Zinc Deficiency in the Premature Infant

K. Michael Hambidge, MD, FRCP(Ed)*

Although zinc was recognized to and convincing reason is the evi-

be essential for the growth of micro- dence that the premature infant is at EDUCATIONAL OBJECTIVE
organisms during the 19th century, enhanced risk of severe, life-
121. Appropriate awareness of the
and for the growth of mammals 50 threatening zinc deficiency syn-
picture presented by acrodermati-
years ago, interest in the role of zinc drome.
tis caused by zinc deficiency in
in human nutrition has developed only For convenience, zinc deficiency
infants born prematurely (84/85
in the last 20 years. Hence, in con- may be arbitrarily divided into three
Recent Advances).
trast to iron and iodine, zinc can be classifications: severe, moderate,
regarded as one of the “newer” trace and mild (Table 1 ). In severe zinc
elements in this context. Human de- deficiency states, plasma zinc con-
ficiencies of several of these newer centrations are typically markedly de-
trace elements are now recognized, pressed. Hypozincemia is also evi-
but human zinc deficiency syndromes dent with more moderate zinc defi-
are of special interest to the clinician. ciency, but plasma zinc levels are
The clinical importance of this trace frequently within the normal range in
mild zinc deficiency states. There is recognized by the International Corn-
element stems from the frequency of
no indisputable evidence that milder mission on Enzyme Nomenclature.
zinc deficiency states relative to
zinc deficiency states are of any din- Zinc is generally present in the pro-
those of the other newer trace ele-
ical significance in the premature in- portion of 1 to 4 atoms to each mol-
ments, the wide variety of circum-
fant. However, zinc deficiency in the ecule of the apoenzyme and fund-
stances in which zinc deficiency may
preterm infant is very unlikely to be tions catalytically at the active center
occur, the number of organ systems
an “all or none” event, ie, of no clinical of enzymes and/or in maintaining the
and major metabolic pathways that
may be affected, and the extent of concern at all, or a life-threatening structure of the protein. In some en-
the clinical consequences. The car- nutritional deficiency disorder. Data zymes different zinc atoms may be
related to the term infant and to the involved in both of these functions.
dinal importance of zinc for normal
young child point to the existence of Although our understanding on the
growth and development, both pre-
natally and postnatally make this mi- a growth-limiting mild nutritional zinc one hand of the biochemistry of zinc
cronutrient of special interest to the deficiency syndrome, which may well and on the other hand of the clinical
have important implications for the consequences of zinc deficiency has
obstetrician and pediatrician.
This article will focus primarily on premature infant. Hence, mild zinc grown rapidly in recent years, the
deficiency will be considered in dis- biochemical correlates of the clinical
the premature infant. Despite the
cussions of the incidence, epidemiol- features of zinc deficiency remain
paucity of information, zinc nutrition
is of particular concern in this nutri- ogy, clinical features, diagnosis, and poorly understood. Most attention
treatment of zinc deficiency in pre- has been focused on the biochemical
tionally challenging population group
for several reasons. First, the rela- mature infants. basis of the growth failure that is such
an outstanding feature of dietary zinc
tively rapid growth of the healthy pre-
restriction in the young. In the exper-
mature infant, after initial stabiliza- BIOCHEMISTRY
imental animal, the poor growth is
tion, suggests the need for relatively
large quantities of zinc to meet the Zinc, atomic number 30, shares attributable, in part, to decreased
with the first transition series of ele- food consumption, the cause of
demands of new tissue, especially
lean body mass. Second, there is dis- ments in the periodic chart the ability which remains undetermined. Be-
turbing evidence that the very low- to form strong bonds with organic yond the effects of decreased food
birth-weight premature infant has ma- ligands such as those found on the intake, impaired food utilization is
jor problems with the gastrointestinal side chains of amino acids. Of the also a major factor in the observed
absorption of this micronutrient dur- many biologic roles that zinc may growth retardation. Many of the en-
ing the first 2 months of postnatal life. have, including likely participation in zymes involved in nucleic acid metab-
As the infant, born either at term or the structure of nucleic acids and cell olism and protein synthesis are
preterm, does not start postnatal life membranes, the most important, or known to be zinc dependent, and the
with recognized stores of zinc, there certainly the most studied, is the role activity of at least some of these, eg,
is presumably a need to achieve pos- of zinc in enzyme systems. Since the DNA and ANA polymerases, has
itive zinc balance without a delay, discovery in 1940 that carbonic an- been found to be impaired in experi-
hydrase was a zinc-containing en- mental zinc deficiency. A great deal
especially when postnatal growth
zyme, more than 200 zinc metalloen- of speculation has centered on the
commences. Third, the most direct
zymes have been identified. Zinc ap- role of impaired activity of one or
pears to be the metal most widely more of these enzymes in the patho-
* Department of Pediatrics, University of Colo- distributed in enzyme systems, with genesis of the impaired growth and
rado Health Sciences Center, 4200 East Ninth at least one zinc metalloenzyme iden- development noted in zinc deficiency.
Aye, Box C233, Denver, CO 80262. tified in every category of enzymes Aecently, however, cogent argu-

