Supplementary appendix

This appendix formed part of the original submission and has been peer reviewed.
We post it as supplied by the authors.

Supplement to: Keats EC, Das JK, Salam RA, et al. Effective interventions to address
maternal and child malnutrition: an update of the evidence. Lancet Child Adolesc Health
2021; published online March 7. https://doi.org/10.1016/S2352-4642(20)30274-1.
 Effective interventions to address maternal and child malnutrition: an update of the evidence
Supplementary Material

Table of Contents
Table S1: Review of direct health system nutrition interventions for women of reproductive age and during pregnancy. ................ 2
Table S2: Review of direct health sector nutrition interventions for neonates. ................................................................................... 6
Table S3: Direct health sector nutrition interventions in infants and children. ................................................................................... 8
Figure S1: Sensitivity analysis showing the effects of vitamin A supplementation on child mortality when combining studies
published pre-1995 with studies published in 1995 and later. .......................................................................................................... 11
Figure S2: Sensitivity analysis showing the effects of preventive zinc supplementation on child height when combining studies that
specifically recruited undernourished children (e.g., stunted, anemic, growth-retarded, or infants born small-for-gestational age or
low birthweight). ............................................................................................................................................................................... 12
Panel S1: Direct and indirect actions outside the health sector......................................................................................................... 13
Panel S2: Comparison of current findings with previous reviews based on eligibility criteria. .......................................................... 14
Panel S3: Methodological considerations of our findings. ................................................................................................................ 14

1
Table S1: Review of direct health system nutrition interventions for women of reproductive age and during pregnancy.
Estimates
Notes
Intervention Location Population Evidence reviewed Maternal outcomes Fetal/newborn outcomes Childhood outcomes
Iron folic acid China (3), Healthy, Systematic review of 7 Perinatal mortality: RR
supplementation vs Tanzania, The pregnant women RCTs 0·88, 95% CI 0·71-1·08,
folic acid or placebo Gambia, four studies, GRADE:
Nepal, Iran moderate; neonatal
mortality: RR 0·85, 95%
CI 0·55 to 1·31, three
studies; infant mortality:
RR 1·10, 95% CI 0·84 to
1·45, three studies; SGA:
RR 1·03, 95% CI 0·87 to
1·23, four studies; preterm
birth: RR 0·96, 95% CI
0·64 to 1·44, five studies
MMN Ghana (2), Healthy, Systematic review of 33 Maternal mortality: RR 1·04, 95% CI Caesarean section: RR Stunting: RR 0·99,
supplementation vs Malawi (2), pregnant women RCTs 0·71 to 1·51, seven studies, GRADE: 1·00, 95% CI 0·94 to 1·07, 95% CI 0·92 to 1·07,
iron with or without Burkina Faso, in LMICs moderate; maternal anemia: RR 1·02, 11 studies; perinatal seven studies;
folic acid The Gambia, 95% CI 0·95 to 1·10, 16 studies, mortality: RR 1·00, 95% wasting: RR 1·02, 95%
Guinea- GRADE: high; iron deficiency anemia: CI 0·90 to 1·11, 16 CI 0·88 to 1·18, five
Bissau, RR 1·12, 95% CI 0·62 to 2·02, four studies, GRADE: high; studies; underweight:
Tanzania, studies, GRADE: very low; iron congenital anomalies: RR RR 0·95, 95% CI 0·84
Zimbabwe, deficiency: RR 1·39, 95% CI 0·88 to 0·73, 95% CI 0·41 to 1·29, to 1·07, four studies;
Niger, 2·20, three studies; hemoglobin seven studies; neonatal general intelligence:
Indonesia (4), concentration: MD -0·34 g/L, 95% CI - mortality: RR 0·98, 95% SMD 0·00, 95% CI -
Vietnam (2), 1·53 to 0·86, 16 studies; ferritin CI 0·90 to 1·06, 17 0·06 to 0·07, eight
China (2), concentration: MD -2·37 µg/L, 95% CI studies; infant mortality: studies; motor
Bangladesh -7·84 to 3·10, 11 studies; serum folate: RR 0·99, 95% CI 0·92 to function: SMD -0·02,
(5), Nepal (2), MD -1·66 nmol/L, 95% CI -4·39 to 1·08, 10 studies 95% CI -0·17 to 0·13,
Pakistan (2), 1·08, five studies; miscarriage: RR seven studies; verbal
Peru (2), 0·99, 95% CI 0·94, 1·04, 13 studies comprehension: SMD
Mexico, Iran 0·02, 95% CI -0·13 to
(3) 0·16, four studies;
hemoglobin: MD 0·01
g/L, 95% CI -0·63 to
0·66, seven studies;
ferritin concentration:
MD 1·85 µg/L, 95% CI
-0·81 to 4·50, four
studies; zinc
concentration: MD 0·04
µmol/L, 95% CI -0·21
to 0·30, three studies;
anemia: RR 0·83, 95%
CI 0·54 to 1·28, three
studies

