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Relationship

of Milk Intake

and Vitamin

K

Supplementation

to Vitamin

K

Status

in Newborns

Kunihiko

Motohara,

MD, PhD,

Ikuro

Matsukane,

MD,

Fumio

Endo,

MD, PhD,

Yuji Kiyota,

MD, PhD,

and

Ichiro

Matsuda,

MD, PhD

From the Department of Internal Medicine, Kamiamakusa General Hospital, the Department of Pediatrics, Kumamoto University Hospital, and the Department of Obstetrics and Gynecology, Kumamoto Red Cross Hospital, Kumamoto, Japan

ABSTRACT. Vitamin K status was evaluated by

meas-uning blood acarboxyprothrombin (PIVKA-II) levels on the fifth day of life. The incidence of PIVKA-II-positive infants was higher in breast-fed babies than in those given supplementary (mixed) feeding. The median of total amount of milk intake during the first 3 days was significantly lower in PIVKA-II-positive infants than in

PIVKA-II-negative infants among infants given both

types of feedings. In addition, there was a significant negative correlation between a positive PIVKA-II pro-portion and the amount of milk intake in the breast-fed

babies. The minimum dose of vitamin K, necessary to

prevent a positive PIVKA-II reading was 15 jzg among babies with a normal absorption potential. Pediatrics 1989;84:90-93; vitamin K, acarboxyprothrombin,

breast-feeding.

ABBREVIATIONS. AU, arbitrary units; PIVKA-II, acarboxy-prothrombin.

Vitamin K deficiency in neonates occurs more frequently in infants who are breast-fed than in infants who receive formula or those who are breast- and formula-fed.1 A lower vitamin K con-tent in breast milk appears to be the cause.2

How-ever, the deficiency was not common even among

infants who were exclusively breast-fed; hence, the amount of milk ingested must also be considered.

We evaluated the relationship between the quantity

of milk intake and the extent of vitamin K

defi-Received for publication Dec 2, 1987; accepted Apr 27, 1988.

Reprint requests to (KM.) Kamiakusa General Hospital, Su-moto, Amakusa, Kumamoto 861-63, Japan.

PEDIATRICS (ISSN 0031 4005). Copyright © 1989 by the

American Academy of Pediatrics.

ciency, as well as the effect of different doses of oral vitamin K on vitamin K deficiency. The mm-imum dietary requirement of vitamin K during the

early neonatal period was shown by our data.

SUBJECTS

AND

METHODS

Study 1

The subjects were healthy full-term infants who were breast-fed (n = 259) and infants who received

supplementary formula (breast and formula, n =

273). Vitamin K prophylaxis was not given at birth

or throughout the study. The amount of milk

in-gested, estimated by a body weight increment

im-mediately before and after the feeding, was recorded for all infants at every feeding. The total amount of milk intake during the first 3 days of life was calculated for each infant. Blood sampling was pen-formed (with parents’ permission) by dried blood

spotting on filter paper on the fifth day of life. Acarboxyprothrombin (PIVKA-II) content in the

dried blood spot was measured as described,3 using a monoclonal antibody against PIVKA-II.4 The de-tection limit of blood PIVKA-II was 1.0 to 32.0

arbitrary units (AU) per milliliter (1 AU

corre-sponds to 1 tg ofpunified prothrombin). As reported

elsewhere,5 in some breast-fed infants given vita-mm K on day 1, PIVKA-II was present on day 5, the maximum level being 1.3 AU/mL. Therefore,

in the present study, infants with a PIVKA-II level

greater than 1.4 AU/mL were considered to be

PIVKA-II positive (vitamin K deficiency).

Study 2

(2)

4,2-‘-4

1i1

100

(%)

75,

50 25

0

#{149}:PIVKA-II(+) 0: PIVKAII()

TABLE. Acarboxyprothrombin (PIVKA-II) Positivity

in Breast-Fed Infants*

ARTICLES

91

methy-3 -all-transtetrapnenyl- 1 ,4-naphthoqui-none) orally in varying doses 6 hours after birth, as shown in the Table. Vitamin K, is not available in syrup form in Japan. On the fifth neonatal day, the

blood PIVKA-II level was measured and evaluated.

