Zinc in Child Health and Disease
Shinjini Bhatnagar and Uma Chandra Mouli Natchu
Abstract. Zinc deficiency is common in children from developing countries due to lack of intake of animal foods, high dietary
phytate content, inadequate food intake and increased fecal losses during diarrhea. Zinc has a fundamental role in cellular
metabolism, with profound effects on the immune system and the intestinal mucosa. Zinc supplementation has shown
significant benefits in prevention and treatment of diarrhea and pneumonia. Routine zinc supplementation given to low birth
weight babies for a year has resulted in substantial reduction in mortality. Zinc deficiency may have adverse effects on physical
growth and neurodevelopment. WHO Task Force, 2001, and the National task Force of lAP has recommended use of zinc in
the treatment of diarrhea. It is also recommended as part of standard case management in persistent diarrhea and in those
with severe malnutrition. Further evidence is required for qualifying its use in treatment of other infective diseases like
pneumonia and malaria. Improved dietary quality & intake, food fortification and cultivation of zinc dense plants are some ways
of mitigating zinc deficiency. [Indian J Pediatr 2004; 71 (11) : 991-995] E-mail : [email protected]
Key words :
Zinc has received increasing attention because of the
recently available evidence that its deficiency may have
grave consequences in humans. 1-3 Zinc is an essential
component of various enzyme molecules, other proteins
and biomembranes. It is required to maintain the normal
structure a n d / o r ftmction of multiple enzymes, including
those that are involved in transcription and translation.of
genetic material and cell division. In animal models, zinc
deficiency has s h o w n to affect skin, gastrointestinal,
immune, respiratory, skeletal and reproductive systems.
Because of the fundamental role that zinc plays in cellular
metabolism, its effect is substantial in cells with a rapid
turnover such as the immune system and is therefore said
to modulate host resistance to various infections. 4 Zinc
d e f i c i e n c y d u r i n g p r e g n a n c y has i m m u n o l o g i c a l
consequences for the fetus, which may persist into infancy
and later life.
Based on serum or plasma levels, around 30-50% of
children residing in low income settings have low serum
or plasma zinc. Mild to m o d e r a t e zinc deficiency is
common in these countries because of a low dietary intake
of zinc-rich animal-source foods in which zinc is more
bioavaliable, high c o n s u m p t i o n of cereal grains and
legumes, which contain inhibitors of zinc absorption and s
and an overall poor dietary intake. Children in these
countries are also frequently affected by enteric infections,
which result in excess fecal losses of zinc. 6
Role of Zinc in I n f e c t i o n s
Case reports and observational studies provided initial
e v i d e n c e of a c o r r e l a t i o n b e t w e e n low p l a s m a - z i n c
concentrations in children and a greater susceptibility to
Correspondence and Reprint requests : Dr. Shinjini Bhatnagar,
Centre for Diarrheal Disease and Nutrition Research,Department of
Pediatrics, All India Institute of Medical Sciences,New Delhi.
Indian Journal of Pediatrics, Volume 71--November, 2004
infections. 7 Relative inadequacy of plasma or serum zinc
as markers of deficiency, lack of appropriate cutoffs and
possible effects of coexisting nutritional deficiencies limit
their use as markers of zinc deficiency. However, most
reliable evidence of effect of zinc on childhood infectious
diseases f r o m i n c r e a s e d zinc intake c o m e s f r o m
intervention trials of adequate size and design in diarrhea,
pneumonia, and malaria.
