Vitamin E and Retinopathy of Prematurity

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LETTERS TO THE EDITOR

329

was published, several individuals have asked me (1)

why we changed the recommendation for cuff size from one that covers two thirds to one that covers three

quar-ters ofthe upper arm and (2) what data formed the basis for this change in recommendations?

When Ireread the published report to verify cuff size recommendations, it appeared to me that somewhere

along the line a transcription error had taken place. As a member of the task force, it is my clear memory that

it was the consensus of the pediatricians on the com-mittee that we would not change the recommendation

for cuff size made by the first task force. The major reasons for this decision were twofold: first, there were no convincing data to support the need for a change in recommendations and, second, in their absence, a

ca-pnicious change would only lead to confusion. In clinical

practice, where it is uncommon to actually measure the

length and circumference of a child’s arm before

se-lecting a cuff, the two thirds cufflength is a fairly easy clinical estimate. We continue to use and recommend it routinely in our clinic and in this community.

JENNIFER LocoIE, MD

Children’s Hospital Research Foundation

Elland and Bethesda Ave

Cincinnati, OH 45229

More

Problems

With

New

Pampers

To the

Editor.-The new “superabsorbent” Pampers have been

re-ported to complicate pediatric care in two instances: they can create the misleading impression of oligunia in well infants,’ and because of their effective absonp-tion of ambient humidity, their use may interfere with the measurement of urine output in sick premature in-fants.2 There is another clinical problem with the new “Ultra” Pampers: these diapers render impossible the valuable technique of measurement of urine specific

gravity from a damp diaper. For years nurses have used

the trick of packing damp diaper fibers into the barrel of a iO-mL syringe and squeezing out a drop of urine for refractometry, thus adding to the immediately available data on a potentially dehydrated infant. On my first (and last) unwitting attempt to squeeze urine

from an “Ultra” Pamper in our emergency room, I was

momentarily horrified to see a clear gel snake from the

syringe to the refractometer, until a nearby nurse as-sured me this did not represent some obscure metabolic derangement but rather the latest “advance” in diaper

technology. We will no longer be able to get specific

gravities from diapers if the use of new diapers such as

the “Ultra” Pamper becomes widespread. Can we

ex-pect the manufacturer to respond only to market forces

(ie, profit) or will these clinical considerations be taken into account?

ALAN MEYERS, MD, MPH

Department of Pediatrics Boston City Hospital Boston, MA

REFERENCES

1. Lavin A: Super effective diaper can cause confusion.

Pe-diatrics 1986;78:1173

2. Hermansen MC, Buches M: Super diapers and premature infants. Pediatrics i987;79:i056-i057

Vitamin E and Retinopathy of Prematurity

To the

Editor.-In the 1987 April issue ofPediatrics’ Dr Phelps and

colleagues reported the results of their study of

pro-phylactic vitamin E and retinopathy of prematurity and related them to those of other trials. They con-cluded that the evidence for efficacy of tocopherol in decreasing “severe” retinopathy of prematurity is not convincing and that its use in infants weighing si,000

g at birth may be contraindicated and even produce

death.

With regard to toxicity, the reader needs to be

re-minded that the fatalities referred to followed admin-istration of high doses of a preparation of IV tocopherol acetate (E-Ferol) which was not subjected to field test-ing and was not used in any of the clinical trials. The toxicity of this preparation, which was marketed

with-out FDA approval and subsequently withdrawn, has

been attributed by most workers to its polysorbate ye-hide rather than to vitamin E.24

