IRON DEFICIENCY IN THE PREMATURE INFANT

(1)

IRON DEFICIENCYIN THE PREMATURE INFANT

Signifkance, and Prevention by the Intramuscular

Administration of Iron-dextran

John A. James, M.B., M.R.C.P., and MoIIie Combes, M.D. Department of Pediatrics, University of Texas Southwestern Medical School, and Parkland

Memorial Hospital, Dallas

I NFANTS born prematurely experience a greater than usual number of serious illnesses throughout the first 2 years of life.1-4 We have previously reported5 that 1 out of every 4 premature infants discharged from our nursery required re-admission to the hospital before the second birthday, usually for treatment of pneumonia or diar rheal disease. The great majority of these babies were also found to have iron defi

ciency anemia. In view of the widely-held

clinical belief that iron deficiency anemia is associated with an increased incidence of infections,@7 it seemed desirable to study the health record of a group of premature infants maintained in a state of abundant iron nutrition; evidence that the number of infections in such a group was reduced would be of considerable theoretic and clin ical interest. Another object of this study was to determine whether the â€œ¿prophylac ticâ€•use of intramuscular injections of iron dextran during the nursery stay was a method of preventing iron deficiency ane mia suitable for use in clinical practice.

SUBJECTSAND METHODS

Two hundred and five, consecutive, prema turely born babies, who weighed 2,000 grams

or less and had survived for at least 24 hours, were allocated by random selection to a group to receive iron-dextran and a control group. On reaching 2,000 grams in weight, babies

in the iron-dextran group were given 1 ml of iron-dextranÂ° daily by deep intramuscular in

oImferonâ€”supplied through the courtesy of Lake side Laboratories, Inc. Each milliliter of this iron dextran complex provides the equivalent of 50 mg of elemental iron.

jection in alternate buttocks for 5 days. This

dosage supplied a total of 250 mg of elemental iron, the quantity used in a similar study;8 ac

cording to the calculations of Sturgeon,9 this

quantity should be sufficient to provide the iron requirements necessitated by growth during the

first year in most infants, even if no additional iron was absorbed from the intestinal tract. After discharge from the nursery, the babies were seen in the premature clinic monthly by one of

us and both groups were given similar advice

regarding increases of milk formula and intro

duction of solid foods.

Duplicate determinations of hemoglobin

(oxyhemoglobin) and the micro-hematocrit'Â° were carried out weekly in the nursery and

monthly at follow-up visits; blood smears and

sickle-cell preparations were examined in all anemic infants. Babies in the control group usually received no supplemental iron, unless the hemoglobin declined below 7 gm/100 ml; then, oral administration of iron preparationsÂ°

(supplying 60 mg of elemental iron daily) was

used for 1 or 2 months.

Additional data concerning morbidity and

mortality in both groups of infants were ob tained from study of the hospital records and from the Vital Statistics of the Dallas City and

County Health Departments, which frequently yielded information about infants whose clinic

follow-up record was deficient. Since some of the babies lost to follow-up may have become ill or died in hospitals outside the city area, these data may not be complete, but there seems no reason to suppose that this would affect comparison between the two groups.

* Either ferrous sulfate (Fer-in-Sol, supplied

through courtesy of Mead Johnson and Company), or iron choline citrate (Chel-Iron, courtesy of Kin

ney and Company, Inc.).

This investigation was supported by grants (4413-215, 4413-309, 4413-410) from the Texas State De partment of Health.

ADDRESS: (J.A.J.) 5323 Harry Hines Boulevard, Dallas 19, Texas.

PEDIATRIcS, September 1960

(2)

DurationTreated with Iron-dextran (%)â€¢ Controls (%)Over 11 months 6â€”11months Less than 6 months38

@4 3851

@1 @8 Weight (gm)Treated with

Iron-dextranControls<1,@50 1,@50â€”1,499 1,500â€”1,749 1,750â€”1,999 Totals8 13 19 44 8416 11 @4 46 97

Age (weeks)Treated With Iron-dextranControlsP1 4 7â€”8 9â€”10 11â€”1@ 13â€”16 17â€”@0 @1â€”@417.5(67)* 1@.@(58) 9.9 (50) 10.5(@8) 10.7 (30) 11.5(49) [email protected](49) 1@.@(4@)17.8(88) 1@.@(71) 9.6 (55) 9.6(51) 9.8(37) 9.5(56) 9.7(5@) 8.8(44)>.1 â€”¿ > .1 <.01 <.01 <.01 <.01 <.01Over 1 year11.5(@3)â€”â€” ARTICLES TABLE I

