Nu ien s 2012, 4, 841-858; doi:10.3390/nu4080841
nu ien s
ISSN 2072-6643
www.mdpi.com/jou nal/nu ien s
Re iew
The Rela ionship be ween Zinc In ake and Se um/Plasma Zinc
Concen a ion in Child en: A Sys ema ic Re iew and
Dose-Response Me a-Analysis
Vic o ia Hall Mo an
1,
*, Anna-Louise S amme s
2
, Ma isol Wa hon Medina
2
, Suja a Pa el
2
,
Fiona Dykes
1
, Olga W. Sou e ein
3
, Ca la Dullemeije
3
, Ca men Pé ez-Rod igo
4
,
Lluis Se a-Majem
5
, Ma iela Nissensohn
5
and Nicola M. Lowe
2
1
Ma e nal & In an Nu i ion & Nu u e Uni , Uni e si y o Cen al Lancashi e, P es on PR1 2HE,
UK; E-Mail: [email p o ec ed]
2
In e na ional Ins i u e o Nu i ional Sciences and Food Sa e y S udies, Uni e si y o Cen al
Lancashi e, P es on PR1 2HE, UK; E-Mails: [email p o ec ed] (A.-L.S.);
[email p o ec ed] (M.W.M.); [email p o ec ed] (S.P.);
[email p o ec ed] (N.M.L.)
3
Di ision o Human Nu i ion, Wageningen Uni e si y, PO Box 8129, 6700 EV Wageningen,
The Ne he lands; E-Mails: [email p o ec ed]l (O.W.S.); Ca la.Dullem[email p o ec ed] (C.D.)
4
Communi y Nu i ion Uni , Bilbao Ci y Council, Bilbao 48001, Spain;
E-Mail: [email p o ec ed]
5
Depa men o Clinical Sciences, Uni e si y o Las Palmas de G an Cana ia,
Las Palmas de G an Cana ia 35016, Spain; E-Mails: [email p o ec ed]pgc.es (L.S.-M.);
[email p o ec ed] (M.N.)
* Au ho o whom co espondence should be add essed; E-Mail: [email p o ec ed];
Tel.: +44-1772-893830; Fax: +44-1772-892998.
Recei ed: 4 May 2012; in e ised o m: 27 June 2012 / Accep ed: 10 July 2012 /
Published: 26 July 2012
Abs ac : Recommenda ions o zinc in ake du ing childhood a y widely ac oss Eu ope.
The EURRECA p ojec a emp s o consolida e he basis o he de ini ion o mic onu ien
equi emen s, aking in o accoun ela ionships among in ake, s a us and heal h ou comes,
in o de o ha monise hese ecommenda ions. Da a on zinc in ake and bioma ke s o zinc
s a us epo ed in andomised con olled ials (RCTs) can p o ide es ima es o dose- esponse
ela ionships which may be used o unde pinning zinc e e ence alues. This sys ema ic
e iew included all RCTs o appa en ly heal hy child en aged 1–17 yea s published
by Feb ua y 2010 which p o ided da a on zinc in ake and bioma ke s o zinc s a us.
OPEN ACCESS
Nu ien s 2012, 4 842
An in ake-s a us eg ession coe icien (
󰆹) was calcula ed o each indi idual s udy and
calcula ed he o e all pooled 
󰆹 and SE (
󰆹) using andom e ec s me a-analysis on a double
log scale. The pooled dose- esponse ela ionship be ween zinc in ake and zinc s a us
indica ed ha a doubling o he zinc in ake inc eased he se um/plasma zinc s a us by 9%. This
e idence can be u ilised, oge he wi h cu en ly used balance s udies and eple ion/deple ion
s udies, when se ing zinc ecommenda ions as a basis o nu i ion policies.
Keywo ds: zinc; child en; se um zinc; sys ema ic e iew; dose- esponse; die a y
ecommenda ions; EURRECA
1. In oduc ion
Subop imal die a y zinc in ake is inc easingly ecognised as an impo an public heal h issue.