With regard to the possible vitamin E-related risk of intraventnicular hemorrhage, the reader also needs to know that a significant decrease (P .001) in incidence and severity of intraventricular hemorrhage was found in association with vitamin E treatment in the second

randomized trial of Sinha et al5 of IM vitamin E and

intraventricular hemorrhage. These data confirm the

two earlier positive studies referred to by Phelps et al

and suggest that the UCLA finding of an vitamin

E-related increase in intraventricular hemorrhage is unique. As discussed at the February 1986 conference

on retinopathy of prematurity at the Institute of Mod-icine,6 where Chiswick’s then unpublished data were briefly presented, the UCLA results may represent “a fluke” ofrandomization. They may also reflect the rate, timing, and dose of vitamin E used: free a-tocopherol was initiated at a dose of2O mg/kg in a 30- to 60-minute IV infusion given “within 24 hours of birth” and

re-peated on the following one or two days. In premature

infants of this age, mean peak serum vitamin E levels after a single, 60-minute infusion ofhalfthis dose have been found to exceed 15 mg/dL.7 Therefore, since vi-tamin K was given only on day 1 in the UCLA study, the relative concentration of vitamin E to vitamin K in the first 24 hours after birth must have been high in some vitamin-treated infants. The physiologic conse-quences of this are unknown, but, if the 20% incidence of vitamin K deficiency in the normal newborn is con-sidered,8 it is possible that synthesis of vitamin K-de-pendent clotting factors in vitamin E-treated infants

was compromised enough to impair hemostasis9 and

favor development of intraventricular hemorrhage.

at Viet Nam:AAP Sponsored on September 7, 2020 www.aappublications.org/news

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330 PEDIATRICS

Vol. 81 No.

2 February 1988

cause intraventricular hemorrhage is an important

ret-inopathy of prematurity risk factor, the development

of retinopathy of prematurity may also have been

favored.

With regard to the best current estimate of efficacy

of prophylactic vitamin E for retinopathy of prematur-ity, the conclusions of the UCLA group rest heavily on their method of comparing eye findings from their own

and five other clinical trials (see figure 2, page 498), after conversion to the International Classification for

Retinopathy of Prematurity (ICROP). The most impor-tant comparison involves the clinically significant end

point of “severe retinopathy” which the authors define

as equal to or more than stage 3 without regard to the

presence or absence of plus disease, the form of reti-nopathy characterized by prominent dilation and

tor-tuosity ofposterior pole blood vessels. We disagree with

the UCLA definition of severe retinopathy of

pre-maturity and its choice as a comparative end point.

First Palmer and Phelps’#{176} stated that “at least 80% of

infants with stage 3 retinopathy of prematurity will experience spontaneous regression of their retinopathy without significant visual damage,” whereas stage 3-plus retinopathy of prematurity, the point chosen for randomization for cryotherapy in the Multicenter Cryo/ retinopathy of prematurity trial, has a “50% risk level for retinal detachment.” The inclusion of stage 3 reti-nopathy ofprematunity in the severe disease category in

this paper is, therefore, contradictory. Second, because

Phelps” has stated that stage 3 ICROP cannot be

de-fined for the McMaster and Royal Alexandria trials, her use of equal to more than stage 3 as an end point ex-cluded from consideration the 1 1 infants in these trials (8P, 3E) with retinal detachment.

A more valid and clinically meaningful summation of all six clinical trials can be made if severe retinop-athy of prematurity is defined, as in the Cryotherapy

Multicenter Trial, as 5 clock hour stage 3-plus

ICROP. Use of a more advanced end point for compar-ison (ie, stage 4 ICROP) is not possible because, in two of the trials, treatment was instituted at stage 3-plus retinopathy of prematurity. In four trials’

em-ployed classifications which clearly identified the

equivalent ofstage 3-plus ICROP were used. Two, Yale

and UCLA, used classifications which, although

am-biguous as to plus disease per se, recorded information

that allowed identification of this important marker of severity. In the Yale study, retinal drawings ofthe

pos-tenor pole vessels were made at each examination.

These documented plus retinopathy of prematurity

with extravascular neovasculanization in one

placebo-treated infant who weighed 1,500 g at birth.’2 The

UCLA classification did not standardize the recording of dilation and tortuosity of posterior pole vessels (plus disease) but did record prospectively 18 ophthalmologic

findings of retinopathy of prematurity including an

“other” category. The incidence ofequal to or more than

stage 3 plus ICROP has been reported as 5/99P v 5/

97E.”

