(2024) 24:556
Yang et al. BMC Pediatrics
https://doi.org/10.1186/s12887-024-05017-1

BMC Pediatrics

RESEARCH

Open AccessComparison of ranibizumab and conbercept
treatment in type 1 prethreshold retinopathyof prematurity in zone II
Xiu‑Mei Yang1, Qiu‑Ping Li2, Zong‑Hua Wang1 and Mou‑Nian Zhang1*

Abstract
Purpose The treatment with anti-VEGF for Retinopathy of prematurity (ROP) has already been widely applied in clinics even though there are still many concerns about this treatment. In this project we investigated the clinical outcomes of intra-vitreous conbercept (IVC) and ranibizumab (IVR) injection for treating type 1 prethreshold ROP in Zone
II.
Methods The data of ROP infants receiving IVR or IVC from January 2017 to March 2020 who were followed up for atleast 12 months in our hospital was studied in the present retrospective study. Regression, reactivation, complications,and ocular biological parameters were evaluated.
Results One hundred twenty-five eyes (64 infants) in IVC group and 229 eyes (117 infants) in IVR group wereobserved in the study. All infants showed good response to the two anti-VEGF agents. No eyes deteriorated during the observation. No significant difference was found between the two groups as to the regression within one
week and one month, the reactivation rate, and the retreatment interval (p > 0.05) whereas retinal complete vascularization rate at 6 mons after the initial treatment and mean completion time of retinal vascularization after initial
injection showed significant difference (p < 0.05). At 12 mons PMA the ocular parameters also presented no statistical difference between the two treated groups (p > 0.05). However, the ocular showed slight myopic tendencywith the anti-VEGF treatment when compared to the control group (p < 0.05) whereas there was no statistical difference revealed between the two treated groups (p > 0.05).
Conclusions Both conbercept and ranibizumab for treating type 1 prethreshold ROP in Zone II are safeand effective. They had little effect on the development of ocular whereas there was a slight tendency of myopia
after the treatment.
Keywords Retinopathy of prematurity, Conbercept, Ranibizumab, Treatment*Correspondence:
Mou‑Nian Zhang
zhangn301@163.com
1
Department of Ophthalmology, Chinese People’s Liberation Army
General Hospital, Beijing 100039, China
2
Department of Pediatrics, the Seventh Medical Center of Chinese
People’s Liberation Army General Hospital, Beijing 100700, China

Introduction
Retinopathy of prematurity (ROP) is one of the leading
reasons for severe childhood vision loss in the world.
ROP is a retinal vasoproliferative disorder which affects
exclusively in preterm neonates. Especially in the developing countries, the survival rate of premature neonates
has greatly increased, along with the improvement of
neonatal care and respiratory support available today,
thus leading to enlarged number of ROP patients [1,2]. Numerous researches have proved that Vascular© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article orparts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To
view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Yang et al. BMC Pediatrics(2024) 24:556

endothelial growth factor (VEGF) is a key regulator in
ROP development [3, 4]. The peripheral avascular area
induces an anoxic environment and hence elevates local
VEGF level. Laser treatment is accepted to be the conventional standard treatment for type 1 and threshold
ROP patients by ablating peripheral avascular retina for
decades. It can decrease the elevated VEGF level andinduce the recession of abnormal retinal neovascularization. However, this treatment also has several defects
such as time-consuming, visual field loss and refractive
error. Furthermore, laser therapy is limited to be undertaken for lens opacity or pupillary rigidity in severe ROP[5].
Several investigations have illustrated the effectivenessof intra-vitreous anti-VEGF injection on ROP, and so far
several anti-VEGF drugs have demonstrated encouraging signs of biological activity in treating ROP including ranibizumab and conbercept [6–8]. Ranibizumab
is known to be a recombinant humanized monoclonal
antibody fragment derived from bevacizumab. Several
studies including the RAINBOW study have estimatedthe effectiveness and safety of ranibizumab on ROP [9].
Except for the antibodies, soluble VEGF receptors also
prove a very specific neutralization of VEGF thus leading to the anti-angiogenic activity [10]. Conbercept is a
novel humanized VEGF decoy receptor. It is a recombinant humanized fusion protein which consists of partial
VEGF receptor 1(domain 2) and partial VEGF receptor
2 (domain 3 and 4) fused to the constant region (Fc) of
human IgG1 [11]. A series of recent published papers
illustrated that conbercept was effective for treating
aggressive ROP and type 1 ROP [7, 8, 12]. However,clinical comparison between the two anti-VEGF drugs(ranibizumab and conbercept) for treating type 1 prethreshold ROP in Zone II is still not adequate. Therefore,
in the present research we planned to compare the safety
and effectiveness of conbercept and ranibizumab treatment in type 1 prethreshold ROP in Zone II.

