Guideline however, commented that “policy-makers in populations with a high prevalence of nutritional deficiencies might consider the benefits of MMS on maternal health to outweigh the disadvantages, and may choose to give MMS”.

Since the release of the 2016 ANC Guidelines, two important reviews were carried out that provided high quality evidence on the potential benefits to be gained in terms of various antenatal and maternal outcomes by switching from IFA to MMS. Specifically, the IDP meta-analysis found that, when compared to IFA alone, MMS would:

  • Reduce the risk of stillbirth
    • by 8% in the overall population of pregnant women
    • by 21% in the group of anemic pregnant women
  • Reduce the risk of mortality among 6-month infants
    • by 29% in the group of anemic pregnant women
    • by 15% in female infants
  • Reduce the risk of low birth weight (<2500g)
    • by 12% in the overall population of pregnant women
    • by 19% in the group of anemic pregnant women
  • Reduce the risk of preterm (<37 weeks) birth
    • by 8% in the overall population of pregnant women
    • by 16% in the group of underweight women
  • Reduce the risk of being born small-for-gestational age
    • by 3% in the overall population of pregnant women
    • by 8% in the group of anemic pregnant women

In 2020, WHO reviewed the new evidence that became available since the publication of the 2016 ANC Guidelines and updated the recommendations for MMS during pregnancy. These updated Guidelines now state that antenatal MMS that include IFA are recommended in the context of rigorous research.

Reference: Smith ER, Shankar AH, Wu LS-F, et al. Modifiers of the effect of maternal multiple micronutrient supplementation on stillbirth, birth outcomes, and infant mortality: a meta-analysis of individual patient data from 17 randomized trials in low-income and middle-income countries. Lancet Glob Heal. 2017;5(11):e1090-e1100.

MMS and COVID-19

Key Scientific Papers

Reports

Technical Reference Materials

Background Materials

Torheim, L.E., Ferguson, E.L., Penrose, K., Arimond, M. (2010). Women in Resource-Poor Settings Are at Risk of Inadequate Intakes of Multiple Micronutrients. J Nutr, 140(11): 2051S-2058S

Pathak, P., Kapil, U., Yajnik, C. S, Kapoor, S. K., Dwivedi, S. N., & Singh, R. (2007). Iron, Folate, and Vitamin B12 Stores among Pregnant Women in a Rural Area of Haryana State, India. Food and Nutrition Bulletin, 28(4): 435–438.

Lee, S., Talegawkar, S., Merialdi, M., & Caulfield, L. (2013). Dietary intakes of women during pregnancy in low- and middle-income countries. Public Health Nutrition, 16(8): 1340-1353.

Kulkarni, B., Christian, P., LeClerq, S., & Khatry, S. (2010). Determinants of compliance to antenatal micronutrient supplementation and women’s perceptions of supplement use in rural Nepal. Public Health Nutrition, 13(1), 82-90.

Gernand, A. D., Schulze, K. J., Stewart, C. P., West, K. P., & Christian, P. (2016). Micronutrient deficiencies in pregnancy worldwide: health effects and prevention. Nature reviews. Endocrinology, 12(5), 274-89.

Lu, C., Black, M. M., & Richter, L. M. (2016). Risk of poor development in young children in low-income and middle-income countries: an estimation and analysis at the global, regional, and country level. The Lancet. Global health, 4(12), e916-e922.

Jiang, T., Christian, P., Khatry, S.K., Wu, L., West, K.P. (2005). Micronutrient Deficiencies in Early Pregnancy Are Common, Concurrent, and Vary by Season among Rural Nepali Pregnant Women. J Nutr, 135(5), 1106-1112.

Project Outcomes

This initiative, supported by a grant from the Bill & Melinda Gates Foundation, is a collaboration between UNICEF, the MMS Technical Advisory Group, and the New York Academy of Sciences. Activities carried out through this effort include:

  • The development of a Communications Hub to link the various stakeholders (scientists, implementers, multilateral organizations, policy makers and the private sector) involved in MMS programs
  • The coordination of technical support to adopting countries, including the preparation of technical reference materials to explain and organize MMS programs and to train the health workforce in their implementation
  • UNICEF implementation of a MMS rollout in 4 pilot countries (Bangladesh, Madagascar, Burkina Faso and Tanzania)
  • Promote and support MMS programs in additional countries as needed
  • A webinar to disseminate the findings of the scientific task force
  • A systematic review on interventions to increase adherence to micronutrient supplementation during pregnancy

MMS Meeting Workshops

Core Product Specification Workshop, November 11-12, 2019

On November 11th and 12th, 2019, the Academy and the Micronutrient Forum (MNF) co-hosted a workshop in Washington DC to develop a Core Product Specification for multiple micronutrient supplement in pregnancy.