Al hough he lack o gene ally accep ed bioma ke s o zinc s a us has impeded es ima ion o he global
p e alence o zinc de iciency, based on in o ma ion ega ding he amoun o zinc p esen in na ional
ood supplies, i has been es ima ed ha he isk o low die a y in ake o abso bable zinc and
consequen zinc de iciency a ec s be ween one- hi d and one-hal o he wo ld’s popula ion [1] and
a es o de iciency may app oach 73% in some egions [2]. Al hough se e e zinc de iciency is
uncommon in Eu opean popula ions, ma ginal de iciency is likely o be much mo e p e alen [3], wi h
associa ions o immune sys em dys unc ion and es ic ed physical de elopmen [4]. Child en a e
pa icula ly ulne able o subop imal zinc s a us du ing pe iods o apid g ow h ha c ea e inc eased
zinc needs ha may no be me [5,6]. I is es ima ed ha o e 450,000 dea hs pe yea (4.4% o
all mo ali ies) among child en be ween six mon hs and i e yea s o age a e a ibu able o zinc
de iciency [7]. Zinc de iciency also has an impac o child mo bidi y, impai ing g ow h and
con ibu ing o childhood s un ing [8,9].
Physiological equi emen s o zinc peak a he ime o he pube al g ow h spu , he onse o which
a ies acco ding o gende . In gi ls he onse o he g ow h spu (OGS) occu s a 10.1 yea s and peak
heigh eloci y (PHV) occu s a 12.0 yea s. In boys OGS and PHV occu a 11.8 and 14.2 yea s,
espec i ely [10]. E en a e he g ow h spu has ceased, adolescen s may equi e addi ional
zinc o eple e issue zinc pools deple ed du ing pube y [11]. Ma ginal zinc s a us du ing he pube al
g ow h spu has been associa ed wi h slowe skele al g ow h, ma u a ion, and educed bone
mine alisa ion [12–14]. As nea ly a hi d o o al skele al mine al is accumula ed in he 3–4 yea pe iod
immedia ely a e he onse o pube y [15] subop imal zinc in ake may ha e long- e m consequences
on bone heal h.
Al hough a sensi i e and speci ic bioma ke has ye o be iden i ied, a ecen sys ema ic e iew
concluded ha plasma (o se um) zinc concen a ion was esponsi e o bo h zinc supplemen a ion and
deple ion and is he mos widely used bioma ke o zinc [16]. Howe e , me a-analy ic me hods ha e
no ye been used o model zinc s a us as a unc ion o zinc in ake le els. Unde s anding he ela ionship
be ween die a y in ake and mic onu ien s a us is essen ial o de i ing die a y ecommenda ions.
The ecommenda ions o zinc in ake du ing childhood a y widely ac oss Eu ope and compa isons
a e di icul due o di e ences in ca ego isa ion. Fo example be ween 4 and 6 age ca ego ies a e used
Nu ien s 2012, 4 843
o desc ibe mic onu ien ecommenda ions in childhood wi h di e en age cu -o poin s being used
by di e en Eu opean coun ies [17,18]. Recommenda ions o zinc in ake di e be ween males and
emales a he age o 15 yea s in mos coun ies, bu also di e a he age o 10 yea s in some coun ies.
Zinc in ake alues ange om 2.9 o 10.0 mg/day in child en aged 5 yea s, 5.7 o 15.5 mg/day (boys)
and 4.6 o 15.0 mg/day (gi ls) in child en aged 10–15 yea s [17]. The EURRECA p ojec a emp s o
consolida e he basis o he de ini ion o mic onu ien equi emen s ac oss Eu ope, aking in o accoun
ela ionships among in ake, s a us and heal h ou comes, in o de o ha monise hese ecommenda ions [19].
