Evidence to Underpin Vitamin A Requirements and Upper Limits in Children Aged 0 to 48 Months - A Scoping Review

Abstract

Vitamin A deficiency is a major health risk for infants and children in low- and middle- income countries. This scoping review identified, quantified, and mapped research for use in updating nutrient requirements and upper limits for vitamin A in children aged 0 to 48 months, using health- based or modelling-based approaches. Structured searches were run on Medline, EMBASE, and Cochrane Central, from inception to 19 March 2021. Titles and abstracts were assessed independently in duplicate, as were 20% of full texts. Included studies were tabulated by question, methodology and date, with the most relevant data extracted and assessed for risk of bias. We found that the most recent health-based systematic reviews and trials assessed the effects of supplementation, though some addressed the effects of staple food fortification, complementary foods, biofortified maize or cassava, and fortified drinks, on health outcomes. Recent isotopic tracer studies and modelling approaches may help quantify the effects of bio-fortification, fortification, and food-based approaches for increasing vitamin A depots. A systematic review and several trials identified adverse events associated with higher vitamin A intakes, which should be useful for setting upper limits. We have generated and provided a database of relevant research. Full systematic reviews, based on this scoping review, are needed to answer specific questions to set vitamin A requirements and upper limits.

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Citation: Hooper, L.; Esio-Bassey, C.;
Brainard, J.; Fynn, J.; Jennings, A.;
Jones, N.; Tailor, B.V.; Abdelhamid,
A.; Coe, C.; Esgunoglu, L.; et al.
Evidence to Underpin Vitamin A
Requirements and Upper Limits in
Children Aged 0 to 48 Months: A
Scoping Review. Nutrients 2022,14,
407. https://doi.org/10.3390/
nu14030407
Academic Editor:
Begoña Olmedilla-Alonso
Received: 19 November 2021
Accepted: 10 January 2022
Published: 18 January 2022
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nutrients
Systematic Review
Evidence to Underpin Vitamin A Requirements and Upper
Limits in Children Aged 0 to 48 Months: A Scoping Review
Lee Hooper 1, * , Chizoba Esio-Bassey 1, Julii Brainard 1, Judith Fynn 1, Amy Jennings 1, Natalia Jones 2,
Bhavesh V. Tailor 1, Asmaa Abdelhamid 1, Calvin Coe 1, Latife Esgunoglu 1, Ciara Fallon 1,
Ernestina Gyamfi 1, Claire Hill 1, Stephanie Howard Wilsher 1, Nithin Narayanan 1, Titilopemi Oladosu 1,
Ellice Parkinson 3, Emma Prentice 1, Meysoon Qurashi 4, Luke Read 1, Harriet Getley 1, Fujian Song 1,
Ailsa A. Welch 1, Peter Aggett 5,† and Georg Lietz 6
1Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK;
c.nwabichie@uea.ac.uk (C.E.-B.); j.brainard@uea.ac.uk (J.B.); j.fynn@uea.ac.uk (J.F.);
amy.jennings@uea.ac.uk (A.J.); b.tailor@uea.ac.uk (B.V.T.); Asmaa.abdelhamid@uea.ac.uk (A.A.);
calvin.coe@uea.ac.uk (C.C.); l.esgunoglu@uea.ac.uk (L.E.); C.Fallon@uea.ac.uk (C.F.);
tinanana@hotmail.co.uk (E.G.); c.hill2@uea.ac.uk (C.H.); stephanie.howard@uea.ac.uk (S.H.W.);
n.narayanan@uea.ac.uk (N.N.); titi.oladosu@doctors.org.uk (T.O.); emma.prentice@uea.ac.uk or
emmaprentice557@outlook.com (E.P.); luke.read@uea.ac.uk (L.R.); harrietgetley@hotmail.co.uk (H.G.);
fujian.song@uea.ac.uk (F.S.); a.welch@uea.ac.uk (A.A.W.)
2
School of Environmental Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK;
n.jones@uea.ac.uk
3School of Health Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK;
ellice.parkinson@uea.ac.uk
4Department of Medicine, Luton and Dunstable Hospital NHS Foundation Trust, Lewsey Road,
Luton LU4 0DZ, UK; meysoon.qurashi2@nhs.net
5Lancashire School of Postgraduate Medicine and Health, University of Central Lancashire,
Preston PR1 2HE, UK; profpjaggett@aol.com
6Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
georg.lietz@ncl.ac.uk
*Correspondence: l.hooper@uea.ac.uk; Tel.: +44-1603-591268
† Retired Professor.
Abstract:
Vitamin A deficiency is a major health risk for infants and children in low- and middle-
income countries. This scoping review identified, quantified, and mapped research for use in updating
nutrient requirements and upper limits for vitamin A in children aged 0 to 48 months, using health-
based or modelling-based approaches. Structured searches were run on Medline, EMBASE, and
Cochrane Central, from inception to 19 March 2021. Titles and abstracts were assessed independently
in duplicate, as were 20% of full texts. Included studies were tabulated by question, methodology
and date, with the most relevant data extracted and assessed for risk of bias. We found that the most
recent health-based systematic reviews and trials assessed the effects of supplementation, though
some addressed the effects of staple food fortification, complementary foods, biofortified maize
or cassava, and fortified drinks, on health outcomes. Recent isotopic tracer studies and modelling
approaches may help quantify the effects of bio-fortification, fortification, and food-based approaches
for increasing vitamin A depots. A systematic review and several trials identified adverse events
associated with higher vitamin A intakes, which should be useful for setting upper limits. We have
generated and provide a database of relevant research. Full systematic reviews, based on this scoping
review, are needed to answer specific questions to set vitamin A requirements and upper limits.