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 Zinc Deficiency

dietary zinc restriction on growth

TABLE 1. Arbitrary Classification of Zinc Deficiency According to Severity without a measurable decrease in the
zinc concentration in the tissues.
Plasma Zinc
Concentration” Salient Clinical Features
(pg/dL) BODY CONTENT, DISTRIBUTION,
Severe <40 Growth arrest ABSORPTION, AND EXCRETION
(often Acro-orificial skin lesions
<20) Stomatitis; glossitis It has been generally accepted that
Behavioral abnormalities the content of zinc in the body of a
Diarrhea premature infant with a birth weight
Frequent infections/immunoincompetence of 1 ,000 g is approximately 20 mg.
Alopecia More recently, a figure of 40 mg has
May be fatal if untreated been reported. This discrepancy is of
Moderate 40-60 Marked impairment of growth and develop- more than theoretical importance
ment when attempting to calculate the ef-
T-cell dysfunction fect of negative zinc balance in early
? edema and hypoproteinemia postnatal life on body zinc content.
Mild >60 Failure to thrive/low growth percentiles For comparison, the total zinc con-
Diminished food intake tent of a standard male adult has
± impaired taste perception been calculated to approximate 2000
* Normal plasma zinc: 65 to 110 Lg/dL. mg or an overall concentration of ap-
proximately 30 mg of zinc per kilo-
gram of body weight. Approximately
40% of neonatal zinc is in bone, and
much of this zinc may be available for
genome I I I I I I I I I____
other uses during the extensive re-
+Zn modeling that occurs in early post-
activators / repressors natal life. However, it is not at all clear
-Zn to what extent skeletal zinc can be
diminished without affecting skeletal
gene :::: I1llhJII Iffl 1111111111:::: growth and mineralization. At term,
V
J approximately 25% of the body zinc
(+Zn)genes (-Zn) genes is present in the liver. Zinc concentra-
tions in fetal liver are inversely related
transcription transcription
to duration of gestation, and the liver
mRNAs mRNAs accounts for an even higher percent-
age of body zinc in the very low-birth-
translation translation
weight premature infant. The rela-
tively high hepatic zinc concentra-
proteins proteins
tions in the very low-birth-weight pre-
(enzymes, regulatory (enzymes, inhibitory
term infant are probably counterbal-
peptides,etc.) peptides,etc.)
anced by relatively low zinc concen-
growth + trations in skeletal muscle. There are
development + no indications that either the preterm
or term infant starts life with signifi-
differentiation +
cant specific body stores of zinc, like
Fig 1 . Schematic representation of involvement of zinc in gene expression. Expression of some those of copper or iron. Hence, main-
genes is affected by binding of activators and/or receptors, and this process is affected by zinc. tenance of optimal tissue concentra-
Activated (or repressed) genes are then transcribed (or not) into messenger ribonucleic acid tions and the requirements of new
(mRNA). This results in products (or their lack). The consequences of absence of zinc (-Zn) are tissue are both dependent on a more
manifested as alterations or cessation of growth, development and differentiation. (Reprinted with
or less continuous and adequate di-
permission from Vallee BL, Falchuk KH: Zinc and gene expression. Phil Trans R Soc Lond
1981;B294: 185-197.) etary intake of zinc and on adequate
absorption of this cation. Using the
ments have been put forward in sup- hypothesized that this role of zinc original analytical data of Widdow-
port of the concept that zinc is nec- may depend on a very small intracel- son, Shaw calculated that the intra-
essary for gene expression (Fig 1) lular pool of freely exchangeable zinc, uterine accumulation of zinc aver-
and restructuring of chromatin. One and that this pool may rapidly be- aged about 250 tg/kg of body weight
possible mechanism by which zinc come depleted when dietary zinc is per day. Additional estimates are
may be involved at this level of cell restricted. This is an attractive hy- given in Table 2.
activity, is by catalyzing the phos- pothesis because it is compatible The intake of dietary zinc among
phorylation of histones. It has been with the rapid and dramatic effect of adults in Western countries averages

