COMMITTEE ON NUTRITION
134
IRON
BALANCE
AND
REQUIREMENTS
IN
INFANCY
H
UMAN iron requirements andmetabo-lism of iron during the first 18
months of life have been the subjects of a
number of reports, reviews, and
commen-taxies over the past decade.1#{176} Sufficient knowledge has been accumulated to permit
a clear statement of dietary
recommenda-tions. Implementation of these would assure
a satisfactory iron intake for the majority of
North American infants and minimize the
incidence of serious iron deficiency.
Several official recommendations
concern-ing human iron requirements have been
made.9 Not all have emphasized clearly
the unique requirements of infants,
espe-cially low birth weight infants. In addition,
they have failed to agree upon dietary
re-quirements during the first year of life and
have not indicated practical ways of
achiev-ing a satisfactory iron intake. The present
memorandum reviews current knowledge
concerning iron needs of infants, attempts to
quantitate iron requirements in relation to
birth weight and age, and examines
practi-cal methods for assuring adequate iron
in-takes. In addition, certain persistent gaps in
our understanding of iron metabolism,
sub-jects of controversy, and areas of investiga-tive potential are reviewed.
IRON ENDOWMENT OF THE NEWBORN
Data obtained from carcass analysis
per-formed on a small number of stillborn
in-fants indicate that the body of the average
term weight infant contains about 75
mg/kg of iron. There is a considerable
range, however, in the actual values
ob-tained by this measurement.1#{176} The iron
con-tent of the circulating blood can be fairly
accurately estimated from the red cell mass,
and it is evident that more than three
quar-ters of the infant’s iron endowment is in the
red cell. Tissue stores as such probably
ac-count for less than 10 to 20 mg of iron.” No
data are available concerning the effect of
maternal iron depletion upon the
extra-he-moglobin iron stores of the fetus; but,
be-cause of the small size of this iron
compart-ment, its effect on iron endowment must
be minimal. Since iron stores cannot be
measured accurately in living infants, most
attention has centered upon those factors
which influence the initial hemoglobin
mass. In normal newborns, levels of
hemo-globin in cord blood vary from 13.7 to 20.1
gm/ 100 ml” and hematocrits vary from
53% to 79%13 Differences between these
ex-tremes may constitute differences in body
iron amounting to as much as 50 mg. The
factors which contribute to this variability
are not well defined. Most evidence
mdi-cates that the maternal iron status has little
effect on the infant’s initial hemoglobin
level. Multiparity, low socioeconomic
sta-tus, and racial factors are commonly linked
with a high incidence of iron-deficiency
anemia in the older infant. The frequent
as-sociation of these situations with low birth
weight and with an inadequate postnatal
intake of iron are probably far more
impor-tant than any maternal effects on the
in-fant’s iron endowment’4”3 Likewise, the
magnitude of the placental transfusion,
al-though important, does not have the
deci-sive effect upon a broad range of neonatal
hemoglobin values.16”7 A systematic study
of the regulation of fetal erythropoiesis is
needed to provide a better understanding
of the causes of variability in the infant’s
iron endowment.
During the 6 to 8 weeks following birth,
erythropoiesis virtually ceases. The
concen-tration of circulating hemoglobin decreases
at a rate which is proportional to the short
life span of fetal red cellsls and to the
ex-panding volume of distribution. The iron
derived from red cell breakdown is retained
and used when hematopoiesis resumes. The
size of this reserve and the time and rate at
which it is utilized depends upon the size
of the initial hemoglobin mass.
In addition to low birth weight infants
and those with low initial hemoglobin
1ev-els, infants who experience various types of
blood loss are at risk for development of
iron deficiency. The iron endowment of an
occasional infant may be reduced by blood
loss in the perinatal period. Massive
feto-maternal hemorrhages during pregnancy,
though unusual, have been documented19
and iron-deficiency anemia due to chronic
transplacental hemorrhage has been
recog-nized at birth. 20.21 Transfusions between
identical twins, energetic diagnostic
phle-botomy, external hemorrhage, and
ex-change transfusions may significantly
di-minish the hemoglobin mass.