Methods
This research was a single-center retrospective study
comparing the difference of IVR and IVC treatment ontype 1 prethreshold ROP in Zone II. The severity of ROP
was diagnosed by the principles of the International Classification of Retinopathy of Prematurity [13]. One hundred eighty-one infants who were diagnosed as type 1
prethreshold ROP in Zone II with plus disease from February 2017 to March 2020 were enrolled in our research.
From 2013 to 2020 there are only two anti-VEGF
drugs available in our hospital (ranibizumab and conbercept). An informed consent was signed by theguardian of each infant after informing and explaining
the off-label use of the two agents for this disease andPage 2 of 6

possible adverse effects of the treatment. It will be theparents to decide which one they will choose to be used
for their children.
We performed the intravitreal injection following
previous described procedure [14]. The treatment was
carried out by topical anaesthesia with unpreserved
oxybuprocaine eye drops or inhalation anaesthesia.
5% povidone iodine was used to sterilize eyelids andconjunctiva. After inserting a sterilized eyelid speculum 0.25 mg/0.025 mL ranibizumab (Lucentis, Novus,US) /conbercept (Chengdu Kanghong Biotechnologies
Co. Ltd, Sichuan, China) was intra-vitreous injected
through the pars plana 1.5 mm after the corneal limbus.
The inclusive criteria included (1) type 1 prethreshold ROP in Zone II receiving the initial anti-VEGF
treatment and (2) the infants followed up at least for
12 months. While the exclusive criteria were (1) a history of ROP treatment, (2) combined with other oculardiseases which might interfere the development of ROP
and (3) the infants were not recommended to receive
anti-VEGF treatment for systemic defects.
Two experts confirmed the severity of the disease.
Subsequent retinal changes of ROP during the followup were also observed by them. The pupil was dilatedwith 0.5% tropicamide and 0.5% phenylephrine andthen the fundus was examined with indirect ophthalmoscopy routinely after topical anesthesia. The retinal findings before and after the treatment if needed
were documented with RetCam II (Natus Medical,
Inc., Pleasanton, CA, USA). The infants were followed
up at day 1 and day 7 after surgery and then the frequency was either decreased or increased according to
the severity of the disease. Normally we examined theinfants every 2–3 weeks.
Patients were examined following the principles ofChinese expert consensus for ROP. At 12 mons postmenstrual age (PMA) retinoscopy, A and B ultrasonicwere performed to compare the refractive status andocular biological parameters between the two groups
by general anaesthesia.
The reactivation was defined as the return of retinal
ridge or plus signs after the initial recession. Additional
treatment should follow the rules of Retinopathy ofPrematurity (ETROP) protocol if reactivation needed[15].
The quantitative data were compared with the Mann–
Whitney U-test and Student’s t-test while qualitative data
were analysed with the chi-square test or Fisher’s exact
test. Statistical software SPSS (StatLab, SPSS for Windows, version 19.0; SPSS Inc., Chicago, Illinois, USA)was taken for statistical analysis in this study. P < 0.05 wasconsidered statistically significant.

Yang et al. BMC Pediatrics(2024) 24:556

Page 3 of 6

Results
One hundred eighty-one infants (354 eyes) diagnosed as
type 1 prethreshold ROP in Zone II in our hospital fromJanuary 2017 to March 2020 were included in this study
in total. Among them 229 eyes of 117 premature infants(60 M/57F) enrolled in the IVR group while 125 eyes of
64 premature infants (27 M/37F) in the IVC group. The
demographics of the enrolled patients were illustrated inTable 1.
No systemic or severe local adverse effects wereobserved during the follow-up time. The main complications for anti-VEGF injection were preretinal hemorrhage and subconjunctival hemorrhage. No significant
difference was observed between these two groups andthe hemorrhage could be absorbed spontaneously.
After the initial intravitreal injections, all eyes showed
good response to the two drugs including regression ofplus disease and at least partial regression of the ridge of
ROP. One week after the injection the complete regression rate for the disease for ranibizumab group and theconbercept group was 90/163 eyes (55.21%) and 61/103
eyes (59.22%), respectively. And the complete regression rate increased to 107/168 eyes (63.69%) and 67/84
eyes (79.76%) at one month after the treatment. The twogroups showed no statistical significance concerning theinitial treatment effectiveness, and regression of the disease (P > 0.05).