2
Iron supplementation China (3), Healthy, Systematic review of 12 Preterm births: RR 0·94,
Indonesia, pregnant women RCTs 95% CI 0·63 to 1·41, six
Iran (4), studies; neonatal
Tanzania, The mortality: RR 0·85, 95%
Gambia, CI 0·55 to 1·31, three
Niger, Nepal studies; perinatal
mortality: RR 0·88, 95%
CI 0·71 to 1·08, four
studies, GRADE: high;
infant mortality: RR 1·10,
95% CI 0·84 to 1·45, three
studies; SGA: RR 1·04,
95% CI 0·87 to 1·24, four
studies
Calcium Argentina, Healthy, Systematic review of 4 Caesarean section: RR 0·99, 95% CI
supplementation vs Ecuador, pregnant women RCTs 0·84 to 1·15, 3 studies
placebo India, multi- with low calcium
country study intakes
(Peru, South
Africa,
Vietnam,
India)
Vitamin A Ghana (2), Healthy, Systematic review of 8 Serum retinol: MD 0·13 µmol/L, 95% Stillbirths: RR 1·01, 95% Two trials included
supplementation vs Malawi, pregnant women RCTs CI 0·03 to 0·30, six studies CI 0·96 to 1·07, three a co-intervention
placebo Tanzania, studies of IFA (as the
Indonesia (2), Maternal mortality: RR 0·90, 95% CI standard of care).
Nepal, 0·68 to 1·18, three studies, GRADE:
Bangladesh low; hemoglobin concentration: MD
0·51 g/L, 95% CI -2·42 to 3·43, five
studies
Vitamin D Bangladesh Healthy, Systematic review of 11 Vitamin D concentrations: MD 44·70 *Preterm birth: RR 0·64, Looked at
supplementation vs (2), Pakistan pregnant women RCTs µmol/L, 95% CI 21·94 to 67·45, nine 95% CI 0·40 to 1·04, supplementation
placebo (2), India (2), studies seven studies with strictly vitamin
Iran (5) D and vitamin D
Caesarean section: RR 1·05, 95% CI SGA: RR 0·93, 95% CI plus additional
0·94 to 1·18, five studies; 0·51 to 1·53, three studies micronutrients
serum/plasma calcium concentration: (i.e., IFA as
MD -0·06, 95% CI -0·21 to 0·09, five *Subgroup difference for standard of care).
studies preterm birth between
vitamin D alone (RR 0·33,
95% CI 0·17 to 0·62, two
studies) and with
additional IFA
supplementation (RR
0·94, 95% CI 0·64 to 1·36,
five studies)
SQ-LNS vs MMN Malawi, Healthy, Systematic review of 4 LBW: RR 0·92, 95% CI
Ghana, pregnant women RCTs 0·75 to 1·13, four studies,
Burkina Faso, in LMICs GRADE: moderate;
The Gambia perinatal mortality: RR

3
 1·01, 95% CI 0·65 to 1·65,
three studies, GRADE:
low; neonatal mortality:
RR 0·81, 95% CI 0·45 to
1·45, three studies;
preterm birth: RR 1·15,
95% CI 0·93 to 1·42, four
studies; SGA: RR 0·96,
95% CI 0·86 to 1·07, four
studies; miscarriage: RR
1·12, 95% CI 0·69 to 1·80,
three studies
SQ-LNS vs IFA Ghana, Healthy, Systematic review of 4 Anemia: RR 2·35, 95% CI 1·67 to Birth weight: MD 53·28 g, Walking alone at 12
Malawi, pregnant women RCTs 3·30, one study, GRADE: moderate; 95% CI 28·22 to 78·33, 3 months reported in 2
Burkina Faso, in LMICs duration of gestation: MD 0·18 weeks, studies, GRADE: studies (no meta-
Bangladesh 95% CI 0·04 to 0·32, three studies, moderate; length at birth: analysis performed)
GRADE: moderate MD 0·24 cm, 95% CI 0·11
to 0·36, three studies,
Gestational weight gain per week: GRADE: moderate; SGA:
SMD 0·46, 95% CI -0·44 to 1·36, two RR 0·94, 95% CI 0·89 to
studies; maternal mortality: RR 0·53, 0·99, three studies,
95% CI 0·12 to 2·41, three studies, GRADE: moderate;
GRADE: moderate stunting in first 6 months:
RR 0·82, 95% CI 0·71-
0·94, two studies; head
circumference z-score:
MD 0·11, 95% CI 0·04 to
0·18, three studies

LBW: RR 0·87, 95% CI

0·72 to 1·05, three
studies, GRADE:
moderate; preterm birth:
RR 0·94, 95% CI 0·80 to
1·11, three studies,
GRADE: moderate;
miscarriage: RR 0·87,
95% CI 0·66 to 1·14, two
studies; stillbirth: RR 1·14,
95% CI 0·52 to 2·48, three
studies; MUAC: MD 0·12,
95% CI -0·02 to 0·26, two
studies; underweight in
first 6 months: RR 0·84,
95% CI 0·63 to 1·13, two
studies; neonatal death:
RR 0·72, 95% CI 0·47 to
1·1, three studies