The incidence of severe disease using equal to or

more than stage 3-plus retinopathy of prematurity as the comparative end point, with 95% confidence limits for each of the trials for infants with birth weights i,500 g is shown in the table. It also gives the results of a coanalysis of the trials for this end point by the Mantel-Haenszel technique for combining disparate studies. This indicates a significant vitamin E-associ-ated decrease in sight-threatening retinopathy of pre-maturity (P < .02). If only infants with birth weights

1 ,000 g are considered, coanalysis of the six trials for incidence of sight-threatening retinopathy of

prema-turity also shows a significant vitamin E-associated

benefit (P < .05). The Houston study, in itself, is sig-nificant for either birth weight group ( 1 ,500 g, P < .01; i,000 g, P < .05).

Finally, fig 2 (p 498) contains several inconsistencies

and numerical errors. (1) For the Yale study,’2 confi-dence limits for both portions of the figure refer to the entire study population with eye data (n = 74). The n

= 40 on the lower horizontal bar is in error and implies

that only the 40 infants with birth weights < 1,500 g are

being considered. In contrast, confidence limits for the Philadelphia study do not include the 331 (30%) infants with birth weights >1,500 g. Finally, although the

UCLA confidence limits include infants with birth

weights >1,500 g, providing their gestational age was

less than 33 weeks, the number of such infants must

have been small because the mean birth weight for

pla-cebo-treated infants was 1,205 g and for vitamin

E-treated infants it was 1,181 g. (2) For equal to or more than stage 3 ICROP confidence limits for the

Phila-delphia study include infants with plus disease but no

extravascular neovasculanization (ie, stage 2 plus

ICROP) and relate to 328 infants at 1 year follow-up,

not to the 424 infants with acute stage (3) UCLA

confidence limits for occurrence of retinopathy of

pre-Comparison of Resu

Across Tnials- 1,5

lts of Vitamin ElRetinop 00 Grams Birth Weight*

athy of Prematurity (ROP) Prophylaxis

Clinical Trial Placebo Vitamin E 95%

Confidence Limits Total 3+ ROP

No. or Worse

Total 3+ ROP No. or Worse

Baylor 51 5 50 0 -18.0 to - 1.6

McMaster 114 5 111 3 -6.6 to +3.2

Yale 20 1 22 0 -14.6to +4.6

Royal Alexandria 51 4 48 2 - 12.9 to + 5.6

UCLA 99 5 97 5 -6.1 to +6.3

Philadelphia 216 9 208 3 - 5.9 to + 0.3

*

x2

5.78 by Mantel-Haenszel technique for combining independent studies, P < .02.

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LETTERS TO THE EDITOR 331

maturity are not comparable to any of the other trials

because they exclude infants with retinopathy of pre-maturity who died or were lost to follow-up with active disease (16P, liE).

The above considerations all support a more positive view of the potential benefit of vitamin E prophylaxis for retinopathy of prematurity and intraventricular

hemorrhage than is presented by Phelps et al. If the results of their trial are indeed unique, they need to be

interpreted as such.

Neonatal Medicine: Retinopathy of Prematurity. Boston,

Blackwell Scientific Publications, 1985, pp 181-205 12. Ehrenkranz R: Response to Hittner HM. Letters to the

Editor. Ophthalmology 1982;89:987-989

13. Schaffer DB, Johnson L, Quinn GE, et a!: Vitamin E and retinopathy of prematurity, Follow-up at one year. Oph-thalmology 1985;92:1005

REFERENCES

LoIs JOHNSON, MD

Department of Pediatrics

SORAYA ABBASI, MD

University of Pennsylvania School of Medicine

Children’s Hospital of Philadelphia

GRAHAM E. QUINN, MD Department of Ophthalmology

University of Pennsylvania

School of Medicine

Children’s Hospital of Philadelphia

CHARI OTIs, MS

Department of Biostatistics

University of Pennsylvania School of Medicine

Philadelphia

FRANK W. BOWEN, JR, MD

Department of Pediatrics

University of Pennsylvania

School of Medicine

Pennsylvania Hospital

Philadelphia

1. Phelps DL, Rosenbaum AL, Isenberg SJ, et al: Tocopherol efficacy and safety for preventing retinopathy of prema-turity: A randomized, controlled, double-masked trial. Pe-diatrics 1987;79:489-500