Statistical

Analysis

The 2test, Student’s t test, and linear regression analysis were used for statistical analysis.

RESULTS

Study I

The proportion of PIVKA-II-positive infants on day 5 was 26.2% among the breast-fed infants and 12.8% among those receiving a mixed feeding. The median of total amount of ingested milk was 228 mL (range 38 to 956) and 379 mL (range 42 to 982) in the former and the latter, respectively, the dif-ferences being statistically significant (P <

.01,

P

< .01). Among breast-fed infants, the median of the amount of ingested milk was significantly different

in PIVKA-II-positive infants and

PIVKA-II-nega-tive infants (129 mL vs 274 mL, P < .05). Similarly, the median intake of milk was significantly

differ-ent in PIVKA-II-positive infants and PIVKA-II-negative infants given mixed feedings (185 mL vs

428 mL, P < .05). The maximum amount of total

milk intake was 478 mL and 950 mL in PIVKA-II-positive and PIVKA-II-negative infants, respec-tively, and 95% of the PIVKA-II-positive infants

ingested less than 350 mL of breast milk (Fig 1). A similar figure was obtained from the babies who

received mixed feeding (data not shown).

When breast-fed infants were grouped into eight ordered categories based on total milk intake for 3

days (:s50 mL, n = 18; 5 to 100 mL, n = 40; 101 to

Vitamin K2 No. (%) of

Dose (rg)

PIVKA-II-Positive Infants

(N = 185)t

0 13/50 (26.0)

2.5 2/11 (18.2)

5.0 3/12 (25.0)

10.0 1/10 (10.0)

15.0 0/14 (0)

25.0 1/56 (1.8)

30.0 0/16 (0)

100.0 0/16 (0)

* Acarboxyprothrombin presence was measured on day 5 of life in infants given different doses of oral vitamin K on day 1 of life.

t Denominators represent all infants, both positive and negative.

1 I t I 1 I I I

-.100

-300

.500

-700

OOO

Total intake of breast milk for the

first 3 days of life

Fig 1. Cumulative distribution of acarboxyprothrombin

(PIVKA-II)-positive or negative newborns, depending on total intake of breast milk during first 3 days of life,

measured in 50-mL intervals from 100 to 500 mL.

150 mL, n = 26; 151 to 200 mL, n = 32; 201 to 250

mL, n = 25; 251 to 300 mL, n = 30; 301 to 350 mL, n = 20; >350 mL, n = 68), a significant negative

correlation was found between the incidence of

PIVKA-II positivity in infants and the amount of

milk ingested, as shown in Fig 2 (y = .95, P < .01).

A PIVKA-II level greater than 20 AU/mL,

mdi-cating a severe vitamin K deficiency,3’6 was evident in three of 259 breast-fed infants. These infants had PIVKA-II levels of 20.1, 29.9, and 32.0 AU! mL, and total milk ingestion of 25, 52, and 66 mL, respectively.

Study 2

As shown in the Table, the PIVKA-II-positive

proportion was essentially unchanged in infants receiving 0 to 5 g of vitamin K2. With 10 g of vitamin K2, the PIVKA-II-positive proportion de-dined to levels of approximately half of those of

the former group. In infants given more than 15 tg

to 100 only one of 102 infants had a positive

PIVKA-II level. This baby was given 25 g of the

vitamin with no ensuing untoward effects such as jaundice or diarrhea.

DISCUSSION

Transport of vitamin K from the mother to the

fetus through the placenta is limited7 and

produc-tion of vitamin K by intestinal flora is negligible in

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(3)

50 S S

(U

30 -10 -0 0 U a 6) ‘-4 U a .4 6) ‘-4 .‘J ‘-4 In 0 04 S

I I I I I

-100 -200 -300

Total intake of breast milk for the

first 3 days of life

Fig 2. Correlation between acarboxyprothrombin (PIVKA-II)-positive incidence and total amount of breast

milk ingestion by eight groups of neonates during the

first 3 days of life. Y = -0.12X + 53.4, ‘y= 0.95, P < .01, where Y represents proportion of PIVKA-II-positive in-fants and X represents quantity of milk intake.