DISTRIBUTION OF INFANTS SURVIVING THE NEONATAL PERIOD

TABLE II

PERIODS OF FOLLOW-UP OF SURVIVING INFANTS

38% were followed in the clinic for 11 months or more, and 62% were followed for at least 6 months. In the untreated group the corresponding figures were 51% and 72%. Over 30% of the total number of surviving infants were lost to follow-up before 6

months of age, mostly for social and eco

nomic reasons. The better clinic attendance record of infants in the control group sug gests a greater maternal desire to provide good care; it is unlikely that the develop ment of iron deficiency anemia in these in fants was in itself responsible for their bet ter attendance, because this condition is usually asymptomatic during this period.

The mean values for hemoglobin in the treated and untreated babies are shown in Table III. Hemoglobin values were slightly lower in the iron-dextran treated babies at 1 week of age but identical with the values in the control group at 4 weeks. By 7 to 8 weeks of age, hemoglobin values were

TABLE III

CONCENTRATION OF HEMOGLOBIN (GM/100 ML)

DURING TIlE EARLY WEEKS OF LIFE RESULTS

Of 205 infants entering the study, 181 sur vived the neonatal period; of the latter, 84 received iron-dextran and 97 did not. No febrile reactions to the intramuscular injec tions of iron-dextran were observed. One in fant developed a sterile abscess at the site of injection, and two others developed flac cid paralysis of one leg below the knee.*

Distribution by birth weight is shown in Table I. Among the babies weighing less than 1,250 grams, 8 received iron-dextran and 16 did not. Because of the small num ber of cases, this difference is probably not sufficient to affect over-all comparisons made between the two groups, although the smaller infants usually show a high inci dence of iron deficiency and post-neonatal illness.5

The follow-up record is shown in Table II. There were five deaths known to occur in the iron-dextran group and three in the control group, during the first year. Of the surviving babies in the iron-dextran group,

@ Both babies received intragluteal injections of

antibiotics in addition to iron-dextran. Similar

lesions following the injection of antibiotics in young infants have been reported by one of us'1

and by others.'2 Personal communications from

other workers using intramuscular injections of

iron-dextran in premature infantsâ€•@Â°state that they have not experienced this difficulty. However, it is possible that despite efforts to keep the injection

confined to the upper and outer quadrant, inap propriate placement of the iron injection may have been responsible for these lesions. We are now using the mid-anterior thigh as the site for all intra

(3)

370 IRON DEFICIENCY

higher in the iron-dextran group; by 9 to 10 weeks, the difference between the groups

became statistically significant and re

mained so thereafter. None of the babies receiving iron-dextran showed any signifi cant anemia during the period of follow-up; the mean hemoglobin level in this group at 1 year of age was 11.5 gm/100 ml (range 9.3

to 13.4 gm/100 ml).

Forty-eight of the control group were fol lowed in the clinic for at least 11 months. The data indicate that almost all the control babies developed a significant degree of iron deficiency anemia during the first year of life. Hemoglobin values below 7.5 gm/ 100 ml, and a hypochromic blood picture, were observed in 24 (50%) and values below 5 gm/100 ml occurred in 4 infants. Values between 7.5 and 9.5 gm/100 ml were ob served in an additional 18 infants. Only five infants reached the age of 1 year with a hemoglobin level greater than 9.5 gm/100 ml without having received supplemental iron.

Weight curves for babies in the ranges of

1@)

9

8

1,500 to 1,749 grams and 1,750 to 2,000 grams are compared in Figure 1. There is no significant difference between the groups that received iron-dextran and those that did not. This is in accordance with the clin ical impression that iron-deficient infants seldom appear underweight, but differs

from observations made in some iron-defi

cient animal species (e.g., growing piglets1@ in which administration of iron supplements

causes a striking increase in weight gain

and nitrogen retention). We did not obtain the impression that there was any signifi cant difference in general development be tween the control group and the group treated with iron-dextran.

Data concerning morbidity and mortality are shown in Tables IV and V. The number of respiratory infections and diarrhea! dis orders requiring outpatient visits and hos pita! admissions were compared in the iron dextran and control groups. It will be seen that there is no significant difference in the number of inpatient or outpatient attend ances, or in the number of outpatient ill

-,l@ @

-â€”¿ II

WEIGHTS IMFEPON

@ CONTROL INFANTS

( (1@

I ([email protected]@-A

NO

@â€¢¿

IMF}7502000

IMF

GRAMS

I

/

(]5)o----.o

NOIMF@15@

1749

GRAMS

(@ IMF. J

ii I I .1 1 I I I I

ii)

0 -I

z

I

I w

7

6

5

4

3

2

5 6 7 8 9 10 11 12 13

AGE IN MONTHS

Fic. 1. Weight gain during first year of life for infants weighing 1,500

to 1,749 and 1,750 to 2,000 grams at birth.

