Effect of Vitamin E Therapy on Blood Coagulation Tests in Newborn Infants

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Effect

of Vitamin

E Therapy

on Blood

Coagulation

Tests

in Newborn

Infants

Alvin

Zipursky,

MD,

Ruth

A. Milner,

BSc,

Victor

S. Blanchette,

MD,

and Marilyn

A. Johnston,

RT

From the Departments of Pediatrics, Clinical Epidemiology and Biostatistics, McMaster

University, Hamilton, Ontario, Canada

ABSTRACT.

A

double-blind randomized trial of vitamin

E therapy was conducted in premature infants whose birth weight was less than 1,500 gm. Treated infants

received 25 mg of Vitamin E daily by mouth for the first

six weeks of life. Detailed studies of plasma coagulation factors were performed prior to therapy and at days 7 and

42. None of the factors differed significantly between the treated and control groups. Although vitamin E therapy has been reported to affect the blood levels of vitamin K dependent coagulation factors, no such effect was noted in this group of premature infants. Pediatrics 66:547-550,

1980; vitamin E, newborn, prematurity, vitamin K, co-agulation.

Newborn infants have significantly lower tissue and plasma vitamin E levels than adults.’ It has been suggested that the oxygen related toxicity of

bronchopulmonary dysplasia,5 retrolental

fibropla-sia,6 and hemolytic anemia78 may be more severe in vitamin E deficient infants. Accordingly newborn infants have been treated with vitamin E to prevent these diseases with some evidence of success.5’6’8 As a result there is now considerable interest in the use of vitamin E in the treatment of premature infants.

Recently several groups have reported that vi-tamin E therapy can affect the plasma levels of certain coagulation factors (factors II, VII, IX, X).

Initially it was reported that vitamin E prolonged

the plasma clotting time in adults fed the vitamin for several months.9 Subsequently it was shown that vitamin E potentiated the effect of dicumarol in lowering the levels of vitamin K dependent fac-tors.’#{176}” Similar findings were reported in rats.”

Since newborn infants have plasma levels of

vi-Received for publication Oct 31, 1979; accepted Jan 9, 1980. Reprint requests to (A.Z.) Department of Pediatrics, McMaster University Medical Center, 1200 Main St W, Hamilton, Ontario, Canada L8S 4J9.

PEDIATRICS (ISSN 0031 4005). Copyright © 1980 by the American Academy of Pediatrics.

tamin K-dependent coagulation factors which are lower than those of adults an additional adverse effect ofvitamin E on these factors could be harmful to them. Accordingly in the present study we have

examined the effects of vitamin E on the levels of plasma coagulation factors in a series of premature infants studied during the first 42 days of life.

METHODS

All infants studied weighed less than 1,500 gm

and were enrolled in the study shortly after admis-sion to the Neonatal Intensive Care Unit of the McMaster University Medical Centre. Informed consent was obtained and the infants were allocated

by random selection to vitamin E or placebo treat-ment. None of the attending staff or investigators knew whether the patient was in the treatment or control group. Vitamin E was given in a dose of 25 IU (daily for six weeks) as a liquid preparation of

dl-a-tocopherol in 0.5 ml of suspension with the control receiving only the same volume of vehicle. Details of these procedures are described else-where.’2 On days 1, 7, and 42, 0.9 ml of blood was

taken by venipuncture of a peripheral vein and added to 0. 1 ml of anticoagulant acid citrate (three parts 0.1 M sodium citrate to two parts 0.1 M citric acid) in a 12- by 75-mm polyethylene tube. This volume of blood was sufficient for all coagulation studies reported herein. The coagulation techniques

used were standard methods adapted to a micro-scale as described elsewhere.’3 Studies on day 7

were stopped early during the trial because of

tech-nical difficulties in obtaining samples and in inter-preting them in the light of procedures and trans-fusions carried out during that time.

RESULTS

Thirty-six babies were studied prior to any

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548

VITAMIN

E THERAPY

drawn for coagulation studies after which the first dose of treatment was given. The mean age of the infants at the time of entry into the trial was similar in the two groups 2.9 ± 2 days in the control group

and 2.7 ± 3 days in the vitamin E therapy group.

