Evaluation of the Retinopathy of Prematurity Activity Scale (ROP-ActS) in a randomised controlled trial aiming for prevention of severe ROP: a substudy of the Mega Donna Mega trial

Aldina Pivodic, Helena Johansson, Lois Eh Smith, Chatarina Löfqvist, Kerstin Albertsson-Wikland, Staffan Nilsson, Ann Hellström, Aldina Pivodic, Helena Johansson, Lois Eh Smith, Chatarina Löfqvist, Kerstin Albertsson-Wikland, Staffan Nilsson, Ann Hellström

Abstract

Objective: The current grading of retinopathy of prematurity (ROP) does not sufficiently discriminate disease severity for evaluation of trial interventions. The published ROP Activity Scales (original: ROP-ActS and modified: mROP-ActS), describing increasing severity of ROP, versus the categorical variables severe ROP, stage, zone and plus disease were evaluated as discriminators of the effect of an ROP preventive treatment.

Methods and analysis: The Mega Donna Mega trial investigated ROP in infants born <28-week gestational age (GA), randomised to arachidonic acid (AA) and docosahexaenoic acid (DHA) supplementation or no supplementation. Of 207 infants, 86% with finalised ROP screening were included in this substudy. ROP-ActS versus standard variables were evaluated using Fisher's non-parametric permutation test, multivariable logistic and linear regression and marginal fractional response models.

Results: The AA:DHA group (n=84) and the control group (n=93) were well balanced. The maximum ROP-ActS measurement was numerically but not significantly lower in the AA:DHA group (mean: 4.0 (95% CI 2.9 to 5.0)) versus the control group (mean: 5.3 (95% CI 4.1 to 6.4)), p=0.11. In infants with any ROP, the corresponding scale measurements were 6.8 (95% CI 5.4 to 8.2) and 8.7 (95% CI 7.5 to 10.0), p=0.039. Longitudinal profiles of the scale were visually distinguished for the categories of sex and GA for the intervention versus control.

Conclusions: The preventive effect of AA:DHA supplementation versus no supplementation was better discriminated by the trial's primary outcome, severe ROP, than by ROP-ActS. The sensitivity and the linear qualities of ROP-ActS require further validations on large data sets and perhaps modifications.

Trial registration number: NCT03201588.

Keywords: Diagnostic tests/Investigation; Retina; Treatment other; Vision.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Study flow chart. AA, arachidonic acid; DHA, docosahexaenoic acid; ROP, retinopathy of prematurity; MDM, Mega Donna Mega.
Figure 2
Figure 2
Longitudinal ROP-ActS values by treatment groups on at risk data set, including all data points from the existing ROP examinations without imputation for (A) all infants, (B) boys, (C) girls, (D) GA 22–24 weeks, (E) GA 25–26 weeks and (F) GA 27 weeks. The estimated mean values are not showing expected mean for the whole prematurely born population in this study, but only for infants that require ROP screening at different postnatal time points. Not all infants have regularly reported values over time, since the ROP screening examinations are individually defined for all infants. AA, arachidonic acid; DHA, docosahexaenoic acid; GA, gestational age; ROP, retinopathy of prematurity; ROP-ActS, Retinopathy of Prematurity Activity Scale.

References

    1. Mora JS, Waite C, Gilbert CE, et al. . A worldwide survey of retinopathy of prematurity screening. Br J Ophthalmol 2018;102:9–13. 10.1136/bjophthalmol-2017-310709
    1. Holmström G, Hellström A, Gränse L, et al. . New modifications of Swedish ROP guidelines based on 10-year data from the SWEDROP register. Br J Ophthalmol 2020;104:943–9. 10.1136/bjophthalmol-2019-314874
    1. Swedish national guidelines for screening and management of ROP 2021, 2022. Available: [Accessed 23 Feb 2022].
    1. Swedish national guidelines for screening and management of ROP 2012, 2022. Available: [Accessed 28 Jan 2022].
    1. Gunn TR, Easdown J, Outerbridge EW, et al. . Risk factors in retrolental fibroplasia. Pediatrics 1980;65:1096–100. 10.1542/peds.65.6.1096
    1. Hellström ASL, Dammann O. Retinopathy of prematurity. Lancet 1991;337:83–4.
    1. Norman M, Hallberg B, Abrahamsson T, et al. . Association between year of birth and 1-year survival among extremely preterm infants in Sweden during 2004-2007 and 2014-2016. JAMA 2019;321:1188–99. 10.1001/jama.2019.2021
    1. Hellström A, Hård A-L. Screening and novel therapies for retinopathy of prematurity - A review. Early Hum Dev 2019;138:104846. 10.1016/j.earlhumdev.2019.104846
    1. International Committee for the Classification of Retinopathy of Prematurity . The International classification of retinopathy of prematurity revisited. Arch Ophthalmol 2005;123:991–9. 10.1001/archopht.123.7.991
    1. Smith LEH, Hellström A, Stahl A, et al. . Development of a retinopathy of prematurity activity scale and clinical outcome measures for use in clinical trials. JAMA Ophthalmol 2019;137:305–11. 10.1001/jamaophthalmol.2018.5984
    1. The FIREFLEYE trial. Available: [Accessed 21 May 2021].
    1. Pivodic A, Nilsson S, Stahl A, et al. . Validation of the retinopathy of prematurity activity scale (ROP-ActS) using retrospective clinical data. Acta Ophthalmol 2021;99:201-206. 10.1111/aos.14532
    1. Hellström A, Nilsson AK, Wackernagel D, et al. . Effect of enteral lipid supplement on severe retinopathy of prematurity: a randomized clinical trial. JAMA Pediatr 2021;175:359–67. 10.1001/jamapediatrics.2020.5653
    1. Niklasson A, Albertsson-Wikland K. Continuous growth reference from 24th week of gestation to 24 months by gender. BMC Pediatr 2008;8:8. 10.1186/1471-2431-8-8
    1. Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986;33:179–201. 10.1016/S0031-3955(16)34975-6
    1. Early Treatment For Retinopathy Of Prematurity Cooperative Group . Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol 2003;121:1684–94. 10.1001/archopht.121.12.1684
    1. Ich topic E 9 statistical principles for clinical trials. Available: [Accessed 21 May 2021].
    1. Connor KM, SanGiovanni JP, Lofqvist C, et al. . Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med 2007;13:868–73. 10.1038/nm1591
    1. Fu Z, Lofqvist CA, Shao Z, et al. . Dietary ω-3 polyunsaturated fatty acids decrease retinal neovascularization by adipose-endoplasmic reticulum stress reduction to increase adiponectin. Am J Clin Nutr 2015;101:879–88. 10.3945/ajcn.114.099291
    1. Löfqvist CA, Najm S, Hellgren G, et al. . Association of retinopathy of prematurity with low levels of arachidonic acid: a secondary analysis of a randomized clinical trial. JAMA Ophthalmol 2018;136:271–7. 10.1001/jamaophthalmol.2017.6658
    1. Bernabe-García M, Villegas-Silva R, Villavicencio-Torres A, et al. . Enteral docosahexaenoic acid and retinopathy of prematurity: a randomized clinical trial. JPEN J Parenter Enteral Nutr 2019;43:874–82. 10.1002/jpen.1497
    1. Chiang MF, Quinn GE, Fielder AR, et al. . International classification of retinopathy of prematurity, third edition. Ophthalmology 2021;128:e51–68. 10.1016/j.ophtha.2021.05.031

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