Technical Report

Task Force on Multiple Micronutrient Supplementation (MMNS) in Pregnancy, April 17-18, 2018

Second of two closed door technical consultation at the Academy. While the first meeting examined the benefits and potential risks of multiple micronutrient supplementation, the second consultation focused primarily on considerations for the development of a roadmap to guide countries considering multiple micronutrient supplement implementation

Meeting Report

Task Force on Multiple Micronutrient Supplementation in Pregnancy, November 15-16, 2017

First of two closed-door technical consultations at the Academy to review recent evidence on the benefits and risks of multiple micronutrient supplementation, identify research gaps, and determine which populations may benefit most from supplementation.

Meeting Report

Contact Us

To learn more about our MMS Initiative, contact us at nutrition@nyas.org.

Funding Support

Bill & Melinda Gates Foundation

Organized By

Multiple Micronutrient Supplementation in Pregnancy

Control and Prevention of Thiamine Deficiency Disorders (TDD)

Thiamine deficiency remains a pressing public health issue. Infantile beriberi, a disease caused by thiamine deficiency, presents during the exclusive breastfeeding period and without treatment commonly results in death within hours of clinical presentation. There is also growing evidence suggesting sub-clinical thiamine deficiency may have a measurable, lasting impact on cognitive development and psychomotor functions.

However, addressing the spectrum of thiamine deficiency disorders (TDD) is impeded by several gaps in knowledge. This initiative seeks to address the key gaps in our knowledge of TDD and to develop a model for control of TDD in the most affected countries. The Academy is engaged in research to reduce the global burden of thiamine deficiency. With funding from the Bill & Melinda Gates Foundation, this project includes a number of research partners around the world and aims to fill several research gaps.

Key Knowledge Gaps

1. Limitations in assessing status.

2. Lack of knowledge about prevalence, particularly in sub-Saharan Africa

3. Lack of strategy to address deficiencies, particularly during lactation

4. No standard approach to surveillance and prevention

5. No standard case definition

Research

In 2017, the Academy convened an expert panel to estimate the global burden of thiamine deficiency and related disease risks and to review possible intervention strategies to reduce the associated burden of disease. The panel concluded that there is a surprising lack of information on this condition, despite its likely importance as a cause of infant mortality in South Asia and possibly in other LMIC, and its known effects on child development. Following the panel’s recommendations, this initiative aimed to address the key knowledge gaps that were identified through the following projects.

Supplementation

Determine the appropriate level of thiamine supplementation during lactation to provide adequate thiamine status for mothers and their infants. A dose response trial of lactating women in Cambodia measured thiamine content in breast milk, as well as in the blood of mother and infants.

Resulting publication:

– Gallant et al (2021) Low-dose thiamine supplementation of lactating Cambodian mothers improves human milk thiamine concentrations: a randomized controlled trial. The American Journal of Clinical Nutrition. 114 (1): 90–100.

Cognitive Outcomes

There is evidence that even asymptomatic thiamine deficiency can cause long-lasting cognitive deficits. The infants enrolled in the supplementation trial underwent neurological testing to look for cognitive differences between supplementation and placebo groups.

Resulting publication:

– Measelle et al (2021) Thiamine supplementation holds neurocognitive benefits for breastfed infants during the first year of life. Ann. N.Y. Acad. Sci., 1498: 116-132.

Fortification

Salt has been identified a good vehicle for thiamine fortification in South-East Asia. This project measured salt consumption in Cambodia to inform the level of thiamine required to adequately fortify salt.

Resulting publications:

– Chan et al (2021) Assessment of salt intake to consider salt as a fortification vehicle for thiamine in Cambodia. Ann. N.Y. Acad. Sci., 1498: 85-95.

– Green et al (2021) Modeling thiamine fortification: a case study from Kuria atoll, Republic of Kiribati. Ann. N.Y. Acad. Sci., 1498: 108-115.

– Whitfield et al (2021) Thiamine fortification strategies in low- and middle-income settings: a review. Ann. N.Y. Acad. Sci., 1498: 29-45.

Biomarkers

The relationship between the two thiamine biomarkers, thiamine diphosphate and the erythrocyte transketolase assay, is being studied to assess which biomarker is best suited to identify thiamine deficiency.

Resulting publication:

– Jones et al (2021) Erythrocyte transketolase activity coefficient (ETKAC) assay protocol for the assessment of thiamine status. Ann. N.Y. Acad. Sci., 1498: 77-84.

African Surveys

Some neurological disorders found in Sub-Saharan Africa have similar symptoms to thiamine deficiency disorders and the increase in rice consumption has raised concern that thiamine deficiency may also be present in Africa. A study was conducted to assess thiamine status in Gambian women of reproductive age.

