- Email: [email protected]
Evaluation of body and organ weights in perinatal pathology
Vitamin K administration hyperbilirubinemia A double-blind
M.
HILL,
JOHN
H.
KENNELL,
Cleveland,
C.
of unknown etiology
study
REBA
ALLAN
M.D.*
BARNES,
M.D. M.D.
Ohio
S I N C E Allison’s report’ in 1955 of the production of hyperbilirubinemia in the newborn by the administration of sodium menadiol diphosphate (Synkayvit), this drug has been used with caution in the neonatal period. More recently the question has been raised as to whether or not the administration to the mother of vitamin K during labor could contribute to the frequency and severity of neonatal icterus. Two problems would immediately appear to be involved: the dosage of vitamin K which is required to produce hyperbilirubinemia in the neonatal period, on the one hand, and the amount which the placenta will transmit to the fetus, on the other. With respect to the first of these questions, it should be noted that the dosages of water-soluble vitamin K (largely in premature infants) which have led to difficulty have been extraordinarily high2J 3* 4: for example, the 6 babies reported on by Laurance” had received 100 mg. each within the first 4 days of life, Since blood levels of vitamin K cannot be measured directly, the question of placental transfer to the fetus
cannot be answered quantitatively. Taylor’s5 study with C4-labeled vitamin K in the rat does not permit complete quantitation since the site and amount of dissociation cannot be determined accurately; certainly, however, not all of the material was found on the fetal side of the placenta. In 1958 Lucey and DolarP reported an increased incidence of hyperbilirubinemia in premature infants. whose mothers had received large doses of menadione sodium bisulfite (Hykinone) . Seven infants with bilirubin levels between 21 and 47 mg. per 100 C.C. were reported on. No mention was made of the results of the Coombs tests in these infants. Because of a real or apparent increase in neonatal jaundice in this hospital, it was decided to see if a 5 mg. intramuscular dose of vitamin K (Hykinone) to the mother during labor would be associated with hyperbilirubinemia in the neonate. Patients
address: Department Baylor University Houston, Texas.
of
College
and
procedures
The study here reported was carried out on a double-blind basis. Two sets of ampules were stocked on the delivery room floor, one set labeled X and the other Y. The ampules in one set contained 2.5 mg. of vitamin K (Hykinone) each, while those in the other set contained normal saline.
From the Departments of Pediatrics and of Obstetrics and Gynecology Western Reserve University School of Medicine. *Present Pediatrics, Medicine,
and neonatal
of
320
Volume Number
82 2
Neonatal
infants
whose
mothers
321
ing with neonatal jaundice of undetermined etiology. The code as to which,ampules contained vitamin K and which were blank was known only to the manufacturer until after the study was completed and these 32 cases had been summarized.
The selection of which patient was to receive X and which was to receive Y was based on whether the hospital registration number was odd or even. No other change was made in the labor room procedure. Two ampules were administered to each mother in labor. If the mother was delivered in an hour or less after receiving the medication, the baby was given a single ampule (of the same code lettering as the mother’s). In 8 instances in the X group and 3 instances of the Y group the time interval was too short and the baby also received medication under this policy. The study was carried out on 533 consecutive patients, 266 of whom received one medication and 267 the other. From an obstetric viewpoint (age, parity, length of labor, intercurrent illnesses, etc.) the two groups were comparable. The records of all babies with clinical jaundice from this group were reviewed, and those with a hematological explanation for the icterus (major or minor blood incompatibility) were eliminated (21 cases or 3.9 per cent). There were 32 babies (6 per cent) remain-
Table I. Nineteen
hyperbilirubinemia
