Treatment for non-type 1 retinopathy of prematurity by intravitreal injection of anti-vascular endothelial growth factor drugs

Abstract

To explore clinical characteristics and treatment reasons for intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) drugs in the treatment of non-type 1 retinopathy of prematurity (ROP). A retrospective study was conducted to screen the non-type 1 ROP from the collected ROP patients who received intravitreal injection of anti-VEGF drugs in Henan Eye Hospital from September 2018 to June 2021. A total of 138 ROP cases (262 eyes) were included in this study, including 39 cases (28.3%) 65 eyes (24.8%) were the non-type 1 ROP. Compared with the type 1 ROP group, the non-type 1 ROP group had slightly later treatment time (41.1±8.9 weeks vs 38.6±5.5 weeks, P<0.05) and a higher proportion of fusion protein drugs(87.2% vs 54.5%, P<0.05). After intravitreal injection of anti-VEGF drugs, 27 eyes (41.5%) were cured and 38 eyes (58.5%) were improved in the non-type 1 ROP group, without recurrence and aggravation cases. There were more lesions in zone II (63 eyes, 96.9%), stage 2 (41 eyes, 63.1%) and stage 3 (22 eyes, 33.8%), and 58 eyes (89.2%) showed pre-plus in the non-type 1 ROP group. Treatment reasons included pre-plus in 58 eyes (89.2%), ridge changes in 22 eyes (33.8%), simultaneous treatment of the contralateral eye in 9 eyes (13.8%), no regression of lesions in persistent stage 2 or 3 over 44 weeks of follow-up in 8 eyes (12.3%), and logistical considerations in 4 eyes (6.2%). Considering some peculiar clinical characteristic, personalized treatment by intravitreal injection of anti-VEGF drugs may be necessary for some non-type 1 ROP in critical conditions.

Introduction

Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease that occurs in premature and low-weight infants, and it most afflicts both eyes and may cause retinal detachment and blindness. Current treatment methods of ROP include laser coagulation and intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs. The Early Treatment for Retinopathy of Prematurity (ETROP) and the latest expert consensus or guidelines recommend treatment for type 1 ROP cases and close follow-up for Type 2 ROP cases ^1,2. However, some ROP eyes have special manifestations in clinical practices, although they have not reached the level of type 1 ROP, manifested as gradually thickened or widened ridges without typical manifestation of plus disease, or no regression of the retinal lesions for a long time of follow-up. This kind of ROP is more serious than type 2 ROP, and it is difficult to decide whether to continue follow-up or give treatment. These non-type 1 ROP eyes may be recommended for treatment to avoid unnecessary medical disputes or irreversible vision damage caused by the aggravation of the disease.

Previous studies have reported that 9–27% affected eyes of patients with non-Type 1 ROP receive treatment in different countries ^3–6. In recent years, intravitreal injection of anti-VEGF agent for the treatment of ROP, with advantages of simple operation, minimal invasion and continuous growing of retinal vessels to the periphery after injection, has gradually become an important treatment method^7–9. There is a lack of relevant research on the treatment of intravitreal injection of anti-VEGF drugs for non-type 1 ROP patients in critical conditions. In this study, non-type 1 ROP cases who had received intravitreal injection of anti-VEGF drugs in our hospital were enrolled to analyze the treatment effect, clinical characteristics, and treatment reasons and to explore the personalized diagnosis and treatment for ROP cases with special clinical characteristics.

Methods

Inclusion And Exclusion Criteria

Diagnostic criteria for type 1 ROP were as follows ¹: (1) ROP at stages 1–3 with plus in zone I; and ROP at stage 3 without plus in zone I (2) stage 2 or 3 ROP with plus in zone II; (3) aggressive ROP (A-ROP). Those who did not meet any above conditions and received intravitreal injection of anti-VEGF drugs were defined as non-type 1 ROP. Infants with unstable vital signs caused by systemic diseases in the heart, brain, and lung or accompanied by other fundus lesions were excluded.

Study Selection

The retinal examination of ROP infants was performed in the neonatal intensive care unit (NICU) and ophthalmic clinic by two experienced doctors under topical anesthesia after mydriasis with RetCam 3. All abnormal retinal images were judged by a senior pediatric retinal professional (Haitao Zhang, associated professor), then diagnosis and treatment suggestions were made. Information of name, gender, gestational age, birth weight, and the time of examination and injection was recorded after the retinal examination. The zone, stage, range, and plus disease of binocular retinal lesions were recorded according to ICROP3 ¹⁰.

