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Dexamethasone eye-drops for treatment of retinopathy of prematurity.

Open AccessPublished:September 10, 2021DOI:https://doi.org/10.1016/j.oret.2021.09.002

      Key words

      Both studies on animals and humans have demonstrated the role of inflammatory mediators on the retinopathy process.
      • Rivera J.C.
      • Holm M.
      • Austeng D.
      • et al.
      Retinopathy of prematurity: inflammation, choroidal degeneration, and novel promising therapeutic strategies.
      ,
      • Lee J.
      • Dammann O.
      Perinatal infection, inflammation, and retinopathy of prematurity.
      Dexamethasone is a glucocorticoid with a known reductive effect on several of these mediators and on the expression of VEGF.
      • Fung A.T.
      • Tran T.
      • Lim L.L.
      • et al.
      Local delivery of corticosteroids in clinical ophthalmology: A review.
      Starting in 2016, infants receiving laser ablation for type 1 ROP at Skåne University Hospital were administered dexamethasone eye-drops postoperatively, usually three times daily. None of the infants receiving postoperative topical steroids needed retreatment, in comparison to a general retreatment frequency of 26% nationally when postoperative dexamethasone wasn’t administered routinely.
      • Holmström G.
      • Hellström A.
      • Gränse L.
      • et al.
      New modifications of Swedish ROP guidelines based on 10-year data from the SWEDROP register.
      During 2018 and 2019, two premature infants started the dexamethasone regimen before the planned laser treatment could be performed and in one the laser could be postponed, in the other the laser treatment was cancelled. Successively, several other infants with type 2 ROP that were considered at very high risk of requiring laser ablation were administered dexamethasone drops preoperatively and the regression of ROP changes were observed on multiple occasions. Consequently, for infants with type 2 ROP born in 2020, all were administered dexamethasone drops before the laser treatment, but usually in a lower dosage of one drop daily.
      We therefore aim to compare the treatment frequency for screened infants in the southern healthcare region of Sweden born during 2016 through 2020 to make a systematic retrospective analysis to compare dexamethasone treated and untreated infants.
      The retrospective study was carried through in accordance with the declaration of Helsinki and received ethical approval from the Swedish ethical board. The study followed the Strengthening and Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.
      All screened children in the southern healthcare region of Sweden born in 2016-2020 were included. They were screened according to national guidelines, in 2016-2019 all infants born at gestational age < 31 weeks and in 2020 gestational age < 30 weeks because of new guidelines.
      • Holmström G.
      • Hellström A.
      • Gränse L.
      • et al.
      New modifications of Swedish ROP guidelines based on 10-year data from the SWEDROP register.
      They were classified and typed according to international guidelines.
      Early Treatment for Retinopathy of Prematurity Cooperative Group
      Revised indications for the treatment of retinopathy of prematurity.
      Forty-eight infants were diagnosed with type 2 ROP and were further analyzed and compared over the birth-years. During the early years the screening was performed with either indirect ophthalmoscopy or using digital widefield photography, (RetCam Shuttle, Natus Medical Inc. Pleasanton, CA, USA). All infants that were administered dexamethasone drops preoperatively were examined at each screening visit with digital widefield photography by a pediatric ophthalmologist and the photographs were discussed to reach a consensus on appropriate treatment strategy at each occasion with an experienced pediatric ophthalmologist (LG) who also performed laser ablation when needed. During the whole time-period, all infants were examined preoperatively with digital widefield photography to confirm the presence of type-1 ROP before any laser treatment was performed.
      To compare the frequency of infants progressing from type 2 to type 1 ROP among dexamethasone treated and untreated infants an odds ratio with 95% confidence interval (CI) was calculated with binary logistic regression. Bot univariate and multivariate analyses were performed. Significance level was set at p <0.05. Statistical analyses were performed with the Statistical Package for the Social Sciences (IBM statistics for Macintosh, version 26.0. IBM Corporation, Armonk, NY: USA).
      763 preterm infants were screened. (Table 1, available at www.ophthalmologyretina.org) One child was excluded due to death between diagnosis of type 2 ROP and possible need for laser ablation. Overall, 48 infants with type 2 ROP were included in the analyses. 31 of these did not receive any dexamethasone eye-drops prior to laser ablation. 17 received dexamethasone eye-drops when type 2 ROP was diagnosed. Sixteen of these had stage 3 in zone 2 and one had stage 2 in zone 1, all without plus disease. Photographs from an infant treated with dexamethasone is displayed in Figure 1 (available at www.ophthalmologyretina.org). Table 2 (available at www.ophthalmologyretina.org) presents the characteristics and co-morbidities for dexamethasone treated and untreated infants. As evident from table 3, the treatment frequency for infants with type 2 ROP that did not receive dexamethasone prior to laser ablation was 74%, in comparison with 24% among the infants who did receive dexamethasone eye-drops for type 2 ROP. The odds ratio between the dexamethasone treated infants in comparison to the untreated infants was 0.11, 95% CI 0.03 – 0.43, p = 0.001 in the univariate analysis. For the other possible covariates from table 2, only bronchopulmonary dysplasia affected the results and in the multivariate analysis, the odds ratio increased to 0.19, 95% CI 0.04 – 0.84, p = 0.03. Treatment frequency was initially three times daily, (seven infants) but successively lowered to an initial dose of twice daily (three infants) and then once daily (seven infants). The dose was gradually tapered off with the final dosage being every other day before ended. The median time on dexamethasone for infants that did not need laser treatment was 28 days, ranging from 14 – 98 days. The median postnatal age when dexamethasone drops were initiated was 10.5 weeks ranging from 7.1 – 12.7 weeks.
      Table 3Comparison of dexamethasone treated and untreated infants with type 2 retinopathy of prematurity.
      No laser ablationlaser ablationTotal
      Untreated infants, n (%)8 (26)23 (74)31
      Dexamethasone-treated infants, n (%)13 (76)4 (24)17
      Total212748
      n = numbers
      Advantages of this study was that all screened preterm infants in the southern healthcare region of Sweden were included. Although it was a retrospective analysis, we selected a time period during which the recommended saturation levels remained unaltered. All infants with type-2 ROP that received dexamethasone drops were examined with digital wide-field photography and assessed by an experienced pediatric ophthalmologist (LG).
      Several earlier studies have demonstrated that inflammation is a key factor in the development of ROP-changes.
      • Rivera J.C.
      • Holm M.
      • Austeng D.
      • et al.
      Retinopathy of prematurity: inflammation, choroidal degeneration, and novel promising therapeutic strategies.
      ,
      • Lee J.
      • Dammann O.
      Perinatal infection, inflammation, and retinopathy of prematurity.
      The results of this pilot study further support this idea. We have not found any previous studies on steroid eye-drops as treatment for type 2 ROP. A randomized study is warranted to corroborate our findings. With a power of 0.8 and type 1 error set at 0.05, a total of 28 infants would be required to reject the null hypothesis with this difference between groups.
      In many countries and remote areas, neonatal anesthesia and laser treatment is not available and anti-VEGF injections with a close follow-up scheme is not feasible. If treatment with steroid drops for infants with type 2 ROP can forestall type 1 ROP from developing and prevent blindness, this simple and low-cost treatment would make a monumental difference for those individuals.
      With a sharp decline in treatment frequency when dexamethasone eye-drops were introduced for type 2 ROP, the results indicate that such eye-drops can prevent these infants from developing type 1 ROP to a large extent.

      Supplementary Data

      References

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