Results Among the 266 patients who received vitamin K, neonatal jaundice of undetermined etiology was noted in 19 babies; among the 267 patients receiving the blank, neonatal jaundice of undetermined etiology was found in 13 babies. This difference is not statistically significant. The information concerning these two groups of jaundiced babies is shown in Tables I and II. Considering the 19 cases of jaundice which occurred in the babies in the vitamin K group, the average peak bilirubin level was 17.6 mg. per cent and exchange transfusions were given to 4 infants. In 2 of the cases listed here, there was an Rhnegative mother with an Rh-positive baby; neither mother had demonstrable antibodies, and the Coombs tests were negative in
were
given
5 mg. of vitamin
K during
labor
No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Sex
Race
Birth weight (grams)
M M F F F M M M F F F F F F M M F M M
W W W W W W w W W W W W W W W W N W W
2,620 3,530 3,560 3,140 3.160 31820 2,430 3,130 3,140 2,980 3.590 31870 2,770 3,140 3,810 3,440 1,560 1,840 2,620
Maternal blood We and Rh
Fetal blood We and Rh
AA+ A+ A+ o+
AA+ 0+ Ao+
o-
cl)-
A+ o+ o+ A+ oA+ A+ B+ A+ o+ A+ A+ B-
A+ o+ o+ A+ o+ A+ A+ B+ A+ o+ o+ 0+ 0+
Coombs test
Age jaundice noted
Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative
49 48 24 24 48 2 2 3 2 1 21 1 2 2 2 5 2 2 1
hours hours hours hours hours days days days days day hours day days days days days days days day
Peak
bilirubin and age (total direct) (w. %)
14.5 -0.5 14.3 -0.47 20.9 -0.8 24.6 -0.8 25.4 12.8 -0.6 21.6 -0.8 12.0 -0.6 12.0 -0.6 22.65-1.5 13.8 -0 12.9 -0.5 16.38-0.47 12.4 -1.0 20.0 -0.5 18.0 -0.6 20.9 -1.6 18.0 -0.7 21.2 -0.7
(5 days) (3 days) (3 days) (4daysj (5 davs) (2daysj (5 days) (3 days) (3 days) (4 days) (3days) (3 days) (3 days) (2days) (5 days) (5 days) (4days) (5 days) (3 days)
EXchange transfusion No No Yes Yes Yes No No No No No No No No No No No No No Yes
322
Hill,
Kennell,
Table II. Thirteen
and
Barnes
control
infants
whose
mothers
were
Birth weight (grams)
Maternal We andRh
Fetal We and Rh
Coombs test
A+ AB+ Oo+ o+ o+ 0+ A+ A+ 0+ A+ o+ A+
Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative
siven
a placebo
during
labor __--
No.
1 2 3 4 5 6 7 8 9 10 11 12 13
Sex
Race
M M F M M F M F F M M F M
W W W W W W W W W W W W W
3,910 4,000 3,260 3,100 3,100 3,610 3.190 3.280 3,280 3,360 3,590 3,470 2,640
A+ AB+ Bo+ .4+ o+ A+ A+ A0+ A+ oA+
both. The 19 babies on this chart constitute 7.2 per cent of the original 266 babies born to mothers who received vitamin K. In 8 of these cases the baby had received 2.5 mg. of the medication under the policy cited above since the maternal medication preceded delivery by too brief a time. The data from the cases of babies born to mothers receiving the blank injection and who developed neonatal jaundice of unknown etiology are summarized in Table II. The average bilirubin peak was 14.5 mg. per cent and no exchange transfusions were given. There were two circumstances in which an Rh-negative mother bore an Rhpositive child but in neither was there a positive Coombs test or a record of maternal antibodies. This group is 4.8 per cent of the original 267 babies born to mothers who received the placebo. In comparing these two groups, it is well to review critically those factors which could introduce variables. For a baby to be listed in either Table I or Table II, three prerequisites had to be fulfilled: a bilirubin determination performed, a predetermined bilirubin level reached, and no explanation for jaundice discovered by standard tests. The decision to request bilirubin determinations rested with the individual private and staff pediatricians involved. This was a sizeable group and variability could have been
l_----^ Ex-
Age jaundice noted
3 7 2 3 3 3 5 4 2 3 3 2 2
days days days days days days days days days days days days days
Peak
bilirubin nnd (total direct) (mg. %)
20.7-0.6 16.7-1.17 17.4-0.4 12.2-0.5 12.8-0.5 12.3-0.4 18.6-0.3 16.9-0.9 12.413.1-0.3 13.1-0.3 12.8-0.9 14.6-0.5
(7 (7 (4 (4 (3 (3 (5 (2
age change
days) days) days) days) days) days) days) days)
(2 days) (4 (4 (5 (3
days) days) days) days)
transfusion
No No No No NO
No No NO
No
No NO
No NO
