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(

Received April 19, 1971 ;revision accepted for publication May 19, 1972.)

Supported in part by United States Public Health Service grants HD-00050-l0, AM-00795, AM-05391,

and RR-0076.

ADDRESS FOR REPRINTS: H.A.G., Ben Taub Hospital, Baylor College of Medicine, Texas Medical Center, houston, Texas 77025.

PEDL&TIUCS, Vol. 50, No. 4, October 1972 584

VITAMIN

B12 AND

FOLIC

ACID

VALUES

IN PREMATURE

INFANTS

Ambadas Pathak, M.D., and Herman A. Godwin, M.D. with the assistance of Luis M. Prudent, M.D.

From the Neonatal Research Laboratory, Boston Hospital for Women, Lying-In Divirion, and the Thor’ndike Memorial Laboratory, Harvard Medical Service, Boston City Hospital, and the

Departments of Pediatrics and Medicine, Harvard Medical School, Boston, Massachusetts

ABSTRACT. The relationship of serum vitamin

B12 and folic acid was studied in 24 premature

infants. In 14 of the 24, low serum vitamin B,2

values were found around 40 days of age. Serum

folic acid concentrations were less frequently

de-pressed and were usually associated with normal

red cell folate values. No correlation between

hematocrits and vitamin B,2 or folate levels was

found. It is suggested that low concentrations of

serum folate and vitamin B,2 result from low

dietary intake coupled with increased demand by

the prematurely born infant. Pediatrics, 50:584, 1972, VITAMIN B,,, FOLIC ACID, RED CELL FOLATE, PREMATURE INFANTS, ANEMIA.

NEMIA, considered to be “physiologic,”

develops in full-term infants during

the neonatal period.’ Premature infants

tend to have exaggeration of the anemia

even though initial cord hemoglobin values

may be the same as in full-term babies.’

The usual explanations for accentuation of

anemia in prematures involve a relatively

lower initial hemoglobin mass, decreased

hemoglobin synthesis in the first weeks of

life, and rapid growth and expansion of

blood volume.’ Iron deficiency does not

ap-pear to play a role in this early phase of

anemia though it does become important if

anemia persists or recurs beyond 3 or 4

months of age.1’

The possible role of vitamin B,2 and folic

acid in the early anemia has not been

ade-quately evaluated. Low levels of serum

folic acid have been noted in some

in-stances, but the contribution of this factor

to the anemia is debatable.46 Low serum

vitamin B12 levels were detected by Chitis

and Canosa6 in five anemic premature

in-fants, in one of whom there were

megalo-blastic changes in the bone marrow. The

purpose of this study is to examine further

the relationship of vitamin B1, and folic

acid to anemia in premature infants.

MATERIALS AND METHODS

All infants in this study were born and

re-ceived initial care at the Boston Hospital

for Women, Lying-In Division. Following

discharge, their management was, in

gen-eral, directed by private pediatricians.

Twenty-three of 24 mothers had received

adequate prenatal care and all were in

good health with no history of hematologic

difficulties.

The premature infants chosen for study

(

less than 37 weeks’ gestation ) were in

good health at the time of evaluation. To

determine the ranges of serum vitamin B

and folic acid in asymptomatic premature

infants in the nursery, a first group of 14

ba-bies (group I), ranging in ages from 16 to

62 days

(

mean 33 days

)

, was examined.

Those with low levels of either vitamin

were studied again at varying intervals.

Croup II, consisting of ten other

prema-ture infants, was studied prospectively

be-ginning within the first 24 hours after birth.

(2)

ma-ARTICLES 585

TABLE I

SERUM VITAMIN B12 AND FOLIC ACID VALUES IN 14 ASYMPTOMATIC PItEIATcuE INFANTS OBTAINED 16 TO 6 DAYS FOLLOWING BIRTh

Group Geslalional Age, weeks

Birth Weight,

gm

In!erval From Birth toStudy,

days

Serum B12, pg/mi

Serum Folic .1cM, ng/ml

IA (5) Mean

Range

29

6-33

1,810

964-1,758

S

1-S9

268

01-401

11.0

6.0-15.5

IB(9) Mean

Range

81

28-36

1,339

680-2,098

38

16-6

104

49-155

1.9

5.3-64.5

jor problem

(

e.g., respiratory distress,

sep-sis, erythroblastosis fetalis, etc.