4
 BEP The Gambia Pregnant women Systematic review of 8 Stillbirth: RR 0·39, 95% CI
supplementation (2), India (2), in LMICs RCTs and quasi- 0·19 to 0·80; three
Iran (1), South experimental studies studies; GRADE: Low;
Africa (1), LBW: RR 0·60, 95% CI
Colombia (1), 0·41 to 0·86, three studies
Thailand (1). GRADE: Low; SGA: RR
0·71, 95% CI 0·54 to 0·94,
five studies; Perinatal
Mortality: RR: 0·50; 95%
CI 0·30 to 0·84, one
study, GRADE: Very Low;
Preterm Birth: RR: 0·86;
95% CI 0·50 to 1·46, two
studies GRADE: Very
Low; Birth weight: MD
107·28 g 95% CI 68·51 to
146·04, eight studies;
Birth length: MD 0·28 cm,
95% CI -0·36 to 0·92, two
studies;

Food distribution Bangladesh Pregnant women Systematic review of 5 Maternal mortality: RR 0·41, 95% CI Perinatal mortality: RR Newborn stunting: RR
(with or without (2), Gambia, in LMICs RCTs 0·07 to 2·49, 2 studies 0·67, 95% CI 0·41 to 1·09, 0·82, 95% CI 0·71 to
dietary counseling) Burundi, two studies, GRADE: low; 0·94, two studies;
vs standard of care Malawi neonatal mortality: RR wasting: RR 0·87, 95%
0·46, 95% CI 0·20 to 1·04, CI 0·78 to 0·97, two
one study, GRADE: Low; studies
LBW: RR 0·92, 95% CI
0·84 to 1·00, four studies, Underweight: RR 0·84,
GRADE: Moderate; 95% CI 0·63 to 1·13,
birthweight: MD 46 g, 95% two studies
CI 45·10 to 46·90, three
studies
Preterm birth: RR 0·92,
95% CI 0·78 to 1·10, three
studies, GRADE:
Moderate; SGA: RR 0·94,
95% CI 0·89 to 1·00, three
studies; head
circumference: MD 0·07
cm, 95% CI -0·22 to 0·36,
two studies; birth length:
MD 0·20cm, 95% CI 0·20
to 0·20, three studies

BEP = balanced energy protein; Hb = hemoglobin; LBW = low birthweight; RCT = random controlled trial; MD = mean difference; CI = confidence interval; SGA = small-for-gestational age; MMN = multi
micronutrient; NTD = neural tube defect; SQ-LNS = small-quantity lipid-based nutrition supplementation; LMIC = low or middle-income country.