Keywords:
scoping review; vitamin A; infant; child; carotenoids; upper limits; recommended dietary
allowances; nutritional requirements; retinol; World Health Organization
Nutrients 2022,14, 407. https://doi.org/10.3390/nu14030407 https://www.mdpi.com/journal/nutrients

Nutrients 2022,14, 407 2 of 18
1. Introduction
Vitamin A deficiency is a major health problem for many children in low- and middle-
income countries. While vitamin A deficiency prevalence has fallen from 39% of children
aged 6 to 59 months in low- and middle-income countries in 1991 to 29% in 2013, prevalence
remains high in sub-Saharan Africa (48%) and South Asia (44%) [
1
]. While deaths due to
deficiency have been reduced in areas with successful vitamin A programs, 2/3 of countries
have no vitamin A deficiency prevalence data from the past decade on which to base
nutrient guidelines [2].
A recent Cochrane systematic review [
3
] found that in populations at increased risk
of deficiency, oral vitamin A supplementation (using doses of 50,000 to 200,000 IU) in
children aged 6 months to 5 years reduced all-cause mortality (RR 0.88, 95% CI 0.83 to 0.93;
1,202,382 participants; high-quality evidence), mortality due to diarrhoea (RR 0.88, 95% CI
0.79 to 0.98; 1,098,538 participants; high-quality evidence), risk of diarrhoea (RR 0.85, 95%
CI 0.82 to 0.87; 15 studies; 77,946 participants; low-quality evidence) and risk of measles
(RR 0.50, 95% CI 0.37 to 0.67; 6 studies; 19,566 participants; moderate-quality evidence).
Another systematic review carried out an individual patient data meta-analysis and found
that vitamin A supplementation (doses of 25,000 to 50,000 IU) given within a few days of
birth did not affect survival to 6 or 12 months of age [
4
]. Supplementation was effective
in specific settings (trials conducted in southern Asia, in those with moderate or severe
vitamin A deficiency, or higher infant mortality rates). However, infant mortality was not
reduced with neonatal supplementation in trials conducted in Africa (RR 1.07; 95% CI
1.00 to 1.15) [
4
], and a further review reiterated that neonatal vitamin A supplementation
did not reduce all-cause mortality [5].
Vitamin A is available in two main forms, as provitamin A carotenoids (including
beta-carotene, found in fruits and vegetables) and preformed vitamin A (including retinol
and retinyl esters, found in animal foods, and used for supplementation programmes).
As absorption and conversion of pro-vitamin A carotenoids to vitamin A is variable, con-
sumption of a plant-rich diet may provide insufficient vitamin A [
6
,
7
]. Retinol equivalents
provide a combined measure of dietary carotenoids and preformed vitamin A, taking
account of imperfect carotenoid conversion, though the appropriate conversion factor is
debated [
6
,
8
]. Status of vitamin A cannot be adequately determined by measuring plasma
retinol, since it is homeostatically maintained across a range of intakes. However, when
liver vitamin A reserves fall too low, plasma retinol concentrations <0.7
µ
moL can be used
as an indicator of deficiency, once inflammation has been assessed [
9
]. Vitamin A stores,
either as total body stores, or liver depots can be assessed by biopsy or estimated by the
retinol isotope dilution (RID) technique [10].
Nutrient requirements may be calculated using approaches that link intakes with
health outcomes (health-based or dose–response approaches) or by calculating and com-
bining data on intake, absorption, conversion, needs for function and growth, depots, and
obligatory losses (the modelling or factorial approach). While older nutrient guidelines
were based on assessing levels of intake that eliminated signs of deficiency [
11
,
12
], mod-
elling approaches have been used in recent decades. For example, US average intakes
(AIs) for vitamin A were set for infants according to vitamin A levels in breast milk, and
in older children using a modelling approach that included an allowance for adequate
liver stores [
6
], while Nordic guidelines derived children’s vitamin A requirements by
extrapolating from adult requirements [
11
]. The retinol isotope-dilution (RID) technique
has also been used to assess retinol intakes needed to maintain status [
13
]. As vitamin
A is stored in the liver, there is a potential for toxicity, so safe upper intake levels (UL)
need to be considered as well as minimum requirements. Toxicity has been defined as
“A change in morphology, physiology, growth, development, reproduction, or lifespan of
a cell, organism, system, or (sub) population that results in an impairment of functional
capacity, and impairment of the capacity to compensate for additional stress, or an increase
in susceptibility to other influences” [14].

Nutrients 2022,14, 407 3 of 18
Given the importance of vitamin A, its changing deficiency patterns and that a sig-
nificant amount of new evidence/data has been generated since the FAO/WHO nutrient
intake values were last updated [
9
], a scoping review was undertaken. We scoped the
literature to inform the updating of the Food and Agriculture Organization of the United
Nations (FAO) and World Health Organization (WHO) nutrient requirements and upper
limits for vitamin A for children aged 0 to 48 months [
9
]. We aimed to identify, quantify, and
map the types and sources of evidence available, and thus identify gaps in existing research.