introduced on the basis of differing indices of suspicion. It has been our experience, however, that with the increasing ease of performance of the blood bilirubin determination the test is overused rather than underused. The finding of such levels as 2.8 mg. per cent and 4.4 mg. per cent, for example, among the records of these 533 babies would make it doubtful that many truly icteric babies were missed. The level of bilirubin selected to “qualify” a baby for inclusion in the tables was 12 mg. per cent for term and premature infants. However, the figures were recalculated with the dividing line as being 16 mg. per cent, and there was still no statistically valid difference between the two groups. The factors of the initial decision to obtain a bilirubin level and the milligrams per cent selected to represent jaundice are not believed to represent significant variables. We feel, however, that the number of exchange transfusions employed could not be considered a reliable index since during the period of this study the exchange transfusion facilities were under the direction of two different members of the staff, and the matter of personal taste and policy might have entered into the decision. One Mongoloid infant who had a bilirubin level above 20 mg. per cent did not receive an exchange transfusion.
Volume Number
82 2
Neonatal
Three additional babies developed bilirubin levels over 12 mg. per cent but were eliminated from consideration because an apparent explanation was readily available and they could not be classified as having jaundice of unknown etiology. Two of these infants were from the placebo group. One was diagnosed as having septicemia (peak bilirubin level 21.3 mg. per cent) and the other as having hemorrhagic disease of the newborn (peak bilirubin level 14.6 mg. per cent). The third infant had a bleeding dyscrasia. He was in the group treated with vitamin K and had a peak bilirubin level of 26.2 mg. per cent at 4 days of age. The statement that the different frequencies of jaundice in the two groups “is not a statistically valid difference” cannot be interpreted as being identical with the statement “the administration of vitamin K has no effect on the development of neonatal icterus.” It means only that the figures derived from a series of this size does not establish a positive etiological relationship; their failure to prove this does not prove the opposite. There are other criteria which can be used to judge whether or not the vitamin K was associated with the appearance of neonatal hyperbilirubinemia. A bilirubin level of 20 mg. per cent is now universally considered to be a potentially dangerous level in relation to the development of kernicterus since the report of Hsia and associates7 in 1952. A scattergram of the 32 cases in which a level of bilirubin over 12 mg. per cent developed is presented in Fig. 1. Eight babies in the group treated with vitamin K reached a level of 20 mg. per
Table III. performed
Prothrombin determinations in second and third day of life Age
Baby
1 2 3 4 5 6
(days) 3 3 2 3 3 2
f’rothrombin
I level (k) 86 65 42 21 86 70
Medication
Vitamin K Vitamin K Vitamin K Placebo Placebo Placebo
6I&i I
2
hyperbilirubinemia
3 4 OAYS OLD
5
323
6
7
Fig. 1. A scattergram of 32 infants with bilirubin levels of 12 mg. Per cent. Eight infants in the vitamin K (Hykinone) group have bilirubin levels of at least 20 mg. per cent and one infant in the placebo group has a bilirubin level of at least 20 mg. per cent. cent or more. Two of these infants were premature by weight, but even excluding these there are 6 babies who reached this danger level whereas only one baby in the placebo group reached 20 mg. per cent or more. During the period of this study 3 babies developed bleeding manifestations. One (first day) was from the vitamin K group and had a prothrombin level of 68 per cent. While the diagnosis is not completely established at the time of writing, it is probable that this child has hemophilia. Two of the babies in the placebo group bled (second day); one had a prothrombin level of less than 7 per cent and the other of less than 5 per cent. As controls, 6 babies-3 from the vitamin K group and 3 from the placebo group-were selected at random for prothrombin determinations and these results are shown in Table III. Not all babies deprived of vitamin K have prothrombin levels which drop to a dangerous point. Conclusions 1. A double-blind study was performed in which 266 women in labor were given vitamin K (Hykinone) and 267 women in labor were given a placebo (saline). The incidence of jaundice of unknown etiology in the progeny of the two groups was compared. 2. The results indicate that 7.2 per cent
324
Hill, Kennell,
August, 1961 Am. .I. Obst. & Gym.
