1918-2018

Hopkins Nutrition

A Century of
Nutritional Discovery for
Public Health

Preventing Micronutrient Deficiencies in Pregnancy:

Public Health Rationale and Evidence Supporting an MMS Policy

Keith P. West, Jr., DrPH, MPH, RD

George G. Graham Professor of Infant and Child Nutrition
Director, Center and Program in Human Nutrition
Department of International Health
Johns Hopkins Bloomberg School of Public Health
Baltimore, Maryland
kwest1@jhu.edu Skype: kpwestjr
 Outline
• Introduction
• Micronutrient requirements and
deficiencies in pregnancy
• UNIMMAP Formulation (rationale)
• Global & regional evidence on impact
• Policy Guidance
• Research agenda: implementation,
clinical, mechanism, assessment
• Indonesia’s global leadership in
micronutrient deficiency research &
prevention 2
 On any undernourished diet, a population
would suffer from several nutrient
deficiencies, not just one.

Preventing only a deficiency disease is not

sufficient, as mothers and their infants may
still suffer, including infant mortality

Borderline (metabolic) malnutrition

resulting from a poor diet may be of far
greater public health importance than
1918 (rarer) clinical nutritional disease.
 Indonesia’s Leadership in Micronutrient Research
for Global Health: Vitamin A and Child Mortality
N = ~165,000 children
Percent Change in Mortality

0%

40%

30%

20%

10%

1986

Significant reduction Sommer A, Tarwotjo I, Djunaedi E, West KP Jr, Loeden AA, Tilden R, Mele L and Aceh Study Group Lancet 1986
Not significant Muhilal, Permeisih D, Idjradinata YR, Muherdiyantiningsih, Karyadi D. Am J Clin Nutr 1988;48:1271-2176.
Sommer A & West KP Jr. Vitamin A Deficiency: Health Survival and Vision. Oxford Press, 1996
Newborn Vitamin A: First Trial Revealing Impact on Infant
Mortality at Cicendo Eye Hospital, Bandung, 1994-96

Humphrey JH, Agoestina T, Wu L et al J Pediatr 1996;128:489

Micronutrients are Essential Throughout Pregnancy &
Gestation
Adverse Health Consequences of
Gestational Micronutrient Deficiency

Gernand A et al Nature Rev Epidemiol 2016

 Nutritional Stress and Disease Risk throughout Life

Nutritional Exposures Coexist Child and Maternal

Health Problems
• Protein-energy deficits
Infant or Child
• Energy Excess
• Infection
• Micronutrient deficiencies
• Inflammation
Vitamins A, E, D,
• Poor growth
B-complex, folate,
• Impaired cognition, motor
zinc, iron, iodine, others
development
• Behavioral Causes
• Mortality
Breast /complementary feeding
SES, hygiene, education, etc. Adolescent or Maternal
• Food Systems Causes • Short stature
Agricultural/animal husbandry, • Thinness…. overweight
seasonality, infrastructure, Photos: Paul Joseph Brown • Infection/sepsis
Markets • Obstetric problems
Poor genomic & metabolic health, • Anemia
• Societal and Political Causes chronic disease, disability, mortality • Mortality
 Micronutrient Deficiencies among Women of Reproductive
Age: A Global View

What isn’t measured

can’t be prevented…
generally

Black dots = data from <3 countries Bourassa MW et al Annals NY Acad Sci 2019;1444(1):6-21
 Multiple Antenatal Micronutrient Deficiencies
Nepal, 1st trimester, NNIPS-3 Bangladesh, 1st Trimester, JiVitA-1
63
61.1
60 60 57.7

39.8 40.3 40.2

40 37.5 37.4
37.4 40
%

35.1

%
31.8 32.8
28.3
30.6

21.7
20
13.9
20
11.1

4.6
0.7 2.4
0
0

Jiang T et al J Nutr 2005 Schulze K et al. J Nutr 2019

(a) The more you look, the more you find

(b) What you find is not the same
(c) More (are likely to) exist than what you measure
Hypothetical Micronutrient Status Distribution and
Health/Function

Target Range for Women

Supplemented with a Multiple
Micronutrient Supplement

Bailey R, West KP Jr, Black RE Ann Rev Metab 201510

 UNIMMAP MMS Formulation
United Nations International Multiple Micronutrient Antenatal Preparation
• UNIMMAP is formulated to
provide a Recommended Dietary
Allowance (RDA) of each
nutrient.1

• From the United Nations

Children’s Fund (UNICEF), World
Health Organization (WHO),
United Nations University (UNU)
Workshop in 1999.