2. Materials and Methods
Methods for these scoping reviews were based on Cochrane, using Covidence and
Microsoft Excel software [
15
,
16
], reported according to PRISMA-ScR guidelines [
17
]. The
review protocol was submitted to the WHO as part of our funding bid (available from the
authors on request). Two main changes have occurred since submission:
1.
Revision to search systematically for and include children aged 0 to 48 months,
but also include any relevant studies identified in infants and children aged up to
10 years (mean age
≤
120 months), so that relevant studies, that may be scaled for
younger children, could be included (WHO originally requested inclusion of studies
on children aged 0 to 36 months).
2.
The WHO requested that we search from the inception of each database (rather than
from 2010 onwards, as suggested in the protocol).
This broadening of our remit was not accompanied by an increase in the resources
provided, which meant that we could not collect the full texts of all potentially relevant
studies (as earlier research is less accessible).
The questions set out within the protocol are shown in Box 1. These questions all
relate to children aged 0 to 48 months in any geographical location. Details of specific
nutrient biomarkers, bioavailability, excretion, body stores or depots, etc. were taken from
recent guidance [
8
]. We considered the types of studies that would help to answer both the
health-based and modelling-based questions in setting the inclusion criteria. The inclusion
criteria are set out in full in Supplementary Table S1.
Box 1. Review questions informing our inclusion criteria.
Health-based questions for vitamin A:
a.
What is the relationship between exclusive or mixed breastfeeding duration and vitamin A status?
b. What is the relationship between duration of formula use and vitamin A status?
c.
What is the relationship between vitamin A intake (from formula, foods and sup-plements)
and any health outcome?
d.
What is the relationship between vitamin A intake (from formula, foods and sup-plements)
and vitamin A status (such as serum retinol and liver stores)?
e.
What is the relationship between vitamin A status and any health outcome (such as night
blindness, xerophthalmia, diarrhoea, infection mortality, all-cause mortality, infection rate,
measures of growth)?
Modelling based questions for vitamin A:
a.
What are the obligatory losses of vitamin A in exclusively breast-fed infants, infants on mixed
feeding (breast and formula), infants on breast milk and weaning foods, infants on formula
and weaning foods, infants on follow-on milk and weaning foods, and fully weaned children?
b. What are vitamin A requirements for growth and storage in infants and children?
c. How large are vitamin A stores and total body vitamin A pools at different ages?
d.
How well are carotene and pre-formed vitamin A from breast milk and infant for-mula, from
specific weaning and other foods, supplements, fortified foods and bio-fortified foods, absorbed?
e.
What evidence do we have on levels of conversion of carotenoids to functional vita-min A in
children aged 6 to 48 months?
f. How is carotene conversion linked to vitamin A status?

Nutrients 2022,14, 407 4 of 18
2.1. Searches
We developed complex electronic searches using text and indexing terms (these are
called MeSH terms in Medline), truncation and controlled language. Searches were run on
Medline (Ovid), EMBASE (Ovid), and Cochrane Central, from inception to 19 March 2021,
based on the format:
[vitamin A intake or status] and [infants or young children] and [human]
As we were awarded contracts for three scoping reviews (for magnesium, iron and
vitamin A) and there was considerable overlap between the results of the searches for each
nutrient, the search strategies were adapted to include all three nutrients (full texts of the
searches are presented in Supplementary Tables S2–S4). Search strategies were not limited
by language, methodology or health outcomes to ensure complete results, including novel
outcomes. We used previous guidelines developing dietary reference values (DRVs) and
upper limits (ULs) [
6
,
8
,
9
,
11
,
12
,
18
–
22
], to help identify key studies, evidence assessments
and methods of analysis. Our subject expert (GL) was asked to check the database of
studies for gaps and identify any particularly useful studies for guideline production.
2.2. Assessment of Inclusion
Titles and abstracts from electronic searches were uploaded into Covidence software
(Veritas Health Innovation, Melbourne, Australia, available at www.covidence.org (ac-
cessed on 31 December 2021). A training set of 222 titles and abstracts was created, assessed
and then discussed by the entire review team to ensure a consistent approach. Inclusion
assessments were carried out independently in duplicate, disagreements were appraised at
weekly meetings and by a third reviewer (LH) where needed. The review team, including
topic experts, met weekly (virtually, with detailed circulated minutes) to discuss inclusion
decisions and clarify inclusion criteria. Full texts of potentially relevant studies were located
and added to Covidence. Some full texts were unavailable, so where inclusion was not
clear from the abstract, these studies were retained in our database for future assessment.
Assessment of inclusion of full texts was completed independently in duplicate for
20% of studies, with remaining studies assessed singly. This was a change to our original
protocol, made necessary by the large number of studies derived from the search strategy.
Our expert panel determined this to be efficient and acceptable due to the high inclusion
rate and low disagreement rates by the reviewers.
2.3. Data Extraction and Tabulation
Potentially relevant studies were included in the scoping reviews, tagged in Covidence
by nutrient, question and study design. Studies were tabulated with bibliographic details,
title, abstract (where available), publication year, with additional data extraction and a risk
of bias assessment for some studies (see below).