Zinc in Diarrheal D i s e a s e s
The effects of zinc supplementation on p r e v e n t i o n of
diarrhea and the therapeutic benefits of zinc given during
a diarrheal episode have been well evaluated. Majority of
TABLE1. Results of Randomized Controlled Trials in Children
with Acute Diarrhea Comparing Effect of Zinc with
Placebo
Study
Effect size (95% CI)
Risk of continuation of diarrhea
Relative hazards
Pooled analysis
Subsequent studies in South Asia
Bahl et al
Bhatnagar et al
Strand et al
0.85 (0.76 to 0.95)
0.89 (0.80 to 0.99)
0.76 (0.59 to 0.97)
0.79 (0.68 to 0.93)
Diarrhea lasting >7 days
Odds Ratio
Pooled analysis
Subsequent studies in South Asia
Bahl et al
Bhatnagar et al
Strand et al
0.78 (0.56 to 1.09)
0.61 (0.33 to 1.12)
0.09 (0.01 to 0.73)
0.57 (0.38 to 0.86)
Stool output
Difference in means or
Ratio of Geometric Means
Roy et aF
Dutta et al ~
Bhatnagar et al
-91g
-900g (-1200to-590)
0.69g/kg (0.48,0.99)
Adapted from reference 11
991
S. Bhatnagar and U.C.M. Natchu
the studies were conducted in South East Asia, where
zinc deficiency is common.
A pooled analysis that included most of the clinical
trials on zinc supplemented pre-school well-nourished
and malnourished children p e r f o r m e d in developing
c o u n t r y settings f o u n d an 18% (CI 7 - 28%) lesser
incidence of acute diarrhea in these children as compared
to those who did not receive zinc s
The results of studies on zinc treatment as an adjunct
in acute diarrhea have been reviewed and the pooled
analyses T M and the findings of subsequent studies are
summarized in Table 1. These r a n d o m i z e d controlled
trials were conducted in children aged between 6 months
and 3 years, and used zinc doses ranging from 10 to 30
mg per day. Zinc supplemented children had 15% faster
recovery (95% CI 4% to 24%) with a 22% reduction (95%
CI 9% to 34%) in the odds of acute episodes lasting >7
days. Subsequent trials show results consistent with the
meta analysis." One s t u d y was of major interest as it
m e a s u r e d impact on stool output, the most objective
marker of severity and a useful proxy indicator for risk of
dehydration, in hospitalized children with acute diarrhea
and dehydration22 In the zinc treated children, the total
stool o u t p u t was reduced by 31% (95% CI 1% to 52%)
than in the placebo group. All studies showed that the
effect of zinc did not v a r y significantly with age, or
nutritional status assessed by anthropometry. The effects
were not d e p e n d e n t u p o n the type of zinc salts: zinc
sulfate, zinc acetate or zinc gluconate. There was little
gain in efficacy w h e n the commonly used 20 mg daily
dose of elemental zinc was increased to 30-40 mg daily. 9
u Ongoing trials, which include young infants, will allow
clearer interpretation of the role of zinc during diarrhea in
children less than 6 months.
The efficacy of 40 mg elemental zinc mixed with a liter
of WHO ORS solution was compared with ORS without
zinc and with zinc syrup administered separately from
ORS. 13While zinc-ORS was superior to ORS alone, it was
less efficacious in reducing duration of the episode than
zinc supplements given separately from the ORS solution.
The data are currently too limited.
