Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Neurodevelopmental Outcomes Following Intravitreal Bevacizumab With Laser Versus Laser Photocoagulation Alone for Retinopathy of Prematurity

Kamran Ahmed, MD; Anam S. Ali, MD; Neil Delwadia, BA; Margaret A. Greven, MD

Abstract

BACKGROUND AND OBJECTIVE:

To assess neurodevelopmental outcomes of infants with treatment-warranted retinopathy of prematurity (TW-ROP) treated with intravitreal bevacizumab (IVB) plus diode laser photocoagulation (DLP) compared to DLP alone.

PATIENTS AND METHODS:

A retrospective review was performed of infants who underwent treatment for TW-ROP with IVB+DLP or DLP alone from 2010 to 2017. Baseline characteristics and coexisting medical comorbidities were recorded. The presence of neurodevelopmental delay (NDD) at 2-year follow-up and composite Bayley-III scores were recorded.

RESULTS:

Sixty-six infants were included in the study; 18 received IVB+DLP, and 48 received DLP alone. Average Bayley-III scores for cognition, language, and motor, as well as rates of documental NDD, did not differ between the groups.

CONCLUSION:

This study does not demonstrate an increased risk of NDD in infants with TW-ROP treated with IVB+DLP compared with DLP alone.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:220–224.]

Abstract

BACKGROUND AND OBJECTIVE:

To assess neurodevelopmental outcomes of infants with treatment-warranted retinopathy of prematurity (TW-ROP) treated with intravitreal bevacizumab (IVB) plus diode laser photocoagulation (DLP) compared to DLP alone.

PATIENTS AND METHODS:

A retrospective review was performed of infants who underwent treatment for TW-ROP with IVB+DLP or DLP alone from 2010 to 2017. Baseline characteristics and coexisting medical comorbidities were recorded. The presence of neurodevelopmental delay (NDD) at 2-year follow-up and composite Bayley-III scores were recorded.

RESULTS:

Sixty-six infants were included in the study; 18 received IVB+DLP, and 48 received DLP alone. Average Bayley-III scores for cognition, language, and motor, as well as rates of documental NDD, did not differ between the groups.

CONCLUSION:

This study does not demonstrate an increased risk of NDD in infants with TW-ROP treated with IVB+DLP compared with DLP alone.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:220–224.]

Introduction

Bevacizumab (Avastin; Genentech, South San Francisco, CA), an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, has demonstrated efficacy in treatment-warranted retinopathy of prematurity (TW-ROP).1–4 Its advantages compared to primary diode laser photocoagulation (DLP) include less induced myopia, ability for the retinal vasculature to continue to develop following treatment, and ease of bedside administration, especially in cases with small pupil or vitreous hemorrhage.1,2,5–7 However, serum VEGF levels are suppressed for at least 8 to 12 weeks following intravitreal injection. The effects of serum VEGF suppression on developing organ systems in premature infants is unknown.8

One particular concern regarding the use of intravitreal bevacizumab (IVB) is risk of neurodevelopmental delay (NDD). VEGF has been shown in vitro to affect cell proliferation, intercellular communication, and cell motility in various neurons and glial cells, and in animal models, VEGF has been shown to stimulate the growth of neuronal axons to form synapses, leading to concerns that VEGF suppression in infants could affect neurodevelopment.9–13 Several studies have sought to answer the question of whether higher rates of NDD occur in infants treated with IVB, with conflicting results.14–20

The purpose of this study was to evaluate our institutional experience with bevacizumab plus DLP (IVB+DLP) compared to DLP alone. The primary aim of this study was to evaluate for differences in developmental progress after treatment with IVB+DLP compared to DLP alone. We hypothesized that there would be no difference in developmental outcomes when IVB is added to DLP for TW-ROP.

Patients and Methods

A retrospective review was performed of all eyes that underwent treatment for retinopathy of prematurity (ROP) at Wake Forest University from 2010 to 2017. The Institutional Review Board of Wake Forest Baptist Health approved the study. Data collection and reporting were in compliance with all Health Insurance Portability and Accountability Act regulations. Patients were included for analysis if they were treated for type 1 retinopathy of prematurity with either IVB or DLP. Patients were excluded if they had less than 2 years of follow-up data or if neurodevelopmental assessment was not performed.

