HYPERBILIRUBINEMIA OF NEWBORN INFANTS ASSOCIATED WITH THE PARENTERAL ADMINISTRATION OF A VITAMIN K ANALOGUE TO THE MOTHERS

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HYPERBILIRUBINEMIA

OF

NEWBORN

INFANTS

ASSOCIATED

WITH

THE

PARENTERAL

ADMINISTRATION

OF

A

VITAMIN

K ANALOGUE

TO

THE

MOTHERS

By Jerold F. Lucey, M.D., and Robert G. Dolan, M.D.

Department of Pediatrics, University of Vermont College of Medicine

(Accepted October 7, 1958; submitted September 2.)

Supported in part by a grant from the Playtex Park Research Institute.

ADDRESS: (J.F.L.) Btmrhington, Vermiiont.

PEDIAi-nlcs, \Iarcli 1959

S

INCi 1955 a number of reports18 have

indicated a relationship between large

doses of water-soluble forms of vitamin K

analogues administered to the newborn

in-fant and the occurrence of

hyperbilirubi-nemia and kernicterus.

Recently we became aware of an

associa-tion between the administration of large

amounts (72 mg) of a vitamin K analogue,

menadione sodium bisulfite (Hykinone!),

intravenously on intramuscularly to mothers

in labor and the occurrence of marked, early

hyperbihirubinemia in newborn premature

infants. This source of vitamin K analogue

nitoxication in infants has not been

previ-ously reported. This report presents data on

eight such cases.

PATIENT

MATERIAL

AND

METHODS

Durimig the 18-month period, January 1, 1957

to July 1, 1958, 198 miewbormi premature

in-famits of less than 2,500 gm birth weight were

admitted to the miurseries of the DeGoesbriand

Memiiorial and Mary Fletcher Hospitals.

Au attempt was made to obtain

determimia-tiomis of bilirubimi imi the serumm of each of these

infamits who was noted to be jaundiced. This

was domie because of the kmiown high incidence

among premature imifants of hyperbilirubimiemia

and kermiicterus miot associated with blood

groimp imicompatibihitv, amid because of the

un-reliability of estimates of levels of serum

biliru-l)imi on the basis of the degree of clinically

ap-parent jaundice. The last 50 infants had routine

determimiations of serum bilirubin on the

sec-ond, fourth and sixth days of life, regardless of

the presemice or absence of jaundice.

Because of the known relatiomiship of

kernic-terums to concemitration of bilirubin in the serum

over 18 to 20 mg/100 ml, and especially over

24 mg/100 ml,9b0 a policy of exchamige

trans-fusion when the serum bihirubimi was over 20

to 25 mg/100 ml durimig the first six days of

life was established. As exchamige transfusiomi

carries a definite risk for the premature

in-fant, some individualization of criteria was

made. In clinically well infamits over 48 hours

of age, exchange tramisfusion was occasionally

withheld for 6 to 12 hours despite levels of

serum bilirubin of 20 to 25 mg/100 ml. If at

the end of that interval, repeat determimiation

of the serum bilirubin showed a spontaneous

decrease, and the baby remained well,

obser-vation without exchamige transfusion was

comi-tinued. Fumrther exchange tramisfusions were

domie according to the same indicatiomis.

All bilirumbin determimiations were made

by

the Evelyn modificatiomi of the van den Bergh

method as adapted by Hsia et al.11

All exchange transfusions were done

cording to the procedumre of Allen amid

Dia-mond2

CLINiCAL

OBSERVATIONS

Under the policies listed, dtmring an

18-month period, 22 prematumne infamits

re-ceived a total of 31 exchange transfusiomis

for hyperbilmrumbinemia. This seemed ami

cx-cessive number, so a retrospective analysis

of the clinical records of all 198 premature

infants delivered in this period, and their

mothers, was carried out. In the light of

recent reports implicating excessive doses

of vitamin K analogues15 andl suilfisoxazole

(

Gantnisin)13 14 as causes of hyperbilirumbi-nemia and kernicterus, particular attention

was given to medications received by the mother or infant.