and Barnes
of the babies in the vitamin K group and 4.8 per cent of the babies in the placebo group developed a bilirubin Ievel of 12 mg. per cent or more. 3. Excluding 2 premature infants in the group treated with vitamin K, the incidence of potentially dangerous levels of bilirubin
1: 669, 1955. 1: 819, 1955. 3. Meyer, T. C., and Angus, J.: Arch. Dis. Childhood 31: 212, 1956. 4.
Allison, Laurance,
A. C.: Lancet B.: Lancet
Bounds, J. 720, 1956.
P.,
and
Telfer,
T.
P.:
Lancet
1:
K
We wish to express our appreciation to Dr. George H. Berryman of Abbott Laboratories for providing the ampules of Hykinone and the matching ampules of saline.
5.
REFERENCES
1. 2.
was five times as great in the vitamin group as in the control group.
6.
Taylor, J. D.: University of Saskatchewan Graduate Studies, Physiology and Pharmacology, April, 1957. Lucey, J. F., and Dolan, R.: J. A. M. A. 167:
1875, 1958. 7. Hsia, D. Y., Allen, Diamond, L. K.: 668, 1952.
F. H., Gellis, S. 8, and
New
England
J. Med.
247:
M.
HILL,
JOHN
H.
KENNELL,
Cleveland,
C.
of unknown etiology
study
REBA
ALLAN
M.D.*
BARNES,
M.D. M.D.
Ohio
S I N C E Allison’s report’ in 1955 of the production of hyperbilirubinemia in the newborn by the administration of sodium menadiol diphosphate (Synkayvit), this drug has been used with caution in the neonatal period. More recently the question has been raised as to whether or not the administration to the mother of vitamin K during labor could contribute to the frequency and severity of neonatal icterus. Two problems would immediately appear to be involved: the dosage of vitamin K which is required to produce hyperbilirubinemia in the neonatal period, on the one hand, and the amount which the placenta will transmit to the fetus, on the other. With respect to the first of these questions, it should be noted that the dosages of water-soluble vitamin K (largely in premature infants) which have led to difficulty have been extraordinarily high2J 3* 4: for example, the 6 babies reported on by Laurance” had received 100 mg. each within the first 4 days of life, Since blood levels of vitamin K cannot be measured directly, the question of placental transfer to the fetus
cannot be answered quantitatively. Taylor’s5 study with C4-labeled vitamin K in the rat does not permit complete quantitation since the site and amount of dissociation cannot be determined accurately; certainly, however, not all of the material was found on the fetal side of the placenta. In 1958 Lucey and DolarP reported an increased incidence of hyperbilirubinemia in premature infants. whose mothers had received large doses of menadione sodium bisulfite (Hykinone) . Seven infants with bilirubin levels between 21 and 47 mg. per 100 C.C. were reported on. No mention was made of the results of the Coombs tests in these infants. Because of a real or apparent increase in neonatal jaundice in this hospital, it was decided to see if a 5 mg. intramuscular dose of vitamin K (Hykinone) to the mother during labor would be associated with hyperbilirubinemia in the neonate. Patients
address: Department Baylor University Houston, Texas.
of
College
and
procedures
The study here reported was carried out on a double-blind basis. Two sets of ampules were stocked on the delivery room floor, one set labeled X and the other Y. The ampules in one set contained 2.5 mg. of vitamin K (Hykinone) each, while those in the other set contained normal saline.