Anti-VEGF drugs used in the study were ranibizumab (0.25mg/0.025ml), conbercept (0.25mg/0.025ml), and aflibercept (1mg/0.025ml). The latter two drugs were fusion proteins. Intravitreal injection for ROP was performed under topical anesthesia. After local disinfection, a 29G needle-equipped syringe was used to penetrate the eyeball wall at 1.0-1.5 mm posterior of the limbus to the vitreous cavity parallel to the optical axis. Antibiotic eye drops were used for 3–5 days to prevent eye infection and the first eye review was conducted within 7 days The interval of the next review (1–3 weeks) shall be determined according to the retinal manifestations, and patients shall be followed up until complete retinal vascularization or for at least 24 weeks.

The characteristics of included subjects were analyzed according to the number of cases. The grouping criteria were as follows: ROP cases were included in the type 1 ROP group if both eyes met the above criteria and received intravitreal injection of anti-VEGF drugs, or one eye met the criteria and received intravitreal injection while the contralateral eye with mild lesions did not receive treatment. ROP infants whose one eye or both eyes did not meet the criteria of type 1 ROP and received intravitreal injection were included in the non-type 1 ROP group. The curative effect, retinal pathological characteristics, and causes for the treatment of non-type 1 ROP were analyzed according to the number of eyes. The characteristics of included subjects were analyzed according to the number of cases.

Quality Assessment

The treatment effect was evaluated as follows: (1) Cured, complete retinal vascularization. Retinal vessels gradually grew to the ora serrata or less than 1 PD (Papillary Diameter) away from the ora serrata around zone III; (2) Improved, the retina was not completely vascularized. The retinal vessels had reached zone III, and there were still non-vascular areas, but without obvious active lesions at the last follow-up. (3) Recurrence. The tortuous dilation of retinal vessels was relived and the ridge became flattened in the early stage after the operation, but then the tortuous dilation of vessels, ridge aggravation, and neovascularization occurred again in the retina. (4) Aggravation. The tortuous dilation of retinal vessels was not significantly reduced, and the proliferation and traction were aggravated, even leading to retinal detachment. The improved cases still required regular examination. The recurrent cases were treated with intravitreal injection of anti-VEGF drugs again or retinal laser photocoagulation. The aggravating cases were treated with laser photocoagulation according to the retinal manifestations or surgery in case of retinal detachment.

The reasons for the treatment of non-Type 1 ROP were as follows: (1) pre-plus diseases in the retina, (2) ridge changes, shown as more obvious ridges or ridge extension, or locally thickened and widened ridges, with a risk of increased proliferation. (3) simultaneous treatment of the contralateral eye; (4) no regression of lesions in persistent stage 2 or 3 for over 44 weeks of follow-up; (5) logistical considerations: follow-up might not be timely due to various reasons (such as living far away, parents’ poor understanding, and epidemic control policy, etc.).

Data Analyses

Data analyses were performed using the SPSS19.0 statistical software. The differences in birth gestational age (GA), birth weight (BW), hospitalization in NICU, first injection time, and follow-up time were compared by t-test, and the differences in gender and drug types were compared by χ ² test. The treatment effect was analyzed according to the number of afflicted eyes and compared by χ ² test. P < 0.05 was considered statistically significant.

Results

Effect Assessment

According to the number of eyes (n = 262), 65 eyes (24.8%) were non-type 1 ROP. After treatment,27 eyes (41.5%) were cured and 38 eyes (58.5%) were improved. There was no recurrence and aggravation. There were 197 eyes of type 1 ROP. After treatment, 79 eyes were cured (40.1%),100 eyes were improved (50.8%), and 18 eyes recurred (9.1%), without aggravation cases. The difference in treatment effects between the two groups was statistically significant (P < 0.05, Table 2). All 18 recurrent eyes in the type 1 ROP group received intravitreal injection of the same anti-VEGF drugs and then the condition improved.