5
Table S2: Review of direct health sector nutrition interventions for neonates.
Estimates

Notes
Intervention Location Population Evidence reviewed Neonatal outcomes

India (4), Guinea- All neonates, Systematic review of Risk of bulging fontanelle: RR 1·53, 95 % CI 1·12 to 2·09, six studies
Bissau (3), irrespective of birth 16 RCTs
Bangladesh (2), weight or gestational All-cause mortality at 1 month of age: RR 0·99, 95% CI 0·90 to 1·08, five studies;
Indonesia, Nepal, age, in LMICs all-cause mortality at 6 months: RR 0·98, 95% CI 0·89 to 1·08, 12 studies; all-
Ghana, Tanzania, cause mortality at 12 months of age: RR 1·04, 95% CI 0·94 to 1·14, eight
Zimbabwe, China, studies); incidence of vomiting: RR 1·00, 95% CI 0·93 to 1·07, five studies
Pakistan
Vitamin A
Indonesia, Nepal, Term neonates and all Systematic review of Risk of bulging fontanelle: RR 1·53, 95% CI 1·11 to 2·11, five studies, GRADE: Haider 201741
supplementation
India, Zimbabwe, neonates (not 12 trials high
Bangladesh, Guinea- specified whether
Bissau (3), Ghana, term) in LMICs Infant mortality at 6 months (term neonates): RR 0·80, 95% CI 0·54 to 1·18,
Tanzania, India, three studies, GRADE: very low; infant mortality at 6 months (all neonates): RR
Pakistan 0·98, 95% CI 0·89 to 1·07, 11 studies, GRADE: high; neonatal mortality (all
neonates): RR 0·99, 95% CI 0·90 to 1·08, five studies, GRADE: high; vomiting:
RR 1·00, 95% CI 0·93 to 1·07, five studies, GRADE: high; diarrhea: RR 0·96,
95% CI 0·81 to 1·13, five studies, GRADE: low
USA (9), Iran (7), India Healthy newborns Update of Moore 2016 Neonatal infections: RR 0·68, 95% CI 0·50 to 0·91, one study; omphalitis: RR
(5), Guatemala (4), (term or late preterm) review48 to include 5 0·58, 95% CI 0·37 to 0·89, one study; exclusive breastfeeding to one month post
Spain (3), Taiwan (3), additional studies birth: RR 1·26, 95% CI 1·07 to 1·50, eight studies; exclusive breastfeeding 6
Germany (2), UK (2), Total: 51 studies weeks to 6 months post birth: RR 1·41, 95% CI 1·18 to 1·69, eight studies; infant
Pakistan (2), Sweden body weight change at day 14: MD 65·58 g, 95% CI 18·42 to 112·75, four
(2), Zambia, South studies
Africa, Thailand,
Nepal, Japan, Neonatal death: RR 0·82, 95% CI 0·41 to 1·65, one study
Vietnam, Israel, Italy,
Russia, Poland,
Canada, Chile
India (11), USA (3), LBW newborns Update of Conde- Mortality at discharge or at 40 to 41 weeks’ postmenstrual age: RR 0·68, 95% CI
KMC vs standard of
Ethiopia (2), Indonesia Agudelo 2016 review49 0·53 to 0·87, 10 studies; mortality at 6 months follow up: RR 0·78, 95% CI 0·63
care
(2), Malaysia, to include 4 additional to 0·96, three studies; mortality at latest follow up: RR 0·74, 95% CI 0·61 to 0·89,
Madagascar, Nepal, studies 14 studies; severe infection/sepsis at latest follow up: RR 0·85, 95% CI 0·79 to
Ecuador, Colombia, Total: 28 studies 0·92, nine studies; nosocomial infection/sepsis at discharge or at 40 to 41 weeks’
Mexico, UK, Australia, postmenstrual age in stabilized infants: RR 0·35, 95% CI 0·22 to 0·54, five
Vietnam, multi-country studies; weight gain at latest follow up: MD 3·66 g/day, 95% CI 2·08 to 5·23, 12
study (Mexico, studies; length gain at latest follow up: MD 0·16 cm/week, 95% CI 0·02 to 0·30,
Ethiopia and four studies; exclusive breastfeeding at discharge or at 40 to 41 weeks’
Indonesia) postmenstrual age: RR 4·11, 95% CI 3·87 to 4·36, eight studies; exclusive
breastfeeding at 1 to 3 months follow up: RR 1·20, 95% CI 1·01 to 1·43, five
studies; exclusive breastfeeding at 6 to 12 months follow up: RR 3·03, 95% CI
2·31 to 3·97, four studies

6
 India (5), Bangladesh LBW or preterm Systematic review of 8 Breastfeeding initiation: MD -2·6 days, 95% CI -3·96 to -1·23, eight studies Mekonnen 2019
(2), Brazil newborns RCTs

Delayed cord USA (12), India (7), Preterm neonates Systematic review of Neonatal death: RR 0·73, 95% CI 0·54 to 0·98, 20 studies, GRADE: moderate; Rabe 2019
clamping vs early UK (4), China (3), (<37 weeks) in mostly 48 studies intraventricular haemorrhage, all grades: RR 0·83, 95% CI 0·70 to 0·99, 15
cord clamping South Africa (3), HICs studies, GRADE: high
Turkey (3), Canada
(2), Germany (2), Iran Severe intraventricular haemorrhage, grades 3 and 4: RR 0·94, 95% CI 0·63 to
(2), Japan (2), 1·39, 10 studies, GRADE: low; periventricular leukomalacia: RR 0·58, 95% CI
Thailand (2), Pakistan, 0·26 to 1·30, four studies, GRADE: low; chronic lung disease – oxygen
Australia, Israel, supplement at 36 weeks: RR 1·04, 95% CI 0·94 to 1·14, six studies, GRADE:
Netherlands, high; maternal blood loss ³500 mL: RR 1·14, 95% CI 0·07 to 17·63, two studies,
Switzerland, multi- GRADE: very low
country study
(Australia, Canada,
New Zealand, Ireland,
Pakistan, USA)
Early cord clamping USA (3), Canada (2), Term neonates Update of McDonald Mean birthweight: MD -86·55, 95% CI -148·96 to -24·14, 14 studies; clinical
vs delayed cord UK (2), India (2), 2014 review to include jaundice: RR 0·76, 95% CI 0·60 to 0·95, seven studies; neurodevelopment -
clamping Nepal, China, 4 additional RCTs ASQ total score at 4 and 12 months: MD -2·77, 95% CI -4·89 to -0·64, two
Argentina, Australia, Total: 19 studies studies
Zambia, Iran, Libya,
Mexico, Saudi Arabia, Neonatal death: RR 0·53, 95% CI 0·10 to 2·82, three studies; Apgar score <7 at
Sweden 5 minutes: RR 1·07, 95% CI 0·69 to 1·65, five studies; any admission to SCN or
NICU: RR 0·80, 95% CI 0·49 to 1·30, five studies; jaundice requiring
phototherapy: RR 0·67, 95% CI 0·46 to 0·97, 10 studies

