nutrients

Review
Impact of Infant and Young Child Feeding (IYCF)
Nutrition Interventions on Breastfeeding Practices,
Growth and Mortality in Low- and Middle-Income
Countries: Systematic Review
Zohra S. Lassi 1, *, Fahad Rind 2 , Omar Irfan 3 , Rabia Hadi 4 , Jai K. Das 4 and
Zulfiqar A. Bhutta 2,3
1 Robinson Research Institute, University of Adelaide, Adelaide 5005, Australia
2 Division of Women and Child Health, Aga Khan University Hospital, Karachi 74800, Pakistan;
[email protected] (F.R.); [email protected] (Z.A.B.)
3 Centre for Global Child Health, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada;
[email protected]
4 Center of Excellence in Women and Child Health, The Aga Khan University, Karachi 74800, Pakistan;
[email protected] (R.H.); [email protected] (J.K.D.)
* Correspondence: [email protected]; Tel.: +61-405-332-094




Received: 8 January 2020; Accepted: 4 March 2020; Published: 10 March 2020


Abstract: Undernutrition is associated with 45% of total infant deaths, totalling 2.7 million globally per
year. The vast majority of the burden is felt in low- and middle-income countries (LMICs). This review
aims to assess the effectiveness of infant and young child feeding (IYCF) interventions. We searched
multiple databases including Cochrane Controlled Trials Register (CENTRAL), MEDLINE, EMBASE.
Title/abstract screening and full-text screening and data extraction filtered 77 studies for inclusion.
Breastfeeding education interventions (n = 38) showed 20% increase in rates of early initiation of
breastfeeding, 102% increase in exclusive breastfeeding (EBF) at 3 months and 53% increase in EBF at
6 months and 24% decreases in diarrheal diseases. Complementary feeding education intervention
(n=12) showed a 0.41 standard deviation (SD) increase in WAZ, and 0.25 SD in HAZ in food secure
setting. Complementary food provision with or without education (n=17) showed a 0.14 SD increase
in HAZ and 36% decrease in stunting. Supplementary food interventions (n=12) showed a significant
0.15 SD increase in WHZ. Subgroup analyses showed healthcare professional led interventions were
largely more effective, especially on breastfeeding outcomes. We believe this is a comprehensive
review of the existing literature on IYCF studies in LMICs. Though breastfeeding education is well
supported in its effectiveness on breastfeeding practices, limited evidence exists for growth outcomes.
Supplementation interventions seem to have better effects at improving growth. However, more
research is required to reach more substantial conclusions.

Keywords: breastfeeding; infants; growth; mortality; LMIC; young child; complementary feeding;
supplementary feeding; malnutrition

1. Introduction
Undernutrition is associated with 2.7 million child deaths worldwide which makes up 45% of all
infant mortality, according to the World Health Organization [1]. Lower- and middle-income countries
(LMICs) take the overwhelming brunt of the tragedy, accounting for 99% of such instances of infant
mortality in Sub-Saharan Africa and South Asia [1]. It is estimated that 250 million children under
the age of five are at risk of sub-optimal development and stunting [1]. Infant malnutrition has been

Nutrients 2020, 12, 722; doi:10.3390/nu12030722 www.mdpi.com/journal/nutrients

Nutrients 2020, 12, 722 2 of 21

associated with increased severity and frequency of infections, raising energy requirements, while
reducing appetite and nutrition absorption [2]. This is ultimately increasing the risk of death [3].
Another effect of malnutrition is cognitive development which can affect school performance and has
negative effects on long term careers [3]. The cognitive development has been known to have economic
effects linked to productivity and gross domestic product (GDP) of the country. Stunting has been
linked to cognitive delays and increased mortality [4], while wasting contributes to stunting itself [5].
Acute malnutrition is estimated to affect 51.5 million children under five years, contributing to 12.6%
of under-five mortality worldwide [6]. Severe acute malnutrition (SAM) is defined as a weight-for-height
at −3 Z-scores of median WHO growth standards with visible severe wasting and/or presence of
nutritional edema [1]. Moderate acute malnutrition (MAM) is defined as a less severe form for SAM,
weight-for-height between −2 and −3 Z-scores of median WHO growth standards [1]. In 2011, 16% of
infants had a weight-for-age Z-scores (WAZ) below −2 Z-score [7].
Breastfeeding and complementary foods make up most of the nutrition in early life. Breastfeeding
has been proven to be the most optimal nutrition for infants. This is due to immunologic, hormonal
and growth advantages which make for a protective and optimal nutrition for a child [8]. Immunologic
protection is provided by antibodies present in the breast milk [8] which can promote quick recovery
from illness [9]. Oligosaccharides inhibit the binding of pathogens and toxins to host receptors, thus
preventing infection [10]. In addition to the obvious benefit of immediate energy, breast milk has been
shown to improve neurodevelopment, namely improve cognition [8]. The participating women also
benefit from reduced rates of ovarian and breast cancer and diabetes due to breastfeeding [11,12]. It is,
therefore, very evident, that breastfeeding is almost essential for maternal and infant health benefits.
Physiologically, breast milk can only provide nutrition till a certain age at which point the infants’
diet requires the addition of solid food. This point comes at six months age. It then becomes necessary
to increase the nutrient intake to ensure optimal growth and development. It is important to note that
early nutrition can have irreparable consequences as after the age of two, stunting and other growth
deficiencies can be very difficult to reverse [13]. Currently, the rates of continued breastfeeding drop from
74% at 12 months to 46% at 24 months of age [14]. One third of children aged 4 to 5 months are incorrectly
already on complementary feeding while conversely one fifth of 10–11-month-olds are exclusively on
breastfeeding. Additionally, it was found that nearly one third of children ages 6–23 months were
receiving a minimally diverse diet [14]. This outlines the importance and need of providing infants with
required nutrition through proper complementary feeding practices. Complementary foods can include
lipid-based, ready-to-use therapeutic foods, grain and starchy foods, meat, fish, vegetables, eggs and
even some traditional foods such as khichuri which is a rich mix of lentils, rice and vegetables in the
subcontinent. Well-known supplementary foods include the Plumpy’doz, rice and lentil packages and
wheat soy blends [15]. Such forms of supplementation can be particularly important and even necessary
in LMICs where monetary impossibilities can impede nutritional potential.
A holistic review of the infant and young child feeding (IYCF) interventions would be valuable as
most reviews are limited to a single study design type, setting, socioeconomic setting, single interventions,
timing and duration of interventions etc. This systematic review could potentially play a large role in
policy-making to maximally improve IYCF outcomes. As a result, this review aims to systematically
review the current evidence body on the effectiveness of IYCF interventions and programs and their
effect on breastfeeding and nutritional outcomes.
In addition, this review aims to study the effectiveness of IYCF interventions on good breastfeeding
practice and growth outcomes.