Reasons For The Treatment

Of all treated eyes with non-type 1 ROP (n = 65) (Table 3), 63 eyes (96.9%) had more lesions in zone II. In terms of stage, there were more lesions in stages 2 and 3, with 41 eyes (63.1%) and 22 eyes (33.8%), respectively. In terms of plus diseases, 58 eyes (89.2%) showed pre-plus. As for treatment reasons, the chief reasons were pre-plus in 58 eyes (89.2%), followed by ridge changes in 22 eyes (33.8%), simultaneous treatment in 9 eyes (13.8%) due to contralateral eye treatment, no regression of lesions in stage 2 or 3 for over 44 weeks of follow-up in 8 eyes (12.3%), and logistical considerations in 4 eyes (6.2%). The above reasons can exist simultaneously (Fig. 1). The preoperative features and specific reasons for treated non-type 1 ROP cases are shown in Table 4.

Discussion

Some previous studies analyzed the treatment reasons of non-Type 1 ROP (seen in Table 5)^3,5,11,16, but the main treatment method in these studies was laser coagulation. No literature had been studied the effect of intravitreal injection of anti-VEGF drugs on the treatment of non-type 1 ROP currently.

Of the 263 eyes treated in this study, 65 eyes (24.8%) were non-type 1 ROP, showing a higher proportion than that in previous studies (9.5–13.7%)^3,5,11. Because that the treatment for ROP cases in this study was intravitreal injection of anti-VEGF drugs, which are simpler and more minimally invasive than laser coagulation¹⁴. Some lesions in critical conditions at risk of aggravation were suggested to be treated. In this study, lesions in all eyes with non-type 1 ROP were relieved after treatment, which was similar to the results of previous studies ¹¹. It was also found that the treatment effect of non-type 1 ROP eyes was better than that of type 1 ROP eyes, which may be related to the mild condition and the use of different types of anti-VEGF drugs. In this study, the proportion of fusion protein drugs used was higher in the non-type 1 ROP group (87.2%) than that in the type 1 ROP group (54.5%). This might be other potential reason for statistically significant difference in treatment effects between the two groups. Some studies found that the recurrence rate of ROP eyes treated with fusion protein drugs (conbercept or aflibercept) was lower than that of ROP eyes treated with ranibizumab ^12,13. The drug selection in our study was associated with the time to market in China.

Of eyes with non-type 1 ROP treated in this study, 63 cases (96.9%) had more lesions in zone II, and 41 eyes (63.1%) and 22 eyes (33.8%) had more lesions in stages 2 and 3, respectively. The characteristics of pathological manifestation were similar to those of the finding of Gupta MP et al ³, in which, 11 eyes (84.6%) had lesions in zone II, and 12 eyes (92.3%) had lesions in stages 2 and 3. While in the study of Liu T et al⁵, most eyes (66%) had pre-plus lesions in zone II stage 3. The above evidence suggests that ROP should be checked carefully about the changes of lesions at stage 2 or 3 in zone II.

The main treatment reason for non-type 1 ROP eyes in this study was the pre-plus disease (89.2%), which was different from previous studies. In the study of Gupta MP et al and Rajan RP et al., the most important treatment reason was structural changes in the fundus caused by the traction of the ridge (69.2% and 72.7%, respectively) ^3,11. Pre-plus disease (33.3%) was the second reason in the study of Rajan RP et al¹¹. The major reason in Liu et al’s study was the contralateral eye with type 1 ROP (43%), followed by stage 3 ROP with pre-plus (30%)⁵. As for pre-plus and plus disease, ICROP3 defined it as a continuous spectrum of retinal vascular changes from normal, to pre-plus, and finally to plus disease. Consistent judgments of different scholars only in the normal and last plus stages¹⁰. This suggests a high possibility of clinical disagreement over pre-plus lesions, resulting in no typical plus lesions in some ROP eyes and further risk of retinal traction with progressive worsening of the ridge. Due to the use of anti-VEGF drugs, we paid more attention to the judgment of pre-plus in the ROP examination.