The only practical indicators of the
new-born’s iron endowment are body weight
and initial hemoglobin level. Measurement
of hemoglobin or hematocrit should be
per-formed in all infants in the neonatal period
if an assessment of iron endowment is
sought. This may be performed from free
flowing capillary blood on the third or
fourth day of life. When this value is
exam-ined in relation to birth weight, most
in-fants with greater than normal iron
require-ments during the first year will be
identi-fied.
ASSESSMENT OF IRON STATUS OF THE INFANT
A well defined sequence of changes
oc-curs in progressive iron depletion.
1. The storage forms of iron,
hemosid-erin and ferritin, disappear and cannot be
demonstrated in bone marrow and other
re-ticuloendothelial tissues.
2. The level of serum iron decreases and
concomitantly the serum iron-binding
ca-pacity increases, resulting in a decreased
percent iron saturation. A serum iron
satu-ration of less than 15% is indicative of iron
depletion.
3. A slight decrease in the circulating red
cell mass occurs.
4. Changes in red cell morphology,
in-eluding microcytosis and hypochromia, and
poikilocytosis appear.
5. Anemia of a progressive degree of
se-verity supervenes.
6. Decreases of the intracellular iron
content of enzymes ultimately develop,
al-though the point at which this depletion
begins is uncertain.”
During infancy, normal values for the
various measures of iron balance differ
con-siderably from those observed in adults. Unless appropriate standards based upon
age are used when evaluating infants in the
first 18 months of life, misinterpretations
are unavoidable. Bone marrow
hemosid-erin, a form of storage iron that is easily
ac-cessible to study, is virtually absent after 6
months of age.” Levels of serum iron in
healthy infants are lower than are those of
adults. The ranges of hemoglobin and
he-matocrit values are considerably lower than
those of the adult. The practice of reporting
hemoglobin values of infants as a percent
of an arbitrary adult standard should be
abandoned to avoid an unwarranted
diag-nosis of anemia.
Hemoglobin concentration and
hemato-crit are widely used to assess iron
ade-quacy. Sturgeon4 reported that, when
nor-mal infants were provided with relatively
generous amounts of food or medicinal iron
(
between 1 to 2 mg/kg/day), the meanhe-moglobin level at 1 year of age was 11.6
gm/ 100 ml. Administration of parenteral
iron to such infants at 9 months of age
in-creased the mean hemoglobin by less than
1 gm/100 ml (mean, 12.3 gm/100 ml).
Be-tween 3 and 18 months of age, a
hemoglo-bin of about 12 gm/ 100 ml, or a hematocrit
of 36%, may be considered optimal. Since
hemoglobin and hematocrit values will
as-sume a “normal” or Gaussian distribution,
hemoglobin levels as low as 11 gm/100 ml,
and hematocrits as low as 33% will fall
within one and a half standard deviations
of these means and should be considered
“normal.”
The prevalence of iron depletion or iron
deficiency depend upon the criteria
136
degrees of anemia develop due to
made-quate hemoglobin synthesis, iron deficiency
is fairly advanced and morphologic
abnor-malities of the red cells are evident. The
need to fulfill at least minimum diagnostic
criteria for iron deficiency anemia must be
emphasized. Minimum criteria include
mi-crocytosis and hypochromia of the red cells
in a smear of peripheral blood and a
re-sponse to specific therapy. A careful history
(including family history), physical
exami-nation, and examination of the blood smear
may suggest other forms of anemia, for
which iron therapy will be ineffectual.