From the Departments of Pediatrics and of Obstetrics and Gynecology Western Reserve University School of Medicine. *Present Pediatrics, Medicine,
and neonatal
of
320
Volume Number
82 2
Neonatal
infants
whose
mothers
321
ing with neonatal jaundice of undetermined etiology. The code as to which,ampules contained vitamin K and which were blank was known only to the manufacturer until after the study was completed and these 32 cases had been summarized.
The selection of which patient was to receive X and which was to receive Y was based on whether the hospital registration number was odd or even. No other change was made in the labor room procedure. Two ampules were administered to each mother in labor. If the mother was delivered in an hour or less after receiving the medication, the baby was given a single ampule (of the same code lettering as the mother’s). In 8 instances in the X group and 3 instances of the Y group the time interval was too short and the baby also received medication under this policy. The study was carried out on 533 consecutive patients, 266 of whom received one medication and 267 the other. From an obstetric viewpoint (age, parity, length of labor, intercurrent illnesses, etc.) the two groups were comparable. The records of all babies with clinical jaundice from this group were reviewed, and those with a hematological explanation for the icterus (major or minor blood incompatibility) were eliminated (21 cases or 3.9 per cent). There were 32 babies (6 per cent) remain-
Table I. Nineteen
hyperbilirubinemia
Results Among the 266 patients who received vitamin K, neonatal jaundice of undetermined etiology was noted in 19 babies; among the 267 patients receiving the blank, neonatal jaundice of undetermined etiology was found in 13 babies. This difference is not statistically significant. The information concerning these two groups of jaundiced babies is shown in Tables I and II. Considering the 19 cases of jaundice which occurred in the babies in the vitamin K group, the average peak bilirubin level was 17.6 mg. per cent and exchange transfusions were given to 4 infants. In 2 of the cases listed here, there was an Rhnegative mother with an Rh-positive baby; neither mother had demonstrable antibodies, and the Coombs tests were negative in
were
given
5 mg. of vitamin
K during
labor
No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Sex
Race
Birth weight (grams)
M M F F F M M M F F F F F F M M F M M
W W W W W W w W W W W W W W W W N W W
2,620 3,530 3,560 3,140 3.160 31820 2,430 3,130 3,140 2,980 3.590 31870 2,770 3,140 3,810 3,440 1,560 1,840 2,620
Maternal blood We and Rh
Fetal blood We and Rh
AA+ A+ A+ o+
AA+ 0+ Ao+
o-
cl)-
A+ o+ o+ A+ oA+ A+ B+ A+ o+ A+ A+ B-
A+ o+ o+ A+ o+ A+ A+ B+ A+ o+ o+ 0+ 0+
Coombs test
Age jaundice noted
Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative
49 48 24 24 48 2 2 3 2 1 21 1 2 2 2 5 2 2 1
hours hours hours hours hours days days days days day hours day days days days days days days day
Peak
bilirubin and age (total direct) (w. %)
14.5 -0.5 14.3 -0.47 20.9 -0.8 24.6 -0.8 25.4 12.8 -0.6 21.6 -0.8 12.0 -0.6 12.0 -0.6 22.65-1.5 13.8 -0 12.9 -0.5 16.38-0.47 12.4 -1.0 20.0 -0.5 18.0 -0.6 20.9 -1.6 18.0 -0.7 21.2 -0.7
(5 days) (3 days) (3 days) (4daysj (5 davs) (2daysj (5 days) (3 days) (3 days) (4 days) (3days) (3 days) (3 days) (2days) (5 days) (5 days) (4days) (5 days) (3 days)
EXchange transfusion No No Yes Yes Yes No No No No No No No No No No No No No Yes
322
Hill,
Kennell,
Table II. Thirteen
and
Barnes
control
infants
whose
mothers
were
Birth weight (grams)
Maternal We andRh
Fetal We and Rh
Coombs test
A+ AB+ Oo+ o+ o+ 0+ A+ A+ 0+ A+ o+ A+
Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative
siven
a placebo
during
labor __--
No.