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 NUTRITION

about 1 0 mg/d. When zinc salts are

given in water, approximately 75% of TABLE 2. Estimates of Daily Rate of Accumulation of Zinc by Human Fetus
the zinc is absorbed by the gastroin- in Utero*
testinal tract. However, on average, Percentile (mg/d)
only about 20% of zinc is absorbed Gestation
(wk) 10% 50% 90%
from composite meals, with a range
from less than 10% to about 40%. 24 0.143 0.209 0.266
The experimental animal will adapt to 26 0.185 0.238 0.287
dietary zinc restriction by increasing 28 0.232 0.287 0.327
the percentage of radiozinc ab- 30 0.286 0.348 0.388
32 0.348 0.427 0.481
sorbed, but it is uncertain whether
34 0.432 0.548 0.611
such adaptive mechanisms could
36 0.553 0.675
lead to increased absorption of die-
* Data from Shaw JCL (Am J Dis Child 1979;1 33:1260).
tary zinc in the human. Hence, al-
though the composition of the meal
has significant effects on zinc absorp-
tion, the latter remains quite low even sequently, rates of excretion decline investigators have reached the ten-
under the most favorable circum- gradually to an average of about 0.01 tative conclusion that at least part of
stances. In the term infant, there is mg/d by the third month of postnatal the decline reflects zinc depletion.
strong evidence to suggest that ab- life. These losses are trivial in corn- The mean levels of zinc in the plasma
sorption of zinc from human milk is parison with fecal excretion in the of premature infants fed with their
considerably greater than from cow’s orally fed infant. own mothers’ milk do not drop below
milk or from any infant formula. The 70 ,g/dL, in notable contrast to those
precise percentage of zinc absorbed of formula-fed very low-birth-weight
INCIDENCE OF DEFICIENCY IN
and how this may be affected by the premature infants, despite the much
PREMATURE INFANTS
status of the infant’s zinc levels and greater total zinc intake of the latter.
intake are currently unknown. In the The great majority of case reports It is probable that this difference is
premature infant, dietary intake of of severe acquired zinc deficiency due to the more favorable absorption
zinc may vary from as little as 0.2 states in infancy have concerned of zinc from human milk. This sug-
mg/kg of body weight per day up to those who were born prematurely. gests strongly that the extent of hy-
nearly 2 mg/kg of body weight per This may be explained, in part, by the pozincemia (see Fig 2) is primarily
day. The latter figure reflects the high more frequent use of intravenous in- attributable to suboptimal zinc nutri-
levels of supplemental zinc that are stead of oral nutrition in the prema- tion. This degree of hypozincemia, if
currently popular in commercial for- ture infant. However, it is also quite attributable to zinc deficiency, is corn-
mulas especially designed for the pre- clear that the premature infant is pe- parable to that associated with
mature infant. Net absorption and re- culiarly vulnerable to severe zinc de- marked growth failure in term infants
tention of zinc do not appear to cor- ficiency states. Despite this vulnera- and in adolescents, at least when the
relate with the intake of dietary zinc bility, these severe zinc deficiency hypozincernia persists over a sub-
in the very low-birth-weight prema- syndromes are uncommon. More- stantial period of time. Whether the
ture infant. Absorption of zinc occurs over, the frequency is probably de- hypozincernia of the very low-birth-
in the duodenum and jejunum but creasing as zinc supplementation of weight premature infant, especially
significant quantities are also ab- intravenous infusates becomes the when formula fed, is a reflection of a
sorbed in the ileum. The mucosal rule rather than the exception. potentially growth-limiting zinc defi-
cells of the small intestine are respon- There is a great deal of uncertainty ciency state, is currently uncertain.
sible not only for the absorption of about the frequency of milder zinc Long-term, randomized controlled
dietary zinc but for reabsorption of deficiency syndromes in the prema- studies of dietary zinc supplernenta-
the large quantities of endogenous ture infant. The results of traditional tion that aim to start answering some
zinc secreted into the intestinal lu- zinc balance studies indicate that of these questions in the term infant
men, primarily from pancreatic secre- there is a strong tendency for the very and young child, have not been re-
tions. The normal adult probably ex- low-birth-weight premature infant to ported for the very low-birth-weight
cretes 1 to 2 mg of endogenous zinc become quite markedly zinc-depleted premature infant. Without such stud-
in the feces each day. Corresponding during the first 2 months of postnatal ies, it is impossible to reach any de-
figures for healthy, orally fed infants, life. Plasma zinc concentrations that finitive conclusions. Meanwhile, it ap-
including premature infants, are not start a little higher than those of term pears to be fairly certain that some
available. Approximately 0.5 mg of infants or adults decline markedly in degree of zinc depletion is common
zinc per day is excreted in adult urine early postnatal life (Fig 2) and have in the very low-birth-weight prema-
and a similar amount is lost in sweat. been reported not to return to ac- ture infant in early postnatal life.
In the very low-birth-weight prema- cepted normal levels until 6 months
ture infant, urinary losses of zinc av- of age. It is not entirely clear whether
EPIDEMIOLOGY
erage about 0.035 mg/d during the part of the early decline can be con-
first 3 weeks of postnatal life. Sub- sidered to be physiologic but several In recent years, the commonest