The prevalence of reactivation was 36 eyes (19 infants,
15.72%) in IVR group and 18 eyes (10 infants, 14.4%)
in IVC group and it made no statistical significancebetween these two groups (P > 0.05). For the IVR group,
193 eyes accepted only one intravitreal injection, and 36
eyes accepted a second treatment. Among the recurrent
eyes 18 eyes received a second single injection while 14eyes received laser treatment only and 4 eyes received a
combination treatment of a second injection and laser
ablation. At the meantime for the IVC group, 107 eyes
accepted only one injection, while 16 eyes received a second injection and 2 eyes received a second anti-VEGF
injection combined with laser photocoagulation. Theinterval between the treatment and retreatment was
7.87 ± 3.81 wks (range: 2.86 to 15.29 wks) in the ranibizumab group and 9.63 ± 3.90 wks (range: 3 to 14.43 wks)
in the conbercept group which made no statistical significance (P > 0.05). Retinal vascular reached at least zone III
in all eyes at the final exam. Complete retinal vascularization was seen in 170/205 eyes (82.93%) and 49/71 eyes
(69.01%) in both the IVR group and the IVC group at 6mons after the initial treatment, respectively (P < 0.05).
Mean completion time of retinal vascularization after initial treatment was 6.43 ± 3.73 mons and 7.97 ± 3.71 mons,
respectively, which made a statistic significance (P < 0.05).
The comparison of treating effects of the two treatedgroups is stated in Table 2.

Table 1 The demographics of patients with ROP treated with intravitreal injection of two anti-VEGF drugs
IVR

IVC

P Value

Number of infants

117

64

Number of eyes

229

125

> 0.05

M/F

60/57

27/37

> 0.05

BW, mean ± SD (range)

1057.91 ± 337.37 g (range: 480.0 to 3300.0 g)

1078.33 ± 243.99 g (range: 600.0 to 1780.0 g)> 0.05GA, mean ± SD (range)

27.76 ± 1.80 weeks (range: 24.57 to 34.00 weeks)

28.26 ± 1.89 weeks (range: 24.29 to 32.57 weeks)> 0.05

PMA at treatment, mean ± SD (range)

37.99 ± 2.94 weeks (range: 32.29 to 50.0 weeks)

38.67 ± 2.56 weeks (range: 33.14 to 47.57weeks)> 0.05follow-up time, mean ± SD (range)

16.32 ± 3.39 mons (range: 12.00 to 23.00 mons)

18.30 ± 7.44 mons (range: 6.00 to 39.4.00 mons)> 0.05Abbreviations: M/F Male/Female BW, Birth weight, GA Gestational age, PMA post menstrual age, Mon Month

Table 2 Comparison of two anti-VEGF drugs on treating ROP
IVR

IVC

P Value

Initial treatment effective

229 eyes (100%)

125 eyes (100%)> 0.05Complete regression of the disease within 1 week

90/163 eyes (55.21%)

61/103 eyes (59.22%)> 0.05Complete regression of the disease within 1 mon

107/168 eyes (63.69%)

67/84 eyes (79.76%)> 0.05Completion of retinal vascularization after 6 mon

170/205 eyes (82.93%)

49/71 eyes (69.01%)< 0.05

Mean completion time of retinal vascularization after initial
treatment

6.43 ± 3.73 mons

7.97 ± 3.71 mons

< 0.05

Reactivation

36 eyes (19 infants, 15.72%)

18 eyes (10 infants, 14.4%)> 0.05

Mean interval between the treatment and retreatment

9.99 ± 3.24 wks (range: 4 to 15.29 wks)

10.57 ± 3.06 wks (range:7.29
to 14.43 wks)