• Composition of the MMS to be

used in effectiveness trials and
pilot programs among pregnant
women in developing countries
(which has been done!).
1Originally based on NAS NRC in the US estimates of RDA & WHO RNI
Indonesia’s Leadership in Micronutrients for Global
Health: MMS Effectiveness on Pregnancy Outcomes

MMS reduced infant mortality by 18%

• 25% if mother undernourished
• 38% if mother anemic

MMS reduced [fetal loss + neonatal deaths] by 11%

• 15% if mother undernourished Kaplan-Meier plot of infant survival to 3 months of age among
• 29% if mothers anemic infants born to mothers assigned to receive MMS (purple) vs IFA
(green)
MMS reduced LBW by 14%
Lancet 2008;371:215 12
 JiVitA Project
Established 2000
18 Unions
4 x area of Wash DC
Population: 600,000
RANGPUR Density: 1130 /km2
60 Field Offices
750 Project Staff

GAIBANDHA
(Field Station)

The 450 km2 JiVitA Project Area Labrique AB et al

BMC Trials 2011
 MMS Evidence: JiVitA-3 Trial in Bangladesh: MMS vs IFA

• RDA amounts of vit A, D, E, B1, B2, B3,

B6, folic acid, B12, C, Fe, Zn, Cu, Se, I
JAMA 2014;312(24):2649-2658.
vs Fe and folic acid alone (MM vs IFA)
• 44,567 pregnancies; 28,516 live births
• Increased GA by 0.3 weeks and thus:
birth weight by 54 g, therefore -
− Reduced preterm by 15%
− Reduced LBW by 12%
− Reduced still birth by 11%
− Reduced infant mortality – in girls but
not boys
Funded by the Bill and Melinda Gates Foundation ▪ Led to a healthier pregnancy & infant
Beximco & DSM through Sight & Life produced 16 m supplements & provided
▪ May not have resolved most MNDs
technical assistance
 JiVitA-3 Trial in Bangladesh: Micronutrient Deficiencies in
Third Trimester in MMS vs IFA Groups
IFA
M
M

No or little effect on
iron or folate deficiencies

Schulze K et al J Nutr 2019

Prevalence (%)
 MMS Evidence: Effects of MMS vs IFA on Birth Outcomes
Cochrane Review (15 RCTs) IPD Meta-Analysis (17 RCTs)
Outcomes
Relative Risks (RR (95% CI)) Relative Risks (RR (95% CI))
Small for Gestational Age 0.92 (0.88-0.97)a 0.97 (0.96-0.99)b
(<10th percentile)
Low Birth Weight (<2500g) 0.88 (0.85-0.91) 0.88 (0.85-0.90)
Very Low Birth Weight (<2000g) Not Reported 0.78 (0.72-0.85)
Preterm Birth (<37 weeks) 0.95 (0.90-1.01) 0.92 (0.88-0.95)
Very Preterm Birth (<34 weeks) Not Tested 0.87 (0.79-0.95)
Large for Gestational Age Not Tested 1.05 (0.95-1.15)
(>90th percentile Oken)
Large for Gestational Age (>90th Not Tested 1.11 (1.04-1.19)
percentile INTERGROWTH)
Stillbirth 0.95 (0.86-1.04) 0.92 (0.86-0.99)
Neonatal Mortality (<28 days) 1.00 (0.89-1.12) 0.98 (0.90-1.05)
Infant Mortality Not Reported 0.97 (0.88-1.06)
aSGA bSGA
defined by authors of trials; defined by the INTERGROWTH-21 standard MMS, multiple micronutrient supplementation; IFA iron with or
without folic acid; IPD, individual participant data; RCTs, randomized controlled trials. RR in green show a significant decrease in RR.