the newborn. Therefore, the diet may be the main source of vitamin K, especially in the neonatal

period. Gellis and Lyon8 showed that early supple-mental feeding of breast milk or evaporated milk could prevent the reduction of the one-stage pro-thrombin time during the first week of life. Similar results have been reported by other investigators.9

In the present study, these early observations were

confirmed, as well as the fact that the amount of ingested breast milk and the amount of

supplemen-tary formula milk are important factors in vitamin

K status. These findings were based on the follow-ing: (1) the amount of milk intake was significantly reduced in PIVKA-II-positive infants compared

with PIVKA-II-negative infants who received breast and supplementary feedings, (2) there were significant negative correlations between PIVKA-Il-positive proportions and the amount of breast milk ingested, and (3) severe vitamin K deficiency was associated with an extremely small amount of

breast milk ingested. Accordingly, the greater

mci-dence of vitamin K deficiency in breast-fed infants

is probably due to an insufficient production

(in-take) of breast milk in addition to a lesser vitamin

K content in breast than in formula milk. Von

Knies et al’#{176}reported similar observations that

PIVKA-II-positive babies had received only small

amounts of milk during the first 4 days of life.

According to the data obtained in the first study, no baby who received more than 500 mL of total breast milk during the first 3 days of life showed positive PIVKA-II levels, and a mean vitamin K

(K1 + K2) concentration of breast milk after 2 to 4 days of lactation was 18.0 tg/L (range, 4 to 34 g/

L) in Japanese women (T. Itoda, personal

commu-nication, October 1987). We therefore speculate that at least 10 g of vitamin K intake during this period seemed necessary to prevent a positive read-ing in PIVKA-II level. According to the data ob-tamed in the second study, the minimum

supple-mentary dose of vitamin K2 necessary to prevent a

positive PIVKA-II reading in a breast-fed baby is 15 g. In one infant given 25 g of vitamin K2, the

PIVKA-II level remained positive, presumably

be-cause of malabsorption.”

Therefore, if neonates absorb vitamin K

nor-mally, the minimal requirement of this vitamin

during the first 3 days of life is 10 to 15 g. These figures are close to the estimated safe and adequate

dietary intake of vitamin K recommended by the National Academy of Science in 1980 of 12 g/d.’2

The recommendation of the American Academy of Pediatrics’3 that 1.0 to 2.0 mg be given orally seems

rational to prevent vitamin K deficiency in the neonate when the presence of a few infants with

malabsorption of the vitamin is taken into account.

ACKNOWLEDGMENTS

We thank M. Ohara, Kyushu University, for pertinent comments on the manuscript and T. Itoda, Technology Research Institute, Snow Brand Milk Products Co, Ltd, for information concerning vitamin K levels in colostrum.

REFERENCES

1. Sutherland JM, Glveck HI, Gleser G. Haemorrhagic disease of the newborn: breast feeding as a necessary factor in the pathogenesis. Am J Dis Child. 1976;113:524-533

2. Haroon Y, Shearer MJ, Gunn WG, McEnery G, Barkhan P. The content of phylloquinone (vitamin K1) in human milk, cow’s milk and infant formula determined by high-performance liquid chromatography. J Nutr. 1982;112:

1105-1117

3. Motohara K, Endo F, Matsuda I. Screening for late neonatal vitamin K deficiency by acarboxyprothrombin in dried blood spots.Arch Dis Child. 1987;62:370-375

4. Motohara K, Kuroki Y, Kan H, Endo F, Matsuda I. Detec-tion of vitamin K deficiency by use of an enzyme-linked immunosorbent assay for circulating abnormal prothrom-bin. Pediatr Res. l985;19:354-357

5. Motohara K, Endo F, Matsuda I. Effect of vitamin K ad-ministration on acarboxyprothrombin (PIVKA-II) levels in newborns. Lancet. 1985;2:242-244

6. Motohara K, Matsukura M, Matsuda I, et a!. Severe vitamin K deficiency in breast-fed infants. J Pediatr. 1984;105:943-945