We created separate spreadsheet tables (in Microsoft Excel) for each nutrient (vitamin
A, magnesium, iron). Within each we created separate sheets for each relationship with
these titles: Intake Outcome; Intake Status; Status Outcome; Factorial Relationships; and
Adverse effects/Toxicity/Overload. Each table was split by study design: Systematic
reviews; Isotopic studies; randomised controlled trials (RCTs) and other trials; Cohort and
Case control studies; Cross sectional studies; and Non-systematic reviews (collected to
help gather further primary references for any future systematic reviews) and ordered
by publication year. Recent studies were defined as those published since January 2013
(2 years before the European Food Safety Authority (EFSA) guidance [
8
]), and highlighted
in the Excel sheets for emphasis.
As a critical question for the commissioning of the WHO guidelines group is whether
to move to the intake-health model from the factorial approach to set DRVs; we focused on
assessing intake-health data. Additional data extraction was carried out for some studies:
(a)
Intake-status-outcome studies (Excel sheets 2A, 2B, 2C): We undertook limited data
extraction to clarify available outcomes (e.g., mortality, growth, infections), adverse
effects and sample sizes for recent systematic reviews and trials.

Nutrients 2022,14, 407 5 of 18
(b)
For outcomes assessed in
≥
6 trials, or trials including at least 1000 children, we
carried out additional data extraction on relevant trials. This second layer of data
extraction included:
i.
Interventions (e.g., dose, frequency, duration & type of vitamin A plus whether
further nutrients were included in the intervention)
ii. Details on participant age, country, and baseline health status
iii. How the outcome was measured
iv. Allocation method
Adverse effect, toxicity and overload studies: where systematic reviews and trials
assessing intake-health (Dataset, can see Supplementary Materials Excel sheets 2A, 2B or
2C) reported adverse effects or toxicity in some way, these studies were copied into the
adverse effects sheet (Dataset, can see Supplementary Materials Excel sheet 4).
2.4. Risk of Bias Assessment
As this is a scoping review, we did not carry out detailed risk of bias assessment for
most of the included studies (this would be appropriate in a focused systematic review).
However, as they are crucial, we did carry out rapid risk of bias assessment using Am-
star [
23
] for relevant systematic reviews of intake-status-outcome studies (Dataset, can see
Supplementary Materials Excel sheets 2A, 2B, 2C). Allocation method was also noted for
particularly relevant RCTs (as above).
3. Results
3.1. Search Results
Electronic searches retrieved 48,747 titles and abstracts of potentially relevant studies
on magnesium, iron and vitamin A, reduced to 35,347 on de-duplication and merging of
papers into studies (Figure 1). Of these, 30,146 were excluded. The remaining 5201 papers
underwent full-text assessment, but full texts could not be obtained for 775, of which
278 were potentially relevant studies of vitamin A (see Dataset Excel sheet 1 Awaiting
Assessment, which is a list of studies that could be obtained in full text and re-assessed for
inclusion for any future full systematic review). A total of 1251 were excluded (with reasons,
see Figure 1), and 3175 included for one or more of the iron, vitamin A or magnesium
scoping reviews; 899 contributed information on the topic of vitamin A and are represented
in the Excel database (Figure 1). Some studies appear on several sheets.
3.2. Data Relevant to Setting Dietary Reference Values (DRVs)
3.2.1. Intake Outcome Relationships
Studies assessing the relationship between vitamin A intake and health, growth or
development outcomes are key to the health-based method of setting dietary reference
values. These studies are found in Excel sheet 2A Intake Outcome. We identified 18 recent
systematic reviews (published since early 2013, shown with data extraction and risk of
bias assessment), 26 older systematic reviews, 43 recent RCTs (with data extraction), and
134 earlier trials. Additionally, nine recent and 26 older cohort and case–control studies,
14 recent and 21 older cross-sectional studies and seven recent and 23 older non-systematic
reviews are noted.
Studies assessing the relationship between vitamin A intake and a marker of vitamin A
status (Excel sheet 2B Intake Status) and between status and health, growth, or development
outcomes (Excel sheet 2C Status Outcome) may in combination support the data directly
assessing intake and outcomes. For Intake Status studies, we included three systematic
reviews published since early 2013 [
24
–
26
], which were data-extracted and assessed for
risk of bias (plus two older systematic reviews), 31 recent trials, of which 12 appeared
particularly recent and relevant [
27
–
38
] (and 80 older trials). Alongside these we noted
12 recent cohort or case–control studies, 15 earlier studies, nine recent cross-sectional
studies, 25 older studies, and nine non-systematic reviews. For studies assessing the
relationship between vitamin A status and health, growth or development outcomes we

Nutrients 2022,14, 407 6 of 18
identified no systematic reviews, two recent RCTs (with additional data extraction), 39 older
RCTs, 17 recent observational studies of which eight appeared particularly
relevant [39–46]
,
42 earlier cohort or case–control studies, 19 recent cross-sectional studies, 56 earlier cross-
sectional studies and eight potentially relevant non-systematic reviews.
Nutrients 2022, 14, x FOR PEER REVIEW 6 of 19
Figure 1. PRISMA flow chart.
3.2. Data Relevant to Setting Dietary Reference Values (DRVs)
3.2.1. Intake Outcome Relationships
Studies assessing the relationship between vitamin A intake and health, growth or
development outcomes are key to the health-based method of setting dietary reference
values. These studies are found in Excel sheet 2A Intake Outcome. We identified 18 recent
systematic reviews (published since early 2013, shown with data extraction and risk of
bias assessment), 26 older systematic reviews, 43 recent RCTs (with data extraction), and
134 earlier trials. Additionally, nine recent and 26 older cohort and case–control studies,
14 recent and 21 older cross-sectional studies and seven recent and 23 older non-system-
atic reviews are noted.