2. Alade SL, Brown RE, Paquet A: Polysorbate 80 and E-Ferol toxicity. Pediatrics 1986;77:593-597

3. Bove KE, Kosmetatos N, Wedig KE, et al: Vasculopathic hepatotoxicity associated with E-Ferol syndrome in low-birth-weight infants. JAMA 1985; 254:2422-2430

4. Conyers RAJ, Bais R, Rofe AM: Oxalosis and the E-Ferol toxicity syndrome, letter. JAMA 1986;256:2677-2678 5. Sinha 5, Davies J, Toner N, et al: Vitamin E

supplemen-tation reduces frequency of periventricular haemorrhage in very preterm babies. Lancet 1987;1:466

6. Institute of Medicine: Vitamin E and Retinopathy of Pre-maturity, publication IOM-86-02. Washington, DC, Na-tional Academy Press, June 1986

7. Abbasi S, Jensen BK, Johnson L, et al: Vitamin E phar-macokinetics: Comparison of 1 versus 8 hour infusion, ab-stracted. Pediatr Res 1987;21:231a

8. Shapiro AD, Jacobson LI, Armon ME, et al: Vitamin K deficiency in the newborn infant: Prevalence and perinatal risk factors. J Pediatr 1986; 109:675-680

9. Helson L: The effect of intravenous vitamin E and men-adiol sodium diphosphate on vitamin K dependent clotting factors. Thromb Res 1984;35:11-18

10. Palmer EA, Phelps D: Multicenter trial ofcryotherapy for retinopathy of prematurity. Pediatrics 1986;77:428-429 11. Phelps DL: Vitamin E in retinopathy of prematurity, in

Silverman WA, Flynn JT (eds): Controversies in Fetal and

Bacteremia:

Occult

or Nonoccult?

To the

Editor.-For those many pediatricians who have wondered

whether antigen detection would provide a superior means for screening febrile children for bacteremia,

Rubin and Carmody (Pediatrics 1987;80:92-96) have

provided a thoughtful and needed study.

Unfortu-nately, their results lead one to the conclusion that

cur-rent technique is not sufficiently discriminating, when

applied to all infants at risk for occult bacteremia, to

be clinically valuable.

I am concerned, however, whether their study did in fact address the question of occult bacteremia, and I request a clarification of the authors’ methods. As

writ-ten, the article implies that febnile infants were entered

into the study even when a likely focus of infection by

physical examination (other than meningitis or

epi-glottitis). Those infants, however, do not present the

cli-nician with nearly the same dilemma as do the febrile infants for whom the etiology of fever is not clinically apparent at the first visit. For example, ofthe five in-fants with Haemophilus influen.zae type b bacteremia, two had cellulitis and one had arthritis. If these foci of likely bacterial infection were recognized at the first

visit, then the approach to those infants would be mark-edly simplified. That approach calls for presumptive

treatment with antibiotics to treat the likely

patho-gens, pending the outcome of cultures. The clinician

might still use antigen detection to arrive at a rapid,

specific bacterial dianosis, but the issue of whether to treat with antibiotics and the risk of sending a febnile, potentially bacteremic infant home without antibiotic therapy are eliminated by the physical examination, before any laboratory tests are ordered. Similarly, the recognition of a readily apparent viral infection (eg, vanicella or enteroviral hand-foot-mouth disease) at

first presentation would reassure the clinician

im-mensely that bacterial disease is absent and that an-tibiotics are not needed. It is an open question as to whether applying antigen detection to a population of infants with truly occult H influenzae type bbacteremia

would provide the same sensitivity that this study

found.

To provide more useful data, investigators designing future studies should confine their inquiry to the ap-plication of screening tests to the population that pro-vides the greatest clinical predicament, namely, those

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1988;81;329

Pediatrics

W. BOWEN, JR

LOIS JOHNSON, SORAYA ABBASI, GRAHAM E. QUINN, CHARI OTIS and FRANK