2. Materials and Methods

The original protocol for this systematic review was published on 30 December 2018 [16].
Nutrients 2020, 12, 722 3 of 21

2.1. Objectives
The overall objectives are to assess the effectiveness of the following on child health and nutritional
status:

• Interventions to promote early and exclusive breastfeeding;

• Interventions to promote continued breastfeeding;
• Interventions to promote appropriate complementary feeding (education or provision of
complementary food) during infancy and childhood;
• Effectiveness of community-based interventions to prevent moderate and severe acute malnutrition.

2.1.1. Types of Studies and Participants

We included primary studies, including large-scale program evaluations to assess the efficacy
and/or effectiveness of interventions. We included randomized controlled trials (RCTs) randomized at
the individual or cluster level (i.e., in cluster randomized controlled trial), cross-over study designs.
We also included non-randomized studies such as quasi-experimental designs, including controlled
before-after studies (CBA), interrupted time series (ITS) studies, natural experiments and regression
discontinuity designs. Non-controlled pre-post studies were not included.

2.1.2. Types of Participants

Our target population of study was mothers/nursing mothers of children under 2 years of age living
in lower middle-income countries (LMICs) of reproductive age, regardless of comorbid and general
health status. Participants could be pregnant while interventions were applied. We also included studies
in which only a portion of the study sample fit our inclusion criteria, provided they were compared
independently to a control group and analyzed independently. Conversely, if arms of an included study
did not fit our inclusion criteria, those arms of interventions were not included in our analysis.

2.1.3. Types of Interventions

This review focused on the effects of the following interventions:

1. Interventions designed to promote early initiation, exclusive and continued breastfeeding, such as
education and support of early and exclusive breastfeeding practices.
2. Interventions to promote dietary diversification and appropriate complementary feeding. These
will be divided in interventions that provide only education and interventions in which the
provision of complementary food for healthy individuals takes place regardless of education.
3. Interventions to prevent moderate and severe acute malnutrition, such as educative interventions
and supplementary food for children suffering from MAM or SAM.

Interventions were supervised by healthcare professionals, community health workers and through
telephone network platforms e.g., text messages, phone apps. Interventions were compared to control
groups receiving no interventions or standard of care.

2.1.4. Types of Outcome Measures

Primary outcomes: Early initiation of breastfeeding (within an hour of birth), exclusive breastfeeding
(EBF) at 3 and 6 months of age, infant growth (weight gain (kg), height gain (cm), Z-scores for
height-for-age (HAZ), weight-for-age (WAZ), weight-for-height (WHZ), stunting (HAZ < 2), wasting
(WAZ < 2), underweight (WHZ < 2)). Our secondary outcomes included neonatal mortality (death
from all causes within a month of birth per total live births), infant mortality (death from all causes
within 12 months of age per total live births), neonatal sepsis (the proportion of neonates dying due to
possible serious bacterial infections among all neonates), incidence of acute respiratory infections (ARI),
incidence of diarrheal illness, any adverse events including gastrointestinal symptoms, non-compliance or
Nutrients 2020, 12, 722 4 of 21

decreased feeding, cost-effectiveness of the intervention (reported in narrative text) and the psychosocial
health of the infant (different scales for psychomotor development, cognitive development, attention,
memory, language).
Studies were excluded if they did not report any of the outlined outcomes.

2.2. Literature Search

The literature review was conducted on the following databases: Cochrane Controlled Trials Register
(CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, ERIC, Sociofiles, HMIS (Health Management
Information Consortium), CAB Global Health (https://www.cabi.org/publishing-products/online-
information-resources/global-health/), the WHO nutrition databases (http://www.who.int/nutrition/
databases/en/), Popline (https://www.popline.org), Epistemonikos (https://www.epistemonikos.org/en/),
Social Science Citation Index, Dissertation Abstracts International, and WHO Global Health Index which
covers the WHO Regional journals from Latin America (LILACS), Africa (AFRO) etc. We also searched
the web sites of selected development agencies or research firms (for example, JOLIS, IDEAS, IFPRI,
NBER, USAID, World Bank and Eldis.org). The trials registry Clinicaltrials.gov and WHO’s ICRTP were
searched for ongoing trials. Additionally, EPOC filters were used for quantitative designs (EPOC 2017b).
Every effort was made to contact the relevant organization, institutions and experts for the
identification of unpublished and ongoing studies. Google Scholar and the Web of Sciences were
searched for citations and the references sections and annotated bibliographies were cross referenced
for bonus eligible studies.

2.3. Data Collection and Analysis

Data collection and analysis was conducted in accordance with the Cochrane Handbook for
Systematic Reviews of Interventions [17]. The selected literature was double screened at the title and
abstract level by two independent review authors. The resulting full-texts were similarly double-screened
by two independent authors with reasons recorded for exclusions. Disagreements were resolved by the
consultation of a third senior review author. Duplicates were excluded. Multiple reports of the same
study were collated to ensure each study was the unit of interest in this review. The selection process was
recorded sufficient to construct a Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) flow diagram (see Figure 1) [18].
Two independent review authors extracted data on data extraction sheets on Microsoft Excel.
Independent data extraction sheets were matched, and disagreements were resolved by discussion
and third senior review author was consulted, if the need arose. We used a piloted data collection form
for study characteristics and outcome data. If any information from the study was unclear or missing
or could not be from the publications, the authors were contacted for further clarification.
Data was exported and analyzed on RevMan v5.3. Risk ratios (RR) were used for dichotomous
outcomes, mean differences (MD) were calculated for continuous outcomes and standard mean
differences were calculated for continuous outcomes reporting the same outcome but measured on
a different scale within the same meta-analysis. A 95% confidence interval was used for all estimates
of effect. We analyzed outcomes from studies with multiple groups in an appropriate way to avoid
double counting of participants by adding them as an appropriately duplicated entry with an added
footnote specifying the differences between groups.
 abstract level by two independent review authors. The resulting full-texts were similarly double-
screened by two independent authors with reasons recorded for exclusions. Disagreements were
resolved by the consultation of a third senior review author. Duplicates were excluded. Multiple
reports of the same study were collated to ensure each study was the unit of interest in this review.
The selection
Nutrients 2020, 12,process
722 was recorded sufficient to construct a Preferred Reporting Items for Systematic
5 of 21
Reviews and Meta-Analyses (PRISMA) flow diagram (see Figure 1) [18].

