Table 1.
Summary of original studies on anti-vascular endothelial growth factor in treatment of retinopathy of prematurity.
| Studies | Type of study | Participants | Country/region | Interventions | Study arms | Duration | Significant findings zone 1 | Ocular efficacy outcome | Significant findings zone 2 | Ocular efficacy outcome | Significant findings overall | Ocular efficacy outcome | Limitation/potential source of error | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Bevacizumab, Ranibizumab | Alyamaç Sukgen, E. (2016) | retrospective study | 45 | Turkey | Intravitreal injection of anti-VEGF | i. 0.625 mg bevacizumab; ii. 0.25 mg ranibizumab. | From Oct 2013 to Jun 2015 | Higher prevalence of recurrence in IVR group when compared to IVB group | P = 0.023 | retrospective study and lacking in wide field fundus photography | ||||
| Chandra., P. et al. (2020) | retrospective study | 9 | India | Vitrectomy combined with intravitreal anti-VEGF therapy | i. Vitrectomy combined with intravitreal bevacizumab (0.625 mg) ii.Vitrectomy combined with ranibizumab (0.25 mg) | From Aug 2017 to Jul 2018 | The usage of Anti-VEGF treatment together with vitrectomy was found to be able to regressadvanced stage 4 ROP withextensive neovascular proliferationrapidly | NA | Retrospective study | |||||
| Erol., M., K., et.al (2015) | retrospective study | 20 | Turkey | Anti-VEGF treatment as first-line monotherapy | i. 0.25 mg ranibizumab ii.0.625 bevacizumab | From Aug 2011 to Feb 2013 | Higher percentage of relapse of type 1 ROP in IVR eyes than IVB eyes | NA | Retrospective study | |||||
| Wu et al. (2017) | Prospective study | 10 | Taiwan | Intravitreal injection of ranibizumab and bevacizumab | i: 0.25 mg ranibizumab ii. 0.625 mg bevacizumab | From Feb 2013 to Dec 2014 | The suppression of systemic VEGF was more pronounced in IVB when compared to IVR | N/A | Small sample size | |||||
| Bevacizumab, Laser therapy | Harder et al. (2013) | retrospective study | 12 | N/A | Intravitreal bevacizumab or laser therapy | i. 0.375 mg or 0.625 mg bevacizumab ii. argon laser therapy | NA | Less myopia was found in eyes received IVB when compared with argon laser | P = 0.02 | retrospective study, relatively short follow up for refractive error outcome | ||||
| Chen, Y. C., et al. (2019) | retrospective study | 25 | Taiwan | Intravitreal bevacizumab injection or laser therapy | i. 0.625 mg bevacizumab ii. laser photocoagulation | From Jan 2010 to Dec 2012 | A significantly higher myopia was found in eyes treated with laser when compared with intravitreal anti-VEGF | P = 0.01 | Relatively small patient sample size and potential selection bias due to exclusion of eyes with poor image quality | |||||
| Geloneck, M. M. et al. (2014) | RCT | 131 | USA | Intravitreal bevacizumab monotherapy or laser therapy | i. 0.625 mg bevacizumab; ii. laser therapy | From Mar 13, 2008 to Aug 4, 2010 | IVB eyes had less myopia when compared with eyes with laser treatment | P < 0.001 | Eyes reviewed IVB had less myopia than eyes received laser treatment | P < 0.001 | 22 out of 131 infants did not follow up and potential observer bias | |||
| Gunay, M., et al. (2016) | prospective study | 30 | N/A | Intravitreal bevacizumab injection or laser therapy | i. 0.625 mg bevacizumab ii.laser photocoagulation iii. Spontaneously regressed ROP | NA | The prevalence of myopia was found to be lower in eyes without treatment when compared with eyes treated either IVB or laser therapy | P = 0.028 | Not randomized study and small sample size | |||||
| Hwang et al. (2015) | retrospective study | 28 | Georgia | laser therapy or bevacizumab | i: laser therapy ii: 0.625 mg bevacizumab | From Jan 2008 to Dec 2012 | Zone I ROP was associated with high myopia in eyes regardless of the treatment group assigned | P = 0.007 | Intravitreal bevacizumab and laser are effective treatment options for Type 1 ROP and have low complication rates | N/A | retrospective study | |||