> 0.05

Yang et al. BMC Pediatrics(2024) 24:556

Page 4 of 6

At 12 months PMA the ocular biological parameters of the two treated groups were also measured andcompared with ROP infants who received no treatment and the ROP disease recessed naturally: the meananterior chamber depth for ranibizumab group was
3.21 ± 0.24 mm, while that was 3.09 ± 0.17 mm for conbercept group. Mean lens thickness was 3.85 ± 0.15 mm
and 3.82 ± 0.10 mm for ranibizumab group and conbercept group respectively. The mean axial length for theformer group was 20.52 ± 0.77 mm and 20.75 ± 1.01 mm
for the latter. All these parameters made no statisticalsignificance compared to the control group (P > 0.05).
As to the refractive status the results showed that both
IVR group and IVC group presented a significant difference compared to control group when comparing themean spherical equivalence and mean spherical power(P < 0.05). The astigmatism rate also increased after thetreatment (P < 0.05). As to the mean cylinder power thetwo treated groups made no statistical difference compared to the control group (P > 0.05). The data of comparing the ocular biological parameters and the refractive
status after the treatment was listed in Table 3.

Discussion
In recent research, VEGF has been believed to be themain mediator for ROP development illustrated in bothanimal models and in humans [16–18]. Several antiVEGF drugs so far are available including bevacizumab,
ranibizumab, aflibercept and conbercept in treating
ROP [6–8, 12]. Ranibizumab is the most widely used intreating ocular neovascularization related diseases. As
a humanized monoclonal antibody it shows high binding affinity to VEGF-A thus renders it inactive. Whereas
conbercept is a novel agent. As a soluble receptor decoy
it can target to VEGF-A, VEGF-B and placental growth
factor[12].
In this study, we found both conbercept and ranibizumab had a strong initial effect on type 1 prethreshold
ROP in Zone II. Plus disease recessed in all infants soonafter the treatment. 1 week after injection retinal ridge
completely diminished in 90/163 eyes 55.21% and 61/103
eyes (59.22%) while the rate increased to 107/168 eyes
(63.69%) and 67/84 eyes (79.76%) in one month in boththe IVR and IVC groups, respectively. The initial injection periods found in previous studies vary between 32 to
36 weeks PMA while in our cases the timepoint for treatment is 37.99 ± 2.94 weeks (range: 32.29 to 50.0 weeks)and 38.67 ± 2.56 weeks (range: 33.14 to 47.57 weeks) for
IVR and IVC groups respectively [19, 20]. The prolonged
treating time may be because in the previous studies thestages of ROP were mainly zone I and posterior zone IIpatients which were more severe than ours. Another reason could be racial difference, screening criterion difference. In Fig. 1 we showed two cases who accepted either
IVC or IVR treatment illustrated both the complete
regression and partial regression of the disease.
In this study the reactivation occurred in 36 eyes (19infants, 15.72%) for IVR group and 18 eyes (10 infants,
14.4%) for IVC group which was lower compared withthe previous studies. [1, 6–8] The recurrent rate variation may be because of the small size of the study andthe severity difference also could be a possible reason.
For IVR treatment in China, in the previous studies, themean reactivation interval was 8.57 ± 3.73 weeks in Fenget al.’s study, 8.3 ± 2.7 weeks in Huang et al.’s study and8.40 ± 0.88 (6–10.5) weeks in Zone II ROP in Cheng et al.’s
study [6, 12, 21]. Our results showed that the mean reactivation interval for IVR was 9.99 ± 3.24 weeks (range: 4 to
15.29 weeks) which was consistent with previous studies.
Moreover, in our study we found that the interval for IVC
group is slightly longer than the IVR group even though
it made no statistical significance. This may be associatedwith the different structure and the prolonged half-timeof conbercept compared with ranibizumab. Even though
the exact underlying pathogenesis remains to be further
explored and verified.
The previous studies estimated that even thoughintravitreal anti-VEGF injection could dramatically

Table 3 Comparison of the ocular biological parameters and the refractive status after the treatment
IVR