This pape p esen s a sys ema ic e iew o he da a om all a ailable andomised con olled ials
(RCTs) mee ing EURRECA’s quali y s anda d [20], which in es iga ed zinc in ake and bioma ke s o
zinc s a us, and combines hese s udies in me a-analyses o model zinc concen a ions in se um o
plasma as a unc ion o zinc in ake.
2. Me hods
2.1. Sea ch S a egy
This esea ch was conduc ed wi hin he amewo k o he Eu opean Mic onu ien Recommenda ions
Aligned (EURRECA) Ne wo k o Excellence ha aims o iden i y he mic onu ien equi emen s o
op imal heal h in Eu opean popula ions (EURRECA [21]). This e iew was pa o a wide e iew
p ocess o iden i y s udies assessing he e ec o zinc in ake on di e en ou comes (bioma ke s o zinc
s a us and heal h ou comes). The wide sea ches we e pe o med o li e a u e published up o and
including Feb ua y 2010 using MEDLINE, Embase, and Coch ane using sea ch e ms o “s udy
designs in humans” and “zinc” and “in ake OR s a us”. Bo h indexing and ex e ms we e used and
languages included we e es ic ed o hose spoken in he EURRECA Ne wo k (English, Du ch,
F ench, Ge man, Hunga ian, I alian, No wegian, Polish, Spanish, G eek, and Se bian). The ull O id
MEDLINE sea ch s a egy can be ound in Table 1. Re e ence lis s o e ie ed a icles and published
li e a u e e iews we e also checked o ele an s udies. Au ho s we e con ac ed o eques missing
da a o cla i y me hods o esul s. The sea ch p ocess is illus a ed in Figu e 1.
Table 1. Sea ch s a egy: MEDLINE Feb ua y 2010 [22].
No. Sea ch Te m Resul s
1 andomised con olled ial.p . 280,821
2 con olled clinical ial.p . 79,998
3 andomised.ab. 196,604
4 placebo.ab. 117,891
5 clinical ials as opic.sh. 146,242
6 andomly.ab. 145,491
7 ial.ab. 203,467
8 andomised.ab. 38,423
9 6 o 3 o 7 o 2 o 8 o 1 o 4 o 5 734,511
10 (animals no (human and animals)).sh. 4,482,479
11 9 no 10 642,665
12 (coho * o “case con ol*” o c oss-sec ional* o “c oss sec ional” o case-con ol*
o p ospec i e o “sys ema ic e iew*”).mp.
768,885
Nu ien s 2012, 4 844
Table 1. Con .
13 exp me a-analysis/ o expmul icen e s udy/ o ollow-up s udies/ o p ospec i e
s udies/ o in e en ion s udies/ o epidemiologic s udies/ o case-con ol s udies/ o
exp coho s udies/ o longi udinal s udies/ o c oss-sec ional s udies/
1,013,635
14 13 o 12 1,203,767
15 14 no 10 1,154,385
16 11 o 15 1,599,094
17 ((zinc o Zn o zinc sulpha e o zinc glucona e o zinc ace a e o me hionine o zinc
iso ope*) adj3 (in ake* o die * o supplemen * o deple * o s a us o se um o
plasma o leukocy e o concen a ion* o expos* o o i * o u ine o hai )). i,ab.
16,681
18 Nu i ional Suppo / o Die a y Supplemen s/ o nu i ional equi emen s/ o B eas
eeding/ o exp in an ood/ o bo le eeding/ o in an o mula/
63,098
19 exp Nu i ional S a us/ o exp De iciency Diseases/ o supplemen a ion/ o die
supplemen a ion/ o die a y in ake/ o exp die es ic ion/ o exp mine al in ake/ o
Die / o Food, Fo i ied/ o nu i ion assessmen / o Nu i i e Value/
176,014
20 (in ake* o die * o supplemen * o deple * o s a us o se um o plasma o
leukocy e o concen a ion* o expos* o o i * o u ine o hai ). i,ab.