Studies assessing the relationship between vitamin A intake and a marker of vitamin
A status (Excel sheet 2B Intake Status) and between status and health, growth, or devel-
opment outcomes (Excel sheet 2C Status Outcome) may in combination support the data
directly assessing intake and outcomes. For Intake Status studies, we included three sys-
tematic reviews published since early 2013 [24–26], which were data-extracted and as-
sessed for risk of bias (plus two older systematic reviews), 31 recent trials, of which 12
appeared particularly recent and relevant [27–38] (and 80 older trials). Alongside these
we noted 12 recent cohort or case–control studies, 15 earlier studies, nine recent cross-
sectional studies, 25 older studies, and nine non-systematic reviews. For studies assessing
the relationship between vitamin A status and health, growth or development outcomes
Figure 1. PRISMA flow chart.
3.2.2. Evidence Addressing Health-Based Questions for Vitamin A
The evidence addressing health-based questions, including the number of each type
of study and references of key papers, is summarised in Table 1.
Table 1.
Mapping of relevant research addressing health-based questions: number of relevant studies
of each methodology, plus references to the most relevant studies.
Systematic Reviews RCTs & Trials Cohort &
Case-Control Studies
Cross-Sectional
Studies
2013+ Pre-2013 2013+ Pre-2013 2013+ Pre-2013 2013+ Pre-2013
What is the relationship
between exclusive or mixed
breastfeeding duration and
vitamin A status
in children?
4
[47–50]
1
[51]

Nutrients 2022,14, 407 7 of 18
Table 1. Cont.
Systematic Reviews RCTs & Trials Cohort &
Case-Control Studies
Cross-Sectional
Studies
What is the relationship
between duration of
formula use and vitamin A
status in children?
3
[47,48,50]0
What is the relationship
between vitamin A intake
(from formula, foods and
supplements) in infants and
children and any health
outcome? (See Excel sheet
2A Intake Outcome)
18
[3,4,25,52]
26
[53]
43
[28,29,33,38,54–
68]
134 9 26 14 21
What is the relationship
between vitamin A intake
(from formula, foods and
supplements) and vitamin
A status? (See Excel sheet
2B Intake Status)
3
[24–26]2
31
[27,31,33–37,65–
67,69–73]
80 12 15 9 25
What is the relationship
between vitamin A status
and any health outcome?
(See Excel sheet 2C
Status Outcome)
0 0 2 39 17
[39–46]42 19 56
a.
What is the relationship between exclusive or mixed breastfeeding duration and
vitamin A status in children?
The most relevant studies measuring vitamin A intake appear on Excel sheet 5 Po-
tentially Useful Reviews. Five relevant systematic reviews, including one undertaken to
inform the US 2020 Dietary Guidelines Advisory Committee (search September 2019) [
47
],
one carried out by the USDA Nutrition Evidence Systematic Review Team and Complemen-
tary Feeding Technical Expert Collaborative (search March 2016) [
48
], a Cochrane review
(not updated since June 2011) [51], and two further reviews [49,50].
b.
What is the relationship between duration of formula use and vitamin A status
in children?
Three systematic reviews mentioned in the previous section also addressed this ques-
tion [47,48,50].
c.
What is the relationship between vitamin A intake (from formula, foods and supple-
ments) in infants and children and any health outcome?
This evidence is found in Excel sheet 2A Intake Outcome. High quality individual pa-
tient data meta-analysis and Cochrane systematic reviews assessed the relationship between
vitamin A intake and health outcomes. Three assessed the relationship between vitamin A
intake (by supplementation) and mortality in the first few days of life (11 trials including
163,000 neonates) [
4
], in infants aged one to 6 months (12 trials, 24,000 infants) [
52
] and chil-
dren aged 6 months to 5 years (47 trials, 1.2 million children) [
3
]. These same two reviews
also assessed effects on cause-specific mortality, morbidity, vision, and side effects [
3
,
52
].
Only one of the 18 recent systematic reviews assessed effects of vitamin A sources other than
high-dose preformed vitamin A supplements, assessing fortification of staple foods [
25
] (as
did one of the 26 older systematic reviews, assessing agricultural interventions [
53
]). Recent
trials report effects of increasing vitamin A intake in infants and children on mortality and
a variety of types of morbidity such as immune
response [28,29,54–56]
, atopy [
57
,
58
], respi-
ratory infection [
59
], cognition [
60
,
61
], eye health [
33
,
38
,
62
] and growth [
38
,
63
]. Most of the
43 recent trials assessed effects of supplementation (though two assessed effects of comple-
mentary foods, one alongside home fortification [
64
,
65
], two biofortified maize [
33
,
62
], one
biofortified cassava [66], one carotenoid enriched juice [67], and one fortified milk [68]).

Nutrients 2022,14, 407 8 of 18
d.
What is the relationship between vitamin A intake (from formula, foods and supple-
ments) and vitamin A status (such as serum retinol and liver stores)?