The

results of all coagulation studies performed on day 0 are shown in Table 1. There is no signifi-cant difference between the two groups in any of the values prior to the study. In Table 2 the results on day 7 of the study are shown. Only 17 infants were studied at that time. The birth weights of the vitamin E-treated infants (1,085 ± 366 gm) did not differ significantly from the control infants (1,201

± 239 gm). Similarly the gestational ages of the two groups (28.6 ± 2.7 weeks and 30.9 ± 3.3 weeks, respectively) did not differ significantly.

In Table 2 the results of the coagulation studies are shown and it can be seen that the vitamin E-treated group did not appear to differ from the control group. The day 0 coagulation studies of the eight treated and nine control infants did not differ significantly from one another or from the total group shown in Table 1. Forty-seven babies were studied on day 42 (Table 3). The birth weights of the vitamin E-treated (1,137 ± 258 gm) did not differ significantly from that of the control group

(1,073 ± 210 gm). The weight gain during the six-week study period in the control group was 414 ±

209 gm similar to that of the vitamin E treated

group of 370 ± 208 gm. The gestational ages also were similar in the two groups 29.6 ± 2 months in

the vitamin E-treated and 28.9 ± 1.9 months in the controls. In these infants large volumes of blood were sampled and transfused during the first 42 days of life. The amounts were determined in 18 subjects of each group. In the treated group, 24.8

± 10.7 ml of red blood cells were sampled compared to 23.4 ± 10.7 ml of red blood cells in the control group; similarly the volume of red blood cells trans-fused was 24.3 ± 18 in the treated group compared to 17.7 ± 14.9 in the control group; these differences were not statistically significant.

A

greater variety of tests of the coagulation sys-tern were done on day 42 than earlier. No significant differences between the two groups were found in any of these tests.

DISCUSSION

In this study the treated patients received 25 mg of dl-a-tocopherol daily by mouth for six weeks. We have shown previously’2 that this produces a rapid

TABLE 1. Coagulation Factor Levels on Day 0

Vitamin E Control

No. of Mean ± SD No. of Mean ± SD

Subjects Subjects

PTt (nec) 19 15.4 ± 2.5 17 14.0 ± 1.9

PTT (sec) 19 66.7 ± 18.1 17 68.9 ± 10.2

TCT (sec) 19 24.7 ± 3.6 17 24.0 ± 3.17

Factor II (%) 15 35.8 ± 9.1 14 38.8 ± 16.5

Factor IV (%) 16 63.9 ± 27.2 14 81.2 ± 33.6

Factor VII + X (%) 15 39.9 ± 10.2 14 45.9 ± 13.9

Factor X (%) 13 42.8 ± 14.1 14 38.1 ± 15.1

Fibrinogen (mg/100 ml) 19 290.7 ± 204.9 16 300.1 ± 131.27

* For all tests no significant differences were found between vitamin E and control groups. t PT, prothrombin time; PTT partial thromboplastin time; TCT, 2-unit thrombin clotting time.

TABLE 2. Effect of Vitamin E Therapy on Plasma Levels of Coagulation Factors on

Day 7*

Vitamin E (8)t Control (9)t

PT (sec) 13.2 ± 1.8 13.1 ± 1.5

PTT (sec) 69.1 ± 18.5 69.3 ± 8.3

TCT (sec) 21.9 ± 2.1 23.3 ± 3.5

Factor II (%) 73.6 ± 16.4 63.0 ± 16.0

Factor V (%) 113.6 ± 37.8 100.7 ± 17.8

Factor VII ± X (%) 68.1 ± 25.4 77.6 ± 37.0

Factor X (%) 59.1 ± 21.0 50.7 ± 21.7

Fibrinogen (mg/100 ml) 280.5 ± 96.0 280.6 ± 98.0

* For all tests no significant differences were found between vitamin E and control groups.

Abbreviations as in Table 1.

t Figures in parentheses represent the number of subjects studied. However, factor assays were performed on only seven control subjects.

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TABLE

3.

Effect of Vitam Day 42*

in E Therapy on Plasma Le vels of Coagulation Factors on

Vitamin E Control

No. of Mean ± SD No. of Mean ± SD

Subjects Subjects

PT (sec) 23 12.5 ± 0.8 24 12.6 ± 1.0

PTT (sec) 23 60.5 ± 17.2 24 63.9 ± 16.1

TCT (sec) 23 22.7 ± 1.8 24 22.9 ± 2.6

Factor II (%) 22 57.8 ± 14.4 24 62.5 ± 20.2

Factor V (%) 22 105.4 ± 27.1 24 108.7 ± 34.1

Factor VII + X

(%)

22 69.4 ± 15.5 24 75.6 ± 27.3

Factor X (%) 22 56.8 ± 17.7 24 54.4 ± 18.8

Factor VIII (%) 14 97.4 ± 40.0 17 88.8 ± 24.6

Factor IX (%) 20 33.9 ± 12.1 20 31.2 ± 7.3

Fibrinogen (mg/100 ml) 23 323.0 ± 109.0 24 274 ± 113.0

Antithrombin, 3

(%)

20 48.0 ± 11.5 21 51.5 ± 14.0

Antitrypsin, 1 (%) 20 124.0 ± 35.0 21 118.5 ± 24.7

Macroglobulin, 2

(%)

20 170.2 ± 29.4 21 161.4 ± 26.7

Factor XI (%) 19 56.0 ± 18.6 18 47 ± 13.0

Factor XII (%) 19 47.6 ± 16.9 18 48.3 ± 22.1

* For all tests no significant differences were found between vitamin E and control groups. Abbreviations as in Table 1.

rise in plasma tocopherol levels within 24 hours and that the plasma levels are in the adult range throughout the six weeks.’2 In contrast, control

subjects had significantly lower tocopherol levels;

at six weeks mean plasma tocopherol levels (0.5 ± 0.1 mg/100 ml) were significantly below adult val-ues.’2

Despite the administration of vitamin E and the achievement of adult concentrations of plasma to-copherol, the plasma levels of coagulation factors did not differ significantly from those of the control group. This is reassuring because of the evidence cited earlier that vitamin E therapy can reduce the plasma levels of vitamin K dependent coagulation factors. This is particularly important because vi-tamin E has been reported to interfere also

with

other components ofhemostasis namely the platelet release reaction’4 and fibrinolysis.’5 We recognize, however, that because of our small sample size there is a risk of incorrectly concluding that no difference exists between the results for the treated

and control babies (type II errors). However since none of the coagulation studies showed any signifi-cant difference we consider our conclusions valid.

Vitamin E therapy has been studied and used in premature infants in other centers.8 The doses recommended are high (ie, about 25 lU/kg)

corn-pared to those of adults, and, therefore, the

possi-biity of toxicity must be considered. The evaluation of the effectiveness of vitamin E therapy in the treatment of newborn infants demands that its safety be considered as well. As a result of the present study we conclude that oral vitamin E therapy (25 lU/day), sufficient to maintain plasma tocopherol levels in the adult range,’2 is not harmful

to the coagulation system of premature infants dur-ing the first six weeks of life.

ACKNOWLEDGMENTS

This study was supported by grants from the National

Foundation March of Dimes and the Ontario Heart Foun-dation.

We thank Hoffman-LaRoche Company for their gen-erous supply of vitamin E and for their advice. ALso, we are grateful for the technical assistance of the staff of the Coagulation Laboratories, McMaster University Medical Centre and St. Joseph’s Hospital and to the staff of the Neonatal Intensive Care Unit and Pharmacy Department of the McMaster University Medical Centre who were responsible for the operation of much of the clinical trial. We also thank Kelly Neale for her help with the statistics of this study.

REFERENCES

1. Dju MY, Mason KE, Filer U Jr: Vitamin E (tocopherol) in human fetuses and placenate. Etud Neonat 1:49, 1952 2. Moyer WT: Vitamin E levels in term and premature newborn

infants. Pediatrics 6:893, 1950

3. Wright SW, Filer IA Jr, Mason KE: Vitamin E blood levels in premature and full term infants. Pediatrics 7:386, 1951 4. Leonard PJ, Doyle E, Harrington W: LeveLs of vitamin E in

the plasma of newborn infants and of the mothers. Am J

Clin Nutr 25:480, 1972

5. Ehrenkranz RA, Bonta BW, Ablow RC, et al: Amelioration of bronchopulmonary dysplasia after vitamin E administra-tion: A preliminary report. N EngI J Med 299:564, 1978 6. Johnson L, Schaffer D, Boggs TR Jr: The premature infant,

vitamin E deficiency and retrolental fibroplasia. Am J Clin Nutr27:1158, 1974

7. Oski FA, Barness LA: Vitamin E deficiency: A previously unrecognized cause of hemolytic anemia in the premature infant. JPediatr 70:211, 1967

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550 VITAMIN E THERAPY

9. Korsan-Bensten K, Elmfeldt D, Hoim T: Prolonged plasma small premature infants. Pediatrics 63:830, 1979

clotting time and decreased fibrinolysis after long term treat- 13. Zipursky A, Johnston M, DeSa D, et al: Clinical and labo-ment with alpha-tocopherol. Thromb Diath Haemorrh 31: ratory diagnosis of hemostatic disorders in newborn infants.

505, 1974 Am J Pediatr Hematol Oncol 1:217, 1979

10. Corrigan JJ, Marcus Fl: Coagulopathy associated with vi- 14. Steiner M, Anastasi J: An inhibitor of the platelet release tamin E ingestion. JAMA 230:1300, 1974 reaction. J Clin Invest 57:732, 1976

11. Schrogie JJ: Letter to the editor. JAMA 232:19, 1975 15. Moroz LA, Gilmore NJ: Inhibition of plasmin-medicated 12. Bell EF, Brown EJ, Milner R, et al: Vitamin E absorption in fibrinolysis by vitamin E. Nature 259:235, 1976

DES DAUGHTERS:

FURTHER

STUDIES

OF PREGNANCY

WASTAGE

A previous report indicated that 62 pregnancies of DES daughters produced only 26 liveborn infants (Berger MJ, Goldstein DP: Obstet Gynecol 55:25, 1980).

A

just-published report (Herbst AL, et a!: J Reprod Med 24:62, 1980), studied the daughters of women in a clinical trial of DES in 1951-1952 at the Chicago Lying-In Hospital. The objective then was to test the efficacy of DES, and none was found. The daily dose was 5 mg in the seventh week of pregnancy, increased progressively to 150 mg daily in the 35th week. The outcome of the first

completed pregnancy of the DES daughters in the late 1970s for 64 DES-exposed vs 84 nonexposed subjects was: full-term live births, 47% vs 85%; premature live births, 22% vs 7%; premature nonviable pregnancies,

miscar-riages, and ectopic pregnancies, 31% vs 8% (P < .0005).

Another report (Barnes AB, et al: N Engi JMed 302:609, 1980) followed with the results ofthe NCI-sponsored National Cooperative DES Adenosis (DESAD) Project. Four medical centers acquired information on fertility and the outcome

of pregnancy from 618 women with prenatal exposure to DES as compared with 155 sisters and 463 matched control subjects (total 618). Increased relative risks

(RR) were highly significant statistically with respect to unfavorable outcome (RR = 1.69; P < .001), miscarriages (RR = 1.61; P = < .008), and never had a

full-term live birth (RR = 3.9; P < .001). The last category involved 42 (19.2%)

of 220 DES daughters vs 11 (4.9%) of the 224 control subjects.

The DESAD study detected no difference in pregnancy outcome when DES daughters with cervical/vaginal ridges were compared with DES daughters without the anomaly. The authors implied that inheritance or interactions might account for the unfavorable outcome of pregnancy for the DES daughters.

The case-control study mentioned above would rule out the possibility that a heritable uterine anomaly of the mother rather than DES accounted for the pregnancy wastage in the daughters. The specific abnormality in DES-daughters as revealed by hysterosalpingogram in earlier studies is a small intrauterine cavity with a short endocervical canal.

Robert W. Miller, MD

Childhood Cancer Etiology Newsletter #65

March 15, 1980

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1980;66;547

Pediatrics

Alvin Zipursky, Ruth A. Milner, Victor S. Blanchette and Marilyn A. Johnston

Effect of Vitamin E Therapy on Blood Coagulation Tests in Newborn Infants

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1980;66;547

Pediatrics

Alvin Zipursky, Ruth A. Milner, Victor S. Blanchette and Marilyn A. Johnston

Effect of Vitamin E Therapy on Blood Coagulation Tests in Newborn Infants

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