Vitamin E for ROP

V i t a m i n E for R O P To the Editor: Raju et al 1 conducted a meta-analysis of the published randomized clinical trials of vitamin E prophylaxis to determine weather vitamin E reduced the incidence of severe retinopathy of prematurity (ROP) in the subset of infants weighing 1500 g or less. Six trials qualified for the meta-analysis. The information was pooled, and the overall odds ratio suggested a protective effect of vitamin E treatment for severe retinopathy" odds ratio 0.44, 95% confidence interval 0.21, 0.81, P < .02. The authors conclude that normalizing vitamin E nutritional status may help reduce severe retinopathy and recommend a large multicenter trial to test the efficacy and safety of this intervention. We recognize the interest of the study from Raju et al but would like to stress its limitations. The problem of pooling a limited number of studies is partially discussed by the authors. A nonsignificant test of homogeneity gives no evidence for variations confounding the effect of vitamin E among the different trials. However, this does not prove that the trials are homogeneous, particularly considering the low power of a test of homogeneity performed on only 6 studies. The authors perform a sensitivity analysis of their meta-analysis by omitting either the study with the largest treatment effect2 or the study showing no treatment effect. 3 The odds ratio varies from 0.86 (95% confidence interval: 0.63, 1.11) to 0.32 (95% confidence interval: 0.12, 0.75), respectively, which in our opinion demonstrates the lack of robustness of the meta-analysis. Furthermore, when examining graphically the results of the meta-analysis in a funnel plot (in which the estimates of effect size obtained are plotted against the sample size of the study), we notice that the largest treatment effects arise from tri-

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als with small number of patients, 2'4 which suggests a potential for publication bias? Finally, we agree with Raju et al that a "large" multicenter trial is necessary to test the efficacy of vitamin E treatment. To demonstrate a reduction of severe retinopathy from 5.3% to 2.4% after treatment with a power of 0.9, a 2-sided test, and an 0~-level of 0.05, then 990 infants in each arm must complete the study, and probably approximately 2600 must be enrolled.

S. A. Zamora, MD A. Maret, MD Department of Pediatrics University of Geneva Geneva, Switzerland 9/35/93773

REFERENCES 1. Raju TNK, Langenberg E Bhutani V, Quinn GE. Vitamin E prophylaxis to reduce retmopathy of prematurity: a reappraisal of published trials. J Pediatr 1997;131:844-50. 2. Hittner HM, Godio LB, Rudolph AJ, Adams JM, Garcia-Prats JA, Friedman Z, et al. Retrolental fibroplasia: efficacy of vitamin E in a double-blind clinical study of preterm infants. N Engl J Med 1981;305: 1365-7. Phelps DL, Rosenbaum AL, Isenberg SJ, Leake RD, Dorey FJ. Tocopherol efficacy and safety for preventing retinopathy of prematurity: a randomized, controlled, double-masked trial. Pediatrics 1987;79:489-500. 4. Puklin JE, Simon RM, Ehkenkrantz RA. Influence on retrolental fibroplasia of intramuscular vitamin E administration during respiratory distress syndrome. Ophthalmology 1982;89: 96-103. 5. Egger M, Davey Sminth G. Misleading meta-analysis: lessons from an "effective, safe, simple" intervention that wasn't. BMJ 1995;310:752-4.

Reply To the Editor: Drs Zamora and Marais appropriately reiterate 2 of the several well-known limitations in meta-analysis, publication bias and problems resulting from the small number of studies. We were closely involved in several ROP and vitamin E studies during the 1980s and in touch with most major work in the field. It is therefore unlikely that we have missed important, unpublished, negative trials. Meta-analysis can generate new findings and provide an impetus for testing them. A therapeutically significant and biologically plausible effect from vitamin E on severe, 3+ ROP prompted us to cautiously recommend that a large multicenter trial be done. We are pleased that Drs Zamora and Marais agree. Notwithstanding a large sample size required for such trials, the important issue to be addressed is the cost-versus-benefit of the use of vitamin E to reduce 3+ ROE devastating epidemic among today's extremely low birth weight infants.

Tonse N. If.. Raju, MD Division of Neonatology University of Illinois at Chicago Patricia Lanqenberg, PhD Department of Epidemiology and Preventative Medicine University of Maryland, Baltimore Vinod BhutanL MD Section in Newborn Pediatrics, Pennsylvania Hospital Philadelphia Graham Quinn, MD Department of Pediatric Ophthalmology University of Pennsylvania School of Medicine and Children'sHospital of Philadelphia 9/35/93 774 BehTet's disease in children To the Editor: We have read with great interest the article by Kon~-Paut et al. 1 The au-

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