Figure 1. Search flow chart displaying the number of reports screened and then finally included in the
review. n = number of studies.

2.3.1. Assessment of Risk of Bias in Included Studies

Two review authors independently assessed the risk of bias of randomized controlled trials using
the Cochrane Collaboration Risk of Bias tool [17] for selection bias, performance bias, attrition bias,
reporting bias and other sources of bias. The risk of bias was rated either “high”, “low” or “unclear”.
For non-randomized controlled trials, controlled before-after studies and interrupted time series,
we used EPOC methods (EPOC 2017a) to assess the risk of bias according to the following domains:
random sequence generation, allocation concealment, baseline outcome measurements, baseline
characteristic, incomplete outcomes, knowledge of allocated interventions adequately prevented
during the study, protection against contamination, selective outcome reporting and other sources of
bias. The risk of bias was rated either “high”, “low” or “unclear”.

2.3.2. Assessment of Quality Evidence

A “Summary of Findings” table was constructed for all primary outcomes using the Grading of
Recommendations Assessment, Development and Evaluation (GRADE) criteria [19] which involves
consideration of within-study risk of bias (methodological quality), directness of evidence, heterogeneity,
precision of effect estimates and risk of publication bias. The tool then rated quality of evidence as “high”,
“moderate”, “low” and “very low”. Observational studies stood to be upgraded if they exhibited a large
magnitude of effect, dose-response relationships and/or effect of plausible residual confounding as they
begin at a “low” level of quality of evidence.
Breastfeeding education interventions had the following outcomes GRADEd: rates of early
initiation of breastfeeding (within an hour of birth), rates of exclusive breastfeeding (at 3 and 6 months
of age) and rates of continued breastfeeding (at 12, 18 and 24 months)
Complementary feeding education and provision studies and supplementary feeding interventions
had the following outcomes GRADEd: mean Z-score for height-for-age, mean Z score for weight-for-height,
mean Z score for weight-for-age, stunting, wasting, underweight.
Nutrients 2020, 12, 722 6 of 21

2.3.3. Subgroup Analysis, Investigation of Heterogeneity and Sensitivity Analysis

We conducted the following subgroup analyses where there were at least three studies in each
sub-group, in adherence with Cochrane collaboration recommendations. Subgroups were divided by
setting (home-based, facility-based or community-based), timing of intervention (prenatal, postnatal
or a combination), duration of intervention (less than or equal to six months or greater than six
months), observer (self-reported or clinically observed outcomes), moderators (community health
worker (CHW)/volunteers or healthcare professionals) and by training of personnel (with WHO or
United Nations International Children’s Education Fund (UNICEF) materials or from other sources)
for breastfeeding education studies. Complementary feeding and supplementary feeding studies
were subgroup analyzed by the level of food security of their settings using information available in
the full texts of the articles. Sensitivity analyses were also performed to consider the impact of the
following: high risk of bias in allocation concealment methodology, high risk of attrition bias due to
lost participants and differences in outcomes due to different methods of calculating cluster adjustment

3. Results

3.1. Study Selection

We identified 4151 records from the search of multiple databases. After title and abstract screening and
removal of duplicates, 131 studies were selected for full text screening. After full-text screening, 69 studies
were excluded, and 77 studies were accepted for inclusion in the review. Four articles were also added
from cross referencing of included studies. Of the 77 studies [20–97], 38 were on breastfeeding education
interventions [21–27,29,32,33,37–39,42,44,49,51,53,54,56–58,63,65–68,70,73,75,81,83,87,88,91,93,94], 28 were
on complementary feeding [20,28,30,31,34,43,46,48,55,60–62,64,69,71,72,74,76–80,82,85,92,93,95,96] and 12
investigated supplementary feeding interventions. The last search was carried out on 15 April 2019.
The included studies consisted of 44 individually randomized trials [20–25,29,30,32,33,35,39,40,42,
45,48,51,54,56,58,59,62–64,66,69–72,75–77,79,81,85–89,91–93,95,96], 22 cluster randomized trials [26–28,
31,34,37,38,41,43,44,46,47,49,50,53,55,57,65,67,73,74,80,82–84] and five quasi-experimental studies [52,61,
68,90,94]. One study consisted of two parts, a longitudinal study and a randomized controlled trial [60].
One study was a non-randomized controlled trial [78]. (see Tables S1–S9 in Supplementary Data)
Seventy-one studies published between 1980 and 2019 involving 739, 343 participants met the inclusion
criteria for this review (see Table S6: Characteristics of included studies in Supplementary Data 1). Outcome
analysis data were contributed by 75 studies [20–35,37–51,53–96]. There were 26 studies [21,22,24–26,32–35,
39,42,51,54,58,63,72,75,76,79,81,84,86–88,93,95] which were conducted in health care settings, whereas 51 [20,
23,27–31,36–38,40,41,43–50,52,53,55–57,59–62,64–71,73,74,77,78,80,82,83,85,89–92,94,96] were conducted in
home or community settings.

3.2. Comparison 1: Breastfeeding Education Interventions vs. Control

We included a total of 38 studies [21–27,29,32,33,37–39,42,44,49,51,53,54,56–58,63,65–68,70,73,75,
81,83,86–88,91,94,95] as a part of the breastfeeding education comparison (see Table 1).
The breastfeeding education studies were con4ducted in a wide range of countries spanning four
continents, i.e., twelve studies in Africa; one in Egypt [22]; two in Ghana [23,57]; two in Uganda [37,63];
one in Nigeria [38]; two in Tanzania [44,73]; two in Kenya [56,70]; one in South Africa [49]; one study
in three countries of Africa [92]; Burkina Faso, Uganda and South Africa. Twenty-four studies were
conducted in Asia; six in Bangladesh [26,27,51,53,89,95]; three in India [29,65,67]; one in Nepal [32];
two in Iran [39,75]; one in China [42]; one in Jordan [54]; one in Thailand [58]; one in Pakistan [83]; one
in Malaysia [87]; two in Turkey [24,33]; one in Philippines [21]. One study was conducted in North
America; in Mexico [66] and five in South America; in Brazil [25,68,81,86,93].
Nutrients 2020, 12, 722 7 of 21

Table 1. Estimates of effect of the interventions and outcomes.