NON-HEMOGLOBIN ASPECTS OF
IRON DEFICIENCY
Iron is an important constituent of
sev-eral intracellular oxidative enzymes. The
activities of various iron-containing
en-zymes have been studied in iron-deficient
animals and humans. Activity of some
en-zymes, and cofactors such as cytochrome C
and aconitase, is decreased while activity of
others, such as catalase and cytochrome
oxi-dase, is unchanged.24”5 Whether or not
these decreases have functional
signifi-cance is uncertain. For example, the
respi-ration of leukocytes from iron-deficient
pa-tients is normal’6 and oxygen consumption
by the iron-deficient patient does not differ
from normal.27 On the other hand, oxidative
metabolism in muscle homogenates from
se-verely iron-deficient rats is significantly
impaired.25
An increase in the frequency of
respira-tory infections has been reported in infants
with iron deficiency, as well as a reduced
incidence in such infections in children
re-ceiving iron supplements, even when
signif-icant anemia was absent.28 Confirmation of
such effects would imply previously
unsus-pected metabolic functions of iron in hu
mans. The proper design and control of
prospective studies to document this
obser-vation are extremely difficult and, at
pres-ent, such effects of iron deficiency or of
therapy must be considered unproven.
Symptoms such as fatigue, weakness, and
pallor, commonly ascribed to iron
defi-ciency, have been shown to be unrelated to
the levels of hemoglobin and hematocrit in
surveys of otherwise healthy individuals.’9
The entire question of tissue effects of iron
depletion is of great interest and demands
imaginative investigation.30
IRON ABSORPTION
Iron is absorbed from both dietary and
medicinal sources even early in life.31’3’
However, in the term infant, only a
rela-tively small amount of absorbed iron is
in-corporated into circulating hemoglobin
dur-ing the first 6 months of life. This point was
demonstrated convincingly by the studies
of Smith and associates,33 who labeled the
hemoglobin of infants in utero with Fe55.
By 6 months of age, the specific activity of
the hemoglobin had decreased by only
about 20%. These data indicate that only a
small amount of postnatally absorbed iron
is incorporated into hemoglobin and
sup-port the observations that iron
supplemen-tation of the diets of full-term infants has a
minimal effect on hemoglobin levels during
the first 4 to 5 months of life.’8 Iron which
is absorbed in the early weeks of life,
however, may exert a prophylactic effect
against iron deficiency anemia in the later
months of infancy.’8 By contrast, premature
infants incorporate considerable amounts of
dietary iron into hemoglobin by 2 to 4
months of age.34
The efficiency of absorption of various
forms of dietary iron depends to some
ex-tent upon the food in which it is contained.
In most estimates of dietary iron
require-ments, an absorption of 10% is assumed.
This value is merely a convenient
approxi-mation and may not be valid for an
individ-ual patient. Non-anemic infants may absorb
between 5 and 20% of iron from eggs,
meats, and cereals. In contrast, premature
infants have been shown to absorb an
aver-age of 32% of iron contained in fortified
milks.31’34 This is comparable to absorption
of medicinal iron by infants with iron
defi-ciency.35
Dietary constituents such as ascorbic
ap-137
parently by maintaining ionic iron in the
ferrous form.6 Other substances such as
phosphates and phytates may decrease iron
absorption by forming insoluble complexes,
although the effect of phytates present in
the usual diet is probably not significant.3
IRON EXCRETION AND BLOOD LOSS
Physiological iron excretion is probably
negligible during infancy,’ but blood loss of
any sort imposes an increased need for iron.
The possibility of blood loss should be
con-sidered in every infant or child with severe
iron deficiency. Wilson and associates have
described a syndrome of chronic blood loss
due to gastrointestinal intolerance to whole
cows milk and believe it to be a common
cause of iron deficiency anemia.38’39 A
lively controversy is now in progress
con-cerning the importance of this condition.
Diamond states that he has recognized it
only once or twice in his large experience40
and believes blood loss is a secondary
gas-trointestinal manifestation of iron
defi-ciency rather than a primary cause. The prevalence of this syndrome must be
deter-mined in anemic infants before its
impor-tance as a cause of iron deficiency anemia
can be established. In some areas of the
country hookworm infestation may be a
common cause of iron deficiency.
IRON CONTENTS OF FOODS
Human and cows milk contain little iron
(about 1.5 mg/l and 0.5 mg/l,
respec-tively) 41 42 About 15 quarts of cows milk
would have to be consumed each day to
provide enough iron to meet the
require-ments of normal infants during the first
year of life! When milk accounts for a large
proportion of the infant’s calories, the diet
will perforce be grossly deficient in iron.