3,166,092
21 18 o 19 o 20 3,263,114
22 zinc/ 41,027
23 22 and 21 20,745
24 23 o 17 26,943
25 24 and 16 2410
2.2. C i e ia o he Conside a ion o S udies o This Re iew
Included s udies we e RCTs in appa en ly heal hy child (human) popula ions aged om 1 o 17 yea s
ha supplied zinc supplemen a ion ei he as capsules o pa o a o i ied meal. I supplemen al zinc
was p o ided as a componen o a o i ied meal, s udies we e only conside ed accep able i zinc was
he only cons i uen ha was di e en be ween ea men g oups. Only s udies ha measu ed zinc
s a us as se um o plasma zinc we e included; and hose ha epo ed su icien da a o had su icien
da a ob ainable om he au ho s o es ima e 
󰆹 and SE (
󰆹) o he assumed linea ela ion on he log
e
–log
e
scale. S udies we e excluded i hey we e a g oup RCT (communi y ial), o we e commen a ies,
e iews, o duplica e publica ions om he same s udy. S udies we e excluded i child en we e
hospi alised, had se e e p o ein-ene gy malnu i ion o a ch onic disease o i supplemen al zinc was
p o ided o less han 6 weeks.
2.3. Selec ion o A icles
O 4719 iden i ied a icles in he wide sea ch on zinc in ake, s a us and p io i y heal h ou comes in
all popula ions, 2557 we e excluded based upon sc eening o he i le and abs ac . Two independen
e iewe s sc eened 10% o he abs ac s in duplica e and any disc epancies we e discussed be o e
sc eening he emaining e e ences. Following subdi ision in o app op ia e popula ion g oups he ull
ex s o he 328 manusc ip s we e assessed o de e mine inclusion and exclusion by wo independen
e iewe s and disag eemen s ec i ied h ough discussion. 302 s udies we e excluded because hey did
no mee he inclusion c i e ia. O he emaining 26 s udies, 8 s udies we e excluded as hey had no
Nu ien s 2012, 4 845
in es iga ed he ela ion be ween zinc in ake and zinc ela ed bioma ke s, bu ela ed ei he in ake o
s a us di ec ly o a heal h endpoin . Fo he pu pose o his pape , 18 RCTs emained. Table 2 p esen s
he cha ac e is ics o he included s udies.
Figu e 1. S udy selec ion p ocess o sys ema ic e iew (* some pape s epo ed mo e han
one ela ionship).
2.4. Da a Ex ac ion
Fo each o he iden i ied manusc ip s, da a was ex ac ed independen ly by wo e iewe s in o a
s anda dised da abase. Ex ac ed da a included popula ion cha ac e is ics, dose o elemen al zinc in
in e en ion and placebo supplemen s, du a ion o he s udy, die a y in ake o zinc, and mean
concen a ion o zinc in plasma o se um a he end o he in e en ion pe iod. Se um/plasma zinc
concen a ions we e con e ed o µmol/L when applicable.

Nu ien s 2012, 4 846
Table 2. Summa y o included ials epo ing he e ec o die a y zinc in ake on se um/plasma zinc s a us in child en.
Fi s Au ho ,
Yea , Coun y Pa icipan s T ea men G oups (n)
Mean Zn
In ake
(mg/day)
Mean (SD)
Plasma/Se um Zn
(µmol/L)
Du a ion
Zinc S a us
Bioma ke
[Analy ical Me hod]
Main Resul s
Mahloudji, 1975,
I an [23]
Males & emales
aged 6–12 yea s
Fe only (12);
Fe + 20 mg/day Zn (13)
5.65;
25.65
8.95 (1.80)
8.50 (1.93)
8 mon hs Plasma Zn [AAS] No signi ican di e ence be ween plasma Zn o he
supplemen ed and placebo g oups
Hambidge, 1979,
USA [24]
Males & emales
aged 33–90 mon hs
Male placebo (15);
Male Zn FM 2.57 mg/day (20);
Female placebo (14);
Female Zn FM 2.57 mg/day (11)
6.3;
9.27;
6.3;
9.27
11.06 (2.23)
11.85 (2.23)
10.61 (1.81)
11.96 (1.81)
9 mon hs Plasma Zn [AES] Plasma Zn signi ican ly highe in Zn supplemen ed
compa ed o placebo (gi ls and combined sexes only
p < 0.05)
Wal a ens,
1983, USA [25]
Males & emales
aged 2–6 yea s
Placebo (16);
10 mg/day Zn (16)
4.6;
15.9
11.32 (2.14)
10.86 (2.14)
12 mon hs Plasma Zn [AES] No signi ican di e ence be ween plasma Zn o he
supplemen ed and placebo g oups
Gibson, 1989,
Canada [26]
Males aged
59–95 mon hs
Placebo (21);
10 mg Zn/day (18)
6.4;
16.7
15.8 (3.5)
17.9 (3.4)
6 mon hs Se um Zn [AAS] No signi ican co ela ion be ween se um Zn and die a y
Zn le els
Ca an, 1993,
Gua emala [27]
Males & emales,
mean age
81.5 (±7.0) mon hs
1
Placebo (74);
10 mg Zn/day (71)
5.65;
15.65
14.9 (2.1)
16.2 (2.9)
25 weeks Plasma Zn [AAS] Plasma Zn signi ican ly highe in Zn supplemen ed
compa ed o placebo (p < 0.01)
F iis, 1997,
Zimbabwe [28]
Males and emales
aged 11–17 yea s
Placebo (121);
30–50 mg/day Zn (122)
5.65;
45.65
2
10.89 (2.5)
11.71 (2.4)
12 mon hs Se um Zn [AAS] The decline in zinc concen a ion was signi ican ly lowe
in he Zn supplemen ed g oup compa ed o he placebo
g oup (p < 0.02)
Rosado, 1997,
Mexico [29]
Males & emales
aged 18–36 mon hs
Placebo (55);
20 mg Zn/day (54)
5.65;
25.65
14.4 (4.45)
16.8 (5.88)
12 mon hs Plasma Zn [AAS] Plasma Zn inc eased signi ican ly in he Zn supplemen ed
g oup o e he 12 mon hs pe iod (p < 0.01)
Ruz, 1997,
Chile [30]
Males & emales
aged 27–50 mon hs
Placebo (33);
10 mg/day Zn (36)
6.4;
17.1
17.7 (1.9)
17.6 (2.2)
6 mon hs Plasma Zn [AAS] No signi ican di e ence be ween plasma Zn o he
supplemen ed and placebo g oups
Sands ead, 1998,
China [31]
(3 egions)
Males & emales
aged 6–9 yea s
Chonqing MN, no Zn (35);
20 mg/day Zn + MN (35);
Quindgdao MN, no Zn (36);
20mg/day Zn + MN (36);
Shanghai MN, no Zn (37);
20 mg/day Zn + MN (37)
5.65;
25.65;
5.65;
25.65;
5.65;
25.65
19.83 (4.12)
23.6 (4.12)
20.42 (4.08)
22.97 (4.08)
17.9 (2.75)
17.97 (2.75)
10 weeks Plasma Zn [AAS] Plasma Zn signi ican ly highe in Zn supplemen ed
compa ed o placebo (p < 0.05) in Chonqing and
Quindgdao g oups.
Nu ien s 2012, 4 847
Table 2. Con .
Cla k, 1999,
UK [32]
Pe ipube al
emales, mean age
12.2 (±0.3) yea s
Placebo (19);
15 mg Zn/day (23)
6.6;
21.6
12.6 (1.0)
16.7 (4.9)
6 weeks Se um Zn
[no me hod gi en]
Se um Zn signi ican ly highe in Zn supplemen ed
compa ed o placebo (p < 0.001)
Smi h, 1999,
Belize [33]
Males & emales
aged 22–66 mon hs
Placebo (10);
70 mg Zn/day (12)
5.65;
75.65
11.7 (0.68)
13.5 (0.68)
6 mon hs Se um Zn [AAS] Se um Zn signi ican ly highe in Zn supplemen ed
compa ed o placebo (p < 0.001)
Munoz, 2000,
Mexico [34]
Males & emales
aged 18–36 mon hs
Placebo (54);
20 mg/day Zn (47)
5.65;
25.65
14.3 (4.7)
16.8 (5.6)
6 mon hs Plasma Zn [AAS] Se um Zn signi ican ly highe in Zn supplemen ed
compa ed o placebo (p < 0.0001)
Lopez de Romana,
2005, Pe u [35]
Males & emales
aged 3–4 yea s
Fe FM (12);
Fe + 3 mg/day Zn FM (10);
Fe + 9 mg/day Zn FM (12);
4.71;
8.72;
15.7
11.87 (1.88)
11.65 (1.25)
12.60 (1.51)
70 days Plasma Zn [ICP-MS] No signi ican di e ences in plasma Zn we e ound
be ween ea men s
Sil a, 2006,
B azil [36]
Males & emales
aged 12–59 mon hs
3
Placebo (30);
10 mg/day Zn (28)
5.65;
15.65
8.0 (0.58)
13.4 (0.25)
4 mon hs Se um Zn [AAS] Se um Zn signi ican ly highe in Zn supplemen ed
compa ed o placebo (p < 0.05)
Sands ead, 2008,
USA (Mexican
Ame icans) [37]
Males & emales
aged 6–7 yea s
MN, no Zn (25);
20 mg/day Zn + MN (25)
5.65;
25.65
15.4 (1.5)
15.6 (1.2)
10 weeks Plasma Zn [AAS] Mean plasma Zn inc eased signi ican ly in bo h
g oups compa ed o baseline (p < 0.05)
Wuehle , 2008,
Ecuado [38]
Males & emales
aged 12–30 mon hs
Placebo (56);
3 mg Zn/day (50);
7 mg Zn/day (52);
10 mg Zn/day (54)
5.65;
8.65;
12.65;
15.65
10.6 (1.6)
12.3 (1.6)
13.3 (1.7)
14.0 (1.7)
4
6 mon hs Plasma Zn [ICP-MS] The mean change in plasma zinc concen a ions om
baseline inc eased p og essi ely wi h highe doses o
supplemen al Zn (p < 0.001)
de Oli ei a, 2009,
B azil [39]
Pubescen males,
mean age
13 (
±
0.4) yea s
Placebo (26);
22 mg Zn/day (21)
5.65;
27.65
16.9 (2.1)
18.7 (3.5)
12 weeks Plasma Zn [ICP-MS] Plasma Zn signi ican ly highe in Zn supplemen ed
compa ed o placebo (p < 0.05)
Ucka de, 2009,
Tu key [40]
Males & emales
aged 8–9 yea s
Placebo (109);
15 mg/day Zn (109)
5.65;
20.65
19.19 (1.80)
19.50 (2.41)
10 weeks Se um Zn [CS] Bo h supplemen ed and placebo g oups had
signi ican ly highe se um Zn a ollow up (p < 0.05)
AAS, a omic abso p ion spec oscopy; AES, a omic emission spec oscopy; ICP-MS, induc i ely coupled plasma mass spec ome y; CS, calo ic spec opho ome y; MN, mic onu ien s;
FM, o i ied meal;
1
all pa icipan s also ecei ed MN supplemen s;
2
child en weighing <29.5 kg we e gi en 30 mg Zn/day and hose >29.5 kg we e gi en 50 mg Zn/day, his igu e is an
a e age o he wo doses;
3
all pa icipan s also ecei ed Fe o i ied milk;
4
geome ic means.
Nu ien s 2012, 4 848
2.5. Da a Syn hesis
One s udy ha included wo zinc- ea ed g oups and wo con ol g oups (males and emales) was
ea ed as wo independen es ima es in he analysis [24] and one s udy ha included h ee zinc- ea ed
g oups and h ee con ol g oups ( om di e en egions o China) [31] and was ea ed as h ee
independen es ima es in he analysis. Whe e s udies p o ided ou come da a o wo o mo e
zinc- ea ed g oups hey we e included as sepa a e es ima es in he me a-analysis [35,38]. In one s udy
zinc s a us was measu ed a 6 mon hs and 12 mon hs in he same popula ion [26] and only he measu e
a 6 mon hs was used in he analysis (whe e n was he la ges ). I die a y in ake o zinc (in addi ion o
he in e en ion) was no epo ed we impu ed a alue o 5.65 mg/day, he mean die a y in ake le el
o he RCTs (n = 7) ha did epo die a y zinc in ake. As mean baseline se um/plasma zinc
concen a ions we e in equen ly epo ed, he se um/plasma zinc concen a ions in he con ol g oup
o he RCTs we e used as a p oxy o he baseline se um/plasma zinc concen a ions o ou analyses.
2.6. P e-Speci ied Po en ial Fac o s Modi ying he Associa ion
A pooled me a-analysis was pe o med combining he e idence om all he a ailable RCTs.
In addi ion, we in es iga ed whe he age, dose o zinc, du a ion o he supplemen a ion, and ype o
supplemen (zinc only s. zinc wi h o he mic onu ien s) we e a iables ha modi ied he associa ion.
2.7. S a is ical Analyses
As we wan ed o es ima e he dose- esponse ela ion be ween zinc in ake and se um/plasma zinc,
he da a p esen ed in he s udies had o be ans o med o a common s a is ic, namely a eg ession
coe icien (
󰆹) and he s anda d e o (SE (
󰆹)) o his eg ession coe icien . The ans o ma ions used
o de i e his common single-s udy es ima e om he a ailable summa y s a is ics pe s udy ha e been
desc ibed elsewhe e [41]. In sho , we es ima ed an in ake-s a us eg ession coe icien (
󰆹) o each
indi idual s udy, based on he assump ion o a linea ela ion on he log
e
–log
e
-scale (na u al loga i hm
o in ake s. na u al loga i hm o s a us). This shape o his linea ela ionship on he log
e
–log
e
-scale
co esponds o a mono onic conca e unc ion on he o iginal scale o β < 1. This shape is assumed o
be ealis ic o he biological ela ionship be ween zinc in ake and plasma/se um zinc concen a ions.
As he ue dose- esponse cu e is unknown, his app oxima ion p o ides a p ac ical me hodology o
es ima e he dose- esponse ela ionship. We calcula ed he o e all pooled 
󰆹 and SE (
󰆹) using andom
e ec s me a-analysis, which es ima es he be ween-s udy a iance using he me hod o De Simonian
and Lai d and used his es ima e o modi y he weigh s used o calcula e he summa y es ima e.
Residual he e ogenei y be ween s udies was e alua ed using he I
2
s a is ic. P e-speci ied po en ial
ac o s ha could modi y he associa ion we e explo ed using s a i ied andom e ec s me a-analyses.
The s a is ical ans o ma ions o ob ain 
󰆹’s and SE (
󰆹)’s we e pe o med using GenS a e sion 13-SP2
(VSN In e na ional L d. [42]) and he me a-analysis was pe o med using STATA e sion 11.0
(College S a ion, TX, USA), wi h s a is ical signi icance de ined as p < 0.05.