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Zinc Deficiency

very low-birth-weight premature in-

fant. Although more extensive and
sophisticated studies will be neces-
sary to define this problem with any
precision, results of traditional zinc
balance studies have indicated that
both net absorption and retention are
a.
negative during the first 2 months of
. postnatal life. Negative balance has
N been documented whatever the type
of feeding, but is more marked in
60 (43) (46)
a. formula-fed infants than in infants fed
with their own mothers’ milk. Similar
so (35) f
(31) I (17) negative balance has not been ob-
( ) NUMBER OF SUBJECTS (21) served in equally small infants who
were born at term and had severe
intrauterine growth retardation.
0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 910 11-13
CLINICAL FEATURES
Post-Natal Ags (weeks)
The hallmark of severe zinc dell-
Fig 2. Plasma zinc concentrations of random samples of very low-birth-weightpremature infants ciency states is the dramatic skin
in the neonatal intensive care unit at University Hospital (dolorado). Samples collected in late rash with its characteristic distribu-
1970s. High percentage of infants were formula fed after initial stabilization. Shaded area depicts
tion at the distal ends of the extrem-
normal adult range. X indicates mean for infants delivered at term.
ities (acral) and adjacent to all body
orifices (Figs 3 to 5). The skin lesions
cause of severe zinc deficiency syn- extraordinarily low zinc intakes of in- are vesiculobullous, pustular, and/or
dromes has been the administration fants breast-fed by an affected eczematoid. In acute stages, their ap-
of intravenous nutrition without the mother, the term infant can grow and pearance is markedly erythematous
addition of adequate zinc to the infus- develop normally without evidence of and the rash may become more gen-
ate. This complication of intravenous zinc deficiency. However, if one of eralized. In one series of case re-
nutrition has also been observed in these mothers happens to deliver ports, which dealt entirely with intra-
the term infant and, indeed, in all age prematurely, classic features of se- venously fed premature infants, the
groups, but it does appear that it is a vere zinc deficiency develop during skin lesions on the face and buttock
problem to which the premature in- the second or third month of post- were described as dry and scaling,
fant is especially prone. Other causes natal life. This circumstance illus- and those on the genitalia and inguin-
of severe zinc deficiency may be seen trates the enhanced vulnerability of ocrural areas showed maceration
in the premature infant, including the the premature infant to the develop- and some crusting. Lesions have
autosomal recessively inherited dis- ment of severe zinc deficiency. It been noted at areas of trauma such
order acrodermatitis enteropathica. should be emphasized that these in- as tape sites and also over an umbil-
Severe, temporary, acquired zinc fants are perfectly normal apart from ical hernia (Fig 4). Crusting cheilitis
deficiency syndromes have also been their severe zinc deficiency, and that may occur. A characteristic change in
observed in orally fed premature in- they progress normally once the zinc the anterior neckfold may occur at an
fants. In some instances, these have deficiency has been corrected. This early stage; the earliest changes are
been observed in breast-fed infants, syndrome is probably the result of an poorly marginated erythema at the
leading to an erroneous impression inherited rather than an acquired de- depth of the fold, which becomes well
that feeding with own mothers’ milk fect. Maternal zinc status appears to demarcated and scaling within five
is disadvantageous with respect to be entirely normal apart from the low days. Later most of the neckfold is
zinc status. In fact, these cases have zinc concentrations in the milk, which involved. Glossitis and stomatitis are
certainly in some instances, and are below the lower end of the normal common early features. Candida can
probably in all, been associated with range. To date, the family histories be cultured quite frequently, but not
a defect in the ability of the mammary are not helpful in determining the consistently, from the mouth, the
gland to secrete normal quantities of mode of inheritance. Indeed, if the tongue, and the intertriginous area of
zinc into the milk at any stage of phenotypic expression of this disor- the neck. Bacterial infections, espe-
lactation. This condition may be sim- der is dependent on a premature de- cially staphylococcal, also occur with
ilar to the lethal milk mutation in mice. livery, the chances of finding a posi- increased frequency in severe zinc
Lethal milk mutant mouse pups de- tive family history will be unusually deficiency states. These may extend
velop acute dermatitis and stunted low. to otitis media and pneumonia if the
growth and die between 5 and 10 Milder degrees of zinc deficiency nutritional deficiency remains un-
days of age because of the zinc def- are attributable primarily to immatu- treated. The skin lesions do not im-
icit in their mothers’ milk. Despite the rity of the gastrointestinal tract in the prove with anticandidal therapy but

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 NUTRITION

only after zinc supplementation, mdi-

dating that the monilial infection is a ACRODERMATITIS
secondary rather than a primary path-
ogen.
Other clinical features of severe 0

zinc deficiency are presented in Table 0

1 . Growth arrest is an early and strik- -j

ing feature, occurring more or less 200

concurrently with the development of CD
the skin lesions (Fig 6). The infant’s 0
0
weight plateaus, and weight gain is 0
150
not resumed until the zinc deficiency 5000
is treated. Loss of appetite is variable 3000 _0-__

and may be severe. Behavioral ab- 0

0 100
normalities are prominent, with imta-
9 %% .0
bility, excessive crying, and inconsol-
ability occurring even during relatively 50
early stages of the disease. There is 1000 z
dramatic improvement in behavior as 0

soon as zinc therapy is commenced.