The most important source of iron in the
diet of American infants is cereal that has
been artificially fortified with reduced iron
or iron-pyrophosphate during processing.
Such cereals contain 8.6 to 22 mg of iron in
each dry ounce. Limited amounts of eggs
and meats are ordinarily consumed during
the first year of life and so usually
contrib-ute a relatively small proportion of the total
iron requirements. Although it is sometimes
believed that the child receiving only
human milk does not become iron deficient,
there is little published data to support this
opinion. In fact, in a small series of
pa-tients, Moe has shown the same incidence
of iron deficiency in babies fed human milk
as in those fed cows milk.’
It has not been widely appreciated that
methods of preparation and cooking affect
the iron content of food. Although Moore has reported that the iron content of some
acid foods prepared at home in iron utensils
may be increased 30 to 100 times over that
of the same food cooked in glass or
alumi-num utensi1s, the effect of cooking vessels on iron content of ordinary foods is far less striking. In certain geographic regions, a high iron level in soil or water may increase the iron content of the diet sufficiently to
invalidate calculations of dietary iron based
only on food composition tables. In fact,
“contamination” of foods by non-food iron
may represent a most significant source of
iron, although the strict sanitary methods
which are used for modern food processing
in fact result in exclusion of much iron from the diet. A recent study showing a striking
geographic variability in the prevalence of
anemia in preschool American children sup-ports the thesis that local factors may appreciably affect iron balance.4
IRON REQUIREMENTS
The amount of iron which should be
pro-vided by the infant’s diet has been
esti-mated by two different methods with
simi-lar results. The first involves calculations based upon estimates of the infant’s
aver-age body iron content at birth and at 1 year
of age. The difference between these two
values approximates the net increase in
body iron which must be realized from the
diet during the first year of life. Using this
approach, Schulman’ derived a value of 0.8
mg/day which must be absorbed by infants
to supply the amount needed after the iron
derived from the high concentration of
hemoglobin synthesis. Thus, he calculated
that the daily diet of the normal term infant
must contain 8 mg of iron by 6 months of
age. The term infant with a low initial iron
endowment requires this amount by 3 to 4
months of age, and the low birth weight
in-fant, requires this amount by 2 months of
age. Gairdner, using similar calculations,
arrived at a comparable requirement.46
The second method of determining
di-etary iron requirements has involved the
administration of various amounts of iron to
groups of infants and observation of effects
on hemoglobin concentration. In extensive
studies of this type Sturgeon4 demonstrated
that highest hemoglobin levels were
at-tained by infants who consistently received
daily iron intake of about 1.0 mg/kg.
Based upon an absorption efficiency of
10%, an intake of 1.0 mg/kg/day to a
maxi-mum of 15 mg, if begun at an appropriate
time with respect to initial iron endowment, will provide sufficient iron to maintain
nor-mal hemoglobin values in most infants. This
figure allows some leeway for individual
variability in absorption and iron
endow-ment. A somewhat greater allowance
(
2.0mg/kg/day begun by age 2 months to a
maximum of 15 mg) is advisable for low
birth weight infants, for infants with low initial hemoglobin values, and for those
who have experienced significant blood
loss. In 1960, the Committee on Nutrition
recommended an iron intake of 1.5
mg/kg/day for all infants.9 Because of the
rather marked differences between the iron
needs of normal term infants and those
in-fants who fall in the foregoing special
cate-gories, it is now believed that the separate
recommendations should be stated.
SPECIFIC DIETARY RECOMMENDATIONS
Food naturally rich in iron such as meats
and eggs are expensive and tend to be
re-stricted especially in the diets of the poorer
segments of the population. Although this
memorandum deals with iron, it is obvious
that nutritional adequacy cannot be assured
by simple iron supplementation, and all
ele-ments of dietary intake must be considered.
Iron content of a diet consisting primarily
of unfortifled milk is always inadequate.
Even when a good mixed diet is consumed,
the intake of iron does not usually exceed
6.0 mg per 1,000 kcal unless foods
artificially enriched with iron are utilized.4
To meet the recommendations of this
mem-orandum, iron supplemented foods are
nec-essary during infancy.