Probiotic India (9), Turkey (6), Low birthweight and/or Systematic review of All-cause mortality: RR 0·80, 95 % CI 0·66 to 0·96, 25 studies, GRADE: high;
supplementation vs Iran (3), China (3), preterm neonates in 32 RCTs necrotizing enterocolitis (NEC): RR 0·46, 95 % CI 0·35 to 0·59, 29 studies,
no probiotics South Africa (2), LMICS GRADE: high; neonatal sepsis: RR 0·78, 95 % CI 0·70 to 0·86, 21 studies,
Mexico (2), Brazil, GRADE: high
Bangladesh,
Colombia, Indonesia,
Nepal, Pakistan,
Thailand
HIC = high-income country; KMC = kangaroo mother care; LMIC = low or middle-income country; RCT = randomized controlled trial; RR = risk ratio; MD = mean difference.

7
Table S3: Direct health sector nutrition interventions in infants and children.
Intervention Location Population Evidence Estimates Notes
Reviewed
Breastfeeding Studies were from both Infants Systematic Stunting: RR 1·00; 95% 0·88 to 1·14; six studies; These educational interventions are effective
promotion vs developing and developed review of 38 wasting: RR 0·94; 95% CI 0·86 to 1·03; two studies; either as facility-based or community-based
standard of care countries: Egypt, Ghana, studies underweight: RR 1·31; 95% CI 0·79 to 2·16; three or home-based and if the intervention is
Jordan, Kenya (2), Nigeria, studies; infant mortality: RR 0·86; 95% CI 0·73 to 1·02; delivered by either CHW/volunteers or
South Africa, Tanzania (2), two studies healthcare professionals
Uganda (2), Uganda, Burkina
Faso, Bangladesh (6), China,
India (3), Iran (2), Malaysia,
Nepal, Pakistan, Philippines,
Thailand, Turkey (2), Mexico,
Brazil (5)
Complementary Studies were from developing Children 6-24 Systematic Food secure population:
feeding education countries: Brazil (2), months of age review of 12 Weight-for-height: MD: 0·22; 95% CI: -0·03 to 0·47; 3
alone vs standard Pakistan (2), Peru, China (2), studies studies, GRADE: moderate; stunting: RR 0·50; 95% CI:
of care Bangladesh, India (4) 0·29 to 1·40; 3 studies, GRADE: low; wasting: RR 0·19;
95% CI: 0·03 to 1·18; 2 studies, GRADE: moderate;
weight gain: MD 0·12; 95% CI: -0·12 to 0·37; two
studies, GRADE: moderate; height gain: MD 0·33; 95%
CI: -0·46 to 1·12; 2 studies, GRADE: low
Food insecure population:
Stunting: RR 0·65; 95% CI: 0·42 to 1·01; 3 studies,
GRADE: low; wasting: RR 1·05; 95% CI: 0·15 to 7·26;
one study, GRADE: moderate; weight gain: MD 0·12;
95% CI: -0·12 to 0·37; three studies, GRADE: low;
height gain: MD -0·09; 95% CI: -0·30 to 0·12; two
studies, GRADE: low
Complementary Studies were from developing Children 6-24 Systematic Food secure population:
feeding provision countries: Burkina Faso, months of age review of 17 Weight-for-age: MD -0·09; 95% CI: -0·34 to 1·16; one
with/without Zambia, India, Nigeria, Vietnam, studies study, GRADE: low; height-for-age: MD -0·12; 95% CI: -
education vs Ghana (2), Ecuador (2), DR 0·46 to 0·22; one study, GRADE: low; weight-for-height:
standard of care Congo, Bangladesh, Malawi (2), MD -0·03; 95% CI: -0·28 to 0·22; one study, GRADE:
Guatemala, Colombia, Brazil, low; height gain: MD -0·23; 95 CI: -1·11 to 0·65; one
China study, GRADE: low; weight gain: MD -0·01; 95% CI: -
0·24 to 0·22; one study, GRADE: low
Food insecure population:
Weight-for-age: MD -0·34; 95% CI: -0·35 to 1·03; ten
studies, GRADE: very low; weight-for-height: MD 0·01;
95% CI: -0·01 to 0·03; 10 studies, GRADE: low; wasting:
RR 0·87; 95% CI: 0·74 to 1·01; six studies, GRADE:
moderate; weight gain: MD 0·62; 95 CI: -0·02 to 1·26;
three studies, GRADE: very low; height gain: MD 0·17;
95 CI: -0·11 to 0·44; two studies, GRADE: moderate
Supplementary Studies were from developing Children 6-24 Systematic Weight for height: MD 0·15; 95% CI: 0·08 to 0·22; six
feeding vs countries: Niger (2), Jamaica months of age review of 12 studies, GRADE: moderate
standard of care (2), Malawi (2), Peru, Indonesia, studies
Kenya, Brazil, Vietnam; and a Weight for age: MD 0·20; 95% CI: -0·12 to 0·52; five
multi-country study in Senegal, studies, GRADE: very low; height-for-age z-score: MD