Diarrhea occurs in 90% of cases of -2 -1 0 1 2 3 4 5 6
acrodermatitis enteropathica and can Birth Commencement of zinc therapy
be severe. However, it is not a prom-
AGE (MONTHS)
inent feature of severe acquired zinc
deficiency in the premature infant. Al- Fig 6. Weight changes of infant shown in Figs 3 to 5. Note relationship to onset of acrodermatitis
opecia, another characteristic feature and to zinc therapy. Premature infant was breast-fed, but zinc concentrations in mother s milk
of acrodermatitis enteropathica, is were abnormally low. Zero as shown on abscissa represents 40 weeks of gestation.
difficult to assess in the premature
infant. There is suggestive evidence that demonstrated a significant effect of
The onset of severe zinc defi- more moderate zinc deficiency can the zinc supplement on growth veloc-
ciency, whether it is associated with cause generalized edema with hypo- ity. This cannot be attributed to any
intravenous nutrition or due to an ab- proteinemia in the very low-birth- pharmacologic action of zinc, and
normally low level of zinc in the moth- weight premature infant at 5 to 9 these studies have provided confir-
er’s milk, is typically late in the second weeks of postnatal age. mation of a preexisting mild zinc de-
month or during the third month of The best documented feature of ficiency syndrome. Significant effects
postnatal life. It may follow a period mild zinc deficiency states is a de- of the zinc supplement on food intake
of rapid growth, which presumably cline in growth percentiles. De- were also demonstrated. There is as
represents an additional burden on creased food intake has also been yet no direct evidence for mild
existing zinc supplies. Not infre- documented in zinc-deficient young growth-limiting zinc deficiency in pre-
quently, it follows the onset of an children. There are unsubstantiated mature infants.
infection, the stress of which may concerns that other features of mild
trigger the severe zinc deficiency or, zinc deficiency could include immu-
PATHOPHYSIOLOGY
on the other hand, the infection may noincompetence and behavior disor-
result from a zinc deficiency state that ders. Aandomized controlled studies Histologic changes in the involved
has not yet caused a detectable skin of dietary zinc supplementation in skin are nonspecific and vary from a
lesion. If untreated, there is typically term infants and in young children in mild lymphocytic infiltrate in the early
progressive failure to thrive, with fre- selected circumstances in which mild lesions to a mixed inflammatory infil-
quent infections. zinc deficiency was suspected, have trate in the deeper necrotic sites.

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Zinc Deficiency

currently available laboratory assays

TABLE 3. Daily Intravenous Zinc Requirements for Very Low-Birth-Weight are insufficiently reliable and sensi-
Premature Infants Fed Intravenously tive. A plasma zinc determination is
worthwhile, but interpretation of the
Zinc (pg/kg of Body Weight)
result may be difficult. Indeed, a nor-
Urinary eXcretion” 40-180 mal plasma zinc concentration does
Fecal 25 not rule out the possibility of a
Other 10 growth-limiting zinc deficiency state.
Calculated requirements, excluding needs for 75-215 Aesponse to zinc supplementation
growth provides the most reliable diagnostic
tool.
Growth needs, based on intrauterine accumulation: 250
Calculated requirements for premature infants (total): 325-465 MANAGEMENT AND

* Urinary excretion rates depend on commercial source of amino acids used in PREVENTION
infusate.
Intravenous Nutrition