During this period, the mothers of nine

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re-* MENADIONE SODIUM BISULFITE

ceived 72 mg of menadione bisulfite

(Hy-kinone#{174}) ante partum, either intravenously

or intramuscularly. Six infants of these

mothers subsequently developed

hyper-bilirubinemia of sufficient degree to receive

an exchange transfusion according to the

criteria described. In the three infants who

did not receive an exchange transfusion the serumm bilirubin of one (infant 7, Table I)

had risen to 22 mg/100 ml on the fourth

day of life, but subsided spontaneously

without treatment. No determinations of

serum bilirubin were done on the remaining two infants.

The incidence of hyperbihirubinemia and

exchange transfusion in this Hykinone#{174}

group was high. In contrast, among 189 “normal” premature infants (mothers not treated with Hykinone#{174}), only 16 infants

were observed to develop sufficient

hyper-bihirubinemia to require an exchange

trans-fusion accordimig to the criteria employed.

The incidlence of 8, in this group of

Pre-mature infants, with umnexplained

hyper-bihirumbinemia (serum levels oven 20 mg/100

ml) is within the range of that reported by

other authors.ml in

The clinical records of these 16 infants and their mothers did not reveal any one

medication which liadi been received!

con-sistently enough to implicate it as an

etio-logic agent.

Information from thie Hykinone group

is summmarized in Table I. Infants 1-7 were

prematurely born. There were foumr niales

and three females. A major blood-group

in-compatibility existed! in only one instamice

(

infant 6). All of these infants had a

nega-TABLE I

INFORMATION REGARDING (;ioup OF 8 INFANTS WhOSE MOTIIEIIS RE(EIVEI) A

VmTAMmN K ANALOGUE Pmtmou TO 1)LI1Emy

-INFANT WEIGHT

(GRAMS)

BLOOD GROUP

INFANT MOTHER

HYKINONEI DOSAGE IGHEST

BILIRUN

(MG%)

FOLLOW UP

AMOUNT ROUTE

HOURS PRIOR TO DELIVERY

I. 575 0 0 72 IM. 112 35 DIED- KERNICTERUS.

2. 2353 O B+ 72 IV. 34 21 NORMAL-AGE I YEAR.

3. 680 A+ 5+ 72 IM. 0 28 NORMAL-AGE II MONTHS.

4 1530 8+ B+ 72 IV. 5 26

DIED- AGE I MONTH LIVER ABSCESS,

SEPSIS.

5. 1431 A A+ 72 I V. 2 4 2 8 NORMAL

-

AGE 9 MONTHS.

6. 2013 A+ 0+ 72 IV. 2 46 NORMAL-AGE 6 MONTHS.

7 2225 A4 A+ 72 IV. 4 22 NORMAL-AGE 6 MONTHS.

FULL

TERM 2792 O O 72 IV. 3 47

RETARDED

(3)

I0 0 10 . E 0 0 E C -a

I 2 3 4 5 5 7

CASE S. 40

$0

I’

0

7

1

1.L(TN.

S I 2 3 4 5 5

Age (days)

4 S S 7

vitamiiin K analogue. Broken line indicates an exchange transfusion was done between

deter-minations. tive Coombs’ test. The mothers all had

neg-ative serologic tests for syphilis. None of

the imifamits were suspected of having sepsis

1)rior to exchange transfusion. In only one

infant (infant 4) was the hemoglobin

de-terminedi prior to exchange transfusion; it

v_s 14.0 gmn/100 ml. Blood cultumnes,

reticu-locvte coumnts or search for Heinz bod!ies

were miot (lone. The principal criterion for

cxchamige transfusion was invariably the

hyperbilirumbmnemia, secondarily niodified by

cons:deration of the patient’s age and

gen-eral condition.

All of these infants received 2.5 mg of

Hykinone’ , intramumsculariy, at birth and 2.5

mg on the third d.iy of life, a total dosage

of 5 mg. This amoumnt has not been shown

to have an effect upon levels of bihirubin in

the serum. ‘ s Five of the mothers had

re-ceived 72 mg of Hykinon&’, intravenously,

from 2 to 34 hours prior to delivery. The

niothers of two infants (1 and 3) had

re-ceived 72 mg intramuscularly (112 and 10

hioumrs, respectively) prior to delivery.