(4)

DiagnosisTreated

with Iron-dextran

Itos- Out pital patientControls

los- Out pilaf patientLower

respiratory infections

Upper respiratory infections Diarrhea24

1

720

35

923

1

52.S

44 20

Treated with Iron-dex tran (84)Controls (97)Infants

admitted Number of admissions

Deaths

Attending outpatient dept.

Number of outpatient illnesses Average number of illnesses per infant attending outpatient dept.24

32

5

35 64

1.8320

29

3

47 87

1.85

ARTICLES

TABLE IV

HOSPITAL ADMISSIONS AND NUMBER OF OUTPATIENT

ATTENDANCES FOR RESPIRATORY INFEUTIONS AND DIARRHEA IN BABIES I TO 12 MONTHS OF AGE

TABLE V

HOSPITAL ADMISSIONS AND OUTPATIENT VISITS BY

DIAGNOSIS IN INFANTS I TO 12 MONTHS OF AGE

from conventional diets to keep up with this demand.

Although early administration of strained meat2' or the use of milk fortified with iron22 may provide dietary iron sufficient to meet requirements, the common practice at the present time involves the oral use of supplemental iron salts. The latter proce dure is entirely effective when properly used, but the results of this study and others in medically indigent clinic populations show that optimal results are often not obtained. Patients may default from the clinic and never receive a prescription for iron, or the iron preparation may not be procured for financial or other reasons. Other mothers fail to give the medication for the prolonged period required or give it incorrectly. Facil ities for making the indicated hematologic determinations are not available in many well-child clinics so that the need for treat ment and the response to it cannot be evaluated.

Intramuscular injection of iron-dextran complex is a rapid and effective method for the correction of iron deficiency. Side ef fects from the use of the material in clinical practice are relatively rare; allergic and fe brile responses have been reported in adult patients23'24 and staining of the tissues at the site of injection may occur. The use of massive doses (50 or more times the clini

cally effective dose given over several weeks

or months) in rats has led to siderosis of organs and deposition of ceroid pigment in the tissues (similar to that induced by vita nesses per attending infant. The readmis

sion rate does not differ significantly from the high figure previously obtained5 for babies weighing less than 2,000 grams. Ta ble V shows that the types of disease re sponsible for inpatient and outpatient at tendances in the two groups were similar. The relative incidence of upper and lower respiratory infections and of diarrhea does not appear to differ in any way.

DISCUSSION

(5)

372 IRON DEFICIENCY

min E deficiency25); testicular fibrosis and sarcomas at the sites of injection may also occur,26 but these effects seem to have little bearing on the customary use of the mate rial in clinical circumstances. The injection of 250 mg of iron-dextran in a 2,000-gm premature infant (125 mg/kg), when the infant does not have iron deficiency, may reasonably be expected to lead to some temporary organ siderosis; however, his tologic evidence concerning the tissue dis tribution of intramuscularly injected iron in human infants is lacking. Much of the in jected iron is apparently incorporated into hemoglobin later in the first year of life, and it therefore seems most improbable that temporary overloading of this degree could lead to harmful effects in later life. Prelim inary studies indicate that the injection of much larger doses of iron-dextran (1,500 mg/kg) into newborn rats results in some siderosis of the liver, spleen, lung and pan creas, but the testes have been unaffected.27 The results of the present study are in agreement with other reports8' 2830 and leave no doubt that the iron deficiency ane mia of prematurity can be prevented by the prophylactic use of intramuscular injections of iron in the nursery. Of interest was the statistically significant finding that the con centration of hemoglobin was higher in the babies treated with iron-dextran as early as 10 weeks of age, which is in contrast to the results obtained by Smith et a!.â€• in full term babies of a higher socio-economic group. These workers were unable to find evidence that dietary iron was incorporated into circulating hemoglobin before 3 or 4 months of age. The present data and those of others28 suggest either a) that the iron economy of these premature babies was un der stress as early as the second month or b) that the injected iron was used for hemo globin synthesis in preference to, and earlier than, endogenous sources of iron in storage. The results in the control group of infants offer ample confirmation of the frequency with which iron deficiency anemia develops in prematurely born babies who do not re ceive supplemental iron. It has been shown

that the circulating hemoglobin mass is re duced in infants born to mothers with se vere iron deficiency,'5 and it is probable that this factor accounts in part for the fre quency of anemia seen in the present group of infants. There is no experimental evi dence that the iron content of the human fetus can be raised above normal by paren teral administration of iron to the mother, although this effect has been demonstrated in the rabbit.32