Zinc was also found to have significant therapeutic
effects in persistent diarrhea by decreasing duration of
episodes, lowering stool frequency and resulting in a 40%
reduction of treatment failures or deaths. 9
Therapeutic benefits of zinc administration during
diarrhea are biologically plausible because of its effects on
various components of the immune system and its direct
gastrointestinal effects. Zinc is said to improve absorption
of water and electrolytes by helping in early regeneration
of intestinal mucosa, restoration of enteric enzymes and
e n h a n c i n g h u m o r a l a n d cellular i m m u n i t y . 1,2,4 In
malnourished guinea pigs zinc has also been shown to
have antisecretory properties. 14
Zinc in Respiratory I n f e c t i o n s
Fewer clinical trials h a v e a d d r e s s e d the p r e v e n t i v e
992
TABLE2. Effect of Zinc Supplementation on Lower Respiratory
Tract Infections
Study
Study size
Zinc/control
Vietnam
India
Jamaica
Peru
India
73/73
286/293
31/30
80/79
1241/1241
Effectof zinc on ALRTI*
or clinical pneumonia
44% reduction
43% reduction
88% reduction
15% reduction
26% reduction in clinical
pneumonia
* Achieved statistical significance
benefits of zinc supplementation on lower respiratory
tract i n f e c t i o n s t h a n for d i a r r h e a l diseases. The
determination of the exact effect has been hampered by
the variability in definitions of lower respiratory tract
infections and pneumonia and because most of the trials
were designed to establish the effect on diarrhea, where
respiratory infections were studied secondarily. When
results of 5 studies, s,l~of zinc supplementation in children
aged b e t w e e n 4 and 36 m o n t h s w e r e p o o l e d , the
commutative reduction in episodes of pneumonia was
41% (95% CI 17-59%) (Table 2). A large trial from India
had sufficient power to measure the 26% reduction in
clinical pneumonia diagnosed by two physicians using
pre-defined criteria. 15
Two recently reported randomized controlled trials
from india and Bangladesh evaluated whether zinc, along
with antibiotics, would improve the outcome of severe
ALRI or p n e u m o n i a in children less than 2 years of
age. 16,17In Bangladesh, zinc supplementation resulted in
30% r e d u c t i o n in d u r a t i o n of severe p n e u m o n i a and
significant shorter duration of individual markers of
disease severity such as fast breathing, chest in drawing
and hypoxia. There was a m e a n r e d u c t i o n of 25% in
hospital stay, which is equivalent to one hospital day. In
the other trial from Kolkatta. 17zinc treatment significantly
increased recovery rates from very ill status of severe
ALRI by 2.6 times but these effects were only seen in
boys.
Zinc in Malaria
Data on effect of zinc on m a l a r i a l i n c i d e n c e is
heterogeneous given the varied definitions that have
b e e n u s e d for d e f i n i n g a m a l a r i a l e p i s o d e . While
supplementation with zinc showed no effect on various
malarial indices in a c o m m u n i t y based cross sectional
surveillance it was f o u n d to r e d u c e visits to h e a l t h
facilities for Plasmodium falciparum febrile episodes
defined as fever with parasitemia in Papua New Guinea
a n d The Gambia. TM In p o p u l a t i o n s w h e r e rates of
parasitemia are high, clinically confirmed cases of malaria
would be an important measure of the malarial burden.
Another trial in Burkina Faso f o u n d no effect of zinc
supplementation on rates of fever in a community based
surveillance of malaria29 The Zinc Against Plasmodium
Study Group 2~evaluated the therapeutic effect of zinc
Indian Journal of Pediatrics, Volume 71--November, 2004
Zinc in Child Health and Disease
given as an adjuvant to standard therapy during acute
malaria in a large double-blind, r a n d o m i z e d placeboc o n t r o l l e d clinical trial across 5 countries in Africa.
Despite an improvement in mean serum zinc levels there
was no effect on the median time to reduction of fever,
parasitemia or a change in hemoglobin concentration in
the initial 72 hours or during the four week follow up.