| Karkhaneh, R et al. (2016) | RCT | 79 | Iran | Conventional indirect laser therapy or intravitreal bevacizumab injections | i. 0.625 mg bevacizumab; ii. laser therapy | From Sep 2012 to Sep 2013 | A significantly larger amount of eyes treated with IVB require retreatment when compared with laser group | P = 0.018 | NA | |||||
| Kennedy, K. A. and H. A. Mintz-Hittner (2018) | RCT | 150 | USA | Conventional indirect laser therapy or Intravitreal bevacizumab injections | i. 0.625 mg bevacizumab; ii. laser therapy | From Mar 2008 to Apr 2010 | No difference was found between infants treated with IVB or laser therapy in adverse neurodevelopmental outcomes | NA | NA | |||||
| Kong, L., et al. (2015) | RCT | 24 | USA | Intravitreal bevacizumab or laser therapy for infants with type 1 ROP | i. 0.625 mg bevacizumab; ii.0.25 mg bevacizumab; iii. laser therapy | From Jul 2012 to Jan 2014 | Both laser therapy and IVB reduce the serum IGF-1 level | NA | Small sample size | |||||
| Lepore, D., et al. (2014) | RCT | 13 | Italy | Intravitreal bevacizumab or laser therapy | i. 0.5 mg bevacizumab on one eye; ii. laser therapy on the other eye | From Sep 2009 to Dec 2010 | Macular abnormalities were more common to be found in eyes treated with IVB when compared with laser | P < 0.05 | Small sample size | |||||
| Lepore, D., et al. (2018) | RCT | 21 | Italy | Intravitreal injection of bevacizumab and conventional laser photoablation | i. 0.5 bevacizumab ii. conventional laser photoablation | From Sep 2009 to Mar 2012 | Eyes treated with IVB continue to have extensive areas of non-vascularized peripheral retina | NA | Within-subject randomization due to leakage of IVB from the eye into systemic circulation | |||||
| Mintz-Hittner, H. A. (2012) | RCT | (eye: 152) | USA | Pegaptanib with laser therapy or bevacizumab monotherapy | NA | NA | The use of anti-VEGF therapy for ROP has been shown to be effective and safe without any report of toxicity. | NA | NA | |||||
| Mintz-Hittner, H. A., et al. (2011) | RCT | 150 | USA | Intravitreal bevacizumab or conventional laser therapy | i. 0.625 bevacizumab (injected 2.5 mm from the limbus) ii. conventional laser therapy | From Mar 2008 to Aug 2010 | Rate of recurrence was found to be higher in eyes treated with laser therapy than with IVB | P = 0.002 | NA | |||||
| Moran, S., et al. (2014) | RCT | 15 | N/A | Intravitreal Bevacizumab or laser | i.1.25 mg of Bevacizumab ii.Treatment with diode laser | NA | Bevacizumab is less destructive and more convenient to use when compared to laser treatment. | NA | Small sample size | |||||
| Morin et al. (2016) | Retrospective study | 125 | Canada | laser therapy or Intravitreal bevacizumab | i: laser therapy ii: Bevacizumab | From Jan 2010 to Sep 2011 | Infants treated with IVB had higher odds of severe neurodevelopmental disabilities when to laser therapy. | N/A | retrospective study and limited by lost of infants for follow up | |||||
| Kuo et al. (2015) | retrospective study | 54 | Taiwan | laser therapy or intravitreal bevacizumab | i. laser therapy; ii. 0.5 mg bevacizumab | From 2003 to 2012 | The difference in the myopic status between laser and IVB treatment was not statistically significant. | p < 0.001 | Retrospective study and small sample size | |||||
| Lien et al. (2016) | Retrospective observational case series | 61 | Taiwan | laser therapy or Intravitreal bevacizumab or combination of both | i: laser only ii: 0.625 mg Bevacizumab only iii: a combination of 0.625 mg Bevacizumab and laser treatment | From Dec 2007 to Dec 2010 | There was no difference in neurodevelopmental outcome between 0.625 mg IVB group and laser group, but the combination group showed a higher incidence of psychomotor and mental impairment of infants at the 24 months of age. | N/A | Retrospective study and small number of enrolled patients | |||||