8
 Intervention Location Population Evidence Estimates Notes
Reviewed
Bolivia, Congo, and New 0·11; 95% CI: -0·03 to 0·24; six studies, GRADE: low;
Caledonia stunting: RR 1·31; 95% CI: 0·95 to 1·81; four studies,
GRADE: low; wasting: RR 0·80; 95% CI: 0·55 to 1·17;
four studies, GRADE: low
Preventive vitamin Studies were from developing Children 1-59 Systematic *All-cause mortality: RR 0·90, 95% CI 0·80 to 1·02; four
A countries: India (3), Mexico (2), months of age review of 16 studies; diarrhea: RR: 0·97, 95% CI: 0·83 to 1·14; seven
supplementation Ghana (2), Indonesia (2), Nepal, studies studies; lower respiratory tract infection: RR: 1·13, 95%
vs placebo/no Papua New Guinea, Ecuador, CI 0·90 to 1·42; five studies
intervention Bangladesh, Guinea Bissau,
Gambia, China, Kenya, Peru *Sensitivity analysis including older trials revealed
improved mortality: RR 0·80; 95% CI 0·70 to 0·92; 11
studies
Iron Studies were from developing Children 1 to 59 Systematic Anemia: RR: 0·55, 95% CI 0·44 to 0·70; 14 studies; There are still concerns about using iron
supplementation countries: Indonesia (5), months of age review of 28 hemoglobin: MD: 6·02 g/L; 95% CI 4·28 to 7·76; 24 supplements in malaria-endemic areas
vs placebo/no Tanzania (3), Vietnam (3), studies studies; iron deficiency: RR: 0·21, 95% CI 0·12 to 0·39;
intervention Turkey (2), China (2), India (2), 11 studies; iron deficiency anemia: RR 0·14; 95% CI
Honduras, Togo, Costa Rica, 0·04 to 0·54; six studies; mental development: SMD:
Thailand, Peru, Brazil, 0·14, 95% CI 0·01 to 0·28; four studies; motor
Bangladesh, South Africa, development: SMD: 0·28, 95% CI 0·15 to 0·40; three
Benin, Mexico, Pakistan studies

Prevalence of stunting: RR: 0·96, 95% CI 0·77 to 1·18;

four studies; wasting: RR: 1·21, 95% CI 0·82 to 1·79;
three studies
Multiple Studies were from developing Children 1 to 59 Systematic Anemia: RR: 0·69, 95% CI 0·56 to 0·85; seven studies; The improved effect was greater with daily
micronutrient countries: Tanzania (3), months of age review of 14 height: MD: 0·36 cm, 95% CI 0·01 to 0·71; four studies; supplementation when compared to
supplementation Bangladesh (2), South Africa studies hemoglobin: MD: 4·40 g/L, 95% CI 2·91 to 5·90; 12 intermittent supplementation
including iron vs (2), Vietnam (2), Mexico (2), studies; height-for-age z-score: MD 0·09, 95% CI 0·00-
placebo/no Indonesia (2), Nepal, India, 0·17, 10 studies; iron deficiency: RR 0·41, 95% CI 0·25-
intervention Peru, Ghana 0·66, six studies

Diarrhea: RR: 0·97, 95% CI 0·87 to 1·09; five studies;

zinc deficiency: RR: 0·65, 95% CI 0·37 to 1·15; four
studies; weight: MD: -0·04kg, 95% CI -0·19 to 0·11; four
studies; weight-for-age z-score: MD: 0·06, 95% CI -0·00
to 0·12; 10 studies; weight-for-height z-score: MD: -0·02,
95% CI -0·09 to 0·06; 10 studies; vitamin A deficiency:
RR: 1·01, 95% CI 0·48 to 2·14; three studies
Micronutrient Studies were from developing Children 1 to 59 Systematic Stunting: 1·04, 95% CI 0·95 to 1·13; seven studies; Increased diarrhea prevalence with MNPs
powders vs countries: India (4), Kenya (3), months of age review of 34 underweight: RR: 1·02, 95% CI 0·95 to 1·09; seven
placebo/no China (3), Bangladesh (2), RCTs studies; wasting: RR: 1·03, 95% CI 0·93 to 1·14; seven
intervention Brazil (2), Ghana (2), Cambodia studies; cognitive function: OR: 1·94, 95% CI 0·55 to
(2), Lao PDR (2), Pakistan, 6·80; three studies
Honduras, Mali, Ethiopia,
Guatemala, North Korea, Nepal,
Haiti, South Africa, Kyrgyzstan,
Columbia, Nicaragua, Africa