Iron requirements of normal infants can
be met in a number of ways. Daily
con-sumption of 3 oz dry weight of iron
en-riched baby cereal (2 to 3 dry tablespoons
or 30 to 45 cc of reconstituted cereal
)
be-ginning by 6 weeks of age and
progres-sively increasing to % oz dry weight (5
to 6 dry tablespoons or 60 to 90 cc of
recon-stituted cereal) by 6 months of age assures
an adequate iron intake for all infants
ex-cept those with low initial endowment.
Commercial infant cereals provide 8.6 to 22
mg of iron/ dry ounce of cereal.
Consumption of iron-enriched milk
for-mulas also assures adequate iron intake.
Several studies have indicated that
iron-de-ficiency anemia can be prevented by the use
of cows milk formula to which iron has
been added.’8’47”8
Unfortunately, because of cost or
prac-tice by mothers, these excellent sources are
not regularly utilized. The consumption of
iron-fortified baby cereals decreases
markedly during the second 6 months of
life, so that by 12 months of age most
in-fants no longer receive these cereals. In
common usage, few infants continue to
re-ceive proprietary milk formulas after 6
months of age.5#{176}Although experience
indi-cates that many robust infants consuming a
balanced, varied diet with abundant meats
and eggs may not develop iron deficiency
anemia, pediatricians should emphasize the
importance of inclusion in the diet of
iron-supplemented foods for at least 18 months
in order to assure optimal iron intake for
their patients.
This Committee suggests the most
effec-tive way to prevent iron deficiency on a
large scale is to provide an iron-fortified
weeks of age for infant consumption. Milk
or carbohydrate staples
(
cereal, bread,grits, rice
)
have been shown to be suitablefor fortification. The most appropriate food
selected for iron enrichment may vary in
different sections of the country and in
dif-ferent ethnic and social groups. At present
such supplemented food staples are not in
general use and efforts to identify and
de-velop suitable vehicles for enrichment are
mandatory if optimal iron nutrition is to be
assured. Research into the most suitable
chemical form of the iron supplement must
be continued, since absorption of several
iron additives may vary considerably.51 The
low birth weight infant and infants with
re-duced iron endowment, as previously
de-scribed, need relatively larger amounts of
iron. It is doubtful that diet alone, even
when iron supplemented cereals are used,
can provide sufficient iron for these greater
requirements. Iron fortified milk or
medici-nal iron should be prescribed in order to
as-sure an iron intake of at least 2 mg/kg/day
to a maximum of 15 mg/day for infants
with reduced iron endowment.
IRON DEFICIENCY AFTER INFANCY
Recent surveys from widely separated
areas in the United States suggest that
se-vere nutritional anemia is not an important
universal problem by 4 to 6 years of age,
even in children from low socioeconomic
backgrounds. For example, in Chicago only
5.5% of such children had hematocrits
below 32%, and the mean hematocrit (36%)
for these children did not differ
signifi-cantly from normal.45 This is in the same
lo-cale where a 25 to 30% incidence of severe
iron deficiency of infancy has been
described.’ Therefore, it seems likely that,
except for anemias secondary to blood loss,
symptomatic problems of iron nutrition in
childhood are largely restricted to the first
2 years of life.
IRON THERAPY
When iron deficiency anemia is
diag-nosed, specific therapy is usually
recom-mended. Oral therapy with simple ferrous
salts
(
sulfate, gluconate, fumarate)
pro-vides an inexpensive and predictably
satis-factory response. There is no evidence that
addition of any trace metal, additional
he-matinic substance or vitamin, increases
appreciably the clinical response to simple
ferrous salts. Indeed, absorption of other
iron compounds or chelates may be
sub-op-timal occasionally, and therapeutic
“fail-ures” may result when such compounds are
used.5253
The therapeutic dosage of iron must be
calculated in terms of elemental iron. A
total of 6 mg/kg/day of elemental iron
given in three divided doses between meals
provides an adequate amount of iron for
the stimulated bone marrow to utilize.