Outcomes MD RR 95% CI n No. of Studies GRADE p-Value

Breastfeeding Education Interventions
Early initiation of
1.20 1.12 to 1.28 84092 14 LOW <0.001
breastfeeding
EBF @ 3 months 2.02 1.88 to 2.17 4063 6 VERY-LOW <0.001
EBF @ 6 months 1.53 1.47 to 1.58 13926 19 VERY-LOW <0.001
HAZ 0.10 −0.04 to 0.25 5620 6 - 0.17
WAZ −0.04 −0.12 to 0.05 4565 3 - 0.42
WHZ 0.01 −0.07 to 0.09 4514 3 - 0.83
stunting 1.00 0.88 to 1.14 6518 6 - 0.99
Underweight 1.31 0.79 to 2.16 3448 3 - 0.30
WAWasting 0.94 0.86 to 1.03 3925 2 - 0.19
Neonatal mortality
1.10 0.90 to 1.24 22752 2 - 0.35
(%)
Infant mortality (%) 0.86 0.73 to 1.02 35943 2 - 0.08
Diarrheal disease 0.76 0.67 to 0.85 4585 8 - <0.001
Incidence of
1.96 0.65 to 5.93 1831 3 - 0.23
infection
Complementary Feeding Education—Food Secure Settings
WAZ 0.41 0.07 to 0.75 1562 F4 HIGH 0.02
HAZ 0.29 0.04 to 0.54 1560 4 MODERATE 0.03
WHZ 0.22 −0.03 to 0.47 1065 3 MODERATE 0.08
Stunting 0.50 0.18 to 1.40 1006 3 LOW 0.19
Wasting 0.19 0.03 to 1.18 665 2 MODERATE 0.07
Weight gain (kg) 0.12 −0.12 to 0.37 894 2 MODERATE 0.33
Height gain (cm) 0.33 −0.46 to 1.12 894 2 LOW 0.42
Complementary Feeding Education—Food Insecure Settings
WAZ 0.47 0.35 to 0.59 572 1 LOW <0.001
HAZ 0.25 0.09 to 0.41 572 1 HIGH 0.002
WHZ 0.50 0.35 to 0.65 572 1 HIGH <0.001
Stunting 0.65 0.42 to 1.01 1476 3 LOW 0.05
Wasting 1.05 0.15 to 7.26 178 1 MODERATE 0.07
Weight gain (kg) 0.01 −0.07 to 0.08 1213 2 LOW 0.33
Height gain (cm) −0.09 −0.30 to 0.12 1214 2 LOW 0.42
Complementary Feed Provision Interventions—Food Secure Settings
WAZ −0.09 −0.34 to 0.16 172 1 LOW 0.48
HAZ −0.12 −0.46 to 0.22 172 1 LOW 0.49
WHZ −0.03 −0.28 to 0.22 172 1 LOW 0.81
Stunting 0.47 0.37 to 0.59 2896 1 HIGH <0.001
Weight gain (kg) −0.01 −0.24 to 0.22 172 1 LOW 0.93
Height gain (cm) −0.23 −1.11 to 0.65 172 1 LOW 0.61
Complementary Feed Provision Interventions—Food Insecure Settings
WAZ 0.34 −0.35 to 1.03 3570 10 VERY-LOW 0.33
HAZ 0.14 0.04 to 0.24 8996 12 LOW 0.005
WHZ 0.01 −0.01 to 0.03 8197 10 LOW 0.27
Stunting 0.64 0.44 to 0.92 7894 7 LOW 0.02
Wasting 0.87 0.74 to 1.01 7081 6 MODERATE 0.07
Weight gain (kg) 0.62 −0.02 to 1.26 986 3 VERY-LOW 0.06
Height gain (cm) 0.17 −0.11 to 0.44 924 3 MODERATE 0.24
Nutrients 2020, 12, 722 8 of 21

Table 1. Cont.

Outcomes MD RR 95% CI n No. of Studies GRADE p-Value

Supplementary Feeding Interventions
HAZ 0.11 −0.03 to 0.24 3724 6 LOW 0.13
WAZ 0.20 −0.12 to 0.52 711 5 VERY-LOW 0.23
WHZ 0.15 0.08 to 0.22 3664 6 MODERATE <10−5
Stunting 1.31 0.95 to 1.81 1512 4 LOW 0.10
Wasting 0.80 0.55 to 1.17 4299 4 LOW 0.25
Infant mortality
0.61 0.38 to 0.97 4757 2 HIGH 0.04
(%)
Weight gain (kg) 0.06 −0.01 to 0.12 845 5 LOW 0.08
Height gain (cm) 0.13 −0.03 to 0.35 832 5 LOW 0.11
Significant effect considered at p < 0.05. MD = mean difference. RR = risk ratio. HAZ = height-for-age z-scores.
WAZ = weight-for-age z-scores. WHZ = weight-for-height z-scores. HAZ < 2 = stunting. WAZ < 2 = wasting. WHZ
< 2 = underweight. EBF: exclusive breastfeeding. significant estimates are in BOLD.