)

was

pres-ent. In eight instances, paired blood

sam-pies were obtained from neonate and

mother during the first day. Based on

infor-mation obtained from group I, second

stud-ies of these infants were delayed for a mean

interval of 40 days (range, 21 to 60 days);

those infants having low levels of vitamin

B,, or folic acid were then further

evalu-ated.

Venous blood (3 ml) was obtained from

the antecubital vein for hematologic

evalu-ation and determination of vitamin levels.

Serum vitamin B,, was assayed with

Eu-glena gracilis Z strain

(

adult values 200 to

900 pg/mI) while serum folic acid was

measured by the method of Herbert (adult

values 6 to 16 ng/ml) and red cell folate by

the method of Hoffbrand and co-workers8

(

adult values 160 to 640 ng/ml).

Mater-nal venous blood obtained in the paired

specimens was assayed for serum B,,,

Se-rum and red cell folate, and intrinsic factor

antibody.#{176} Unstimulated gastric juice

speci-mens were obtained from five neonates in

group II within the first 24 hours of life for

determination of pH and the presence of

intrinsic factor.9

All infants of both groups were fed a

standard evaporated milk formula#{176}

con-taming approximately 130i.g/liter folic acid

and 0.73g/liter vitamin B,,. During the

second week of life they received a daily

0.3-

to 0.6-ml dose of a multivitamin

prep-arationf free of folic acid and vitamin B,,.

Administration of elemental iron was

gen-erally delayed until the birth weight was

doubled. Solids were offered, in the form

of cereals, at age 4 to 6 weeks when weights

exceeded 2,500 gm, vegetables and fruits at

6 to 8 weeks of age, and meat at 10 to 12

weeks of age.

RESULTS

The results obtained with group I arc

summarized in Table I. Of the 14 babies,

five (IA) when initially studied had serum

vitamin B,, and folic acid levels exceeding

normal adult values and were not further

evaluated. Among the remaining nine

(

lB),

one had a serum folic acid less than 6 ngl

ml (5.3 ng/ml) with a red cell folate of 216

ng/ml. However, all nine had vitamin B1,

levels less than 200 pg/ml

(

mean 104 pg/

ml) with four of these being less than 100

pg/mi. Evaluation of seven of the nine

in-fants at 13 to 15 months revealed return of

serum vitamin B,, to levels exceeding 200

pg/mi. In the other two infants, earlier

sub-sequent determinations demonstrated

con-tinued reduction of serum B1, levels at 54

days and at 61 and 89 days, respectively

(

Fig. 1

)

. Spontaneous return to

concentra-tions above 200 pg/mi was found by 83

and 102 days after birth, respectively. No

correlation was apparent between serum

vi-tamin B1, levels and hematocrit values, and

peripheral blood smears did not show oval

a Similac, Ross Laboratories, Columbus, Ohio. f Trivisol, Mead Johnson Laboratories,

(3)

AGE (Days)

I000

- 500

“4

I00

50

FIG. 1. Serum vitamin B2 values in premature

infants. Nine of ten infants studied within 24

hours after birth (dark circles ) had normal to

increased vitamin levels. Vitamin B2

concentra-tions decreased in all nine (mean, 40 days)

reaching an abnormal range in five. Two other

infants with low serum B12 detected after birth

(

open circles ) are also shown. Spontaneous

re-turn to normal values occurred in all infants

usually iy three to four months.

macrocytes or hypersegmented

polymor-phonuclear neutrophils.

Data from the study of group II are

pre-sented in Table II and Figure 1. At the time

of initial evaluation

(

day 1

),

nine of ten

neonates had serum vitamin B,, levels

cx-ceeding 200 pg/mi. In two babies

(

C and

L

)

, an unexplained elevation of levels

above 900 pg/mi was present. One infant

had a value of 132 pg/mi with no maternal

history for inadequate dietary intake or

malabsorption. Intrinsic factor antibody

was not detected in the mother’s serum, but

further evaluation of this mother was not

possible. In the eight cases in which paired

sera from mother and newborn were

ob-tamed, the serum vitamin B, value was

al-ways greater in the infant. All ten babies

had serum folate concentrations exceeding

6 ng/ml.