The most relevant studies appear on the Excel sheet 2B Intake Status. There are three
relevant systematic reviews [
24
–
26
], plus a set of trials assessing effects of supplementation
on serum retinol and beta-carotene. Many isotopic studies (shown in Table 2) also assessed
intake status relationships. The majority of the 31 recent trials assessing effects of vitamin
A intake on vitamin A status measures (Excel sheet 2B intake status), focused on supple-
mentation. Fifteen trials assessed effects of biofortified cassava [
27
,
34
,
66
], sweet potato [
69
]
or maize [
31
,
33
], complimentary foods [
70
], peanut butter and kale [
71
], high-carotenoid
juice [
67
], different infant formulae [
35
,
37
], fortified rice [
36
], cow peas and amaranth [
72
],
and home fortification with multiple micronutrient powder [65,73].
Table 2. Details of recent isotopic studies.
Study Country Vitamin A Source Children’s Ages Vitamin A Outcomes
Assessed
Ford 2020 [74],
NCT03000543 [75],
NCT03345147,
NCT03030339
Bangladesh,
Guatemala, Philippines
Some supplemented,
others dietary only 9–65 months TBS, retinol kinetics
Ford 2020 [76]
Bangladesh, Phillipines,
Guatemala, Mexico
Dietary and
supplemental intake Birth to 5 years
TBS, liver concentration
Lopez-Teros 2020 [77] Mexico Usual diet &
supplementation 3–6 years Whole-body retinol
kinetics, TBS
Lopez-Teros
2017 [78,79]Mexico
Moringa oleifera leaves
17–35 months VA equivalence, TBS,
retinol kinetics
Lopez-Teros 2017
[80,81]Mexico Breast milk 0–2 years Breast milk intake, VA
intake from breast milk
Lopez-Teros 2013 [82],
Astiazaran-Garcia
2013 [68]
Mexico Fortified milk Pre-school TBS, SR, liver
VA concentration
Mondloch 2015 [83] Zambia Biofortified maize Pre-school
TBS, serum carotenoids,
RBP etc
Muzhingi 2017 [71,84] Zimbabwe Peanut butter and kale 12–36 months Conversion factor
NCT03383744 [32] Cameroon Supplementation 3–5 years TBS, SR, RBP
NCT03801161 [85] Bangladesh Usual dietary intake 9–18 months
SR, TBS, RBP, beta
carotene, CRP,
iron status
NCT02363985,
NCT03194724,
NCT03207308 [86]
Ethiopia, Cameroon,
Botswana, Senegal
Dietary diversity,
supplementation,
biofortification
3–5 years
TBS, SR, Liver stores,
infection, dietary
intake, anthropometry,
morbidity
Palmer 2021 [87],
NCT02804490 Zambia Biofortified or fortified
maize to mother 9 months TBS, breast milk retinol
Pinkaew 2013 [36],
NCT01199445 [88]Thailand Fortified rice School age TBS, SR
Suri 2015 [89],
NCT01061307,
NCT01814891
Thailand, Zambia
Usual intake and status
Pre-school SR, total liver reserves
Van Stuijvenberg 2019
[90], NCT02915731 South Africa
Supplementation,
fortification, sheep
liver intake
Pre-school Hypervitaminosis
A, TBS
SR serum retinol, TBS total body stores, VA vitamin A, RBP retinol binding protein.

Nutrients 2022,14, 407 9 of 18
e.
What is the relationship between vitamin A status in infants and children and any
health outcome (such as night blindness, xerophthalmia, diarrhoea, infection mortality,
all-cause mortality, infection rate, measures of growth)?
As expected from the nature of the question, most of the studies available to address the
relationship between vitamin A status and health outcomes were observational, assessing
relationships between markers of vitamin A status and autism spectrum disorders [
39
],
acute or recurrent respiratory infection [
40
,
43
,
44
,
46
], asthma [
42
], malaria [
41
], infectious
diseases generally [45] and mortality [41] (Excel sheet 2C Status Outcome).
3.2.3. Factorial Relationships
We originally separated out studies on vitamin A absorption, stores, losses and ex-
cretion, needs and metabolism, and balance. However, we discuss them together as there
is a great deal of overlap (Excel sheet 3 Factorial). The most relevant systematic review
(“Metabolism of Neonatal Vitamin A Supplementation” [
24
]) focused on the first 28 days
of life. The authors of that review searched systematically between August 2013 and 5 Jan
2020, with a supplemental Medline search extending to January 2020. Included studies
were of neonatal humans and animals, given single or periodic oral vitamin A (less than
daily). Outcomes were absorption (five human studies assessed short term serum response,
four unabsorbed vitamin A which is most likely not a reliable measurement of vitamin
A absorption due to degradation of vitamin A via the microbiome), transport (no human
studies), storage (one human study), metabolism and detoxification (no human studies) and
organ maturation (one human study). All their included human studies were published
before 1995, and almost all before 1960.
Our review identified 15 newer isotopic studies (published alongside their trials reg-
istry entries and conference abstracts, since early 2013), which between them addressed ab-
sorption, metabolism, balance, body depots and excretion (see
Table 2[32,36,68,74–87,89,90]
,
alongside nine older isotopic studies [
88
,
91
–
98
]). The potentially most relevant recent trials
explored the effects of multiple nutrient supplementation [
99
–
103
], vitamin A supplementa-
tion on iron metabolism [
104
] or supplementation in conjunction with other treatments [
105
].