The minimum population size was 60 infant mother pairs in Ahmed et al. [22] and the maximum
population size was 113,816 females in Baqui et al. [27]. The oldest average age among participants
was 30.75 months in Younes et al. [94]. The timing of the intervention was prenatal in four studies;
postnatal in 17 studies; and both prenatal and postnatal in 17 studies. In 21 studies, the intervention
was provided by community health workers. In 10 studies, intervention was provided by health care
professionals and 8 studies had study investigators as the providers respectively. Twelve studies’
training was sourced from WHO materials. Thirteen studies detailed training which was not based
on WHO authored resources. The duration of training varied greatly from a minimum of two days
in Arifeen et al. [26] and Sikander et al. [84] to a maximum of nine to 14 days in Nair et al. [67].
The training details are expanded in Table S6 (see Supplementary Data S1). The training methods were
not specified in 13 studies, thus, they could not be included in the training/timing of training subgroup
analyses. The risk of bias by study is enumerated in Figure 2.
Breastfeeding intervention may have caused a 20% increase in the prevalence of early initiation of
breastfeeding, as reported by 14 studies [24,25,27,33,38,44,49,51,57,63,73,75,88]. Sensitivity analysis for high risk
allocation concealment showed a 20% increase (RR 1.20, 95% CI 1.11 to 1.29; 10 studies; 83,565 participants) as ten
studies remained [25,27,38,44,49,57,63,73,88]. Sensitivity analysis for attrition bias caused a 20% increase (RR 1.20,
95% CI 1.11 to 1.29; 12 studies; 83,868 participants) due the removal of two studies [25,33]. Subgroup analysis
by setting showed facility-based [24,25,27,33,51,63,75,88] and community-based [38,49,57,73,83] had significant
effects without significant heterogeneity between subgroups. Subgroup analysis by timing of intervention
showed postnatal [24,25,88] and prenatal/postnatal interventions [27,33,44,49,57,73,75,83] both had a significant
effect, whereas prenatal interventions [38,51,63] had no effect on early initiation of breastfeeding. Subgroup
analysis by duration of intervention showed interventions lasting less than six months [24,25,33,49,63,75,88]
had a significant effect, whereas interventions lasting more than six months [27,38,44,51,57,73,83] had no
effect. Subgroup analysis by moderators showed CHW/volunteers [24,27,38,44,49,57,63,73,83] and healthcare
professionals [25,33,51,75,88] as moderators both had significant effects. Subgroup analysis by the content
of training moderators received showed training from other resources [27,44,51,57,63,73,83] had a significant
effect while WHO/UNICEF resources [24,25,49] training did not.
We are unsure of the 102% increase reported in rates of EBF at three months, due to the very
low-quality of evidence found by GRADE analysis [22,29,39,42,66,91]. Sensitivity analysis for allocation
concealment removed five studies [22,39,42,66,91] and had a 65% increase (RR 1.65, 95% CI 1.48 to 1.84;
one study; 895 participants) on EBF at three months. Similarly, sensitivity analysis by attrition bias
removed one study [29] and showed a 123% increase in EBF at three months. Subgroup analysis by
setting showed interventions conducted in facilities [22,39,42] and community settings [29,66,92] both
had significant effects. Subgroup analysis by duration of intervention showed intervention lasting less
than six months and those lasting more than six months both had a significant effect on the rate of EBF
at three months.
Nutrients 2020, 12, 722 9 of 21

Nutrients 2020, 12, x FOR PEER REVIEW 8 of 20

Figure2.2.Traffic
Figure Trafficlight
lightplots
plots presenting
presenting thethe
riskrisk of bias
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in studies. RedRed circles
circles represent
represent a higha high
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dots represent a lowarisk
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and yellow dots represent
dots represent an unclear
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We are unsure of
Breastfeeding the 53% increase
intervention may havein breastfeeding
caused a 20% interventions
increase in thehad on the rates
prevalence of EBF
of early at six
initiation
months due to the very low-quality of evidence (see Figure 3) [21,23–26,29,32,38,42,54,56,58,70,83,86,87,
of breastfeeding, as reported by 14 studies [24,25,27,33,38,44,49,51,57,63,73,75,88]. Sensitivity analysis
91,93,94]. Sensitivity
for high risk analysis
allocation for high showed
concealment risk allocation
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83,565 a 37% increaseas (RR
ten 1.37 95% remained
studies CI 1.32 to 1.42; 14 studies; 10,527 participants;
[25,27,38,44,49,57,63,73,88]. Heterogeneity:
Sensitivity analysis for
Chi 2 p < 0.00001; I2 = 91%) rates of breastfeeding at six months. Similarly, sensitivity analysis for
attrition bias caused a 20% increase (RR 1.20, 95% CI 1.11 to 1.29; 12 studies; 83,868 participants) due
attrition bias removed
the removal of twofive studies[25,33].
studies [25,29,32,54,70]
Subgroup andanalysis
had a 47% byincrease
setting(RR 1.47, 95%
showed CI 1.42 to
facility-based
1.52;
[24,25,27,33,51,63,75,88] and community-based [38,49,57,73,83] had significant effects showed
14 studies; 11966 participants) in EBF at six months. Subgroup analysis for setting without
facility [21,24–26,32,42,54,58,86,87,93]
significant and community-based
heterogeneity between subgroups. Subgroup analysis [23,29,38,56,70,83,91,94] interventions
by timing of intervention showed
postnatal [24,25,88] and prenatal/postnatal interventions [27,33,44,49,57,73,75,83] both had a
significant effect, whereas prenatal interventions [38,51,63] had no effect on early initiation of
breastfeeding. Subgroup analysis by duration of intervention showed interventions lasting less than
six months [24,25,33,49,63,75,88] had a significant effect, whereas interventions lasting more than six
Nutrients 2020, 12, 722 10 of 21

both had significant effects. Subgroup analysis by timing of intervention showed postnatal [21,24–26,32,
42,54,56,86,87,93,94] and prenatal/postnatal interventions [23,58,70,83,91] both had significant 10
Nutrients 2020, 12, x FOR PEER REVIEW
effects.
of 20

Figure 3. Forest plot displaying the meta-analysis of studies reporting on the effect of
of breastfeeding
breastfeeding
of exclusive
education interventions of the rate of exclusive breastfeeding
breastfeeding at
at six
six months.
months.