Second samples obtained at a mean age

of 40 days showed a decrease in serum

vita-mm B2 and folic acid concentrations in

nine babies. In five of these nine, serum B

fell below 200 pg/mi reaching a level of

77 pg/mi in one infant. One of the babies

with a B,, level of 115 pg/mI also had a

serum folate of 2.2 ng/ml. Of the four

re-maining infants with B,, values above 200

pg/ml, two had serum folic acid values of

3.3 and 3.4 ng/ml, respectively, with red cell

folate concentrations exceeding 160 ng/ml.

There were no detectable differences in

clinical or hematologic status between those

in whom serum vitamin concentrations

de-creased below the accepted normal adult

values and those in whom values remained

above these levels. Specifically, there was

no correlation of vitamin levels with

hema-tocrit, and peripheral blood smears did not

show oval macrocytes or hypersegmented

poiymorphs.

Serum vitamin B,, concentrations

re-turned to levels exceeding 200 pg/mi in all

five infants, generally by the age of 3 to 4

months. Serum folate remained below 6 ng

/1111

(

3.6) in one infant for 60 days with a

simultaneously determined red cell folate

being 205 ng/ml.

All gastric aspirates obtained from

neo-nates in group II contained intrinsic factor

(

five infants

)

and acid. Eight maternal sera

did not contain intrinsic factor antibodies.

There was no proteinuria in any of the

in-fants with low vitamin B12 levels. All

in-fants followed in both groups were

devel-oping normally during the period of study.

DISCUSSION

During the first two months postnatally,

serum vitamin B,, concentrations were less

than 200 pg/mi in 14 of 24 premature

in-fants

(

groups I and II combined

)

. In five

infants the concentrations (less than 100 pg

/mi) were those usually seen only in

pa-tients with pernicious anemia or

malabsorp-tive states. Among ten infants in whom the

initial blood specimen was obtained on the

(4)

ARTICLES 587

TABLE II

SERUM VITAMIN B1, AND FoLIc ACID VALUES IN TEN PREMATURE INFANTS STUDIED PROSPECrIVELY, PAIRED

SAMPLES WERE OBTAINED FROM THE NEONATE AND MOTHER DURING THE FIRST DAY IN EIGHT CASES

. Gestational . Age, weeks . Birth , . i eight, gm I

-

nitial Values

-

Interval, days Second

---infant B,,, pg/mi Values Maternal B,2, pg/mi infant B12, pg/in1

-infant Folic . Acid, ng/ini

---infant Folic . Acid, ng/inl A C (1 Wh \Vi 11 L MeN It Me 34 37 32 36 31 33 30 29 34 33 1,857 1,587 1,871 1,828 1,375 1,701 1,701 1,049 1,658 1,701 11 153 ‘233 ‘248 -138 -268 194 50 36 2,760 384 341 232 301 1,196 976 904 132 66 300 245 300 11.0 110 245 18.8 270 110 60 42 35 43 35 42 28 ‘21 37 56 1’ 77 168 126 115 ‘276 509 624 216 391 23 15.5 22 6.6 2.2 3.3 3.4 27 7.9 62

Mean 33 1,633 176 7 168 40 26 17.3

lower vitamin B,, level at the time of a

see-ond sample, even though only five of the

group reached a level less than 200 pg/ml.

Other workers have commented on a

de-dine in serum vitamin B1, values during

the neonatal period but did not report such

low levels.10 As has been previously

re-ported,11 all first-day samples from the

in-fants contained a greater concentration of

vitamin B,, than found to be in maternal

blood.

There was a spontaneous rise to normal

adult serum B,, concentrations with

ad-vancing age and increasing dietary intake.

The time interval required for achieving

such B,, levels was between three and four

months. The hematologic significance of

re-duced serum vitamin B,, was not clinically

apparent in that there were no significant

differences in hematological values in

in-fants with B,, levels either above or below

200 pg/mi. Megalobiastic changes in bone

marrow, which was not examined, could

have occurred, however, without any

reflec-tion of this in the peripheral blood.

The explanation for the postnatal

de-crease in vitamin B1, concentration is not

clear. The possible causes for a reduction in

serum vitamin B,, level include

(

1

)

defec-five absorption due either to a deficiency of

intrinsic factor or to intestinal

malabsorp-tion,

(

2) abnormalities of serum binders for

B,2, (3) intake of diets deficient in animal

or bacterial products, (4

)

increased

re-quirements for B,,, or

(

5

)

a combination of two or more of these factors.