Older trials assessed the effects of vegetables and green leaves [
96
,
106
], milk formula [
107
],
fortified seasoning powder [
108
], micronutrient supplement [
109
] and high-dose supple-
mentation [
110
–
118
]. The observational studies and non-systematic reviews are noted on
Excel sheet 3.
3.2.4. Methodologies Used in Previous DRV Development
The methods used to develop DRVs in previous guidelines are included in Supple-
mentary Text S5. The table of references used within previous guidance, and their context,
appears in Supplementary Table S6. Guidelines tend to cite previous guidelines (Sup-
plementary Table S7). Note that the text of Supplementary Text S5 and Supplementary
Tables S6, S8 and S9 are largely “cut and paste”—for information only.
3.3. Data Relevant to Setting Upper Limits (ULs)
3.3.1. Studies on Vitamin A Adverse Effects, Toxicity, and Overload
Studies on toxicity and adverse effects of vitamin A in healthy infants and children are
shown in Excel sheet 4, Adverse Effects. Some studies were identified as primarily assessing
toxicity (for example, acute accidental poisoning), but most were included elsewhere in the
review, for example, addressing the relationship between intake and health outcomes, or
intake and status, where adverse or negative effects of high vitamin A intakes were assessed.
Six recent systematic reviews reported adverse effects of vitamin A supplementation
or overload [
3
,
5
,
24
,
52
,
119
,
120
], and a useful older systematic review collated case reports
on toxicity due to retinol or retinyl esters in foods or supplements [
121
]. Two recent
isotopic studies provided data on hypervitaminosis A [
90
,
122
], and 13 recent trials reported
adverse effects of vitamin A supplementation [
37
,
38
,
57
,
65
,
123
–
130
]. Additionally, we
note 19 recent and 23 older observational (non-isotopic) studies (six of which reported on

Nutrients 2022,14, 407 10 of 18
hypercarotenaemia), plus three recent and three older non-systematic reviews. A subset of
studies that may be particularly useful for assessing upper limits has been highlighted by
GL (shown at the bottom of Excel sheet 4 Adverse Effects) [121,131–133].
3.3.2. Methodologies Used in Previous Vitamin A UL Development
Methods of UL development from previous guidelines are cut and pasted into Sup-
plementary Table S8, and references used within previous guidelines to underpin UL
derivation appear in Supplementary Table S9.
4. Discussion
This scoping review identifies and details the most relevant research for use in updat-
ing nutrient requirements and upper limits for vitamin A for children aged 0 to 48 months.
A body of new research (published since early 2103, two years before publication of the most
recent EFSA opinion [
8
]) has been published and is available for use in setting guidance,
whether a health-based or modelling-based approach is chosen.
Although this is a scoping review and not a systematic review, we have used systematic
methods to identify, quantify, and map research for use in updating nutrient requirements
and upper limits for vitamin A in children. However, we acknowledge limitations, includ-
ing the lack of access to older full text papers, which was due to a lack of resource. We
also present only limited information on the risk of bias, methods, and outcomes of each
included study.
4.1. Health-Based Approach to Nutrient Requirements
Data mapping suggests that there may be sufficient data to set DRVs using intake out-
come and intake status trials, even omitting trials of supplementation. Research assessing
effects of vitamin A intakes from breastfeeding, formula feeds, complementary and other
foods from a range of cultural settings are potentially most useful, and trials assessing the
effects of supplementation on immune response, serum retinol, and beta-carotene could
support mortality data. The effects of vitamin A supplementation on mortality have been
recently systematically reviewed, with searches run to early 2016. Undertaking a com-
prehensive systematic review assessing the quantitative relationship between vitamin A
intake (in a variety of forms, including usual foods, formula, fortified and biofortified foods,
added fortification vitamin A, but not vitamin A supplements) on health, development,
growth, adverse events and key (defined) measures of vitamin A status in infants and
children (with assessment of basal vitamin A intake and status) would appear useful to
underpin health-based guidance. Ideally, primary studies will assess vitamin A intakes
from provitamin A carotenoids and preformed vitamin A in breastmilk, formula, comple-
mentary foods, supplements and fortified foods when assessing the effects or associations
with health outcomes. Further primary studies assessing the effects of quantified vitamin
A intake from dietary, fortification and supplementary sources in infants and children on
health, development, growth and adverse events would be useful.
4.2. Modelling-Based Approach to Nutrient Requirements
Our scoping review identified recent isotope tracer data which are likely to be a good
approach for quantifying effects of bio-fortification, fortification and food-based vitamin
A on vitamin A total body and liver stores, losses, needs and balance. The identified
recent studies should enable the assessment of bioefficacy (the combination of absorption
and bioconversion) of provitamin A carotenoids and provitamin A conversion factors
under field conditions [
8
]. Mathematical modelling using “super-person” designs with
adequate datasets will allow calculation of the “fractional catabolic rate”, which gives a
good indication of daily vitamin A losses, hence vitamin A excretion. Such study results
could be incorporated into the final analysis of DRVs for infants and children.
Vitamin A absorption has traditionally been assessed by measuring levels of excreted
vitamin A in faeces and urine, but logistical problems in field and laboratory, and bacterial

Nutrients 2022,14, 407 11 of 18
degradation of retinoids in the microbiome, likely reduce the accuracy of this approach.