Breastfeeding
Breastfeeding interventions
education hadhad no decrease
a 24% effect onon HAZ, as reported
the rates by six
of diarrhea asstudies
reported [26,37,53,67,68,81].
by eight studies
When filtering studies for risk of biased allocation concealment, three
[21,26,29,39,66,68,89,95]. Sensitivity analysis for high risk of selection bias removedstudies remained [26,37,67], which
four studies
suggested
[39,66,68,94] a 0.17
andstandard deviation
indicated a 24% increase (MD (RR
decrease 0.17, 95%
0.76,CI95%
0.04 to
CI0.30;
0.67three
to studies;
0.85; four3380studies;
participants).
1613
Similarly, sensitivity analysis for attrition bias left two studies [26,67], indicating a 0.21
participants). Sensitivity analysis by attrition bias removed two studies and indicated a 29% decrease standard deviation
increase
(RR 0.71,(MD 95%0.21. 95%toCI
CI 0.63 0.10six
0.81; to studies;
0.31, two1863
studies, 2917 participants).
participants) in diarrhealSubgroup
diseases.analysis
Subgroup by timing of
analysis
intervention indicated both purely postnatal [26,37,81] and prenatal/postnatal
by setting showed community-based interventions [29,66,68,94] and facility-based interventions [53,67,68] had no effect.
Breastfeeding
[21,26,39,89] interventions
both prevented had disease
diarrheal no effect byon WAZmagnitudes.
similar [37,53,67], WHZ [26,53,67],
Subgroup analysisprevalence
by duration of
stunting [26,27,37,67,68,81],
of intervention wasting [26,67],
showed interventions lastingunderweight
less than six[27,37,67], neonatal mortality
months [21,66,88] and those[27,65],
lastingnor on
more
infant mortality [26,67]. Sensitivity analyses by high risk allocation
than six months [26,29,39,68,94] both had significant effects on diarrheal disease. concealment and attrition bias had
no effect on the results
Breastfeeding of WAZ,
education had stunting,
no effectwasting, infant mortality.
on the incidence of infection, as reported by three studies
Breastfeeding
[26,54,63]. Sensitivity education
analysis by had a 24% decrease
allocation concealment on the rates of diarrhea
methodology was not as reported
possible as allbystudies
eight
studies
were at a low risk of bias. However, sensitivity analysis for attrition bias removed one study [54]four
[21,26,29,39,66,68,89,95]. Sensitivity analysis for high risk of selection bias removed and
studies [39,66,68,94]
still showed no effect and
on theindicated
incidence a of
24% decrease (RR 0.76, 95% CI 0.67 to 0.85; four studies;
infections.
1613 participants). Sensitivity analysis by attrition bias removed two studies and indicated a 29%
decrease (RR 0.71,
3.3. Comparison 95% CI 0.63Feeding
2a: Complementary to 0.81; six studies; 1863 participants) in diarrheal diseases.
Education
Subgroup analysis by setting showed community-based interventions [29,66,68,94] and facility-based
We included 12 studies in the complementary feeding education comparisons
interventions [21,26,39,89] both prevented diarrheal disease by similar magnitudes. Subgroup analysis
[30,31,43,55,74,76,77,79,82,92,93,95].
by duration of intervention showed interventions lasting less than six months [21,66,88] and those
Five studies reported data on WAZ [43,74,76,79,95], HAZ [43,74,76,79,95] and WHZ
lasting more than six months [26,29,39,68,94] both had significant effects on diarrheal disease.
[74,76,79,95], six reported prevalence of stunting [30,31,43,74,77,92], three on the prevalence of
wasting [30,43,77] and four studies reported data on weight [30,31,79,82] and height gain
[30,31,79,82].
The complementary feeding education interventions spanned two continents. Asia housed nine
studies; three in India [30,31,92], two in China [43,82], two in Pakistan [77,95] and two in Bangladesh
Nutrients 2020, 12, 722 11 of 21

Breastfeeding education had no effect on the incidence of infection, as reported by three

studies [26,54,63]. Sensitivity analysis by allocation concealment methodology was not possible
as all studies were at a low risk of bias. However, sensitivity analysis for attrition bias removed one
study [54] and still showed no effect on the incidence of infections.

3.3. Comparison 2a: Complementary Feeding Education

We included 12 studies in the complementary feeding education comparisons [30,31,43,55,74,76,
77,79,82,92,93,95].
Five studies reported data on WAZ [43,74,76,79,95], HAZ [43,74,76,79,95] and WHZ [74,76,79,95],
six reported prevalence of stunting [30,31,43,74,77,92], three on the prevalence of wasting [30,43,77]
and four studies reported data on weight [30,31,79,82] and height gain [30,31,79,82].
The complementary feeding education interventions spanned two continents. Asia housed nine
studies; three in India [30,31,92], two in China [43,82], two in Pakistan [77,95] and two in Bangladesh [55,76].
Three studies were carried out in South America; two studies were carried out in Brazil [79,93] and one
in Peru [74].
The range of the populations was from 212 at its minimum [76] and 1025 at its maximum [31].
The ages of participants ranged from 37 weeks of gestation at the minimum to 15.45 months at the
maximum. There was also some variation in the intricacies of the interventions provided. The risk of
bias by study is enumerated in Figure 2.
Complementary feeding education interventions caused a 0.41 SD increase in WAZ in food secure
settings [43,74,79,95] and a 0.47 SD increase in food insecure settings [76] when compared with control
groups (see Table 1).
Complementary feeding interventions had a significant effect in HAZ in food secure
settings [43,74,79,95] and caused a 0.26 SD increase in food insecure settings [76] (see Table 1).
Complementary feeding education interventions had no significant effect on WHZ in food secure
settings [74,79,95] and a 0.50 SD increase in a food insecure setting [76] when compared with control
groups (see Table 1).
Complementary feeding education interventions caused a non-significant 50% decrease in
the prevalence of stunting in food secure settings [43,74,77] and a 35% decrease in food insecure
settings [30,31,92] when compared with control groups (see Table 1).

3.4. Comparison 2b: Complementary Feeding Provision with or without Education vs. Control
Seventeen trials were included that addressed the effect of complementary feed provision studies
regardless of the provision of education. HAZ was reported by 12 studies, WAZ was reported by
10 studies, WHZ was reported by 10 studies, stunting was reported by seven studies, wasting was
reported by five studies, weight was reported by four studies and height gain by three studies (see
Table 1).
The studies spanned three continents. Seven studies were conducted in Africa i.e., two in
Ghana [20,60], two in Malawi [62,85], and one each in Burkina Faso [46], Democratic Republic of
Congo [28], Nigeria [69] and South Africa [71]. Five studies were conducted in South America i.e., two
in Ecuador [48,61] and one each in Guatemala [64], Colombia [72] and Brazil [78]. Four studies were
conducted in Asia i.e., one each in India [30], Bangladesh [34], China [96] and Vietnam [80].
Complementary feeding provision had a significant effect on HAZ in food insecure
settings [20,28,34,46,48,61,62,69,71,72,80,85] but had no effect in a food secure setting [78] when
compared with control groups (see Table 1).
Complementary feeding provision had significant effects on the prevalence of stunting in food
secure [97] and food insecure settings [28,34,46,48,61,62,80] when compared with control groups (see
Table 1).
Nutrients 2020, 12, 722 12 of 21