Resulting publication:

– Bourassa et al (2021) Thiamine deficiency in Gambian women of reproductive age. Ann. N.Y. Acad. Sci.

Surveillance and Control Programs

Thiamine deficiency is most well known in South Asia and despite the efforts in the region, it remains a pervasive problem. We supported countries to develop surveillance and control programs to reduce the burden thiamine deficiency through fortification, supplementation, education, behavior change and surveillance programs. Technical Reference Materials have been developed for his purpose.

Thiamine Deficiency Disorder Case Definition

A clear case definition for TDD has not been established and creates challenges in efficiently diagnosing TDD. A case control study is being carried to establish a case definition based on cohorts of infants and children in Laos.

Resulting publications:

– Hess et al (2020) Establishing a case definition of thiamine responsive disorders among infants and young children in Lao PDR: protocol for a prospective cohort study. BMJ Open. 2020 Feb 13;10(2):e036539.

– Smith et al (2021) Traditional postpartum food restrictions among women in northern Laos: Preliminary analysis of an ongoing prospective cohort study. Proceedings of the Nutrition Society, 80(OCE1), E30.

– Smith et al (2021) Thiamine deficiency disorders: a clinical perspective. Ann. N.Y. Acad. Sci., 1498: 9-28.

– Koshy et al (2021) The rediscovery of thiamine deficiency disorders at a secondary level mission hospital in Northeast India. Ann. N.Y. Acad. Sci., 1498: 96-107.

Thiamine Deficiency in High-Income Countries

Thiamine deficiency has been typically associated with alcoholism in high-income countries, or as a prevalent problem in low- and middle-income countries whose populations rely on staple foods with a low content of thiamine. Several literature reviews and retrospective studies suggested that, in high resource settings, non-alcoholic thiamine deficiency can be prevalent when associated with certain health conditions or lifestyles.

Resulting publications:

– Gomes et al (2021) Thiamine deficiency unrelated to alcohol consumption in high-income countries: a literature review. Ann. N.Y. Acad. Sci., 1498: 46-56.

– Rakotoambinina et al (2021) Pediatric thiamine deficiency disorders in high-income countries between 2000 and 2020: a clinical reappraisal. Ann. N.Y. Acad. Sci., 1498: 57-76.

– Mates et al (2021) A Retrospective Case Series of Thiamine Deficiency in Non-Alcoholic Hospitalized Veterans: An Important Cause of Delirium and Falling?. Journal of clinical medicine, 10(7), 1449.

– Gibson et al (2020) Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial . J Alzheimers Dis. 78(3):989-1010.

Resources

Recent publications

2021 Thiamine Special Issue

Useful Documents

Technical Reference Materials 

Thiamine Workshop 1 Report

Thiamine Workshop 2 Report

Thiamine content of foods in key countries 

Cambodia 

Laos

Thiamine availability based on food balance sheets (2011)

Thiamine availability below 1.2 mg/capita/day

High % of energy from low-thiamine staple crops

Analysis of thiamine biomarkers

Guidance to assess thiamine biomarkers

Analytical requirements of ThDP and ETKA

Large-scale survey on thiamine status

Women of reproductive age

Infants 

Food fortification with thiamine

Countries with existing thiamine fortification programs

Educational materials 

For healthcare professionals: “Thiamine deficiency disorders: identification and treatment”

For healthcare professionals: “Infantile beriberi: clinical symptoms and case studies”

For healthcare professionals: “A guide to increase thiamine intake and prevent thiamine deficiency”.

For pregnant women and lactating mothers: “The importance of thiamine during pregnancy, breastfeeding and infancy”

Relevant websites

Global Fortification Data Exchange

Food Fortification Initiative

OpeN-Global

Key scientific publications

Whitfield, K.C., Bourassa, M.W., Adamolekun, B., et al. (2018). Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs. Annals of the New York Academy of Sciences, 1430(1), 3-43.

Hiffler, L., Adamolekun, B., Fischer, P.R., Fattal-Vavleski, A. (2017). Thiamine content of F‐75 therapeutic milk for complicated severe acute malnutrition: time for a change? Annals of the New York Academy of Sciences, 1404(1), 20-26.

Adamolekun, B., Hiffler, L. (2017). A diagnosis and treatment gap for thiamine deficiency disorders in sub-Saharan Africa? Annals of the New York Academy of Sciences, 1408(1), 15-19.

Whitfield, K.C., Karakochuk, C.D., Kroeun, H., et al. (2017). Household consumption of thiamin-fortified fish sauce increases erythrocyte thiamin concentrations among rural Cambodian women and their children younger than 5 years of age: a randomized controlled efficacy trial. The Journal of Pediatrics, 181, 242-247.