| Rodriguez et al. (2019) | Retrospective study | 86 | N/A | laser therapy or Intravitreal bevacizumab | i: laser therapy ii: Bevacizumab | From 2006 to 2016 | There were no significant differences in primary outcome measures between the two groups except laser therapy had a higher adjusted odds of causing bilateral visual impairment. IVB was not found to be associated with severe neurodevelopmental disabilities. | P = 0.038 | Retrospective study | |||||
| Bevacizumab | Chang et al. (2019) | Retrospective study | 114 | Taiwan | Intravitreous bevacizumab injections | i: 0.625 mg Bevacizumab ii: control (no treatment) | From 2008 to 2014 | No significant differences in body weight and neurodevelopmental outcomes were observed between the IVB and control groups up to 2 years of age | P = 0.389 | Retrospective design, small sample size, lack of serum VEGF data | ||||
| Fan et al. (2019) | Prospective study | 148 | Taiwan | Intravitreous bevacizumab injections | i: 0.625 mg Bevacizumab | From Jun 2014 to Jan 2019 | At 1.5-year mean age, ROP children with prior history of IVB use and those without the need of treatment showed similar refractive and neurodevelopmental outcomes. | N/A | Non-randomized design, limited number of patients | |||||
| Crouch et al. (2020) | Prospective study | 61 | N/A | Intravitreous bevacizumab injections of 0.625 mg to 0.031 mg | i: 0.25 mg Bevacizumab ii: 0.125 mg Bevacizumab iii: 0.063 mg Bevacizumab iv: 0.031 mg Bevaizumab | From Apr 2016 to Oct 2017 | The rate of high myopia of low dose bevacizumab was consistent with rates reported in higher dosages | N/A | Small sample size | |||||
| Wallace, D. K., et al. (2018) | prospective study | 61 | N/A | Intravitreal bevacizumab injection | i. 0.25 mg bevacizumab ii. 0.125 mg bevacizumab iii. 0.063 bevacizumab, iv.0.031 mg bevacizumab | NA | Retinal structural outcomes are good after reducing the bevacizumab dose to as low as 0.031 mg. | NA | small sample size | |||||
| Wallace, D. K., et al. (2017) | prospective study | 58 | N/A | Intravitreal bevacizumab | i. 25 mg bevacizumab | From May 2015 to Sep 2016 | Intravitreal bevacizumab therapy as low as 0.031 mg, or 5% of the previously mentioned dose, was found to be efficacious. | NA | Small sample size | |||||
| Ranibizumab | Stahl, A., et al. (2018) | RCT | 19 | Germany | Baseline ranibizumab injection per eye | i.0.12 mg ranibizumab ii. 0.2 mg ranibizumab | From Sep 2014 to Jul 2016 | Ranibizumab is effective in treating ROP. Physiologic intraretinal vascularization to the ora serrata was found to be more favorable in the 0.12-mg than the 0.20-mg group. Systemic level of VEGF was not suppressed in either group. | NA | Small sample size and a early primary endpoint | ||||
| Ranibizumab, Laser therapy | Stahl, A., et al. (2019) | RCT | 214 | multiple countries:USA, Austria, Belgium, Croatia, Czechia, Denmark, Egypt, Estonia, France, Germany, Greece, Hungary, India, Italy, Japan, Lithuania, Malaysia, Mexico, Poland, Romania, Russian Federation, Saudi Arabia, Slovakia, Taiwan, Turkey, United Kingdom | Intravitreal ranibizumab or laser therapy | i. 0.2 mg ranibizumab ii. 0.1 mg ranibizumab iii. Laser therapy at baseline | From Dec 2015 to Jun 2017 | 68% of eyes treated with 0.2 mg IVR achieved primary outcome(survival without achieve retinopathy). 70% of eyes treated with 0.1 mg IVR achieved primary outcome | NA | 88% eyes treated with 0.2 mg IVR achieved primary outcome. 78% eyes treated with 0.1 mg IVR achieved primary outcome. | NA | Infants received 0.1 mg IVR had a higher treatment success odd ratio when compared with laser therapy | P = 0.051 | Clinicians providing care were from a wide range of settings and no training in the use of fundoscopy were provided to clinicians. |