3.5. Comparison 3: Supplementary Feeding Programs vs. Control

The studies spanned five continents. Africa housed five studies i.e., two in Niger [41,50], two in
Malawi [59,89], one in Kenya [90]. Two studies were conducted in Asia i.e., one in Indonesia [47] and
one in Vietnam [80]. Two studies were conducted in only North America in Jamaica [40,45]. One study
was conducted in only South America in Brazil [35] and Peru [36]. Simondon et al. [84] was conducted
in four different countries in Congo, Senegal, Bolivia and New Caledonia (i.e., Africa, Africa, South
America and Oceania, respectively).
The risk of bias by study is enumerated in Figure 2. Only 11 of the 13 supplementary feeding F
studies contributed to the meta-analysis [35,40,41,45,47,50,59,80,84,89,90].
There was no composite effect of supplementary feeding interventions on HAZ. Supplementary
feeding interventions had a significant effect on HAZ in a food secure setting [47] but had no significant
effect in food insecure settings [50,59,80,89,90] when compared to control groups (see Table 1).
Supplementary feeding interventions had a significant effect (MD 0.30; 95% CI 0.10 to 0.50;
one study; 113 participants) on WAZ in a food secure setting [47] but had no significant effect (MD 0.19;
95% CI −0.18 to 0.55; four studies; 598 participants) in food insecure settings [59,80,89,90] (see Table 1).
Supplementary feeding interventions had a significant composite effect (MD 0.15; 95% CI 0.08 to
0.22; six studies; 3664 participants; GRADE) on WHZ when compared with control groups. All included
studies were from food insecure settings [40,50,59,80,89,90] (see Table 1).
Supplementary feeding interventions had no significant composite effect (RR 1.31; 95% CI 0.95 to
1.81; four studies; 1512 participants) on the prevalence of stunting. Supplementary feeding similarly
had no effect in food secure (RR 1.29; 95% CI 0.88 to 1.89; three study; 1335 participants) [41,80,91] and
food insecure (RR 1.81; 95% CI 0.34 to 9.62; one study; 177 participants) settings [35] (see Table 1).
Supplementary feeding interventions had no significant composite effect (RR 0.80; 95% CI 0.55 to
1.17; four studies; 4299 participants) on the prevalence of wasting. All included studies were in food
insecure settings [41,50,80,90] (see Table 1).
Supplementary feeding interventions caused a significant decrease (RR 0.61; 95% CI 0.38 to
0.97; two studies; 4757 participants) in infant mortality rates when compared with control groups.
All included studies were conducted in food insecure settings [41,50] (see Table 1).
Supplementary feeding interventions had no significant composite effect (MD 0.06; 95% CI −0.01
to 0.12; five studies; 845 participants; GRADE) on weight gain when compared with control groups.
Similarly, no effect was seen in a food secure setting (MD −0.07; 95% CI −0.15 to 0.01; one study;
90 participants). However, food insecure settings saw a statistically significant 0.08 kg increase (MD
0.08; 95% CI 0.01 to 0.14; five studies; 755 participants) in mean weight gain (see Table 1).
Supplementary feeding intervention had no significant composite effect (MD 0.13; 95% CI −0.03 to
0.29; five studies; 832 participants) on mean height gain when compared with control groups. Similarly,
no effect was detected in food secure nor food insecure settings (see Table 1).

4. Discussion
This review includes 66 studies of which 38 studies contributed to breastfeeding education
comparisons, 17 studies contributed to complementary feed provision regardless of, 12 studies
contributed to complementary feeding education only and 13 studies contributed to supplementary
feeding comparisons. All primary outcomes were reported except for continued breastfeeding at 12
and 24 months of age. The included studies span 29 countries from four continents, all contributing to
a comprehensive review of evidence.
Breastfeeding intervention caused a 20% increase in rates of early initiation of breastfeeding,
a 102% increase in the rates of EBF at 3 months and 53% increase in EBF at six months. It was also
associated in a 24% decrease in diarrheal disease. Complementary feeding was associated in 0.12
SD increase in height-for-age Z-scores, a 13% decrease in stunting and 11% decrease in wasting.
Supplementary feeding caused a 39% decrease in the rates of infant mortality. Other outcomes did not
report significant associations.
Nutrients 2020, 12, 722 13 of 21

Subgroup analyses revealed information on the study characteristics that went into producing
significant results. Early initiation of breastfeeding was only supported by significant effects in facility-
and community-based interventions, postnatal or prenatal/postnatal CHW/volunteer or healthcare
professional led, interventions lasting more than six months, trained on other resources. Moreover,
strictly prenatal interventions and those lasting less than six months had no effect. That is to say
that the moderators’ profession and setting do not necessarily matter, but that the duration and
timing of intervention are more crucial points in study design aiming to maximize early initiation of
breastfeeding. It is worth mentioning that healthcare professional moderated interventions had double
the effectiveness of those moderated by CHW/volunteers.
Exclusive breastfeeding at 3 months of age was supported by significant effects in both community
and facility-based interventions. Of note, facility-based interventions were more than 3 times more
effective than the community-based interventions.
Exclusive breastfeeding at 6 months of age was supported by significant effects in all subgroups
allowing the conclusion that the outlined subgroups can all be utilized for significant improvements
in breastfeeding practices at 3 months. However, it was found that community-based interventions
delivered in prenatal and postnatal period for periods less than six months based on WHO/UNICEF
materials had more efficacious magnitudes of effect than their subgroup counterparts. This information
can be used to design a maximally effective intervention if the goal is maximizing EBF at 3 months.
Complementary feeding education had significant effects on WAZ and HAZ in all food security
settings. Complementary feeding education had significant effects on WHZ in only food insecure settings.
Complementary feed provision interventions had significant effects on HAZ in food insecure
settings and on stunting in food secure and insecure settings. Supplementary feeding interventions
had significant effects on HAZ and WAZ in food secure settings and on WHZ and infant mortality in
food insecure settings.
The quality of outcomes was determined with the GRADE method [35]. In breastfeeding education
interventions, early initiation of breastfeeding was graded low due to very serious inconsistencies, EBF
at 3 months was graded very low due to serious inconsistency and EBF at 6 months was graded very
low due to serious risk of bias and very serious inconsistency. Every effort was made to minimize the
sources of bias including independent screening and assessment of data.
Our findings appear to agree with other systematic reviews of the relevant literature.
Sinha et al. [97] reported a 66% increase in early initiation of breastfeeding in studies conducted
in LMICs. The same study also conducted subgroup analyses and found facility-based interventions
caused a 12% increase in early initiation of breastfeeding, which compare closely with the 18% increase
observed in our subgroup analyses. Sinha et al. [98] also found community-based interventions caused
an 86% increase in early initiation of breastfeeding which is significant but much larger than the 17%
increase found in our subgroup analyses. It should be noted that the subgroup analyses do not strictly
capture the effect of LMICs.
Rollins et al. [1,98] also had a significant 11% increase in rates of early breastfeeding which was in
agreement with our findings but to a smaller magnitude.
Balogun et al. [99] was also in agreement, finding a 22% increase in the rates of early breastfeeding.
Additionally, subgroup analyses performed by moderators showed healthcare professional led
interventions had a 43% increase in early initiation of breastfeeding. These results were significant and
in agreement with our subgroup analyses finding a 33% increase in healthcare professional moderated
interventions’ effect on early initiation of breastfeeding.
Rates of EBF at six months were reported in two systematic reviews [100,101]. Sinha’s review
found interventions in LMICs increased rates of EBF at six months by 69% [101]. This compares closely
as a significant effect with the 53% increase found in our meta-analysis. Additionally, Sinha et al.
conducted a subgroup analysis by setting which found facility-based interventions to have a significant
46% increase in EBF at six months [101]. This is again concordant with the 20% increase concluded by
our subgroup analysis.
Nutrients 2020, 12, 722 14 of 21