Source: Keats EC, et al. Cochrane Rev 2019; Smith ER, et al Lancet Global Health 2017
 Global MMS Policy Guidance

Remarks:
• Based on trials testing 13-15 nutrients, INCLUDING IRON and folic acid, and the
UNIMMAP with 15 nutrients providing 30 mg iron and 400 mcg folic acid
• Research in this context includes –
Controlled trials
Where MMS is being considered, IMPLEMENTATION RESEARCH
• Consideration should be given to the magnitude, distribution and determinants of anemia
• Pregnant women should be encouraged to eat a healthy, balanced diet

Source: WHO, Geneva, 2020.

https://apps.who.int/iris/bitstream/handle/10665/33
3561/9789240007789-eng.pdf,
Global MMS Policy Guidance

Source: UNICEF, 2020

https://link.edgepilot.com/s/3688eb5a/G2ZzaAjIfE2H6yD5Zd444w?u=http://www.nyas.org/mm
s_guide
 MMS Evidence: Effects of MMS vs IFA on Birth Outcomes
Lancet Child Adolesc Health 2021

“Evidence on the effectiveness of antenatal multiple micronutrient

supplementation in reducing the risk of stillbirths, low birthweight,
and babies born small-for-gestational age has strengthened.”
20
Lancet Series on Maternal & Child Undernutrition (2021)

The follow-on Series serves as an important milestone moment to inform the nutrition
community and re-energize champions to propel the nutrition agenda forward.
“THE ELEVEN SAMURAI”
Large-scale food fortification for prevention of MN deficiencies
Maternal calcium supplementation in low intake populations
Maternal BEP supplementation in undernourished populations Antenatal MMS is included
as a recommended
Maternal MMN supplementation
intervention for the
Vitamin A supplementation in deficient contexts
prevention of maternal and
Breastfeeding promotion and counselling
child undernutrition.
Complementary feeding education and food provision (food insecure);
complementary feeding education (food secure)
Preventive zinc supplementation
RUSF for management of acute malnutrition
Therapeutic zinc supplementation for diarrhea Source: The Lancet Series on Maternal and Child
Preventive SQ-LNS for optimizing health & growth in children Undernutrition Progress (2021)
Global MMS Technical Guidance
Micronutrient supplements increasing in availability
and use
UNIMMAP Multiple Micronutrient Supplement
Moving from Evidence to Policy

With efficacy & safety of MMS demonstrated, what are the key issues for
developing MMS policies and scaling MMS programs in relation to:
► Assessment/Prevalence?
► Dosage?
► Formulation?
► Implementation?
► Coverage?
► Adherence?
► Impact?
► Cost?
► Discovery?
Power for Mothers: Bringing a Solution for Better
Nutrition to All
Indonesia’s Leadership in Micronutrients for
Global Health: MMS Implementation Research

30
MMS Implementation Research Efforts in Indonesia

Hasanuddin University Airlangga University JHU-University of Indonesia

11 Districts 5 Districts 25 Districts
MMS Implementation Research: Global Efforts

Based on the evidence and new WHO recommendation, countries have started exploring MMS use
by utilizing implementation research to inform the introduction and scaling as part of ANC.

ASIA
Bangladesh
Cambodia
Indonesia
Myanmar
Philippines
Vietnam

AFRICA
Burkina Faso
DRC
Ethiopia
Madagascar
Tanzania
South Africa
LAC
Haiti
Mexico
MMS Clinical Research Efforts in Indonesia
Source: Widasari, 2021.
34
Indonesia’s Leadership in Micronutrients for Global
Health: MMS Mechanisms to Promote Health

35
 Ninety-nine Evans HM, Bishop KS.
Preconception years ago… On the Existence of a Hitherto
vitamin E Unrecognized Dietary Factor
Factor “X” Essential for Reproduction.
deficiency was found Science 1922;56:650-1
occurs in to restore
LMICs fertility in
rats fed
Fresh
Animals suffering from purified diets
Lettuce
sterility do not differ so
profoundly from normal
in their ovarian function
as they do in placental
behavior.
… the placentas are Dried
abnormal… Alfalfa
Resorption invariably
overtakes the products
of conception
United Nations Relief and Works Agency for Palestine Refugees in the Near East, Amman, Jordan
 Prevention
Politics,
Policies & Resources
Public Health Action
Epidemiological Research &
Intervention Trials

Biological Research
Nutriture – Molecular Function – Disease Mechanisms
 Prevention

Public Health
Concern

Biology – Nutriture - Disease

Conclusions on MMS: Not vs… but beyond IFA

✓ MMS is efficacious. Strong evidence for reduction in LBW, SGA, preterm births
and stillbirths and potential reduction in neonatal deaths. As effective as IFA in
preventing IDA.