Johnson, C. R., Fischer, P. R., Thacher, T. D., et al. (2019). Thiamin deficiency in low- and middle-income countries: Disorders, prevalences, previous interventions and current recommendations. Nutrition and Health. 

Workshops

Thiamine Workshops

Two technical workshops are planned in order to support the development of surveillance and control programs in countries where thiamine deficiency is a public health problem. While the first workshop was held in November 2019, both workshops aim to discuss steps to be taken by each country to roll out a TDD control and prevention program in their specific context; and provide necessary knowledge and training to establish their program. 

Workshop 1, November 19-21, 2019, Luang Prabang

The first regional workshop was held in Luang Prabang, Lao PDR, with participation from several other countries in the region where thiamine deficiency is a public health problem. Participating countries included, Lao PDR, Myanmar, Cambodia, Bhutan, Thailand, Vietnam and India (Assam and Kashmir). The aims of this workshop were: to bring experts and the most current knowledge about prevalence, assessment, and possibly interventions for thiamine deficiency; assess individual country situation and need; and to introduce the Technical Reference Materials (TRMs). Discussions focused on the inputs and activities needed to enable country officials to begin planning their TDD control program.

Workshop 2, March 9 and 11, 2021

The second meeting of the Global Thiamine Alliance was hosted virtually. The first day of the workshop was held as a public webinar, where recent developments in thiamine research were widely disseminated. On the second day of the workshop, which was limited to the participants of the first workshop, we discussed the progress and barriers that individual countries had on their proposed action plan and the future needs of the Global Thiamine Alliance.

Contact Us

To learn more about our TDD project, contact us at nutrition@nyas.org.

Nutrition Modeling Consortium

Through a grant provided by the Bill & Melinda Gates Foundation, The New York Academy of Sciences created a consortium for nutrition modeling aimed at improving the usability of tools for nutrition policy making and at increasing their uptake by low middle income countries (LMIC). In April 2017, the Institute partnered with the Micronutrient Forum to convene a two-day technical consultation to review seven tools designed to help decision makers in LMICs develop and streamline their nutrition programs and interventions.

These tools were selected on the basis of their ability to elaborate nutrition policy scenarios adapted to national priorities and contexts, whether through the use of mathematical optimization routines or other evidence-based analytical approaches. Services provided by those tools range from advocacy to allocative efficiency to budget planning. The meeting highlighted the deep capabilities of those tools, and several examples were presented of successful use that confirmed their potential utility to nutrition policy making.

What is Nutrition Modeling?

Nutrition Modeling refers to computer assisted optimization routines that seek to select a best solution with regard to a nutrition objective among a set of available policy or program alternatives. Some tools on the Consortium follow mathematical optimization algorithms, some use spreadsheet formula, some use qualitative methods to drill down on nutrition data. Regardless of design, they all share the intent of improving the use of available knowledge and data in designing nutrition policies and programs.

The mandate of the Nutrition Modeling Consortium is to:

  • Increase end-users’ input in the specification of services to be provided by these tools.
  • Help end-users understand better how those tool can serve their nutrition programming needs.
  • Advance the joint utility and effectiveness of the modeling tools through a collective effort by nutrition modelers in order to enhance their technical inter-operability, and improve their usability to end-users.

How the Consortium Works

The Consortium of Nutrition Modelers aims to improve the use of the evidence base in policy and program decision making through the use of mathematical modeling of nutrition activities. It is led by a Scientific Organizing committee composed of nutrition modelers and end-users. The Secretariat has the responsibility of linking the SOC to the modeling community and to end-users, to coordinate the work of the Consortium and to organize and convene meetings of the Consortium.

Contact Us

To learn more about the Nutrition Modeling Consortium, contact us at nutrition@nyas.org.

Calcium in Global Health and Nutrition

Calcium is an essential micronutrient for human health. An estimated 3.5 billion people around the globe are at risk of inadequate dietary intake of calcium. While primarily associated with bone health, calcium has also been shown to reduce the risk of preeclampsia and associated complications, which are leading causes of maternal morbidity and mortality. This webinar is the first in a two-part series on Calcium in Global Health and Nutrition, and will highlight the conclusions of the Calcium Task Force convened by the Nutrition Science Program at The New York Academy of Sciences.

Calcium

In March and April 2021, the Nutrition Science Program of The New York Academy of Sciences in partnership with the Children’s Investment Fund Foundation, convened a Calcium Task Force and hosted two virtual meetings. The task force comprises experts in micronutrients, malnutrition, pediatrics, gynecology and obstetrics, biochemistry, public health and strategies for supplementation and fortification. The papers in this virtual issue derive from deliberations of the task force. See https://www.nyas.org/programs/addressing-global-calcium-deficiency/. Or click https://nyaspubs.onlinelibrary.wiley.com/doi/toc/10.1111/(ISSN)1749-6632.calcium.