Calculated intravenous zinc re-

None of these histologic changes is zinc deficiency in a premature infant quirements for very low-birth-weight
specific for zinc deficiency. The should be considered in the presence premature infants receiving their nu-
pathophysiology of the skin lesions, of the characteristic acro-orificial skin trients parenterally are shown in Ta-
including their unusual and intriguing rash. The alert pediatrician may sus- ble 3. In contrast to the orally fed
distribution, has not been deter- pect the diagnosis at the earliest infant, the major excretory route for
mined. It has been hypothesized that signs of such a rash on the neck, zinc in the intravenously fed infant is
the effects of zinc deficiency on the face, diaper area, or extremities, es- via the kidneys. There are large dif-
skin are mediated through secondary pecially in the presence of predispos- ferences in the rates of urinary zinc
abnormalities of essential fatty acid ing circumstances such as intrave- excretion depending on the commer-
and prostaglandmn metabolism, but nous nutrition, short bowel syn- cial source of amino acids. These var-
there is little clearcut evidence in sup- drome, malabsorption syndromes, or iations appear to be independent of
port of this possibility. chronic diarrhea. The diagnosis can the zinc content of the infusate and
As is the case with experimental be confirmed with a plasma zinc de- are not readily explained by differ-
animals, the effects of zinc deficiency termination. The plasma/serum zinc ences in the amino acid composition.
on growth may be mediated, in part, concentration would be expected to Mean excretory rates for infants re-
through decreased food consump- be less than 40 zg/dL and probably ceiving either Freamine Ill (McGaw)
tion. Possible reasons for poor utili- less than 20 ,g/dL. The major prob- or Vamin (Pharmacia, Montreal) ap-
zation of ingested food have been lem with zinc determinations is the proximate 180 g of zinc per kilogram
discussed under “Biochemistry.” risk of contamination of the sample, of body weight per day, whereas
Negative nitrogen balance in adults especially if, unknown to the clinician rates for infants receiving Aminosyn
receiving intravenous nutrition has concerned, zinc-containing ointments (Abbott Laboratories) approximate
been reversed with zinc supplemen- have been used on the skin lesions. 40 tg/kg of body weight per day. The
tation. The adverse effects of zinc on The commonest source of contami- final requirement figure given in Table
growth particularly affect lean body nation is from the collecting tubes. 3 also includes that necessary for
mass and the energy cost of growth Plastic ware is usually, though not new tissue, based on rates of accu-
is increased by zinc deficiency. always, satisfactory. Ideally the tube mulation of zinc by the fetus in utero.
The high incidence of monilial and should be provided by a laboratory Obviously, this applies only for the
bacterial infections is assumed to be experienced in trace element analy- premature infant who is growing; dur-
attributable to the abnormalities of ses. Hemolyzed samples should be ing the first 1 to 2 weeks of postnatal
immunocompetence that result from rejected. If it is impossible to obtain a life it is appropriate to limit intrave-
zinc deficiency. These include espe- plasma zinc determination, low se- nous zinc to the quantity required to
cially abnormalities of T-cell function, rum alkaline phosphatase activity is replace obligatory losses only.
the evidence for which include de- supportive of the diagnosis. How- Aesolution of the skin rashes of
layed cutaneous hypersensitivity and ever, this is a poor second to an severe zinc deficiency states in intra-
decreased lymphoblastic response to accurate plasma zinc determination. venously fed premature infants can
mitogens. Thymic size may be re- The possibility of a milder zinc de- be achieved with remarkably small
duced. Neutrophil and mononuclear ficiency state should be considered in quantities of zinc, ie, 100 ag/kg of
leukocyte chernotaxis may also be the differential diagnosis whenever body weight per day or less. Ob-
impaired in the zinc-deficient state. there is poor weight gain and unex- viously from the foregoing consider-
plained failure to thrive. The diagnosis ations, it is desirable to provide more
of these milder zinc deficiency syn- than this to achieve optimal zinc sta-
DIAGNOSIS
dromes remains problematic. The tus. As in the adult, it is possible that
Clinically, the diagnosis of severe clinical features are nonspecific, and intravenous zinc requirements may