The second cause of treatment in this study was ridge changes (33.8%), shown as more obvious or/and more extent, or thickened and widened locally. Actually, the ridge changes were often accompanied by pre-plus (Fig. 1). Koucheki R et al confirmed that pre-plus was significantly correlated with increased ridges (≥2 continuous clock hours of persistent stage 3 crossing the temporal horizontal midline) in the eyes with stage-3 ROP persisting ≥40 weeks of PMA¹⁶. The ridge changes in this study were slightly lighter than the structural fundus changes mentioned in previous studies^3,5,11, and no macular traction, retinal traction, or folds were produced due to the tangential traction caused by the straightening of the temporal vessels in the fundus. Under these proliferation conditions, intravitreal injection of anti-VEGF drugs may not be recommended because of the risk of aggravated proliferation^17,18.

In this study, the simultaneous treatment of contralateral eyes accounted for 13.8%. Most previous studies considered that acute ROP commonly occurs in both eyes. For example, 79.1% of ROP infants have high-risk pre-threshold disease in both eyes at the time of enrollment in an ETROP study¹. A study on Telemedicine Approaches to Evaluating of Acute-Phase Retinopathy of Prematurity (e-ROP) found that 72.7% of infants had the same severity of ROP in both eyes among ROP image sessions¹⁵.

However, our study does not recommend arbitrary early treatment for non-type 1 ROP. Previous studies suggested that ROP with stage 3 can be treated when no regression is found after 41 weeks of PMA³ or continuous 6 weeks of follow-up^5,11. In this study, the average time of the first treatment for eyes with type 1 ROP was 38.6 weeks, while the follow-up of another 6 weeks was 44 weeks for non-type I ROP eyes with some of the above particular retinal features. Meanwhile, due to the use of anti-VEGF drugs, in order to avoid obvious fibrosis, we paid attention to the progression of lesions at stage 2 and stage 3. Therefore, our study considered a treatment for ROP infants with lesions at persistent stages 2 and 3 without regression at the corrected gestational age of 44 weeks or more, and whether there were other retinal manifestations was also taken into consideration. In this study, 4 cases (8 eyes) (12.3%) were followed up for ≥ 44 weeks and then received drug treatment, but the fundus was accompanied by pre-plus lesions or ridge aggravation or logistical considerations before treatment.

In this study, 4 eyes (6.2%) were treated for the logistical considerations that result in not timely follow-up. The logistical considerations of Liu T et al ’s study were the difficulty in follow-up or general anesthesia for non-ROP surgery (3%)⁵. The intravitreal injection for ROP infants in this study was performed under topical anesthesia and there was no treatment under general anesthesia due to other diseases. For some ROP cases with difficulty in follow-up, detailed communication with the family before treatment is recommended to emphasize the importance of follow-up, especially after anti-VEGF drug treatment that requires longer follow-up.

This study still had some limitations. To avoid medical disputes caused by delayed treatment during clinical practice, no control group was set. So, it was unable to accurately judge the progression of non-type 1 ROP that did not receive treatment. The sample in the study group shall gradually be increased to collect untreated cases with non-type 1 ROP so as to investigate reasonable treatment methods in the future.

To summarize, non-type 1 ROP with some characteristics, such as pre-plus, ridge changes, treatment with contralateral eyes, no regression in persistent stage 2 or 3 for follow-up time ≥ 44 weeks, and logistical considerations, were cured or improved after intravitreal injection of anti-VEGF drugs. It is suggested that in clinical practice, personalized treatment can be carefully considered for some ROP in critical conditions based on expert consensus or guidelines.

Declarations

Acknowledgements 

Funded by Project of Henan Science and Technology Development Plan (182102311209).

Data availability

The datasets generated and/or analyzed during the current study are not publicly available due to limitations of ethical approval involving the patient data and anonymity but are available from the corresponding author on reasonable request.

Competing interests

The author(s) declare no competing interests.

Privacy Statements

This study was conducted with the approval of the Medical Ethics Committee of Henan Eye Hospital (Approval Number HNEECKY-2021 (49)). All infants’ legal guardian(s) signed written informed consent including research purpose, process, benefits and risks, privacy protection, etc. In the privacy protection part of each informed consent, it was written informed that all research members and research related parties must keep the identities of infants and their guardians confidential. All data files would be kept in a locked filing cabinet for researchers' reference only. When necessary, members of the government administration or Medical Ethics Committee could access your personal data in the research unit according to regulations. If some information or images may be involved in an online open-access publication, patient names must be removed to protect children's privacy.

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