Kim et al. included an extensive review of subgroups very similar to ours, allowing for a rich
parallel comparison [97]. As a composite outcome, they found a 173% increase in the odds of EBF
at six months (compared to the 53% increase found in our meta-analysis) [97]. Subgroup analysis by
setting showed community-based interventions had a 177% increase in the odds of EBF at six months
(compared to the 90% increase found in our meta-analysis) [97]. Kim et al. also conducted a subgroup
analysis by timing of interventions and found prenatal interventions had no effect on EBF at six months,
postnatal interventions caused 165% increased odds and pre/postnatal interventions caused an 83%
increase [97]. Again, this is in agreement with our findings of prenatal interventions having no effect,
postnatal interventions causing an 89% increase and pre/postnatal interventions causing a 71% increase
in the rates of EBF at six months. Overall, wherever possible to draw a comparison, Kim et al.’s findings
seems to be qualitatively in agreement with our findings [97]. However, Kim et al.’s findings consist of
larger magnitudes of effect and are calculated as odd ratios [97].
Complementary feeding studies were divided into those providing only complementary feeding
education and those providing only complementary feeding provision. Arikpo et al. [102] were studying
only education interventions and reported no effects of interventions on the prevalence of stunting,
wasting and underweight. Similarly, our review found no effect of complementary feeding education on
stunting and wasting.
Lassi et al. [103] found significant effect of CF on HAZ and WAZ in food secure and food insecure
settings which matched the findings of our review. Lassi et al. also found significant reductions in
stunting in a food insecure setting, whereas our review included more studies but found no association
in both food insecure and food secure settings.
Supplementary feeding programs were extensively analyzed as subgroups in Kristjansson et al.’s
review [104]. This allowed for some comparison with RCT only outcomes of Kristjansson et al. [104]
since the composite results included a wide variety of study designs. Subgroup analysis by LMICs
showed there was no effect on WHZ and increases in weight gain (MD 0.12 kg), height gain (0.27 cm),
change in WAZ (MD 0.15) and height gain (MD 0.85). These results are in complete agreement with
the results of Kuusipalo et al. [59] as reviewed by us, as these outcomes were only reported by this
study. Other supplementary feeding studies in the literature were not comparable, as, for example,
Beaton et al. [105] focused on the effects of interval growth, Pollitt et al. [106] focused on the effect on
cognitive performance.
The updated and extensive nature of this review offers much utility to policy-making bodies in the
interest of maximizing resources for the betterment of infant nutrition. The present review offers such
utility in breastfeeding education and practice as well as for the provision of complementary nutrition
allowing for maximized growth and minimized states of malnutrition and disease. However, owing
to the exclusive inclusion of studies from LMICs, the data presented is not necessarily generalizable
outside of such socioeconomic settings.

5. Conclusions
We believe the present review provides a comprehensive review of the literature and has much to
contribute to the literature in the forms of extensive subgroup analyses. The updated and extensive
nature of this review offers much utility to policy-making bodies in the interest of maximizing resources
for the betterment of infant nutrition in LMICs. The present review offers much utility in breastfeeding
education and practice as well as for the provision of complementary nutrition allowing for maximized
growth and minimized states of malnutrition and disease in the socioeconomic settings of our interest.
The beneficial effects of breastfeeding interventions on future research in the area of supplementary
feeding would allow more robust meta-analyses as current data is largely inconclusive. Another point
of research could be investigating the cost effectiveness of such interventions as has been alluded to by
many of the included studies but only reported by two of the studies.

Supplementary Materials: The following are available online at http://www.mdpi.com/2072-6643/12/3/722/s1.

Table S1: Breastfeeding education meta-analyses; Table S2: Complementary feeding education and provision
Nutrients 2020, 12, 722 15 of 21

meta-analyses; Table S3: Supplementary feeding meta-analyses; Table S4: Single study outcomes; Table S5: Search
strategy; Table S6: Characteristics of included studies; Table S7: Summary of findings table of breastfeeding
education; Table S8: Summary of findings table of complementary feeding; Table S9: Summary of findings table of
supplementary feeding.
Author Contributions: Conceptualization, Z.S.L., J.K.D. and Z.A.B.; Methodology, Z.S.L., J.K.D. and Z.A.B.;
Software Review Manager v5.3, MS Excel, Validation, Z.S.L.; Formal analysis, F.R.; data extraction and Curation,
F.R., O.I. and R.H.; Writing—original draft preparation, F.R.; Writing—review and editing, F.R. and Z.S.L.;
Supervision, Z.S.L. and J.K.D.; Project administration, Z.S.L. All authors have read and agreed to the published
version of the manuscript.
Funding: Funding for this review came from a grant from the Bill & Melinda Gates Foundation to the Centre for
Global Child Health at The Hospital for Sick Children (Grant No. OPP1137750).
Conflicts of Interest: The authors declare no conflict of interest.

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