Doses in excess of 6 mg/kg/day will not
re-sult in a more rapid hematologic response
and may, in fact, increase the possibility of
intolerance when administered, although
intolerance to oral iron is extremely rare in
pediatric practice. Decreased absorption of
oral iron has not been convincingly
docu-mented as a cause of iron deficiency or
therapeutic failure.
Only one effective parenteral iron
prepa-ration, iron-dextran
(
Imferon)
is currentlyavailable for pediatric use. Oncogenic
prop-erties of this preparation in experimental
animals have not been substantiated in
humans.5 However, there is no proof that
the hematologic response to parenteral iron
is significantly faster or more complete than
that to properly administered oral iron, and
its use for prophylaxis is unwarranted. In
most instances the indication for
adminis-tration of parenteral iron for treatment of
infants and children is a social one; that is,
a parent who for social or intellectual
rea-sons cannot be relied upon to properly
ad-minister oral iron.
Medicinal iron should be continued for a
month or so after normal hemoglobin levels
have been attained to assure replacement of
the child’s iron stores. Although there are
potential harmful effects of iron overload in
the tissues of the body in the normal
indi-vidual, these complications result only after
doses of medicinal iron. On the other hand,
in chronic anemias such as thalassemia
major, which are associated with greatly
in-creased iron absorption, medicinal iron may
signfficantly increase the body burden of
iron and contribute to an earlier death.
Acute poisoning due to accidental
inges-tion of medicinal iron is a serious problem.
The importance of keeping containers of
iron medications from the reach of young
children cannot be overemphasized. SUMMARY
1. The iron endowment of the newborn
is proportional to the initial hemoglobin
mass. This in turn depends upon the birth
weight and initial hemoglobin level. The
presence of low birth weight or decreased
hemoglobin level in the first few days of
life may identify infants with special iron
requirements during the first 18 months of
life.
2. It is recommended that the diet of
normal term infants provide 1.0 mg/kg/day
of iron by 3 months of age to a maximum
in-take of 15 mg/day. This requirement can
be easily met by inclusion in the diet of
appropriate amounts of foods which have
been enriched with iron, such as infant
cereals or milk formulas.
3. Infants with low birth weight and
oth-ers with reduced iron endowment require
as much as 2.0 mg of iron per kilogram per
day beginning by 2 months of age. This
amount of iron will not ordinarily be
pro-vided by the diet, even if
iron-supple-mented cereals are given. Attainment of
these larger amounts requires the use of
me-dicinal iron or iron-supplemented milk
for-mula.
4. Attention should be directed to
pro-viding a variety of iron-enriched dietary
staples to be used routinely for feeding
American infants during the period of life
from 3 to 18 months of age and to more
pre-cisely determining the best form of iron
supplementation. At the present time iron
fortified baby cereals and milk formulas are
the iron supplemented foods most generally
available. These are not utilized by the
seg-ments of the American population which
have the greatest need for them.
Crius U. Lowi, M.D., Chairman
DAVID B. CounslN, M.D. LLOYD
J.
FILER, JR., M.D. FELIX P. HEALD, M.D.MALCOLM A. HOLLIDAY, M.D.
D0N0uGH O’BRIEN, M.D.
GEORGE M. OWEN, M.D.
Howuw A. PEuisoN, M.D.
CHARLES R. Saiwn, M.D.
REFERENCES
1. Moe, P. J.: Iron requirements in infancy. Longitudinal studies of iron requirements during the first year of life. Acta Paediat. (Suppl. 150), 1-67, 1963.
2. Josephs, H. W. : Absorption of iron as a
prob-lem in human physiology. Blood, 13: 1, 1958. 3. Sturgeon, P. : Iron metabolism : A review with
special consideration of iron requirements
during normal infancy. PEDIATRICS, 18:267, 1956.
4. Sturgeon, P. : Studies of iron requirements in infants and children. In Wallerstein, R. 0.,
and Mettier, S. R., ed. : Iron in Clinical Med-icine. Berkeley: University of California Press, p. 183, 1958.
5. Gardner, D. : Haematology of infancy. In Re-cent Advances in Paediatrics, ed. 2. Boston:
Little, Brown and Company, p. 50, 1958.