The concentration of serum bihirubin in

the sx infants who received exchange

trans-fusions are recorded in Figure 1. Infant 7

was foumnd to have a serumm bilirubin of 15

so So 20 CASE L

/1

/V

I0

i 2 3 4 5

CASE 4. 40 30 to tO 1 ,

2 3 45

mg/100 ml at 53 hours of age. This level

increased slowly, reaching a peak of 22

mg/100 ml at 100 hours, and subsided

spon-taneously thereafter.

In all seven infants, the initial bihirubin determinations were ol)tained between 40 and 72 hours of age, the average being 54 houmrs. The initial concentrations of

hili-rubin ranged between 15 and! 31 ing, wthi

an average of 21 mg/100 ml. Foumr of these infants receved! two exchange transfusions each. The influmence of this procedumre on

the concentration of serum bilirubin is

ml-lustrated in Figure 1. For infant 6 an cx-change transfumsion was considered to be indicatedl at 68 hours of age but was not at-tempted hecaumse of cardiac arrhythmia. A second attempt at 96 hours of age was stopped at 330 ml of whole blood because

of the development of cardiac arrhythmia

dumring the procedure.

Only determinations of total bilinimbin were done with infants 1-5. For infants 6

and 7 determinations of direct and total bilirubin were done, andi in both instances

the values for direct-reacting l)ihmubin were found to be less than 2 mg/100 ml.

One infant (infant 1) died on the fourth

CASE 2.

40

E

CASE 3.

I 2 3 4 5 S 7

10

30

A

CASE S.

20

0

S 3

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556

day of life. At necropsy he was found to

have kernicterus. A second infant (infant 4)

died at the age of 1 month from sepsis dume

to hemolytic Staphylococcus aureus. At

ne-cropsy he was found to have a liver abscess.

He had received antibiotics following both

exchange transfusions and also dumring the

last 11 days of life.

The five remaining infants were alive at

the time of this report and ranged in age

from 6 nionths to 1 year. They were con-sidered to be normal. No special studies,

such as psychometric examination or liver

function tests, have been done.

Dumning the sumrvey of prematumre infants

whose mothers had received large amounts

of Hykinone#{174}, one infant was encountered

who was mature by weight but was born 2 weeks before the expected date of

confine-ment (2,792-gram female, blood group 0,

Rh+ , born to a group 0, Rh+ mother). The mother received 72 mg of Hykinone#{174},

intravenously, 3 hours prior to delivery. On

the fourth day of life the infant was noticed

to be deeply jaundiced. The total serum

bilirubin was 47 mg/100 ml. Blood culture, urinalysis and Coombs’ test were negative.

The hemoglobin was 22.5 mg/100 ml. There

was no history of familial anemia. No

neu-rologic abnormalities were noted. This

in-fant was seen in 1956 prior to the use of exchange transfumsion for unexplained late

hyperbihirumbinemia and did not receive an

exchange transfumsion. At the age of 28

months lien motor development was slightly

retarded. She did not walk until the age of

22 months and her gait at 28 months of age

was unsteady; fl() gross hearing loss or signs

of choreo-athetosis were noted.

A survey of mothers of full-term infants

was not carried out as it was the practice of

the obstetric staff to administer parenteral Hykmnone#{174} only for premature labor.

DISCUSSION

Comparison with Physiologic Jaundice

Figure 2 summarizes mean concentrations of serumm bilirubin for premature infants during the early days of life reported by

various authors.152’ The group of seven

in-fants whose mothers received 72 mg of

Hykinone#{174} during labor had a mean con-centration of serum bilinubin of 21 mg/100

ml at 54 hours of age, a figure significantly

above the normal range of valumes. The

series reported by Dine19 is the only one imi

which the median value approaches that of the Hykinone#{174} group. That particumlar study

was carried out prior to the first report that

vitamin K analogues can influence the level

of serum bihirubin, and these infants had

ne-ceived what would now be considered large

doses of a vitamin K analogue.

Although the above evidence correlating

hyperbiliruhinemia of the newborn with

large doses of menadhone bisulfite to the

mother during labor is not conclumsive, it dud

not seem jumstifiable to test the hypothesis

by an alternate-series type of experiment.

The risks of such a study appear to be great from the experience in this group of nine

infants.

In support of the hypothesis the follow-ing points are cited.

Transmission of Vitamin K

Across the Placenta

There are ample studies to establish the

fact that as little as 10 mg vitamin K, given

by mouth ante partum, affects the

pro-thrombin time of infants on the third day of

hife.2224 The intravenous administration of

a water-soluble, low-molecular-weight

corn-pound such as Hykinone#{174} should certainly

enhance the amount reaching the fetus.

Ex-perience with vitamin K analogues has

in-dicated that they are 3 to 15 times more

toxic by injection than when given orally.25

Toxicity of Analogues

To date the only vitamin K analogue

shown to be capable of causing

hyperbili-rubinemia when administered to newborn

infants is sodium menadione diphosphate

(Synkavit#{174}). In animal experiments there is

considerable variation in the toxicity of

various vitamimi K analogues. Two

stud-ies25’ 21i demonstrated that Hykinone is

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19

18

7

6

5

4

3

12

II

10

9

8

7

6

5

4

3

2

0

menadione per milligram as Synkavit#{174};

menadione is thought to be the toxic

por-tion of the compounds.

0

E

I 2 3 4 5 6 7 8 9

Age

(days)

FIG. 2. Sunimiiary of reported studies0’ u521 f miiean concentrations

of bilirtmbin in serumn of premature infants.

several reasonable explanations can be

sug-gested.

IN ERYTHROCYTES : The toxic effect may

. . . be due to a primary action on the erythro-.

Mechanism of Toxicity cytes.

In the clinical

studiesG 7 Heinz bodies

The exact mechanism of vitamin K ana- were reported to occur in increased

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large amounts of a vitamin K analogue. It

was demonstrated that in vitro a sumspension

of the premature infant’s enythrocytes are

made more susceptible to Heinz-body

for-mation by the addition of Synk.ivit#{174} than are the cells of full-term infants.7

Erythro-cytes with a low or unstable glutathione

con-tent are known to be more susceptible to

drug-induced h27 Premature

in-fants are known to have an altered

gluta-thione metabolism and abnormal

glumt.i-thione stability.2 Vitamin K is also said to lower glutathione in the blood of man and

the dog.29

Animal studies have demonstrated that

the toxicity of vitamin K analogues is

en-hanced if the animal is deficient in vitamin

E.25 Newly born infants are known to

have low levels of vitamin E in the blood.

IN

THE LIVER: The administration of

nienadione bisulfite intravenously to dogs,

15 to 40 mg/kg/24 hr, for 15 days causes hepatic cellular damage.3#{176} If large doses of

vitamin K1 are injected intravenously into

chicks an(l rats, it is rapidly deposited in

the liver and spleen; even after 42 days an

estimated 16% of the injected dose remains

in these organs.31 There may he storage or concentration of vitamin K analogues in the

fetal liver following parenteral

administra-tion to the mother.

When vitamin K analogues are given

in-travenously to patients with early hepatitis,

the serum bilirubin increases 2 to 7 mg/100

ml within 1 to 4 hours.32 This suggests that

a liver with impaired function may be

sen-sitive to large amounts. The premature

in-fant’s liver is known to have impaired

func-lion, especially with respect to bilirubin

cx-cretion.

Vitamin K analogues are partly excreted

as glucuronides33 and may compete for

glucuronyltransferase. The premature

in-fant has diminished activity of this enzyme in the liver.34

Some preliminary experiments with the

Gunn strain of jaundiced rats are in keeping with the preceding considerations.35 These

animals have a congenital hepatic enzyme deficiency. Four of these rats were given one intraperitoneal injection of 0.05 mg of Hykinone#{174} per gram of weight. All four

died within 24 hours and at necropsy he-patic cellular damage was observed in three. A control group of four animals received the

same amount of Synkavite#{174} and did not die. This study is being continued.

This is the first sumbstance known to the

authors that, when administered to human

mothers, appears to have an effect upon

neonatal bihirubinemia. If this can be

dem-onstrated conclusively, it raises some

inter-esting speculations concerning the relation

of drugs administered in pregnancy to the

incidence of clinical jaundice and kernic-tenus or other conditions in the

off-spning.335 Review of clinical records and

closer attention to this possibility in current

management of patients may prove

illumi-nating.

There are no indications for

administra-tion of doses of vitamin K as large as 72 mg

to the pregnant woman.

SUMMARY

Seven cases of marked

hyperbilmrubi-nemia occurring among premature infants

within the first 40 to 72 hours of life are

reported. The mothers of these infants had

received 72 mg of a vitamin K analogue

(

Hykmnone#{174}) intramuscularly or

intrave-ncusly from 2 to 112 hours prior to delivery.

The evidence presented indicates that this medication predisposed the infants to

hy-perbilirubinemia.

The hypothesis is presented that the

vita-mm K analogue passed through the placenta

and exerted a hepatotoxic effect upon the

newborn infant. Because of possible serious

consequences to the infant, new drugs

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ARTICLES

REFERENCES

1. Allison, A. C. : Danger of vitamin K to

newborn (Letter to the Editor). Lancet,

1:669, 1955.

2. Laurence, B. : Danger of vitamin K

analogues to newborn (Letter to the Editor). Lancet, 1:819, 1955.

3. Meyer, T. C., and Angus,

J.

: The effect

of large doses of Synkavit#{174} in the

new-born. Arch. Dis. Childhood, 31:212,

1956.

4. Bound,

J.

P., and Teifer, T. P. : Effect of vitamin K dosage on plasma bilirubin

levels in premature infants. Lancet, 1:

720, 1956.

5. Crosse, V. M., Meyer, T. C., and Gerrard,

J.

W. : Kemicterus and prematurity.

Arch. Dis. Childhood, 30:501, 1955.

6. Gasser, C. : Die hamolytische

FrUhgebur-tenan#{228}mie mit spontaner

Innenkorper-bildung. Helvet. paediat. acta, 8:491,

1953.

7. Willi, H. : Synkavit#{174} toxicity in premature

infants. Heivet. paediat. acta, 11:325,

1956.

8. Asteriadou-Samartzis, E., and Leikin, S.:

The relation of vitamin K to

hyperbili-rubinemia. PEDIAmIc5, 21 :397, 1958.

9. Mohhison, P. L., and Cutbush, M. : Method

of measuring severity of series of cases

of hemolytic disease of newborn. Blood,

6:777, 1951.

10. Hsia, D. Y., Allen, F. H., Gellis, S. S., and

Diamond, L. K. : Erythroblastosis fetalis.

New England

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Med., 247:668, 1952.

11. Hsia, D. Y., Hsia, H., and Cellis, S. S.:

A micromethod for serum bilirubin.

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Lab. & Clin. Med., 40:610, 1952.

12. Allen, F. H., and Diamond, L. K. :

Ervthro-blastosis Fetahis. Boston, Little, 1958.

13. Silverman, W. A., Andersen, D. H., Blanc,

W. A., and Crozier, D. N. : A difference

in mortality rate and incidence of

kern-icterus among premature infants alloted

to two prophylactic antibacterial

regi-mens. PEDIATRICS, 18:614, 1956.

14. Harris, R. C., Lucey,

J.

F., and MacLean,

R.

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: Kernicterus in premature infants

associated with low concentrations of

bilirubin in the plasma. PEDIATRICS, 21:

875, 1958.

15. Rapmund, C. , Bowman,

J.,

and Harris,

R. C. : Kernicterus in nonervthroblastotic premature infants. In preparation.

16. Taylor, P. M., Bright, N. M., Birchard,

E. L., and Watson, D. W. : Evaluation

of factors influencing the degree of

neo-natal jaundice. In preparation.

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and Cellis, S. S. : Serum bilirubin levels

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18. Obrinsky, W., Allen, E. L., and Anderson,

E. E. : Physiologic hyperbilirubimiemia in

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19. Dine, M. S.: Hyperbilirubinemia in the newborn premature infant (abstract). Am.

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Dis. Child., 88:810, 1954.

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21. Miller, C. A., and Reed, H. R. : The

re-lation of serum concentrations of

bili-rubin to respiratory function of

pre-mature infants. PEDIATRICS, 21:362,

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J.,

et al.: Hemorrhagic diathesis

of newborn. Am.

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836, 1941.

23. Dyggve, H. : Repeated antenatal contra

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vita-mm K. Danish M. Bull., 3:172, 1956.

24. Dvggve, H., Dam, H., and Sondergaard,

E. : Influence of vitamin K1 and Synkavit

given ante partum on the prothrombin

time of the newborn. Acta obst. &

gynec. scandinav., 33:283, 1954.

25. Allison, A. C., Moore, T., and Sharman,

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M. : Haemolvsis and haemoglobinuria

in vitamin E deficient rats after

injec-tions of vitamin K substitutes. Brit.

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Haemat., 2:197, 1956.

26. Marusich, W., Ritter, E., and Rubin, S. H.:

Hemoglobinuria induced in vitamin E deficient rats

by

massive injections of

water soluble vitamin K (abstract). Fed.

Proc., 15:562, 1956.

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abnormality of red blood cell

predispos-ing to drug-induced hemolvtic anemia. Bull. Johns Hopkins Hosp., 101:115,

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28. Zinkham, W. H. : The mechamiism and

clini-cal significance of an abnormality in glutathione metabolism of ervthrocvtes from normal newborns (abstract). A.M.A.

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Dis. Child., 96:621, 1958.

29. Sebrell, W., Jr., and Harris, R. : The

Vitamins, Vol. 2. New York, Acad.

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sion.

memiadione derivatives.

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Dam, H., Prange, I., and Sondergaard, E.:

Levels of vitamin K1 in blood and

van-oils organs of chicks and rats after the

administration of massive doses. Acta

pharmacol. et toxicol., 10:58, 1954.

32. Gottsegen, G., Horn, Z., and Hary, M. C.:

The effect of vitamin K on hyperbili-rubinemia. Acta med. scandinav., 140:

127, 1951.

33. Solvonuk, P. F., et al.: Experimemits with

C’4 menadione (vitamin K3). Proc. Soc.

Exper. Biol. & Med., 79:597, 1952.

34. Lathe, C. H., and Walker, M. : An enzyme

defect in human neonatal jaundice and

in Gunn’s strain of jaundiced rats.

Biochem.

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35. Lucey,

J.,

and Munkittnick, R. :

Umipub-hished studies.

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C., and Ratner, I. M. :

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37. Lathe, G. H., and Walker, M. : The

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serum, neonatal serum and steroids omi

the conjugation of bilirubin by rat-liver

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38. Heaney, R., and Whedon, C. D. :

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Lab. & Chin. Med., 52:169, 1958.

INCREASING CLINICAL SIGNIFICANCE OF ALTERATIONS IN ENZYMES OF BODY FLUIDS,

Felix \Vr#{243}blewski, M.D. ( Ann. Int. Ml., 50:62, Janumary, 1959.)

Tile extensive investigations of activity of enzynies in various tissues of the body is

being rapidly extemided to provide niethods for estimation of the activity of a great

nuniber of enzymes present in the body flumids, such as blood, urine and cerebrospinal

fluid. Considerable progress has been made in correlating fluctuations in the activity

of these enzymes and many diseased states. Therefore the clinician is now faced with

the necessity of umnderstanding and evaluating the significance of variations in enzyniic

activity in the clinical diagnosis and nianageniemit of pathologic conditions. The present

paper provides an extensive review of the presemit status of the practical application of

(leternunations of cnzymic activity. The presentation covers applications in gastro-enterology, particularly disease.s of the liver, cardiology, neoplastic diseases, and

dis-orders of tile miiuscumlar and miervous systems. It is apparent that there are many

diffi-culties in using determinations of enzymnic activity for specific diagnosis, but in many

instances such determiiinations are helpful in diagnosis, miianagement and facilitation of

niore accurate prognosis. It is pointed out that when used in conjunction with other

techniques, the determination of enzyniic activity in body fluids is frequently a valtmable

addition in the study of patients. The paper is written so as to be readily understood by those who do not have special kmiowleclge of enzyniology. The atmthor includes data

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discus-1959;23;553

Pediatrics

Jerold F. Lucey and Robert G. Dolan

MOTHERS

PARENTERAL ADMINISTRATION OF A VITAMIN K ANALOGUE TO THE

HYPERBILIRUBINEMIA OF NEWBORN INFANTS ASSOCIATED WITH THE

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