Defective absorption seems an unlikely

explanation for the decrease in serum

vita-mm B,, among the infants in this study.

In-trinsic factor and acid were present in the

gastric secretions of five neonates evaluated

on the day of birth. Although outputs of

in-trmnsic factor and hydrochloric acid are low

the first day of life, a gradual and sustained

increase in production of these glandular

secretory components begins immediately

so that at 2 to 3 months of age infants have

intrinsic factor levels comparable to those

observed in older children and aduits.’2

Furthermore, by the second week, the

aver-age infant has intrinsic factor output

suffi-cient to ensure absorption of an adequate

amount of vitamin B,,. Intestinal

malab-sorption of vitamin B,, also seems

improba-bie. There was no history for

gastrointesti-nal abnormalities in any infant and all

babies were growing normally during the

period of study.

Differences in the serum binders of

vita-mm B,, in newborn infants have been

re-ported.13 In addition to the two normal

(5)

588

B,, AND FOLIC ACID IN PREMATURES

II, a third, or “fetal,” binder has been

noted. This binder is the same size as

trans-cobalamin I, but it does not contain

endog-enous B,, nor does it transfer B,, to Hela

cells. The significance of the “fetal” binder

is presently unclear. Binding studies were

not performed on the sera of patients in this

study, although serum protein

electro-phoreses

(

agarose gel method

)

were

unre-markable. Thus, while alterations in serum

proteins could provide an explanation for

the changes seen, direct data are not

avail-able upon which to base such a conclusion.

It is probable that the reduced levels of

vitamin B,, result from a combination of

factors: insufficient dietary intake of B,,,

limited body stores, and increased demands

related to growth. During the early period

in the hospital, the infants received 200 to

300 ml of a formula containing

approxi-mately 0.73tg of B,, per liter. The initial

daily intake would thus be approximately

0.22g, an amount which is less than the

in-take recommended for normal infants on

ar-tificial feeding, i.e., 0.3tg’4; prematurely

born infttnts may have slightly higher

re-quirements. Adequate dietary B12 intake would be expected only after the institution

of solid foods, particularly meats, which

be-gins several weeks following birth.

Further-more, despite the competitive advantage for

B1, demonstrated by the fetus in utero,”

total body stores at birth are probably

re-duced. For example, fetal liver contains

only one-third the concentration of vitamin

B,, as that found in adult liver,” the major

site for storage of this vitamin. Finally, all

infants in this study were clinically well

with normal growth rates. Rapid cellular

replication and myelinization, requiring

sig-nificant quantities of vitamin B,,, would

lead to a further depletion of vitamin

stores. In the absence of adequate dietary

supplementation, a decrease in serum B,,

levels would be expected.

All infants studied at birth (ten of ten)

had serum and red cell folate levels in

ex-cess of normal adult values. All

demon-strated a fall in serum concentrations with

three reaching serum levels less than 6 ng/

ml. Red cell folate concentrations were

con-sistently above 160 ng/mi. Previous

investi-gators have noted a similar pattern which

was attributed to the combination of low

dietary folate intake and exhaustion of the

high

initial stores derived from the mother.’6

Recent studies showing rapid clearance

of folic acid from plasma and diminished

urinary excretion of folic acid in newborns

have suggested an increased demand for

folic acid in the neonatal period and during

the period of early infancy, a demand not

met by dietary foiate.”

From a practical point of view the

de-crease in serum vitamin levels might be

considered “physiologic” in that it occurred

in all infants during the early neonatal

pe-riod with some infants manifesting an

ac-centuation of this trend resulting in

dis-tinctiy low serum concentrations. Because

there did not appear to be any

hematologi-cal or clinical significance to the decreased serum levels, the necessity for supplemental

vitamin therapy is not definite.

Neverthe-less the need for more detailed studies

seems apparent.

REFERENCES

1. Schaffer, A. J.: In Diseases of the Newborn,

ed 2. Philadelphia : W. B. Saunders Co.,

1965, p. 554.

2. Wintrobe, M. M. : In Clinical Hematology, ed 6. Philadelphia : Lea and Febiger, 1967, p. 835.

3. Smith, C. H. : In Blood Diseases of Infancy

and Childhood, ed. 2. St. Louis: C. V.

Mosbv Co., 1966, pp. 196, 206.

4. Shojania, A. NI., and Gross, S. : Folic acid

deficiency and prematurity. J. Pediat., 64:

323, 1964.

5. Gray, 0. P., and Butler, E. B. : Megaloblastic

anaemia in premature infants. Arch. Dis. Child., 40:53, 1965.

6. Ghitis, J., and Canosa, C. : Folate and B12

serum levels in premature infants. With a

note on milk folate. J. Pediat., 67:701,

1965.

7. Herbert, V. : Aseptic addition method for

Lactobacillus casei assay of folate activity

in human sen,m. J. Clin. Path., 19:12,

1966.

8. Hoffbrand, A. V., Newcombe, B. F. A., and

Mollin, D. L. : Method of assay of red cell

(6)

ARTICLES 589

as a test for folate deficiency. J. Clin. Path.,

19:17, 1966.

9. Gottlieb, C., Lau, K., Wasserman, L. R., and

Herbert, V. : Rapid charcoal assay for

in-trinsic factor (IF), gastric juice

unsatu-rated B,2 binding capacity, antibody to IF, and serum unsaturated B,2 binding capacity.

Blood, 25:875, 1965.

10. Luhby, A. L., Feldman, R., Marley, J. F.,

Odang, 0., and Cooperman, J. M. : Serum

vitamin B,2 in infancy (Abstract). Fed.

Proc. 20:451, 1961.

11. Boger, W. P., Bayne, G. M., Wright, L. D.,

and Beck, C. D. : Differential serum

vita-mm B12 concentrations in mothers and

in-fants. New Eng. J. Med., 256:1085, 1957.

12. Agunod, M., Yamaguchi, N., Lopez, R., Luhby,

A. L., and Glass, G. B. J.: Correlative study

of hydrochloric acid, pepsin, and intrinsic

factor secretion in newborns and infants.

Amer. J. Dig. Dis., 14:400, 1969.

13. Kumento, A. : The serum binders of vitamin

B2 in newborn infants (Abstract ). Acta

Paediat. Scand., 58:553, 1969.

14. Report of a Joint FAOIWHO Expert Group

on “Requirements of ascorbic acid, vitamin

D, vitamin B,2, folate, and iron.” Food and

Agriculture Organization of the United

Nations, Rome, 1970, p. 40.

15. Rappazzo, M. E., Salmi, H. A., and Hall,

C. A. : The content of vitamin B,2 in adult and foetal tissue : A comparative study. Brit. J. Haemat., 18:425, 1970.

16. Roberts, P. M., Arrowsmith, D. E., Rau,

S. M., and Monk-Jones, M. E. : Folate

status of premature infants. Arch. Dis. Child., 44:637, 1969.

17. Shojania, A. M., and Hornadv, C.: Folate

metabolism in newborns and during early

infancy: II. Clearance of folic acid in

plas-ma and excretion of folic acid in urine by

newborns. Pediat. Res. 4:422, 1970.

. . . THE PASTORAL FALLACY

The pastoral fallacy is a creation of a section

of the profession, and probably arises as a reac-tion, by those no longer able to keep abreast, to the technical complexities of modern medicine. Its

proponents emphasize the distinction between the

patient and his disease, and claim to treat the

whole man, and to regard the patient as a peron.

They stress the frequency and educational

im-portance of the more trivial disorders and their

interrelation with emotional factors. There is an

implication that much of the elaboration of

mod-em investigation and treatment could be dispensed

with, if doctors were trained to acquire wisdom

rather than to accumulate technical knowledge.

Pervaded by an excessive belief in a unique

thera-peutic relation between doctor and patient, they

aim to substitute a pastoral role for technical care,

which is assumed to be necessarily impersonal or

even inhumane. . . . The essential superficiality, and indeed dishonesty, of this attitude is revealed

when one of its advocates is faced with illness in

himself or in his family. The call then is not for the wise father figure, but for the man who knows most about so-and-so.

A. C. DORNHORST

ALASTAIR Hursn

Fallacies in Medical Education

(7)

1972;50;584

Pediatrics

Ambadas Pathak, Herman A. Godwin and Luis M. Prudent

AND FOLIC ACID VALUES IN PREMATURE INFANTS

12

VITAMIN B

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(8)

1972;50;584

Pediatrics

Ambadas Pathak, Herman A. Godwin and Luis M. Prudent

AND FOLIC ACID VALUES IN PREMATURE INFANTS

12

VITAMIN B

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American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

References

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