6. Erlandson, M. D. : Iron metabolism and iron
deficiency anemia. Pediat. Clin. N. Amer., 9:673, 1962.
7. Schulman, I. : Iron requirements in infancy. J.A.M.A., 175:118, 1961.
8. Recommended Dietary Allowances, ed 6.
Washington, D.C.: National Academy of
Science, National Research Council, Publica-tion 1146, p. 18, 1964.
9. Committee on Nutrition: Trace elements in
human nutrition. PEDIATRICS, 26:715, 1960.
10. Widdowson, E. M., and Spray, C. M.: Chemi-cal development in utero. Arch. Dis. Child.,
26:205, 1951.
11. Gorten, M. K.: Iron metabolism in premature infants. Amer. J. Clin. Nutr., 17:322, 1965.
12. Gatti, R. A.: Hematocrit values of capillary
blood in the newborn infant. J. Pediat.,
70:117, 1967.
13. Oski, F. H., and Naiman, J. L.: Hematologic
Problems in the Newborn. In Schaffer, A. J.,
ed: Major Problems in Clinical Pediatrics.
Philadelphia: W. B. Saunders Company, p. 9,
1966.
14. Pribilla, W., Bothwell, T. H., and Finch, C. A.: Iron transport to the fetus in man. in
Iron in Clinical Medicine. Berkeley: Univer-sity of California Press, p. 58, 1958.
15. Dawson, J., and Desforges, J. F. : Dietary and storage factors in iron deficiency anemia of infancy. J. Dis. Child., 96:169, 1958.
16. Wipple, G. A., Sisson, T. R. C., and Lund,
C. J.: Delayed ligation of the umbilical cord.
Obst. Gynec., 10:603, 1957.
17. Usher, R., Shepard, M., and Lind, J.: The blood volume of the newborn infant and placental transfusion. Acta Paediat., 52:497,
1963.
18. Pearson, H. A. : Life span of the fetal red
blood cell. J. Pediat., 70: 166, 1967.
19. Cohen, F., Zuelzer, W. W., Gustafson, D. C.,
and Evans, M. M. : Mechanisms of
isoin-munization. Blood, 23:621, 1964.
20. Pearson, H. A., and Diamond, L. K. :
Fetoma-ternal hemorrhage. J. Dis. Child., 97:267, 1959.
21. Eshaghpour, E., Oski, F. A., and Naiman, J. L.: Iron deficiency anemia in a newborn
in-fant. J. Pediat., 68:806, 1966.
22. Harris, J. W. : The Red Cell. Cambridge, Mas-sachusetts: Harvard University Press, p. 60,
1963.
23. Smith, N. J., Rosello, S., Say, M. B., and Yeya, K.: Iron storage in the first five years of life.
PEDIATRICS, 16:166, 1955.
24. Beutler, E. : Iron metabolism. Ann. Rev. Med.,
12:195, 1961.
25. Daflman, P. R., and Schwartz, H. : Distribution of cytochrome C and myoglobin in rats with dietary iron deficiency. PEDIATRICS, 35: 677,
1965.
26. Jacobs, A. : Leukocyte oxygen consumption in iron deficiency anaemia. Brit. J. Exper. Path., 46:545, 1965.
27. Beutler, E., Larsh, S. E., and Tanzi, F. : Iron
enzymes in iron deficiency. VIII. Oxygen
consumption measurements in iron deficient
subjects. Amer. J. Med. Sci., 239:759, 1960.
28. Andelman, M. B., and Sered, B. R. : Utilization of dietary iron by term infants. Amer. J. Dis. Child., 111:45, 1966.
29. Wood, M. M., and Elwood, P. C. : Symptoms of iron deficiency anemia, a community survey. Brit. J. Prevent. Soc. Med., 20:117, 1966. 30. Beutler, E.: Tissue Effects of Iron Deficiency in Iron Metabolism, Series Haematologica
No. 6, Bjorkman, S. E., ed. Copenhagen: Munksgaard, p. 41, 1965.