9
 Intervention Location Population Evidence Estimates Notes
Reviewed
Preventive zinc Studies were from developing Children 1 to 59 Systematic Anemia: RR: 1·01, 95% CI 0·96 to 1·06; 10 studies;
supplementation countries: Indonesia (5), months of age review of 31 *height: MD: 0·04, 95% CI -0·12 to 0·20; 18 studies;
vs placebo/no Bangladesh (5), India (4), RCTs stunting: RR: 1·00, 95% CI: 0·89 to 1·14; six studies;
intervention Burkina Faso (3), Tanzania (2), wasting: RR: 0·80, 95% CI 0·62 to 1·05; six studies;
Mexico (2), Guatemala (2), underweight: RR: 0·99, 95% CI: 0·89 to 1·11; 4 studies;
Thailand, Ethiopia, Nepal, lower respiratory tract infections: RR: 0·78, 95% CI 0·53
Brazil, Uganda, Vietnam, Lao to 1·17; seven studies; all-cause mortality: RR: 0·24,
PDR 95% CI 0·04 to 1·62; three studies; mental development:
SMD: 0·06, 95% CI -0·42 to 0·53; six studies; motor
development: SMD: 0·88, -0·83 to 2·59; five studies

*Sensitivity analysis including trials with undernourished

children at baseline demonstrated improved height in
this subgroup only (MD 0·09, 95% CI 0·02 to 0·16, 15
studies versus MD 0·04, 95% CI -0·12 to 0·20, 18
studies)
Studies were from developing Children 2 to 59 Systematic Incidence of pneumonia: RR: 0·87, 95% CI 0·81 to 0·94;
countries: India (2), South Africa months of age review of 6 six studies; GRADE: low; prevalence of pneumonia: RR
(2), Bangladesh, Peru studies 0·59; 95% CI 0·35 to 0·99; one study; GRADE: low

Preventive SQ- Studies were from developing Children 6 to 23 Systematic Severe wasting: RR: 1·74, 95% CI 0·73 to 4·15; two SQ-LNS are more effective if provided over
LNS vs no countries: Malawi (4); months of age review of 17 studies; severe underweight: RR: 0·84, 95% CI: 0·52 to a longer duration of time (over 12 months).
intervention Bangladesh (3); Ghana (2); studies 1·37; two studies And limited evidence also suggests that SQ-
Burkina Faso (1); Chad (1); LNS is more effective than FBF and MNP at
Congo (1); Guatemala (1); Haiti improving growth outcomes
(1); Honduras (1); Kenya (1)
and Peru (1)
CHW = community health worker; CI = confidence interval; EBF = exclusive breastfeeding; FBF = fortified blended food; MD = mean difference; MNP = micronutrient powder; RCT = randomized controlled
trial; RR = risk ratio; SQ-LNS = small-quantity lipid-nutrient supplementation.

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Figure S1: Sensitivity analysis showing the effects of vitamin A supplementation on child mortality when combining studies published
pre-1995 with studies published in 1995 and later.

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Figure S2: Sensitivity analysis showing the effects of preventive zinc supplementation on child height when combining studies that
specifically recruited undernourished children (e.g., stunted, anemic, growth-retarded, or infants born small-for-gestational age or low
birthweight).

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Panel S1: Direct and indirect actions outside the health sector.
Direct
The use of large-scale food fortification (LSFF) as a delivery channel to reach women and children with additional micronutrients is effective at
improving micronutrient concentrations, anemia, and other functional outcomes. A recent systematic review assessed the impact of LSFF
outside of controlled settings through a meta-analysis of 50 effectiveness studies.82 Among WRA, the risk of anemia was reduced by 34%
(24%-42%; 9 studies), iron deficiency by 54% (28%-71%; 4 studies) and serum ferritin concentrations were improved. Pregnant women also
had improvements in anemia by 27% (16%-36%; 3 studies). In addition, urinary iodine (and iodine deficiency), serum folate (and folate
deficiency), and serum retinol concentrations were improved among WRA with iodine, folic acid, and vitamin A fortification of staple foods,
respectively. Fortification of wheat and maize flours with folic acid also notably decreased the prevalence of NTDs. Despite consuming lower
quantities of staple foods relative to adults, children also had nutritional benefits from LSFF. Urinary iodine concentrations were improved,
translating to a reduced risk of iodine deficiency and lower prevalence of goiter among school-age children who had consumed these foods.
Among children <7 years, the risk of anemia was reduced by 39% (4%-62%; 7 studies) and iron deficiency by 64% (36%-79%; 3 studies), owing
to LSFF with iron. Lastly, serum retinol was improved for children under-5 who had consumed either sugar, maize flour or oil that had been
fortified with vitamin A.

Due to scope, we have not summarized the evidence on other direct nutrition actions delivered outside the health sector which include
biofortification, nutrition-related policy action (e.g. to limit marketing of unhealthy foods), and interventions or nutrition promotion delivered
through social protection programs, emergency programs, schools, or mass media.