Measuring serum retinyl ester concentrations after a defined oral dose combined with math-
ematical compartmental analysis offers a potentially more accurate assessment of vitamin A
absorption. Similarly, carotenoid absorption can be estimated from serum concentrations in
the chylomicron fraction 6–8 h postprandially after a defined oral dose. Assessing vitamin
A absorption from foods in infants and children is ethically and logistically challenging as
it requires a series of blood samples taken over 6–8 h. This is an even greater issue in at risk
populations. To overcome this issue a super-child design can be used to obtain accurate
absorption data across a group of children. For provitamin A carotenoids, variation in
absorption and bioconversion both contribute to inter-individual variation. Bioefficacy
determination enables assessment of bioequivalence of provitamin A carotenoids from
different foods. The Retinol Isotope Dilution (RID) technique, or dual isotopes (labelled
preformed retinol combined with labelled provitamin A carotenoids) can accurately assess
bioefficacy. A recent approach to assessing vitamin A absorption uses an area under the
curve approach, which appears promising in field conditions [134].
Vitamin A losses have traditionally been assessed using urinary and faecal losses
after defined dose application or during periods of disease. Research using isotope tracers
combined with mathematical compartmental analysis also allows determination of the
“fractional catabolic rate”, a more accurate assessment of vitamin A losses over time.
Any systematic review would need to make these distinctions clear and include future
recommendations for assessing vitamin A losses. There is a need for future studies to study
the ‘fractional catabolic rate’ during periods of disease.
The scoping review suggests that data are limited on absorption, conversion, stores,
losses, needs and balance of vitamin A from a wide range of normal diets in infants and
children. A systematic review of the existing isotopic studies would be useful to clarify
details of absorption, metabolism, stores, growth, losses and balance in children of different
ages, from different dietary sources in different parts of the world.
4.3. Upper Limits
Understanding the relationship between vitamin A intake and toxicity or side effects
is important in order to set appropriate upper limits for vitamin A in infants and children.
Systematically reviewing adverse effects reported in relevant efficacy trials as well as trials
of negative outcomes would produce a stronger dataset of adverse events.
5. Conclusions
We have produced an extensive dataset of studies that may be relevant in setting
vitamin A DRVs and upper limits in infants and young children. We believe this dataset
will be useful in helping researchers to focus future research, and underpin systematic
reviews on supporting the setting of DRVs and upper limits. Our mapping suggests that
there are potentially sufficient studies to set DRVs for infants and young children for
vitamin A, using both the health-based and modelling-based approaches. To enable either
approach, new or updated systematic reviews of specific sections of the data will be needed.
Ideally, both the health-based and modelling-based approaches to setting DRVs would
be attempted independently, and the results compared to obtain the most robust DRV
estimates. Data for setting upper limits in young children are more limited and may require
extrapolation from older children and adult populations.
Supplementary Materials:
The following are available online at https://www.mdpi.com/article/
10.3390/nu14030407/s1, Table S1: Detailed inclusion criteria for the scoping review on vitamin
A, Table S2: Medline (Ovid) search strategy run 19 March 2021, Table S3: Embase (Ovid) search
strategy run 19 March 2021, Table S4: CENTRAL and Cochrane Database of Systematic reviews
search strategy run 19 March 2021, Supplementary Text S5: Methodologies used in previous DRV
development, Supplementary Table S6: References used in previous guidelines when setting Vitamin
A requirements for infants and children, Supplementary Table S7. Dietary Reference Values and
recommendations cited in existing guidelines, Supplementary Table S8. Methodologies used in setting

Nutrients 2022,14, 407 12 of 18
previous upper limits for vitamin A in infants and children, Supplementary Table S9. References
relating to setting upper limits for vitamin A in infants and children, Supplementary References and
Supplementary dataset which tabulates all relevant included studies.
Author Contributions:
Conceptualization, L.H., A.A.W., P.A. and G.L.; methodology, L.H., J.B., J.F.
and F.S.; software, J.F., J.B. and L.H.; validation and formal analysis, C.E.-B., J.B., J.F., B.V.T. and L.H.;
investigation, L.H., C.E.-B., J.B., J.F., A.J., N.J., B.V.T., A.A., C.C., L.E., C.F., E.G., C.H., S.H.W., N.N.,
T.O., E.P. (Ellice Parkinson), E.P. (Emma Prentice), M.Q., L.R., H.G., F.S., A.A.W., P.A., G.L.; resources
and project administration, J.F. and H.G.; data curation, J.F., C.E.-B. and H.G.; writing—original draft
preparation, L.H. and G.L.; writing—review and editing, all authors; visualization, L.H. and G.L.;
supervision, A.A.W., P.A., F.S. and G.L.; funding acquisition, L.H., J.B., C.E.-B., F.S., P.A. and G.L. All
authors have read and agreed to the published version of the manuscript.
Funding:
This scoping review was funded by the World Health Organization, grant number
2021/1102552-0.
Data Availability Statement:
The data presented in this scoping review are available in the associated
Excel sheet and Supplementary Materials. The protocol (which formed part of the funding application)
is available on request from the authors.
Acknowledgments:
We thank Susan Fairweather-Tait and Jason Montez for encouragement, support
and advice.
Conflicts of Interest:
The authors declare no conflict of interest, except that G.L. was an author
of some of the studies included in the dataset. The funders were involved in setting the question
for the scoping reviews and agreeing the protocols, but had no role in the collection, analyses, or
interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
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