7. Shearer MJ, Rahim 5, Barkhan P, Stimmler L. Plasma

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ARTICLES 93

8. Gellis 55, Lyon RA. The influence ofthe diet ofthe newborn 11. Von Knies R, Becker A, Tangerman R, Robel U. Acarboxy-infant on the prothrombin index. J Pediatr. 1941;19:495- prothrombin activity after oral prophylactic vitamin K. Arch

502 Dis Child. 1987;62:938-940

9. Keenan WJ, Jewett T, Glueck HI. Role of feeding and 12. National Research Council Food and Nutrition Board:

Rec-vitamin K in hypoprothrombinemia of the newborn. Am J ommended Dietary Allowance. 9th ed. Washington, DC:

Na-Dis Child. 1971;121:271-277 tional Academy of Science; 1980

10. Von Kries R, Becker A, Gobel U. Vitamin K in the newborn: 13. American Academy of Pediatrics, Committee on Nutrition.

influence of nutritional factors on acarboxy-prothrombin Vitamin K compounds and the water-soluble analogues: use detectability and factor II and VII clotting activity. Eur J in therapy and prophylaxis in pediatrics. Pediatrics.

Pediatr. 1987;146:123-127 1961;28:501-507

HEALTH

HAZARDS

OF EXCESSIVE

STUDY

IN THE

BOSTON

PUBLIC

SCHOOLS

(1854)

During the mid-nineteenth century American physicians were greatly trou-bled by what they thought were the evils of excessive academic demands placed on children in our public schools. The editorial below, published in 1854 in the

Boston Medical and Surgical Journal, is typical of many of a similar nature.’

Our city prides itself on the superiority of its public schools; and we think Boston is

justly entitled to take the highest rank among the cities of the civilized world for the facilities afforded by its citizens for the education of youth. But notwithstanding the large expenditure of money for the erection of beautiful and commodious school-houses,

for mathematical and other instruments, for teachers, &c., all which give a character to our Boston schools, there exists an evil in the present system of educating, which seriously demands attention, and, if possible, a remedy. It is the ambition of the teachers of our schools, to have their scholars thoroughly instructed, and that they may appear

well before the committees at examinations; and for that purpose, lessons in great numbers and requiring toilsome study, are imposed upon them. No discrimination is

made, as regards the mental or physical capacity of the individual members of the class, but all are required to be perfect in their answers, or else they lose their position in the

class and school. Not one fifth of the time devoted to school hours is allowed for study,

being occupied in recitations; and the severe tasks the poor children have in getting their lessons must be apparent, when it is known that so long a time is required in reciting

them. The scholars of the second class, for instance, have to commit to memory from

twelve to twenty-five pages of geography, three to six pages of arithmetic, the same of

grammar, three pages in spelling, besides exercises in reading, writing, &c. Now these

lessons must be studied out of school, at the time which should be devoted to exercise

and recreation. The imposition of such severe tasks upon the young and growing children,

must enfeeble their constutions, and often incapacitates them, if they arrive at maturity, for enjoying life. We have seen many children who were ambitious to accomplish all that was required of them by teachers; and to do so, the greatest portion of the twenty-four

hours was necessarily devoted to their books, scarcely allowing any time for taking their meals. It must be obvious to every one, that such close application to study, produces, in their turn, a train of diseases which cannot always be eradicated. Aching heads, loss of

appetite, sleepless nights, inflamed eyes, with other deviations from health, are the

accompaniments and the consequences of excessive mental exertion.

Noted by T.E.C., Jr, MD

REFERENCES

1. Editorial. Excessive study in our public schools. Boston Med Surg J. 1854:51:184-185.

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1989;84;90

Pediatrics

Kunihiko Motohara, Ikuro Matsukane, Fumio Endo, Yuji Kiyota and Ichiro Matsuda

Newborns

Relationship of Milk Intake and Vitamin K Supplementation to Vitamin K Status in

Services

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1989;84;90

Pediatrics

Kunihiko Motohara, Ikuro Matsukane, Fumio Endo, Yuji Kiyota and Ichiro Matsuda

Newborns

Relationship of Milk Intake and Vitamin K Supplementation to Vitamin K Status in

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American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1989 by the

been published continuously since 1948. Pediatrics is owned, published, and trademarked by the

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