1 2 3 4 5 6 7 8 9 10 11 12 13
Sex
Race
M M F M M F M F F M M F M
W W W W W W W W W W W W W
3,910 4,000 3,260 3,100 3,100 3,610 3.190 3.280 3,280 3,360 3,590 3,470 2,640
A+ AB+ Bo+ .4+ o+ A+ A+ A0+ A+ oA+
both. The 19 babies on this chart constitute 7.2 per cent of the original 266 babies born to mothers who received vitamin K. In 8 of these cases the baby had received 2.5 mg. of the medication under the policy cited above since the maternal medication preceded delivery by too brief a time. The data from the cases of babies born to mothers receiving the blank injection and who developed neonatal jaundice of unknown etiology are summarized in Table II. The average bilirubin peak was 14.5 mg. per cent and no exchange transfusions were given. There were two circumstances in which an Rh-negative mother bore an Rhpositive child but in neither was there a positive Coombs test or a record of maternal antibodies. This group is 4.8 per cent of the original 267 babies born to mothers who received the placebo. In comparing these two groups, it is well to review critically those factors which could introduce variables. For a baby to be listed in either Table I or Table II, three prerequisites had to be fulfilled: a bilirubin determination performed, a predetermined bilirubin level reached, and no explanation for jaundice discovered by standard tests. The decision to request bilirubin determinations rested with the individual private and staff pediatricians involved. This was a sizeable group and variability could have been
l_----^ Ex-
Age jaundice noted
3 7 2 3 3 3 5 4 2 3 3 2 2
days days days days days days days days days days days days days
Peak
bilirubin nnd (total direct) (mg. %)
20.7-0.6 16.7-1.17 17.4-0.4 12.2-0.5 12.8-0.5 12.3-0.4 18.6-0.3 16.9-0.9 12.413.1-0.3 13.1-0.3 12.8-0.9 14.6-0.5
(7 (7 (4 (4 (3 (3 (5 (2
age change
days) days) days) days) days) days) days) days)
(2 days) (4 (4 (5 (3
days) days) days) days)
transfusion
No No No No NO
No No NO
No
No NO
No NO
introduced on the basis of differing indices of suspicion. It has been our experience, however, that with the increasing ease of performance of the blood bilirubin determination the test is overused rather than underused. The finding of such levels as 2.8 mg. per cent and 4.4 mg. per cent, for example, among the records of these 533 babies would make it doubtful that many truly icteric babies were missed. The level of bilirubin selected to “qualify” a baby for inclusion in the tables was 12 mg. per cent for term and premature infants. However, the figures were recalculated with the dividing line as being 16 mg. per cent, and there was still no statistically valid difference between the two groups. The factors of the initial decision to obtain a bilirubin level and the milligrams per cent selected to represent jaundice are not believed to represent significant variables. We feel, however, that the number of exchange transfusions employed could not be considered a reliable index since during the period of this study the exchange transfusion facilities were under the direction of two different members of the staff, and the matter of personal taste and policy might have entered into the decision. One Mongoloid infant who had a bilirubin level above 20 mg. per cent did not receive an exchange transfusion.