✓ MMS is safe. No evidence of serious adverse effects

✓ MMS is affordable. On the global market, MMS has been demonstrated to have
cost-parity with IFA. Kirk Humanitarian has broken the price barrier.

✓ MMS is cost effective and beneficial. Highly cost-effective compared to

antenatal IFA and other interventions affecting specific birth outcomes or neonatal
deaths, with a wider range of health and development benefits across life stages
 Thank
You

Photo: Paul Joseph Brown Micronutrient Deficiency Prevention Workshop Jakarta, 2020
Effects of Antenatal Multiple Micronutrient vs IFA Supplementation on
Cognition at 9-12 Years of Age, SUMMIT Trial, Indonesia

Follow up study of original trial (SUMMIT Study Group. Lancet 2008)

N=2,879 children tested for cognitive, motor and socioemotional
development. Children born to MM supplemented mothers had a
procedural memory score 0.11 SD higher than in offspring of IFA
supplemented mothers; general intelligence score was 0.18 SD higher in
MM supplemented anemic mothers.
Prado EL et al Lancet 2017;5:e217-28.
UNIMMAP MMS Formulation
United Nations International Multiple Micronutrient Antenatal Preparation

Iron (30mg vs. 60mg)

• Iron absorption in the UNIMMAP formulation is enhanced (as compared to the IFA) due to the inclusion of
vitamin C, vitamin A, and riboflavin.
• Most pregnant women exhibit mild to moderate anemia, which can be addressed with 30 mg of iron.
• Larger amounts of zinc may be needed if 60 mg of iron were used to counteract the possible negative
influence of higher amounts of iron on zinc absorption.
• Increased risk of side effects caused by higher amounts of iron, which may reduce adherence.
• 30 mg of iron is consistent with the WHO Antenatal Guidelines, which state that iron supplementation
should be between 30-60 mg/day.

Selenium (65 mcg)

• Rationale for 65 mcg: 60 and 65 mcg are indistinguishable concentrations
• Below Tolerable Upper Limit level
MMS Evidence: Effects of MMS vs IFA on Birth Outcomes

Cochrane Review Individual Patient Data (IPD) Meta-analysis

2019 update (2017)

Source: Keats, EC. et al. 2019. Cochrane Database Source: Smith E.R. et al. 2017. Lancet Glob. Heal. 5:
Syst. Rev. 3: CD004905 e1090–e1100.
Global MMS Policy Guidance

Source: WHO, Geneva, 2020. Source: UNICEF, 2020

https://apps.who.int/iris/bitstream/handle/10665/33 https://link.edgepilot.com/s/3688eb5a/G2ZzaAjIfE2H6yD5Zd444w?u=http://www.nyas.org/mm
3561/9789240007789-eng.pdf, s_guide
Hanson MA et al. FIGO recommendations
on adolescent, preconception, and maternal
nutrition: “Think Nutrition First”.
Intl J Gynecol Obstet 2015;131:S213-S253.

49
Conflict of Interest
• Financial Research Support:
• The Bill & Melinda Gates Foundation, Seattle WA
• US Agency for International Development, Washington DC
• Kirk Humanitarian, Salt Lake City, Utah
• Johns Hopkins Bloomberg School of Public Health
• In-kind Field Trial Support:
• Micronutrient premix and supplement analyses for nutrient composition for
trials gratis by DSM/Sight and Life, Kaiseraugst, Switzerland
• Supplements produced gratis by Beximco Ltd, Dhaka, Bangladesh
• Other Support:
• Several student scholarships, lectureships through the JHSPH through the
Sight & Life Global Nutrition Research Institute, Baltimore, Maryland