How Does Human Milk Help Developing Babies?

A boy eats a hamburger with a glass of milk.

Organic chemist Steven Townsend of Vanderbilt University explains his research on human milk oligosaccharides (HMOs) and their role in developing babies’ microbiome and preventing infection.

It is well understood that human milk provides numerous benefits to babies as they develop, particularly in its ability to help protect babies from a variety of infections. But what is the mechanism that is doing the work to help keep babies healthy?

Organic chemist Professor Steven Townsend of Vanderbilt University speaks to us about his research on human milk oligosaccharides (HMOs) and their role in developing babies’ microbiome and preventing infection. He also discusses the importance of sharing his science with the general public.

Your work has focused on human milk oligosaccharides. Can you explain what these are and why they are important for an infant’s health?

Oligosaccharide is the scientific term for sugar. Human milk oligosaccharides (HMOs) are the complex sugars that are present in human milk, but not in cow’s milk. In human milk, there are about 200 oligosaccharides. By analogy, cow’s milk only contains small quantities of about 30 to 40 oligosaccharides.

HMOs increase the health of the infant in a number of ways. These molecules selectively feed commensal (good bacteria) over bad bacteria. They also protect against bacterial infection by mimicking molecules that pathogenic bacteria use to attach to the gut – the HMOs bind to these pathogens instead and remove them from the system. Recently my group has discovered that these compounds also have intrinsic antimicrobial activity – they actually inhibit the growth of pathogenic bacteria.

Steven D. Townsend, PhD
Assistant Professor of Chemistry
Vanderbilt University

Together, these factors mean that the microbiome of a breastfed infant is selectively engineered to have more commensal species present, outnumbering pathogens and potential pathogens.

How did you become interested in the biology of human milk?

My interest in human milk first struck when my wife and I were walking through Harlem one day. We saw some advertisements for infant formula. In many parts of the world it’s actually illegal to advertise formula, but here in a poor neighborhood in New York City, were formula advertisements. If you go downtown to the East 50s, a more affluent neighborhood, you don’t see any formula advertisements, you see advertisements for breastfeeding. I wanted to know why breastfed babies are typically healthier.

How does human milk differ from formula?

When it comes to milk broadly, the main constituent macromolecule is typically lactose, a sugar (carbohydrate). Most bigger animals also have a lot of protein in their milk, usually one third of the macromolecules, but human milk is different, as only about 6% of the macromolecules are proteins. For human babies and primate babies, it’s more important for our brains to develop faster than our body, which requires more carbohydrates.

Primate milk has a large quantity of complex sugars with a variety of activities – some of the sugars are involved in brain development and some of them are involved in the development of the immune system. Interestingly, we know that for many of these sugars, the baby does not get calories from them, even though they consume grams of them per day. It turns out that the sugars are actually fermented by bacteria in the gut. These sugars are selectively consumed by good bacteria to give them a growth advantage over bad bacteria. Therefore, if they are not present in formula, then formula-fed babies are going to be at a slight health disadvantage.

Are there any other uses for HMOs besides in the development of an infant’s biome?

There are a lot of companies attempting to put HMOs into different food products, for both infants and adults. For example – some companies are trying to develop products for irritable bowel syndrome and other illnesses that are related to a screwed up microbiome.

In my group, we are investigating if HMOs can help antibiotics work more effectively. Many antibiotics have been mis- and over-used and a lot of them are no longer effective. Our research is finding that co-dosing certain antibiotics with human milk sugars results in a synergistic effect – they work together, which means that you can ultimately use less of the antibiotic to kill a bacteria. That’s cool because antibiotics have a lot of negative side effects, but HMOs don’t have side effects.

You often describe yourself as a humanist. How does this inform your scientific research?

When I say I’m a humanist, I mean I care about people’s day-to-day wellbeing.

The humanist part of me is enhanced by communicating the results of our research with the public and getting feedback on different directions that we could pursue. We’re getting a lot of good project ideas from talking to a broad range of people. It’s very important to me that the general public understand the science we’re doing at a fundamental level because they fund it—I think we owe it to them to explain the research we’re doing and get their feedback.

Improving Birth Outcomes with Multiple Micronutrient Supplementation

Overview

Adequate intake of essential vitamins and minerals is critical for a healthy pregnancy. Unfortunately, many women in low- and middle-income countries (LMICs) struggle to meet the increased dietary demands for a healthy pregnancy through diet alone. Inadequate nutritional intake frequently leads to poor maternal health and adverse birth outcomes, such as maternal mortality; preeclampsia; insufficient gestational weight gain; stunting; low birth weight (LBW); small for gestational age (SGA); and neonatal mortality. Currently, the World Health Organization (WHO) recommends iron-folic acid supplements (IFA) as the routine standard of care in antenatal care programs. However, strong evidence is now available demonstrating the superiority of multiple micronutrient supplements (MMS) over IFA. To help countries determine if they should transition from IFA to MMS in antenatal care, the New York Academy of Sciences assembled a task force. Charged with taking a closer look at MMS, the task force considered several factors, including benefits, risks, and cost-effectiveness. On June 25, 2019, the task force’s findings were presented at the launch of the Special Issue, published in the Annals of the New York Academy of Sciences.

Highlights

  • Data from the 2019 Cochrane Review and the 2017 individual patient data (IPD) meta-analysis demonstrate that MMS has significant added benefits to birth outcomes compared with IFA.
  • The task force concluded that countries where nutritional deficiencies are prevalent should consider MMS, as it is a cost-effective and safe alternative to IFA.
  • The MMS technical advisory group is translating this evidence into practice by assisting in the rollout of MMS demonstration projects in several countries.
  • When compared to IFA, routine MMS supplementation does not increase the risk of adverse effects.
  • During pregnancy, the risk of exceeding the UL with a micronutrient-rich diet and daily micronutrient supplementation is very low.

Speakers

Robert E. Black, MD, MPH
Johns Hopkins University

Megan Bourassa, PhD
The New York Academy of Sciences

Gilles Bergeron, PhD
The New York Academy of Sciences

Emily R. Smith, ScD, MPH
The Bill & Melinda Gates Foundation and Harvard T.H. Chan School of Public Health

Alison Gernand, PhD
Penn State University

Reina Engle-Stone, PhD
University of California, Davis

Sponsors

For Policy Makers and Program Implementers

Speakers

Robert E. Black, MD, MPH
Johns Hopkins University

Gilles Bergeron, PhD
The New York Academy of Sciences

Megan Bourassa, PhD
The New York Academy of Sciences

Micronutrient Status and the Benefits of MMS on Birth Outcomes

Robert Black discussed the benefits of MMS on birth outcomes. While the 2016 WHO antenatal care guidelines recommend IFA for routine use, the guidelines also state that countries “might consider the benefits of MMS on maternal health to outweigh the disadvantages and may choose to give MMS that include iron and folic acid.” New evidence on MMS has since emerged, and after a thorough review, the Academy’s task force found strong research in support of prenatal MMS. The data showed a high prevalence of multiple micronutrient deficiencies in women of reproductive age (WRA) and pregnant women in LMICs, suggesting that these women could significantly benefit from MMS during pregnancy. A Cochrane review (updated in 2019) demonstrated that MMS was superior to IFA in reducing important adverse birth outcomes, including small for gestational age (SGA) and low birth weight (LBW).

Micronutrient deficiencies among WRA not only exist in LMIC, but in women around the world.

An IPD meta-analysis of several MMS trials conducted in pregnant women provides additional evidence in support of prenatal MMS. Published after the WHO antenatal care guidelines, the analysis showed that women receiving MMS, compared with those receiving IFA, had a significant reduction of SGA and LBW births, very low birth weight (VLBW) births, preterm births, and very preterm births. It also identified a number of subgroups that benefitted from MMS. Additionally, women who were underweight at the onset of pregnancy had a greater reduction in preterm births. Given that complications from preterm births are the leading cause of death in children under five years of age in LMICs, Black stressed the significance of these findings that highlight the potential benefits of MMS and the substantive effects that it can have on birth outcomes. Ultimately, Black concluded that the data from both systematic reviews suggest that countries with high rates of nutritional deficiencies should consider the switch from prenatal IFA to MMS.

Task Force Conclusions and Guidance on MMS in Pregnancy

Megan Bourassa explained that during their review of the evidence, the task force took a closer look at the prevalence of micronutrient deficiencies, cost-effectiveness, and the safety of MMS. They concluded that populations with a high prevalence of nutritional deficiencies might have a greater benefit from MMS. The task force also found that MMS is highly cost-effective in comparison to other antenatal care interventions, such as micronutrient fortification or balanced protein energy supplementation for pregnant women. And after examining the safety considerations, they found no serious side effects associated with the use of MMS. Thus, they concluded that MMS is a cost-effective and safe alternative to IFA, and should especially be considered by countries where nutritional deficiencies are prevalent.

The task force outlined a few questions for countries to consider when making their decision on whether or not to switch from IFA to MMS. The first question is whether the country has a high prevalence of nutritional deficiencies, said Bourassa. Since the WHO did not explain how to define a nutrient deficiency, the task force suggested a list of indicators that might be useful to consider, such as dietary intake, underweight prevalence, and biomarker data, among others. Countries can use these indicators to compile and assess available data to decide whether there is sufficient evidence to make the switch.

To successfully transition from IFA to MMS, countries should consider several factors during the planning process. First, MMS should be built into the existing antenatal care program rather than creating a standalone intervention. Second, policymakers should consider taking the opportunity to assess and strengthen their respective antenatal care programs, including the coverage and adherence to supplementation. If the current program has inadequate coverage, MMS likely will not reach the target population, thus yielding insubstantial results. Countries may also want to consider taking on a small demonstration project to test this in a smaller region to identify any potential issues with the supply and distribution chain. Lastly, as with all public health interventions, it is essential to develop a monitoring and evaluation system to ensure the continued coverage and success of a prenatal MMS intervention.

The Future Direction of the Task Force

Since the release of the Special Issue, the task force has made strides in translating evidence into policy and practice in real world-settings, said Gilles Bergeron. For example, a Technical Advisory Group (TAG) on MMS was formed this year to spearhead the development of a series of technical reference materials. The materials are designed to provide countries with more information on MMS and assist interested countries with the transition from IFA to MMS, and much more. Currently, the TAG is in the process of using the Child Health and Nutrition Research Initiative (CHNRI) methodology to inform the direction of research and investments needed to support the implementation of MMS interventions for pregnant women in LMICs.  Bergeron also discussed future directions of the TAG, specifically its partnership with UNICEF and multiple stakeholders, to promote the rollout of MMS through demonstration activities in four countries—Bangladesh, Madagascar, Tanzania, and Burkina Faso—as well as in other potential countries considering the switch.

For Research Scientists and Clinicians

Speakers

Emily R. Smith, ScD, MPH
The Bill & Melinda Gates Foundation and Harvard T.H. Chan School of Public Health

Reina Engle-Stone, PhD
University of California, Davis

Alison Gernand, PhD
Penn State University

Clinical Trials, MMS Adherence, and Adverse Birth Outcomes

The second session focused primarily on information for researchers and clinicians. Emily Smith took a closer look at the results of the clinical trials and discussed the available evidence on side effects and adherence. Her presentation aimed to answer a key question: Is MMS is better than IFA alone for ensuring a positive pregnancy experience? Smith shared results from the most recent and comprehensive reviews on MMS, specifically the 2019 Cochrane Review and the 2017 IPD meta-analysis. The recently updated Cochrane Review evaluated the effects of MMS compared with IFA on pregnancy outcomes, using a total of 20 clinical trials with data from over 140,000 women. Findings showed that MMS resulted in a 12% reduction in LBW and an 8% reduction in SGA births, compared with IFA. While the Cochrane review focused on the overall effects of all available trials, the IPD meta-analysis was primarily aimed at conducting subgroup analyses. This meta-analysis included data from 17 randomized controlled trials from over 100,000 pregnancies in LMICs and found that MMS not only reduces the risk of SGA and LBW, but also reduces the risk of stillbirth, very LBW, early preterm birth, and preterm birth when compared with IFA. The findings from the IPD meta-analysis—26 subgroup analyses were conducted to identify individual characteristics that may further modify the effect of MMS—also showed specific subgroups have a greater benefit from MMS. When compared with IFA, the effects of MMS resulted in a more significant benefit for undernourished women, specifically those who were anemic or underweight (BMI <18.5 kg/m2) or women who gave birth to female infants.

The WHO antenatal care guidelines raised an important point of concern regarding the potential risk of increased neonatal mortality. This concern arose from a subgroup analysis comparing those receiving MMS with 30mg of iron to those in the control group receiving IFA with 60mg of iron. When reviewing the analysis, it was apparent that a few errors and omissions were made. A recent reanalysis of these data, performed by Sudfeld and Smith, included all eligible studies and corrected point estimates and found no increased risk of neonatal mortality associated with MMS. Though limited evidence was available, six of the seven clinical trials (which reported on this outcome) showed no significant differences in the side effects between IFA and MMS. Similarly, differences in adherence rates between IFA and MMS were minimal, with no more than a 2% difference between the intervention groups in 10 trials that reported on adherence. Smith concluded that routine MMS supplementation does not increase the risk of adverse effects, and has a number of additional benefits for mortality and birth outcomes compared with IFA, especially in areas where nutritional deficiencies exist.