Volume Number
82 2
Neonatal
Three additional babies developed bilirubin levels over 12 mg. per cent but were eliminated from consideration because an apparent explanation was readily available and they could not be classified as having jaundice of unknown etiology. Two of these infants were from the placebo group. One was diagnosed as having septicemia (peak bilirubin level 21.3 mg. per cent) and the other as having hemorrhagic disease of the newborn (peak bilirubin level 14.6 mg. per cent). The third infant had a bleeding dyscrasia. He was in the group treated with vitamin K and had a peak bilirubin level of 26.2 mg. per cent at 4 days of age. The statement that the different frequencies of jaundice in the two groups “is not a statistically valid difference” cannot be interpreted as being identical with the statement “the administration of vitamin K has no effect on the development of neonatal icterus.” It means only that the figures derived from a series of this size does not establish a positive etiological relationship; their failure to prove this does not prove the opposite. There are other criteria which can be used to judge whether or not the vitamin K was associated with the appearance of neonatal hyperbilirubinemia. A bilirubin level of 20 mg. per cent is now universally considered to be a potentially dangerous level in relation to the development of kernicterus since the report of Hsia and associates7 in 1952. A scattergram of the 32 cases in which a level of bilirubin over 12 mg. per cent developed is presented in Fig. 1. Eight babies in the group treated with vitamin K reached a level of 20 mg. per
Table III. performed
Prothrombin determinations in second and third day of life Age
Baby
1 2 3 4 5 6
(days) 3 3 2 3 3 2
f’rothrombin
I level (k) 86 65 42 21 86 70
Medication
Vitamin K Vitamin K Vitamin K Placebo Placebo Placebo
6I&i I
2
hyperbilirubinemia
3 4 OAYS OLD
5
323
6
7
Fig. 1. A scattergram of 32 infants with bilirubin levels of 12 mg. Per cent. Eight infants in the vitamin K (Hykinone) group have bilirubin levels of at least 20 mg. per cent and one infant in the placebo group has a bilirubin level of at least 20 mg. per cent. cent or more. Two of these infants were premature by weight, but even excluding these there are 6 babies who reached this danger level whereas only one baby in the placebo group reached 20 mg. per cent or more. During the period of this study 3 babies developed bleeding manifestations. One (first day) was from the vitamin K group and had a prothrombin level of 68 per cent. While the diagnosis is not completely established at the time of writing, it is probable that this child has hemophilia. Two of the babies in the placebo group bled (second day); one had a prothrombin level of less than 7 per cent and the other of less than 5 per cent. As controls, 6 babies-3 from the vitamin K group and 3 from the placebo group-were selected at random for prothrombin determinations and these results are shown in Table III. Not all babies deprived of vitamin K have prothrombin levels which drop to a dangerous point. Conclusions 1. A double-blind study was performed in which 266 women in labor were given vitamin K (Hykinone) and 267 women in labor were given a placebo (saline). The incidence of jaundice of unknown etiology in the progeny of the two groups was compared. 2. The results indicate that 7.2 per cent
324
Hill, Kennell,
August, 1961 Am. .I. Obst. & Gym.
and Barnes
of the babies in the vitamin K group and 4.8 per cent of the babies in the placebo group developed a bilirubin Ievel of 12 mg. per cent or more. 3. Excluding 2 premature infants in the group treated with vitamin K, the incidence of potentially dangerous levels of bilirubin
1: 669, 1955. 1: 819, 1955. 3. Meyer, T. C., and Angus, J.: Arch. Dis. Childhood 31: 212, 1956. 4.
Allison, Laurance,
A. C.: Lancet B.: Lancet
Bounds, J. 720, 1956.
P.,
and
Telfer,
T.
P.:
Lancet
1:
K
We wish to express our appreciation to Dr. George H. Berryman of Abbott Laboratories for providing the ampules of Hykinone and the matching ampules of saline.
5.
REFERENCES
1. 2.
was five times as great in the vitamin group as in the control group.
6.
Taylor, J. D.: University of Saskatchewan Graduate Studies, Physiology and Pharmacology, April, 1957. Lucey, J. F., and Dolan, R.: J. A. M. A. 167:
1875, 1958. 7. Hsia, D. Y., Allen, Diamond, L. K.: 668, 1952.
F. H., Gellis, S. 8, and
New
England
J. Med.
247: