Retinal Hemorrhage in Retinopathy of Prematurity Associated with Tocopherol Treatment ARTHUR L. ROSENBAUM, MD,* DALE L. PHELPS, MD,t SHERWIN J. ISENBERG, MD, 1

' ROSEMARY D. LEAKE, MD,§ FREDRICK DOREY, PhD*

Abstract: Two hundred eighty-seven infants were enrolled in a double masked, randomized, placebo controlled trial of early parenteral tocopherol given from day one. Among the 232 survivors with ophthalmologic follow-up, retinal hemorrhages occurred more frequently in the tocopherol group (16/ 111; 14.4%) than in the placebo group (8/121; 6.6%). The development of retinal hemorrhages correlated strongly with plasma tocopherol levels from three weeks to three months (P < 0.05). Future studies of tocopherol should be aware of potential bleeding diatheses, and study this prospectively. [Key words: prematurity, retinal hemorrhage, retinopathy of prematurity, retrolental fibroplasia, tocopherol, vitamin E.] Ophthalmology 92:1012-1014, 1985

Retinopathy of Prematurity (ROP) describes a complex disease process occurring in the retina of premature infants. Retinal involvement begins at the junction of the vascularized and nonvascularized premature retina. The process may be limited to a clinically insignificant demarcation line at this junction or may progress to such devastating consequences as total tractional retinal detachment and blindness.

The occurrence of retinal hemorrhage in the acute phases of the disease process has been recognized for many years. Usually, these retinal hemorrhages are localized on the surface of the neovascular ridge at the junction mentioned above. Frequently, the hemorrhages are small and restricted to the demarcation zone. Oc­casionally, they may be massive and extend into the vitreous. This report describes our findings regarding retinal hemorrhage in the tocopherol and placebo-treated infants in the randomized trial.

From the Department of Ophthalmology, Jules Stein Eye Institute,* and the Departments of Pediatricst and Orthopedics,:j: UCLA Center for the Health Sciences, Los Angeles, and the Departments of Ophthalmologyll and Pediatrics,§ Harbor-UCLA Medical Center, Torrance.

Funded by the USPHS, National Eye Institute, EY 01939; USPHS Grant #RE00425 (GCRC) from the National Institutes of Health; National Foundation March of Dimes, #6-311, and 6-422; and Office of Academic Computing, University of California.

Reprints requests to Arthur L. Rosenbaum, MD, Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, CA 90024.

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MATERIALS AND METHODS

Between December i 980 and August 1983, informed consent was obtained from the parents of 287 premature infants who were then randomly assigned to receive tocopherol (T), 20 mg/kg, or placebo (P) intravenously within 24 hours of birth. Subsequent doses were adjusted to achieve plasma tocopherol levels of 3.0-3.5 mg/dL in the tocopherol group. All infants received vitamin K1, 0.5-1.0 mg intramuscularly, on day 1 per nursery routine. Infants who were receiving total parenteral nutrition or antibiotics were given vitamin K1 (0.5-1.0 mg IM) weekly to prevent a vitamin K dependent bleeding diathesis which might be exacerbated by T treatment. 1

Indirect ophthalmoscopy was begun at four to six weeks of age depending on the infant's condition and was performed in the unsedated infant by one of two investigators (AR or SI), using a lid speculum and scleral depression. Examinations were repeated at four-week intervals or more frequently if clinically indicated until the retinal vasculature reached the ora serrata, or until any retinopathy was stable for at least six months. The funduscopic findings were recorded descriptively by ( 1) progress of the retinal vasculature from the disc (zone), and (2) by extent of the retina involved with each of the retinopathy findings recorded separately at each

ROSENBAUM, et al • RETINAL HEMORRHAGE IN ROP

Table 1. Retinal Findings Recorded in Clock Hours at Each Examination

Code

0 1 2 3

4 5 6

7 8 9

10 11 12 13 14 15 16 17 18

Finding

Normal vessels to ora Avascular periphery Line of demarcation Ridge of elevated tissue at line

of demarcation Shunt (pink ridge) Vessels anterior to the ridge Abnormal terminal vessel

arborization Dilated terminal vessels Hemorrhage on/in retina Retinal surface

neovascularization Old line, posterior to vessels Vitreal haze Vitreal neovascularization Vitreal hemorrhage Vessel dragging/traction Retinal fold Peripheral retinal detachment Posterior retinal detachment Other (describe)

clockhour. Eighteen different ophthalmologic findings of ROP were recorded at each examination (Table 1). This made it possible to classify our findings retrospec­tively using the International Classification of Acute Retinopathy of Prematurity (ICROP), after its recent publication. 2

In the first year of the study, interobserver variation was evaluated between the two examiners by means of 14 dual examinations on 13 infants. Although variations in the exact number of clockhours of disease occurred, 25 of the 28 eyes examined resulted in the same stage of disease being assigned. In one infant, masked dual reexamination 1 week later resulted in agreement on the stage for those 2 eyes.

Retinal hemorrhage, item 8 in Table 1, was defined as hemorrhage that occurred within the surface of the retina or immediately on the surface of the retina without extension into the vitreous. The number of

Table 2a. Maximum Tocopherol Level (mg/dL)

Maximum tocopherol level (mg/dL)

No Retinal Hemorrhage Retinal Hemorrhage

<1.5

88 6

(7%)

1.5-6.0

76 7

(9%)

>6.0

44 11

(25%)

Total

208 24

retinal clockhours involved with the hemorrhage was noted, but the size or extent of each hemorrhage was not otherwise recorded. These retinal hemorrhage find­ings are the basis of the present report.

Central nervous system (CNS) hemorrhage was re­corded as the most severe grade, 1 through 4 according to the grading system of Papile, 3 documented by ultra­sound, CAT scan and/or autopsy. If none of these had been performed, (as occurred commonly in the first year of the study before ultrasound became readily available), CNS hemorrhage was recorded as clinically absent, suspect, or definite, based on the clinical judgment of the physicians in attendance.

RESULTS

Of the 287 infants enrolled, (147 placebo (P) and 140 tocopherol (T) ), 46 died before first examination and 9 were lost to follow-up. Comparisons of the P and T infants on baseline variables revealed no significant differences, (birthweight, gestation, sex, multiple gesta­tion, 1- or 5-minute APGAR, complications of preg­nancy, mode of delivery or small for gestational age). Of the 232 infants surviving to first eye examination, 152 of these examinations were done at less than six weeks. Among these 232 infants, 9 were lost to follow­up with immature retinae but no ROP on the last examination, (six of these had received placebo and three tocopherol). Of those 80 infants who did develop ROP, 27 were lost to follow-up, 9 because of death and 18 despite our intensive efforts to have the families return, ( 11 P and 7 T). Each category of incomplete ophthalmologic followup was equally distributed between

Table 2. Association Between Retinal Hemorrhages and Plasma Tocopherol Levels (mg/dL)

First T level Mean T, 1st week Mean T, 2nd week Mean T, 3rd week Mean T, 4th week Mean T, 2nd month Mean T, 3rd month Maximum T level reached

T = tocopherol; NS = not significant. * Mean (± SD).

Retinal Hemorrhage (n = 24)

1.69* (1.60) 2.38 2.80 2.23 2.36 1.85 1.97 5.07* (3.41)

No Hemorrhage (n = 208)

1.48 (1.56) 1.92 1.98 1.45 1.48 1.37 1.33 3.49 (3.22)

P value, !-test

NS NS

0.047 0.006 0.005 0.064 0.043 0.025

P value, Wilcoxan rank sum test

NS NS

0.061 0.003 0.001 0.020 0.021 0.0236

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OPHTHALMOLOGY • AUGUST 1985 • VOLUME 92 • NUMBER 8

Table 3. Retinal Hemorrhage and Central Nervous System (CNS) Hemorrhage (232 Infants with at least one eye examination)

No retinal hemorrhage Retinal hemorrhage

Total

Documented* None; or Clinically None

or Suspect

79 4

(5%)

83

Severity of CNS Hemorrhage Confirmed

Documented* Grade 1 or 2

116 13

(10%)

129

Grade 3 or 4* or Clinically Definitet

13 7

(35%)

20

Total

208 24

232

*Assigned by ultrasound, CT scan or autopsy. t Just one infant is included based on clinical judgement. P < 0.007 Fisher's exact test (grade 3-4 vs. grade 0-2).

P and T infants. 99 placebo infants and 97 tocopherol infants completed the study to retinal maturity (mean, 2.5 months) or retinal detachment.

Retinal hemorrhage was more frequent in the T infants. Eight of 121, or 6.6%, in the placebo group had retinal hemorrhages and 16 of Ill, or 14.4%, of the tocopherol group, P < 0.056, Fisher's exact test. (There were no significant differences in the incidence of ROP in the T vs. P infants). Further analysis of these data reveal consistent patterns supporting an increased risk of retinal hemorrhage with vitamin E treatment. Table 2 shows that there was no significant relationship between tocopherol levels on day 2 or in the first week of life and the retinal hemorrhages which are observed at two to three months of age. However, beginning at two weeks, the infants who later developed retinal hemor­rhages had significantly higher plasma tocopherol levels than the infants who never developed retinal hemor­rhages (P < 0.07 in the second week, P < 0.007 in the 3rd week, P < 0.005 in the 4th week, P < 0.07 in the 2nd month, P < 0.05 in the 3rd month, Student's t-test and Wilcoxon rank sum test).

This effect is confirmed in Table 2a, which shows the maximum plasma T levels reached by the infants who developed retinal hemorrhage by categories. This is a useful alternative manner of looking at effects of contin­uous variables where relatively small numbers may be involved. Of those infants who had a maximum T level over 6.0 mg/dL, 20% (11/55) developed retinal hemor­rhage whereas only 6% (6/94) of those with maximum levels below 1.5 mg/dL had retinal hemorrhage.

Cerebral hemorrhage occurs on days 1 to 5 in pre­maturely born infants and is related to their degree of immaturity and illness. The mortality and morbidity can be very significant. The occurrence of retinal hem­orrhage in those surviving infants whose cerebral hem­orrhage diagnosis was based on clinical impression or confirmed by computerized tomography, cerebral ultra­sound or autopsy is shown in Table 3. Seven of 20 (35%) infants with grade 3 or 4 cerebral hemorrhage by day three of life, later developed retinal hemorrhage. Only 13/129 (10%) of the infants with proven grades 0 to 2 CNS hemorrhage developed retinal hemorrhages, and only 4 of 83 (5%) of the infants with no cerebral

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hemorrhage developed later retinal hemorrhage (P < 0.007, Fisher's exact test).

DISCUSSION

In this study, retinal hemorrhages occurred more frequently in premature infants treated with tocopherol than in those comparable infants treated with placebo, and the incidence was positively correlated with plasma tocopherol levels. Such a finding could be due to an unsuspected subtle bleeding diathesis, or it might be related to poor connective tissue support of the newly forming retinal vessels. Ehrlich has demonstrated that tocopherol treatment impairs the deposition of collagen in healing wounds in rats, as well as delaying growth of new vessels into subcutaneously implanted sponges. 6

Such effects in the eye could allow poorly supported vessels to bleed more readily.

The correlation between cerebral and retinal hemor­rhages is interesting but may only reflect compounding of two facts we accept from surveys and case control studies: that the more immature the infant, and the sicker, the higher the risk for both cerebral hemorrhage and ROP, which may include retinal hemorrhage. Al­though no late bleeding diatheses were apparent in these infants, coagulation studies were not done routinely. This study, however, suggests that the possibility of bleeding disorders in infants treated with parenteral tocopherol may exist and should be evaluated in future studies.

REFERENCES

1. Corrigan JJ Jr. Coagulation problems relating to vitamin E. Am J Pediatr Hematol Oncol1979; 1:169-73.

2. The Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Ophthalmol 1984; 102:1130-4.

3. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1 ,500 gm. J Pediatr 1978; 92:529-34.

4. Ehrlich HP, Tarver H, Hunt TK. Inhibitory effects of vitamin E on collagen synthesis and wound repair. Ann Surg 1972; 175:235-40.