Nu ien s 2012, 4 849
2.8. Assessmen o Risk o Bias in Included S udies
In o de o assess he quali y o he included s udies and he isk o bias, indica o s o in e nal
alidi y we e collec ed du ing da a ex ac ion (Table 2). Based on he indica o s wo independen
e iewe s assessed he o e all isk o bias and disag eemen s esol ed by discussion. The c i e ia o
judging hese indica o s we e adap ed om he Coch ane Handbook o Sys ema ic Re iews [43].
3. Resul s
Twen y- ou es ima es o zinc in ake and se um/plasma zinc s a us in 18 RCTs wi h child en we e
eligible o me a-analysis. All s udies we e RCTs published be ween 1975 and 2009 which epo ed
zinc in ake and plasma/se um zinc concen a ions. The 24 es ima es included 1722 pa icipan s in o al
wi h sample sizes anging om 10 o 122. The median du a ion o he ials was 24 weeks ( ange
6–52 weeks). In 11 s udies zinc was supplemen ed alone a doses anging om 3 o 70 mg/day and in
7 s udies pa icipan s also ecei ed o he mic onu ien s. Zinc was p o ided wi h i on supplemen s [23]
o i on o i ied milk [36], as pa o a o i ied meal [24,35], and wi h o he mic onu ien s [27,31,37].
The zinc dose anged om 10 o 20 mg/day when combined wi h o he i amin/mine als and 2.57 o
9 mg/day when p o ided in o i ied meals. Mos s udies (n = 7) p o ided he zinc supplemen s in he
o m o zinc sulpha e, bu o he s used zinc ci a e [32], zinc glucona e [33], zinc ca bona e [23], zinc
me hionine [29,34], amino acid chela e [27], and elemen al zinc in a sy up [28,40]. S udies we e
conduc ed in La in Ame ica (n = 9), No h Ame ica (n = 4), Asia (n = 3), A ica (n = 1) and Eu ope
(n = 1). Habi ual zinc in akes anged om 4.6 o 7.1 mg/day (whe e da a was p o ided) and ages o
child en anged om 2 o 17 yea s. Mos s udies included, bu did no di e en ia e be ween, males and
emales, bu one s udy p o ided sepa a e male and emale da a [24], one included only emales [32],
and one only males [39].
The majo i y o s udies (n = 13) epo ed ha zinc supplemen a ion signi ican ly inc eased zinc
plasma/se um s a us o signi ican ly educed he decline in zinc se um alues compa ed o placebo.
O hese, wo s udies also epo ed inc eased plasma/se um zinc concen a ions in he placebo g oup.
Fi e s udies ailed o ind a signi ican ela ionship be ween zinc supplemen a ion and zinc
s a us [23,25,26,30,35], ou o which p o ided zinc supplemen s o o i ied meals wi h a zinc
concen a ion o 10 mg/day o less.
Ou me a-analysis o a ailable s udies sugges ed ha zinc supplemen a ion was associa ed wi h
inc eased se um/plasma zinc concen a ions. Combining he 18 RCTs in one me a-analysis yielded an
o e all pooled β-coe icien o 0.12 (95% CI 0.04, 0.20; p < 0.005; I
2
97.6%) (Figu e 2). Since we
applied a base-e loga i hmic ans o ma ion on he zinc in ake and se um/plasma zinc concen a ion
be o e calcula ion o he s udy-speci ic 
󰆹’s, he o e all 
󰆹 ep esen s he di e ence in he log
e
ans o med
p edic ed alue o se um/plasma zinc s a us o each one-uni di e ence in he log
e
ans o med alue
in zinc in ake. The e o e, an o e all 
󰆹 o 0.12 means ha o e e y doubling in zinc in ake, he
di e ence in zinc se um o plasma concen a ion is 2
 (2
0.12
= 1.09), which is 9%. This means ha a
pe son wi h a zinc in ake o 14 mg/day has a zinc se um/plasma concen a ion ha is 9% highe han a
pe son who has a zinc in ake o 7 mg/day.
Nu ien s 2012, 4 856
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