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be considerably greater in some in- day by 2 months of postnatal age. It eg, as a growth-limiting factor, a die-
fants if they have unusually high also includes a figure of 25 g of zinc tary zinc supplement of 1 mg/kg of
losses of endogenus zinc via the gas- per kilogram of body weight per day body weight per day would be an
trointestinal tract. The clue to this is of endogenous zinc lost via the gas- appropriate starting point.
the continuing loss of substantial trointestinal tract, even in the ab-
quantities of fluid or feces via the sence of oral feeding. Once rapid
gastrointestinal tract during total par- postnatal growth has commenced, Zinc Overdosage and Misuse
enteral nutrition. Ideally, require- an additional 250 ,g of zinc per kilo- Accidental ingestion of large quan-
ments should be monitored by bal- gram of body weight per day should tities of zinc can cause vomiting and
ance studies, but this is rarely prac- be added. This figure for new tissue drowsiness. Of greater concern to-
ticable. is based on intrauterine accumulation day, is the relatively long-term inges-
rates. Calculations based on postna- tion of moderate excesses of zinc as
Treatment of Severe Zinc tal accumulation of fat-free tissue a result of various zinc therapy or
Deficiency States in Orally Fed containing an average of 30 ,.g of zinc supplementation programs. In
Infants zinc per gram would give a consid- adults, depression of high-density Ii-
Oral zinc requirements for the erably higher retention requirement in poprotein cholesterol has been re-
treatment of severe zinc deficiency many rapidly growing premature in- ported in these circumstances.
states have not been clearly defined. fants. Chronic overdosage with zinc can
They may depend, to some extent, Data from traditional zinc balance cause copper deficiency in persons
on the clinical circumstances and the studies indicate that it may be ex- of all ages, including premature in-
underlying cause of the zinc defi- traordmnarily difficult to reach this re- fants.
ciency. It is reasonable to start with quirement of the rapidly growing pre- Finally, the premature infant later in
5 mg of zinc per kilogram of body mature infant for retained zinc. In- infancy or childhood is not immune to
weight per day. This can be increased deed, it appears to be difficult to therapeutic abuse resulting from sci-
after three days if necessary. The achieve positive zinc balance in the entifically unsubstantiated claims for
dose can be changed according to orally fed very low-birth-weight infant the benefits of zinc supplements.
the clinical response and to plasma during the first 2 months of postnatal These claims are frequently associ-
zinc concentrations. If the clinical life, whatever feeding regimen is em- ated with data and diagnoses based
manifestations are attributable to the ployed. Heavy zinc supplementation on multi-element hair analyses. Par-
autosomal recessively inherited dis- of the special formulas used in the ents of children with chronic dis-
feeding of premature infants does not eases, learning problems, etc are pe-
order, acrodermatitis enteropathica,
treatment will have to be maintained appear to be associated with any irn- culiarly vulnerable to exploitation by
provement whatsoever in zinc reten-
indefinitely. In other circumstances, this kind of pseudoscientific practice.
discontinuation of zinc supplementa- tion. Fortification offormulas with iron
tion can be attempted when the sus- may further impair zinc absorption.
pected etiologic circumstance is no Infants fed with their own mothers’
CONCLUSIONS
longer operative. For example, if the milk may do a little better, despite
syndrome occurs in a breast-fed in- much lower zinc intakes, but again, Acute severe zinc deficiency in pre-
fant and the mother’s milk zinc con- their zinc status appears far from mature infants is uncommon, and its
centration is determined to be abnor-
ideal. The immaturity of the gastroin- incidence is probably decreasing fur-
mally low, zinc supplements can be testinal tract may render any attempt ther as zinc supplementation of intra-
discontinued at weaning. to improve zinc absorption ineffec- venous infusates becomes more rou-
tive. Because of the many unan- tine. However, in comparison with the
swered questions at this time, it is infant born at term, the premature
Nutritional Zinc Requirements of impractical to make a recommenda- infant is undoubtedly at greater risk
“Normal” Very Low-Birth-Weight tion or series of recommendations for for severe zinc deficiency syndromes
Premature Infants Fed Orally oral zinc intake in the very low-birth- and the possibility should always be
Absolute zinc requirements (as- weight-premature infant up to 2 considered in the presence of a
suming 100% absorption of dietary months postnatally. This applies es- suggestive skin rash. Treatment is
zinc and 100% reabsorption of en- pecially to the formula-fed infant. The simple and highly effective, once the
dogenous zinc secreted in pancreatic clinical implications of this situation diagnosis is made, whatever the un-
juices etc in response to a meal) are are, as mentioned earlier, uncertain. derlying cause. Currently, there
probably no more than 75 pg/kg of Poor intestinal absorption may be seems to be no ready answer to the
body weight per day plus whatever is counteracted to some extent by problem of achieving optimal zinc re-
required for new tissue. This figure release of zinc from bone during re- tention in the orally fed, very low-
includes a value of 40 zg of zinc per modeling. However in the circum- birth-weight infant during the first 2
kilogram of body weight per day ex- stances prevailing at this time, we months of postnatal life. Although the
creted in the urine which, though ap- need to be aware that there are spe- clinical implications of this situation
propriate for the first 3 weeks of post- cial reasons why some degree of zinc are far from clear, the possibility of
natal life, falls to a level of approxi- depletion may occur in the premature growth-limiting mild zinc deficiency
mately 10 g of zinc per kilogram per infant. If zinc deficiency is suspected, states should not be ignored.

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 Zinc Deficiency

ACKNOWLEDGMENTS tion and retention of magnesium, zinc, and infants: Evidence for a defect of mammary
copper by low birth weight infants fed pas- zinc secretion. Pediatrics 1982:69:176-183
This work was supported by grant No. 5
teunzed human breast milk. Pediatr Res
R22 AM1 2432 from the National Institute of 1977; 11:991-997
Arthritis, Metabolism and Digestive Diseases
Mild Zinc Deficiency
Hambidge KM, Jacobs MA, Barth AL, et al: Golden MHN, Golden BE: Effects of zinc sup-
(NIAMDD), and grant No. RR-69 from the Na-
Zinc balance in very low birth weight preterm plementation on the dietary intake, rate of
tional Institutes of Health, General Clinical Re-
infants fed own mother’s milk. Pediatr Res weight gain, and energy cost of tissue dep-
search Centers.
1984;18:198A osition in children recovering from severe
malnutrition. Am J Clin Nutr 198134:900-
SUGGESTED READING Zinc Absorption from Milks and Formulas 908
Casey CE, Walravens PA, Hambidge KM: Krebs NF, Hambidge KM, Walravens PA: In-
Books and Review Articles creased food intake of young children re-
Availability of zinc: Loading tests with human
Chesters JK: Metabolism and biochemistry of milk, cow’s milk, and infant formulas. Pedi- ceiving a zinc supplement. Am J Dis Child
zinc, in Clinical, Biochemical and Nutritional atrics 1981 63:394-396 1984:138:270-273
Aspects of Trace Elements. New York, Alan Walravens PA, Krebs NF, Hambidge KM: Lin-
R Liss, nc, 1982, pp 221-238 Severe Zinc Deficiency and Very Low- ear growth of low income preschool children
Hambidge KM: Hair analyses: Worthless for Birth-Weight Infants receiving a zinc supplement. Am J Clin Nutr
vitamins, limited for minerals. Am J Clin Nutr 1983:38:195-201
Arlete JP, Johnston MM: Zinc deficiency der-
1 982;36:943-949 matosis in premature infants receiving pro-
Hambidge KM, Walravens PA: Disorders of longed parenteral alimentation. Am Acad Plasma Zinc
mineral metabolism, in Clinics of Gastroen- Dermatol 1981:5:37-42 Gibson AS, Dewolfe MS: Changes in serum
terology, Philadephia, WB Saunders do, Kumar SP, Anday EK: Edema, hypoprotein- zinc concentrations of some Canadian full
1982, vol 11, pp 87-117 emia, and zinc deficiency in low-birth-weight term and low birthweight infants from birth
Shaw JCL: Trace elements in the fetus and infants. Pediatrics 1 984;73:327-329 to six months. Acta Paediatr Scand
young infant. Am J Dis Child 1979; Sivasubramanian KN, Henkin Al: Behavioral 1981 70:497-500
133:1260-1268 and dermatologic changes and low serum
zinc and copper concentrations in two pre- Requirements
Original Articles mature infants after parenteral alimentation. Zlotkin SH, Buchanan BE: Meeting zinc and
J Pediatr 1978;93:847-851 copper intake requirements in the parenter-
Zinc Balance in Premature Infants Zimmerman AW, Hambidge KM, Lepow ML, ally fed preterm and full-term infant. J Pediatr
Dauncey MJ, Shaw JCL, Urman J: The absorp- et al: Acrodermatitis in breast-fed premature 1983:103:441-446