Effect of Zinc in Mortality
A reduction in childhood mortality is anticipated because
of the large effects of zinc supplementation on reducing
the incidence and severity of some of the most common
c h i l d h o o d infectious diseases. A s t u d y c o n d u c t e d in
B a n g l a d e s h 21 u s e d a c l u s t e r - r a n d o m i z e d d e s i g n to
e v a l u a t e the effect on m o r t a l i t y and m o r b i d i t y of
providing daily zinc for 14 days to children with diarrhea
as part of the d i a r r h e a t r e a t m e n t p r o g r a m m e in the
community. The intervention and the comparison clusters
were b o t h given ORS and advice on feeding d u r i n g
diarrhea. The children in the zinc cluster had a shorter
duration (hazard ratio 0.76, 95% CI 0.65 to 0.90) and lower
incidence of diarrhea (rate ratio 0.85, 95%CI 0.76 to 0.96)
than children in the comparison group. Lesser admission
to hospital of children with diarrhea (rate ratio 0.76, 95%
CI 0.59 to 0.98), and lower mortality due to non-injury
deaths, notably diarrhea or pneumonia (rate ratio 0.49;
95% CI 0.25 to 0.94) was r e p o r t e d in the zinc treated
cluster. P r e l i m i n a r y e v i d e n c e that r o u t i n e zinc
supplementation may have some effect on mortality in
h i g h risk g r o u p comes f r o m a r e c e n t d o u b l e blind
randomized controlled trial in India which showed a 68%
reduction in mortality in small for gestational age full
term infants who were given 5 mg of zinc daily from 30
d a y s to 284 d a y s . 22 In L e s o t h o 23 c o n t i n u o u s zinc
s u p p l e m e n t a t i o n was evaluated for mortality during
hospitalization and morbidity for 3 months post discharge
in severely m a l n o u r i s h e d children. Mortality d u r i n g
h o s p i t a l i z a t i o n was significantly l o w e r in the zincs u p p l e m e n t e d g r o u p (4.7%), compared with 16.7% in
those not receiving zinc. In addition, more than half of the
children who received zinc crossed the 80th percentile of
e x p e c t e d w e i g h t - f o r - a g e 3 m o n t h s after discharge,
compared with 27.6 per cent in the control group. More
conclusive data will be available from the three large
o n g o i n g trials e v a l u a t i n g the effects of zinc
supplementation on child mortality in India, Nepal and
Zanzibar.
Zinc and Physical Growth
Studies from animal models and reports of severe zinc
deficiency resulting in dwarfism and delayed sexual
m a t u r a t i o n in I r a n i a n a n d E g y p t i a n y o u t h s
predominantly on a zinc depleted bread diet, suggested
that zinc supplementation may have a significant role to
play in improved child growth. 1'24Zinc deficiency as early
as d u r i n g the i n t r a u t e r i n e p e r i o d m a y influence the
dynamics of physical and intellectual development in
Indian Journal of Pediatrics, Volume 71--November, 2004
humans. While the role of ante partum zinc deficiency
and s u p p l e m e n t a t i o n on i m m u n e f u n c t i o n is b e i n g
assessed, a few trials have also a t t e m p t e d to assess
intrauterine well being in zinc supplemented mothers. In
a trial of zinc supplementation during pregnancy, women
who received 15 mg of daily zinc, along with iron and
folate supplementation, had fetuses with an increased
fetal heart rate ranges and more vigorous fetal activity
compared to fetuses of nonsupplemented women, z5 Both
measures are indices of fetal well being that m a y be
related to subsequent development.
Results evaluating responses to physical growth with
zinc supplementation are inconsistent in different studies.
Brown et aP 6 in his recent review of 33 studies found a
small positive impact on weight gain and length with zinc
supplementation in prepubertal children. The effect size
on growth was larger, of 0.5 SD units, in children with
baseline weights < 2 Z-scores. Another large subsequent
trial in Burkina Faso 27 has s h o w n no effect of zinc
supplementation on growth where similar range of doses
of zinc was used.
Zinc, Neurodevelopment and Cognition
Zinc may act as a neurotransmitter and by influencing cell
division, maturation, and growth early in fetal life it may
d e t e r m i n e later n e u r o d e v e l o p m e n t and intellect.
A l t h o u g h evidence from animal models, psychiatric
patients and early studies from infants. 2s,29suggests that
zinc deficiency affects cognition, neuro development,
responses to stress and emotion, and motor activity, more
trials will be needed to evaluate the critical period, risk
groups and reversibility of the adverse effects of zinc
deficiency on neurodevelopment.
Other Effects of Zinc
Large doses of zinc may reduce copper absorption from
the gut and have been used in the treatment of Wilson's
disease. 3~Zinc has been found to be of benefit in the
treatment of attention deficit hyperactivity disorder (31).
Zinc lozenges are being used for treatment of common
colds a l t h o u g h the e v i d e n c e p r e s e n t l y at best is
inconclusive. 3~
What are the Policy Implications for Use of Zinc in
Children?
Zinc deficiency appears to be common in India and other
developing countries and it is important to recognize zinc
deficiency as a public health problem. The low serum or
plasma zinc levels are not restricted to children with low
anthropometric status, age group or sex. There is now
sufficient evidence for role of zinc in the treatment of
diarrhea. WHO Task Force, 2001, has recommended use
of zinc in the treatment of diarrhea, given at a dose of 2
RDAs per day (10 to 20 mg per day) for 14 days. 6 They
f u r t h e r r e c o m m e n d e f f e c t i v e n e s s s t u d i e s to assess
different strategies for delivering zinc supplementation to
children with diarrhea. These studies should investigate
993
S. Bhatnagar and U.C.M. Natchu
the f e a s i b i l i t y , s u s t a i n a b i l i t y a n d cost effectiveness of
different zinc delivery mechanisms, and monitor
v a r i a b l e s such as ORS s o l u t i o n c o n s u m p t i o n , antibiotic
use rate, n o n d i a r r h e a m o r b i d i t y a n d overall mortality.
The IAP N a t i o n a l Task Force u o n M a n a g e m e n t of Acute
diarrhea, 2003, e n d o r s e d the r e c o m m e n d a t i o n of 20 m g of
e l e m e n t a l zinc d u r i n g the p e r i o d of d i a r r h e a a n d for 7
d a y s after cessation of d i a r r h e a to c h i l d r e n older t h a n 3
m o n t h s b a s e d o n s t u d i e s i n I n d i a a n d other d e v e l o p i n g
countries. Zinc s u p p l e m e n t a t i o n is also r e c o m m e n d e d as
p a r t of routine, s t a n d a r d case m a n a g e m e n t in persistent
diarrhea a n d i n those w i t h severe m a l n u t r i t i o n .9 Further
evidence is r e q u i r e d for q u a l i f y i n g its use in treatment of
other infective diseases like p n e u m o n i a a n d malaria.
T h e r e a r e s e v e r a l a p p r o a c h e s to m i t i g a t e z i n c
deficiency. 1~The most i m p o r t a n t w o u l d be to i m p r o v e the
d i e t a r y q u a l i t y a n d i n t a k e of i n f a n t s , c h i l d r e n a n d
w o m e n . Routine zinc s u p p l e m e n t a t i o n in y o u n g children
is a d i f f i c u l t task, g i v e n the p a s t e x p e r i e n c e w i t h i r o n
s u p p l e m e n t a t i o n , b u t s u p p l e m e n t a t i o n of s e l e c t e d
s u b g r o u p s at highest risk of death like low birth weight or
the s e v e r e l y m a l n o u r i s h e d m a y b e possible. The other
p r o b l e m w o u l d b e to c o m b i n e z i n c w i t h o t h e r
m i c r o n u t r i e n t s as there m a y be significant i n t e r a c t i o n s
b e t w e e n them resulting i n decreased bioavailability of the
i n d i v i d u a l m i c r o n u t r i e n t s . T h e e f f e c t s of p o s s i b l e
i n t e r a c t i o n s i n a c o m b i n e d f o r m u l a t i o n n e e d to b e
assessed further on disease morbidity. The other
a p p r o a c h is of f o o d f o r t i f i c a t i o n b y e n c o u r a g i n g
c u l t i v a t i o n of z i n c d e n s e p l a n t s or t h o s e t h a t h a v e a
d e c r e a s e d c o n c e n t r a t i o n of zinc a b s o r p t i o n i n h i b i t o r s .
Finally, research in the field of zinc a n d health m u s t be
encouraged.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
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