31. Smith, N. J., and Schulz, J.: The absorption of iron in infants and children. In Wallerstein, R. 0., and Mettier, S. R., ed.: Iron in Clinical
Medicine. Berkeley: University of California Press, p. 65, 1958.
32. Garby, L., and Sj#{246}len,S.: Absorption of la-belled iron in infants less than three months
old. Acta Paediat. (Suppl. 117), 24, 1959.
33. Smith, C. A., Cherry, R. B., Maletkos, C. J., Gibson, J. P., II, Roby, C. C., Caton, W. C., and Reid, D. E. : Persistence and
utiliza-tion of maternal iron for blood formation
during infancy. J. Clin. Invest., 34:1391, 1955.
34. Gorton, M. K., Hepner, R., and \Vorkman, J. B.: Iron metabolism in preniature infants. J. Pediat., 63:1063, 1963.
35. Schulz, J., and Smith, N. J.: A quantitative study of the absorption of iron salts in
in-fants and children. J. Dis. Child., 95:120, 1958.
36. Moore, C. V. : Etiology of iron deficiency ane-mia. in Wallerstein, R. 0., and Mettier, S. R., ed : Iron in Clinical Medicine. Berkeley:
University of California Press, p. 133, 1958. 37. Effect of phytate on iron absorption. Nutr.
Rev., 25:218, 1967.
38. Wilson, J. F., Heiner, D. C., and Lahey, M. E.: Studies on iron metabolism milk-induced
gastrointestinal bleeding in infants with by-pochromic microcytic anemia. J.A.M A.,
189:122, 1964.
39. Lahey, M. E., and Wilson, J. F. : The etiology
of iron deficiency anemia in infants-a reappraisal. J. Pediat., 69:339, 1966.
40. Diamond, L. K., and Naiman, J. L.: Letter to
editor. J. Pediat., 40:304, 1967.
41. U.S. Department of Agriculture Handbook No. 8. Washington, D.C. : Government Printing
Office, Item 1336, p. 39, 1963.
42. The Composition of Milks. Publication No.
254. Washington, D.C. : National Research Council, 1953.
43. Moore, C. V. : Iron Nutrition and Require-ments in Iron Metabolism. Series Haemato-logica No. 6, Bjorkman, S. E., ed. Copen-hagen: Munksgaard, p. 1, 1965.
44. Monson, E. R., Kuhn, I. N., and Finch, C. A.: Iron status of menstruating women. Amer. J. Clin. Nutr., 20:842, 1967.
45. Pearson, H. A., Abrams, I., Fernbach, D. J.,
Gyland, S. P., and Hahn, D. A. : Anemia in
Preschool Children in the United States of
America. Pediat. Res., 1 : 169, 1967.
46. Gairdner, D. : The haematology of infancy. In
Gairdner, D., ed, Recent Advances in
Pae-diatncs. Boston: Little, Brown and Company, p. 63, 1958.
47. Niccum, W. L., Jackson, R. L., and Stearns, C.: Use of ferric and ferrous iron in
preven-tion of hypochromic anemia in infants. Amer. J. Dis. Child., 86:553, 1953. 48. Marsh, A., Long, H., Stierwalt, E.:
Compara-tive hematologic response to iron fortifica-tion of a milk formula for infants. PEDIAT-RICS, 24:404, 1959.
49. Beal, V. A., Meyers, A. J., and McCammon,
growth during the first 2 years of life.
PEDI-ATRICS, 30:518, 1962.
50. Foman, S. J.: Infant Nutrition. Philadelphia:
W. B. Saunders Company, p. 5, 1967.
51. Iron in Flour-Reports on Public Health and Medical Subjects, No. 117. London: Ministry
of Health, H.M.S.O., 1968.
52. Diamond, L. K., Naiman, J. L., Allen, D. M., and Oski, F. A.: The treatment of iron
defi-ciency anemia-palatable but ineffective iron medication. PEDIATRICS, 31:1041, 1963. 53. Beutler, E., and Murkrubs, C.: Letter to the
Editor. New Eng. J. Med., 274:1153, 1966. 54. Woodruff, C. W.: The utilization of iron