Sarcoidosis
EDUCATIONAL OBJECTIVE
Sarcoidosis in Young Children. Hetherington S. Am J Dis Child 1982;1 36:13.
87. ApproprIate familiarity with the Childhood Sarcoidosis Holden KR, et al. Am J Dis Child 1975;1 29:103.
clinical presentation of sarcoidosis Sarcoidosis. Kendig EL. Am J Dis Child 1982;1 36:11.
in children (84/85 Recent Ad- Serum Angiotensin Converting Enzyme for Diagnosis and Therapeutic Evaluation
vances). of Sarcoidosis. Lieberman J, et al. Am Rev Respir Dis 1979;1 20:329.
Sarcoidosis is a granulomatous disorder of undetermined cause involving multiple
organs. The clinical picture varies with age. Hetherington reviewed 8 cases of sarcoid-
osis in children less than 4 years of age. The common presentations were rash (75%),
arthritis (60%), and uveitis (60%). The rash was described as erythematous, maculo-
papular, with slight scaling starting peripherally and then becoming generalized. Joint
symptoms began with early morning stiffness, progressing to boggy, nondeforming,
painless effusions and synovial thickening. Ocular changes included posterior synech-
iae, uveitis, optic atrophy, miliary retinitis, and granulomas of the conjunctivae and
optic nerve. In contrast, Hetherington noted that in children more than 4 years of age
pulmonary involvement was seen in 70%, lymphadenopathy in 45%, uveitis in 40%,
and rash in 35%.
According to Kendig, the hallmark of the disease in older children is radiologic
evidence of bilateral hilar adenopathy with or without parenchymal involvement. Holden
and Heller noted five patterns of pulmonary sarcoidosis. They are: (1) miliary densities,
(2) micronodular lesions, (3) large confluent mass lesions that may progress to
cavitation, (4) interstitial fibrosis, and (5) alveolar sarcoid resembling pulmonary edema.
Laboratory test findings that may help corroborate the diagnosis are hyperglobuli-
nemia, eosinophilia with leukopenia, and increased alkaline phosphatase. Hypercal-
cemia is an uncommon finding in children with sarcoidosis. The Kveim test is thought
to be a specific skin reaction for sarcoidosis, but the scarcity of materials limits its
usefulness. Serum angiotensin-converting enzyme assay has been utilized to support
the diagnosis. A serum angiotensin-converting enzyme assay value of 50 U/mL or
greater appears necessary to distinguish children with active sarcoidosis compared
with a 35 U/mL level in adults (Lieberman et al). This test is also useful to assess the
activity of the disease and the efficacy of steroid therapy. Biopsy of a lymph node or
an organ showing epithelioid noncaseating granulomas is usually essential to prove
the diagnosis unequivocally. (C. Uy, NJ Medical School)

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 Zinc Deficiency in the Premature Infant
K. Michael Hambidge
Pediatrics in Review 1985;6;209
DOI: 10.1542/pir.6-7-209

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 Zinc Deficiency in the Premature Infant
K. Michael Hambidge
Pediatrics in Review 1985;6;209
DOI: 10.1542/pir.6-7-209

The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://pedsinreview.aappublications.org/content/6/7/209

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and
trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143.
Copyright © 1985 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.

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