There is a widespread clinical impression

that babies with iron deficiency anemia have lowered resistance to infections.6'7 A general metabolic disturbance in iron defi ciency is reflected in the diminished activity cf iron-containing enzyme systems (catalase and cytochrome C) in the tissues of iron deficient animals.@â€•@@Until the advent of a suitable iron preparation for parenteral use, it was impossible to separate the effects of iron deficiency per se from those of poor nutrition and inadequate housing and the accompanying high risk of cross-infection. The number of cases involved is small, but the results of the present study do not show a direct association between infection and poor iron nutrition; iron deficiency does not seem to be a major cause for the high incidence of infections observed in prema turely born infants.

Severe iron deficiency anemia is, never theless, a cause for many hospital admis sions and outpatient visits; therefore there is justification for the prophylactic use of intramuscular injections of iron in the pre mature infant while still in the nursery, when oral treatment with iron later in the first year may be difficult to carry out. A dose of 100 mg of iron-dextran may be suffi cient to prevent severe degrees of anemia, while minimizing the possible hazards of repeated injections and an excessive load of iron.

(6)

ARTICLES

cause of the anemia should be thoroughly investigated. A hemolytic process, blood loss, or some other serious condition are likely possibilities in an infant whose re quirements for iron have supposedly been met.

SUMMARY

Iron-dextran was given intramuscularly to 84 small prematurely born babies during their stay in the nursery; 97 similar babies were not so treated and served as controls.

By 8 to 10 weeks of age, values for he

moglobin in the babies who received iron dextran were significantly higher than in the controls and remained high throughout the first year. Virtually all of the control babies became anemic and hemoglobin levels be low 5 gm/100 ml were observed in four infants.

There was no difference in the rate of growth or in the incidence of common in fections in the two groups.

It is concluded that intramuscular injec tions of iron given prophylactically in the nursery will effectively prevent iron-defi ciency anemia in premature infants and that this practice has definite clinical applica bility. (See Addendum.)

Prevention of iron deficiency anemia does not reduce the high incidence of common infections experienced by prematurely born infants.

Acknowledgment

Our thanks are due to Mrs. Barbara Hunter and the premature nursery staff, and to the nurses of the Dallas City and County Health Departments for their interest and cooperation; also to Genevieve Thompson, Jene Nelson and Frances Anderson for technical assistance.

Addendum

Since this paper was submitted, Imferon has been withdrawn from the market by the manu

facturers because of the finding that very large

doses have a carcinogenic effect in animals26

(Editorial: Brit. Med. J., 1:788, March 12, 1960). Whether these results are pertinent to the clinical use of this iron-dextran preparation is not known, and this question raises important

ethical and medicolegal problems for future drug-testing programs. No reports of neoplasms complicating injections of iron-dextran in man have yet appeared despite extensive clinical use of this preparation. It is to be hoped that an expert assessment of the accumulated evidence will soon be forthcoming.

In the meantime, intramuscular injection of iron-dextran should not be used for the purpose suggested in this study. It may be repeated here that similar hematologic results can be obtained with oral preparations of iron, provided an ade quate treatment program is ensured.

REFERENCES

1. Douglas, J. W. B., and Mogford, C.: Health of premature children from birth to four years. Brit. M.J., 1:748, 1953.

2. Aim, I.: Long-term prognosis for prema turely born children. Acta paediat., 42: suppl. 94, 1953.

3. Hutcheson, R. H., and Puffer, R. R.: Use

of statistics on prematurity in Tennessee. Am. J. Pub. Health, 41:49, 1951. 4. Drillien, C. M.: Studies in prematurity.

IV. Development and progress of the prematurely born child in the pre-school period. Arch. Dis. Childhood, 23:69,

1948.

5. James, J. A.: The later health of premature infants: a field for further study. PEDI

ATRICS, 22:154, 1958.

6. Mackay, H. M. M.: Nutritional anemia in infancy with special reference to iron de ficiency. Spec. Rep. Ser., No. 157, Lon don, Med. Res. Council, 1931.