IVC

Ctrl

P Value

Anterior chamber depth (mm)3.21 ± 0.24

3.09 ± 0.17

3.17 ± 0.25

> 0.05

Lens thickness (mm)3.85 ± 0.15

3.82 ± 0.10

3.87 ± 0.22

> 0.05

Axial length (mm)20.52 ± 0.77

20.75 ± 1.01

20.46 ± 0.62

> 0.05

Mean spherical equivalence-0.97 ± -2.01*-1.19 ± -3.22*

0.78 ± 1.02

< 0.05

Mean spherical power-0.64 ± -1.87*-0.76 ± -3.23*

1.03 ± 0.89

< 0.05

Mean cylinder power-0.40 ± 1.56

-0.52 ± 2.28

-0.58 ± 1.79

> 0.05

Astigmatism rate

8/20 (40.00%)*

9/24 (37.50%)*

1/22 (4.55%)< 0.05

IVR or IVC versus ctrl*

P < 0.05

Yang et al. BMC Pediatrics(2024) 24:556

Page 5 of 6

Fig. 1 Zone 2 stage ­3+ ROP before treatement (white arrow, A) and 1 week after intravitreal conbercept injection with complete regression(B). Patient1 information: male, GA:29+1w, BW 1050 g, PMA ­38+5w; Zone 2 stage ­3+ ROP before treatment (white arrow, C) and partial regression
after intravitreal ranibizumab injection (white arrow, D). Patient2 information: female, GA: 27w, BW 1100 g, PMA 38w

decrease the systemic VEGF level however the inhibition effect was temporary (one week for ranibizumab
and two weeks for conbercept) and hence may notcause severe system side effects [10, 22]. Nevertheless,as VEGF is a pleiotropic protein and the ROP patientsare undergoing organogenesis we still cannot exclude
long-term systemic advert events of the drugs. Therefore, a much longer follow-up time and an enlarged
population for study are strongly recommended.
VEGF is essential for retinal vascular growth. A preliminary research estimated that anti-VEGF treatment
might be able to postpone retinal vascularization in
ROP [23]. This phenomenon could because of the lossof microglia due to hypoxia during the developmentof ROP since some researchers believed that microglial cells are essential for proper retinal vascular formation [24, 25]. Previous results showed that the rateof complete retinal vascularization was 71.41% with
ranibizumab and 76.21% with conbercept and 72% with
bevacizumab in ROP [12, 23]. While the rate was evenmore lower in Tahija’s study nearly 45% [26]. Complete
retinal vascularization at 6 months after the initial
treatment in our study is 170/205 eyes (82.93%) in IVR
group and 49/71 eyes (69.01%) in IVC group. There is astatistic difference between the two groups concerning
the rate of retinal vascularization. We still do not know
the exam reason for the difference. One possible reason
might be the different structure and the prolonged halftime of conbercept compared with ranibizumab. Moreresearches are needed to explore this phenomenon.

As to the ocular biological parameters which include
the anterior chamber depth, lens thickness and axial
length they showed no difference comparing to thecontrol group. For the refractive status the two treatedgroups showed mild myopic tendency comparing withthe control group. These findings were consistent withother previous researches [27].

Conclusions
Hence in the current research, we disclosed that antiVEGF treatment with either ranibizumab or conbercept was effective and safe as monotherapy for type 1
prethreshold ROP in Zone II infants and did not show
any serious systemic or local side effects. However,
the increased risk of reactivation compared with laser
treatment and the prolonged retinal complete vascularizaiton alerts the ophthalmologists a demand for alonger follow-up.
Authors’ contributions
Dr. xiu-mei Yang; Dr zong-hua wang and Dr qiu-ping Li performed the clinicalwork for the paper. Dr. xiu-mei Yang; Dr zong-hua wang together collected thedata and following statistical analysing. Dr. xiu-mei Yang wrote the paper while
Dr qiu-ping Li and Prof. mou-nian zhang revised the paper before submitting.
All authors reviewed the manuscript.
Funding
The work was funded by: 64th Chinese Postdoctoral Science Foundation;
Innovation foundation of the Seventh Medical Center of Chinese People’s
Liberation Army General Hospital (qzx-2023–19); Capital Characteristic Clinic
Project (Z181100001718023).

Yang et al. BMC Pediatrics(2024) 24:556

Availability of data and materials
The datasets used and/or analysed during the current study are available fromthe corresponding author on reasonable request.

Declarations
Ethics approval and consent to participate
All experimental protocols were approved by the Ethics Committee of Seventh Medical Center of Chinese PLA General Hospital. And informed consent
was obtained from their legal guardians.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Received: 7 May 2024 Accepted: 16 August 2024

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