Indirect
Water, sanitation, and hygiene (WASH) interventions are an important public health strategy that have been widely touted to have an impact on
nutrition, but the evidence from trials has so far has been inconclusive. An update of a Cochrane review and meta-analysis that evaluated the
effect of interventions to improve water quality and supply, provide adequate sanitation, and promote handwashing with soap on the nutritional
status of children under the age of 18 years suggests no effect on WAZ, WHZ, or HAZ.83 Another review concluded that WASH interventions are
associated with diarrhea risk reductions; with a 53% reduction from point-of-use water filtration, a 31% reduction from point-of-use water
disinfection, and a 27% reduction from hygiene education with soap provision.84

More recently, three large-scale RCTs in Bangladesh, Kenya, and Zimbabwe (the WASH benefits and SHINE trials) evaluating improved
household-level WASH with and without improved IYCF have shown no benefit of WASH on linear growth.85 However, these interventions have
likely not been effective enough in reducing fecal–oral transmission of pathogens to consequently impact growth, despite high enough adherence
to reduce diarrhea (the WASH Benefits Bangladesh trial) and some enteric infections (all three trials). Findings from these trials suggest that high
frequency contact is the only means through which high enough adherence to handwashing and point-of-use water chlorination could be achieved
to reduce diarrhea. Because this level of contact is not feasible for WASH programs at scale, handwashing and point-of-use water chlorination
programs are unlikely to reduce child diarrhea unless alternative innovative means of achieving very high adherence are identified that are feasible
for program implementation. Moreover, the fecal exposure of children in these settings are typically higher compared with children in HICs.85

In contrast to systematic reviews of RCTs, an additional important body of evidence on the relative importance of WASH to childhood growth
derives from the Stunting Exemplars86 country case studies, that evaluate ecological models of drivers of stunting reduction in countries which
have demonstrated outsized progress compared to economic development. Stunting Exemplars employs a mixed-methods approach using
advanced quantitative (ie, multivariable analyses of drivers of change in linear growth) and qualitative methods, including interviews, focus group

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 discussions, a policy/program review, and a nutrition financing analysis, to determine what worked in model countries. Decomposition analysis
from 11 Exemplar countries and four Indian states with low background rates of safe water and improved sanitation suggest that up to 17% of
stunting reduction could be attributed to WASH strategies.12

While not discussed in detail here, the Stunting Exemplars work has highlighted several other key drivers of improved undernutrition that are
categorized as indirect interventions outside of the health sector.12 Along with WASH, these broadly include investments in girls’ education, female
empowerment, agriculture, and social safety nets to reach marginalized populations. Across phase I Exemplar countries (Nepal, Peru, Kyrgyz
Republic, Senegal, and Ethiopia) and despite differing country contexts, it was noted that approximately half of all contributions to improved child
HAZ were derived from actions taken outside the health sector,12 underscoring the need for multisectoral nutrition action and coordination. Phase
II Stunting Exemplars is underway, where a subnational lens will be taken to understand the drivers of and barriers to stunting decline at the
regional level.

Panel S2: Comparison of current findings with previous reviews based on eligibility criteria.
The eligibility criteria for the new set of systematic reviews conducted differed from that of previously reported reviews, which also included
studies from high-income settings, at-risk populations or populations with pre-existing conditions, and generally had no date restriction for study
publication. To illustrate, for maternal calcium supplementation, the number of studies reviewed was reduced due to exclusion of studies from
HICs and among women at risk of hypertensive disorders of pregnancy. Our newly reported estimate, therefore, is more representative of the
general population in LMICs. Similarly, for zinc supplementation among children, several studies (10+) were excluded on the basis of their
recruitment of “unhealthy” children (e.g., children who were born SGA or LBW, or were stunted, malnourished, or anemic at baseline). However,
given the prevalence of these conditions in LMICs, excluding studies on this basis for analyses of zinc supplementation (which is thought to
promote growth) may not be appropriate, and our sensitivity analysis does show a protective benefit of zinc for growth among nutritionally
vulnerable children. In contrast, the sensitivity analysis conducted for VAS may highlight changing epidemiology and contexts, whereby more
recent trials show relatively less impact on mortality due to reduced deaths from other causes (e.g. measles, diarrhea, etc.). Alternatively, some
of the more recent trials were conducted in areas with lower prevalence of vitamin A deficiency at baseline. Despite these nuances, we continue
to recommend both zinc and VAS in vulnerable populations, with the possible use of SQ-LNS as a modality for delivering zinc, iron and other
essential micronutrients.

Panel S3: Methodological considerations of our findings.

Our review differed methodologically from previous exercises. Given the high statistical heterogeneity in many studies due to variability in
clinical contexts and methodologically diverse studies included, we have mainly used random effects models indicative of the average
intervention effect as opposed to the best estimate of the intervention effect. We have thus been cautious in our interpretation of effect where
heterogeneity was high and the effect was small, and also in excluding low quality studies. Context is exceptionally important when interpreting
trial data and overall, there is too little data collected within trials (e.g. micronutrient status) and little use of what is available (e.g. in individual
participant data meta-analyses) such that there becomes a risk in aggregating results.

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