7. Collis, W. R. F., ed.: Fancom and Wall gren's Textbook of Pediatrics. New York, Grune, 1952, p. 362.

8. Gaisford, W., and Jennison, R. F.: Intra

muscular iron in infancy. Brit. M.J., 2@

700, 1955.

9. Sturgeon, P.: Iron metabolismâ€”review with

special consideration of iron require

ments during normal infancy. PEDIAT. RICS, 18:267, 1956.

10. McGovern, J. J., Jones, A. R., and Stein berg, A. G.: The hematocrit of capillary blood. New England J. Med., 253:308, 1955.

11. Scheinberg, L., and Allensworth, M.: Sciatic neuropathy in infants related to antibiotic injections. PEDIATRICS,19:261,

1957.

(7)

374 IRON DEFICIENCY C. F., and James, J. A.: Sciatic nerve

injury in infants resulting from intra gluteal injections. J.A.M.A., to be pub

lished.

14. Spray, C. M., and Widdowson, E. M.: The effect of growth and development on the composition of mammals. Brit. J. Nutri

tion, 4:332, 1950.

15. Sisson, T. R. C., and Lund, C. J.: The in

fluence of maternal iron deficiency on

the newborn. Am. J. Clin. Nutrition, 6:

376, 1958.

16. Whipple, G. A., Sisson, T. R. C., and Lund,

C. J.: Delayed ligation of the umbilical

cord. Obst. & Gynec., 10:603, 1957. 17. Kirkman, H. N., and Riley, H. D.: Post

hemorrhagic anemia and shock in the newborn. PEDIATRICs,24:97, 1959. 18. Bothwell, T. H., Pribilla, W. F., Mebust,

W., and Finch, C. A.: Iron metabolism in the pregnant rabbit. Am. J. Physiol. 193:615, 1958.

19. Pribilla, W., Bothwell, T. H., and Finch,

C. A.: Iron transport to the fetus in man, in Iron in Clinical Medicine, edited by

Wallerstein, R. 0., and Mettier, S. R.

Berkeley, Univ. California Press, 1958, p. 58.

20. Biorck, C.: On myoglobin and its occur rence in man. Acta med. scandinav.,

133: Suppl. 226, 1949.

21. Sisson, T. H. C., and Whalen, L. E.: Meat in the diet of premature infants. II. In

fluence on red cell volume and hemo

globin mass. A.M.A. J. Dis. Child., 95: 626, 1958.

22. Marsh, A., Long, H., and Stierwalt, E.: Comparative hematologic response to

iron fortification of a milk formula for

infants. PEDIATRICS,24:404, 1959. 23. Shafer, A. W., and Marlow, A. A.: Brief

recording: toxic reaction to intramuscu lar injection of iron. New England J.

Med.,260:180,1959.

24. Special Report, Council on Drugs, Amer ican Medical Association. J.A.M.A., 166: 1482, 1958.

25. Golberg, L., Smith, J. P., and Martin, L. E.: Effects of massive iron overload

in the rat. Nature, 179:734, 1957.

26. Richmond, H. G.: Induction of sarcoma in the rat by iron-dextran complex. Brit.

M. J., 1:947, 1959.

27. James, J. A., and Pearce, M.: Unpublished

observations.

28. Hammond, D., and Murphy, A.: The in fluence of exogenous iron on hemoglobin formation in the premature infant (Ab stract). Clin. Res., 7:53, 1959.

29. Leikin, S. L.: The use of intramuscular iron in the prophylaxis of the iron deficiency of prematurity (Abstract). A.M.A. Dis.

Child., 98:482, 1959.

30. Sitarz, A. L., Wolfe, J. A., and Von Hofe, F. H.: The comparative value of intra muscular versus orally administered iron in the prevention of the late anemia of

prematurity (Abstract). A.M.A. J. Dis.

Child., 98:640, 1959.

31. Smith, C. A., et al.: Persistence and utiliza tion of maternal iron for blood formation during infancy. J. Clin. Invest., 34:1391, 1955.

32. Pribilla, W.: Tierexperimentelle Untersu chungen uber den eisenaustausch zwis

chen Mutter und foet nach intravenoser Eisengabe. Acta haematol., 12:371, 1954.

33. Beutler, E.: Iron enzymes in iron de

ficiency. I. Cytochrome C. Am. J. M. Sc., 234:517, 1957.

34. Beutler, E., and Blaisdell, R. K.: Iron en

(8)

1960;26;368

Pediatrics

John A. James and Mollie Combes

by the Intramuscular Administration of Iron-dextran