The Upper Level: Antenatal Supplements and the Risk of Excess Micronutrient Intake

While understanding the global prevalence of micronutrient deficiencies in LMICs and the substantial benefit MMS can provide to alleviate the burden, there can be health risks when intake regularly exceeds a high amount of nutrients, otherwise known as the upper intake level (UL). Alison Gernand outlined what is known about these risks in pregnancy. The WHO defines UL as the “maximum intake from food, water, and supplements that is unlikely to pose the risk of adverse health effects”. It is important to note that the UL values are set for healthy people with good baseline micronutrient status, not for those with deficiencies or medical conditions. Since the prevalence of deficiencies is high in LMICs countries, an intake higher than the UL may be warranted for a limited timeframe to correct the deficits. Little is known about pregnancy-specific risks, so the ULs are the same for pregnant and non-pregnant women, except vitamin A, due to the possibility of birth defects. In general, there is little to no risk of excessive intake for several vitamins—including thiamin, riboflavin, vitamin B12, and vitamin C—from large supplemental doses. Potential adverse effects from excess micronutrients such as niacin, folate, and iron are only due to supplement intake.

Potential adverse effects from daily supplement intake include an excess of niacin, folic acid, and iron.

To assess the risk of reaching the UL with an adequate diet, Gernand compared the Reference Daily Intake (RNI) or Recommended Dietary Allowance (RDA), and compared the amount in the UNIMMAP supplement to both the Institute of Medicine (IOM) and WHO UL values. The results showed that folate intake reached the UL, while iron and niacin slightly exceeded it, with known risks of each nutrient to be mild. For folate, an excess can mask vitamin B12 deficiency; otherwise, toxicity due to excess intake has not been known. Risks due to excess iron intake, specifically nausea and vomiting, can be eliminated if the supplement is taken with food. Finally, for niacin, the risk of flushing resulting in skin reddening and itchiness is due to nicotinic acid, found only in supplements, not in food. Gernand said that limited information on pregnancy-specific risk from excess intake is available, stressing the urgency for more published data. Overall, the risks of exceeding the UL during pregnancy from a micronutrient rich diet and daily MMS are very low and should not result in adverse effects.

Cost Analyses: Replacing IFA with MMA During Pregnancy

According to new evidence compiled by the task force, MMS has additional benefits over IFA, but the tablets are more costly. While there is sufficient evidence to support the transition of IFA to MMS, policymakers need to consider not just the benefits, but also the associated costs. In her presentation, Reina Engle-Stone asked if MMS is a worthwhile investment. With her team at UC Davis, Engle-Stone developed a model to estimate the effects, cost, and cost-effectiveness of replacing IFA with MMS within the context of a supplementation distribution program in Bangladesh and Burkina Faso. A hypothetical one-year scenario with 100% coverage was also applied to both countries using their current national levels of IFA coverage, assuming complete adherence to the recommended regimen (i.e., consumption of 180 supplements per pregnancy). The model used baseline demographic characteristics from the Lives Saved Tool (LiST) and effect sizes from the IPD meta-analysis to generate the marginal effects of replacing IFA with MMS on mortality, adverse birth outcomes, and disability-adjusted life years (DALYs) averted, in both rural and urban settings.

A team at UC Davis created a model structure to calculate the cost effectiveness of MMS in the context of an ongoing supplement distribution program.

The results showed replacing IFA with MMS could avert over 15,000 deaths and 30,000 cases of preterm birth annually in Bangladesh, and over 5,000 deaths and 5,000 cases of preterm birth in Burkina Faso, assuming 100% coverage and adherence. The cost per death averted was estimated to be $175-$185 in Bangladesh and $112-$125 in Burkina Faso. Lastly, the cost per DALY averted ranged from $3-$15, depending on the country and consideration of sub-groups. Engle-Stone noted that the estimate is very sensitive to the cost of the tablet. For one, the costs associated with shifting from IFA to MMS will be significant, given that MMS are approximately 35% more costly than IFA tablets. Based on the hypothetical scenario, a complete switch to MMS in Bangladesh given current coverage levels (50% nationally) would cost approximately $1.7 million. In a scenario assuming 100% coverage, where all women receive and consume 180 tablets, the additional cost to replace the IFA with MMS would increase to $2.7 million. A complete switch in Burkina Faso with current coverage levels (10.2% nationally) would cost approximately $60,000 and would rise to $600,000 for 100% coverage.

In sum, the switch would come at an added cost, and if the cost of the supplement rises, so will the cost-effectiveness. However, an increase in demand of MMS with improvements in program delivery and supplement adherence could improve the cost-effectiveness. Engle-Stone noted that further research is needed to provide a more realistic scenario for the transition from IFA to MMS, specifically on the delivery platform performance and supplement adherence. Nonetheless, the cost-effectiveness of this short, one-year analysis suggests that policymakers should consider adopting the underlying model with necessary modifications to fit their context and use it to better inform policy discussions around the shift from IFA to MMS.