| Zhang, G., et al.(2017) | RCT | 50 | China | Conventional laser therapy or single dose intravitreal injection of ranibizumab | i. Conventional laser therapy (indirect infrared diode laser 810 nm) ii. 0.3 mg single dose ranibizumab | From Jan 2014–Dec 2014 (12 m) | Eyes treated with IVR was found to have a greater recurrence rate of ROP when compared to eyes treated with laser | P = 0.001 | Relatively small sample size, short follow-up of patients | |||||
| Aflibercept | Vedantham, V. et al. (2019) | retrospective study | 23 | India | Intravitreal Aflibercept | i.1 mg aflibercept | NA | All ROP Eyes treated with IVF was found to be able to achieve regression of ROP | NA | Retrospective study | ||||
| Aflibercept, Bevacizumab | Huang et al. (2018) | Prospective study | 14 | Taiwan | Intravitreal injection of aflibercept and bevacizumab | i: 1 mg aflibercept ii. 0.625 mg bevacizumab | From Sep 2014 to Aug 2016 | Despite a lower concentration of IVB used when compared to IVA, systemic VEGF was more suppressed in the IVB group than the IVA patients | P = 0.273 | Small cohort study and unequal distribution of two study arm group | ||||
| Conbercept | Bai, Y., et al. (2018) | retrospective study | 24 | China | Intravitreal conbercept | i. 0.25 mg conbercept | From Jun 2015 to Jul 2016 | All eyes injected with IVC achieved ROP regression | NA | Small sample size and retrospective study | ||||
| Cheng et al. (2020) | case series | 70 | China | Intravitreal conbercept injections or no treatment | i: 0.25 mg Conbercept ii: control (no treatment) | From Nov 2017 to Sep 2018 | The plasma levels of VEGF-A and VEGF-D were suppressed at 1 week after injection of 0.25 mg IVC, but their levels returned to baseline at 4 weeks. | P = 0.021 | case series | |||||
| Cheng, Y., et al. (2018) | retrospective study | 20 | China | Intravitreal conbercept | i. 0.15 mg conbercept | From Aug 2016 to Nov 2016 | 84.2% of eyes was able to achieve primary effectiveness with IVC 0.15 mg alone | NA | Retrospective study | |||||
| Conbercept, Ranibizumab | Cheng, Y., et al. (2020) | retrospective study | 145 | China | Intravitreal conbercept or Intravitreal ranibizumab | i. 0.25 mg conbercept ii. 0.25 mg ranibizumab | From Jul 2012 to Mar 2018 | The prevalence of recurrence was found to be significantly higher in IVR when compared with IVC | P = 0.006 | Retrospective study | ||||
| Cryotherapy | Multicenter Trial of Cryotherapy for Retinopathy of Prematurity: ophthalmological outcomes at 10 years. (2001) | RCT | 291 | Multiple countries: United Kingdom, USA | cryotherapy or no cryotherapy | i. cryotherapy in one eye ii. no cryotherapy in another eye | NA | Visual field reduction is an expected finding after cryotherapy even if retinal detachment is prevented | N/A | N/A | ||||
| Quinn et al. (1996) | RCT | 78 | USA | cryotherapy | i. cryotherapy in one eye ii. no cryotherapy in another eye | NA | In 5.5-year, an average visual field reduction of 6.4° in treated eyes was observed when compared to untreated control eyes of the same patient. | N/A | N/A | |||||
| Laser therapy | Fallaha et al. (2001) | Retrospective study | 47 | Georgia | Conventional laser therapy | i: confluent diode laser photoablation | From Aug 1997 to Jul 2000 | Anterior segment ischemia after laser ablation for APROP is rare | N/A | retrospective study | ||||
| Good et al. (2004) | RCT | 317 | USA | Early retinal ablative treatment or conventional treatment | i. early retinal ablative treatment in one eye ii: conventional treatment in another eye | From Oct 2000 to Sep 2002 | Early laser ablation resulted in a reduction in unfavorable visual acuity outcomes from 19.8% to 14.3%. | P < .005 | N/A | |||||
| Gunay et al. (2015) | Retrospective study | 175 | Turkey | Conventional laser therapy | i. Laser ablations with a head-mounted 810 nm diode laser | From Nov 2010 to Dec 2013 | Anterior segment ischemia after laser ablation for APROP is rare | N/A | Retrospective study |