Patient characteristics including gestational age, birth weight, gender, corrected age at time of ROP treatment, treated eye(s), time between IVB and DLP treatment, stage and zone of ROP at time of treatment, presence of pre-plus or plus disease, systemic comorbidities, ventilator dependence, oxygen requirement upon discharge from NICU, and other surgical procedures requiring general anesthesia were recorded.

NICU follow-up and neurodevelopmental assessments performed by pediatric developmental specialists were reviewed. The documented presence of neurodevelopmental delay was recorded. Results of developmental assessment performed at 2 years of age using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), were recorded. The BSID-III is an individually administered instrument analyzing cognitive, language, and motor function in infants and toddlers 1 to 42 months of age. It is a widely used method for studying neurodevelopment in pediatric research.21–23 Corrected age at the time of developmental evaluation was recorded. Age-adjusted composite scores were recorded for the areas of cognition, language, and motor development. NDD was defined as scores below 1 standard deviation from the mean.

Analysis

Continuous variables were presented as the mean and were analyzed using the Student's t-test with a two-tailed distribution and unequal variance between the two groups. The chi-square test was applied to categorical variables for analysis. Microsoft Excel software was used for the statistical analysis. A P value less than .05 was considered to indicate statistical significance.

Results

Sixty-six infants were included in the study: 18 received IVB+DLP, and 48 received DLP alone. Of the IVB+DLP infants, nine received DLP at the same time as IVB. The other nine received IVB with DLP performed at a later date. Two of the 18 infants received a second IVB treatment. One infant received the second IVB only in the right eye, and the other infant received the second IVB in both eyes. Mean gestational age in the IVB+DLP infants was 24.5 weeks compared with 25.3 weeks in the DLP alone group (P = .08), and birth weight was 650 grams and 700 grams (P = .44) in the two groups, respectively. Table 1 shows additional infant characteristics in the two groups.

Characteristics of Infants Treated With IVB+DLP Versus DLP Only

Table 1:

Characteristics of Infants Treated With IVB+DLP Versus DLP Only

The majority of infants in both groups were ventilator-dependent at some point during their NICU stay: 89% for the IVB+DLP group and 87% for the DLP group (P = .99). Both groups also had a similar incidence of surgeries involving general anesthesia for unrelated medical issues: 61% for the IVB+DLP group and 60% for the DLP group (P = .99). Both groups had a similar rate of intracranial hemorrhage: 56% for the IVB+DLP group and 48% for the DLP group (P = .93). There was also a similar rate of necrotizing enterocolitis in the two groups: 22% for the IVB+DLP group and 15% for the DLP group (P = .89). Oxygen requirement upon discharge from the NICU was 28% for the IVB+DLP group and 52% for the DLP group (P = .78).

The average corrected age was 36.7 weeks at the time of primary IVB and 37.8 weeks at the time of primary DLP (P = .28). The majority of infants in both groups had zone II, stage 1, 2, or 3 with plus disease at the time of treatment (72% for IVB+DLP and 73% for DLP). Though not statistically significant, the IVB+DLP group had more patients with zone I disease as compared to DLP (three out of 18 (17%) for IVB and one out of 48 (2%) for DLP; P = .65). Average time between IVB and delayed DLP treatment was 71 days but ranged from 5 to 244 days. For further information on ROP characteristics at the time of treatment, see Table 2.

Treatment Characteristics of Infants Treated for TW-ROP

Table 2:

Treatment Characteristics of Infants Treated for TW-ROP

The percentage of infants with documented developmental delay at 2 years was 78% in the IVB+DLP group and 81% in the DLP group (P = .98). Average BSID-III scores (IVB+DLP versus DLP) were 82 versus 82 for cognitive (P = .99), 76 versus 86 for language (P = .22), and 79 versus 85 for motor (P = .35). Average corrected age at follow-up was 24.0 months for the IVB+DLP group and 27.7 months for the DLP group (P = .01). Table 3 summarizes these developmental outcomes.

Comparison of Neurodevelopmental Outcomes of IVB+DLP and DLP-Only Groups

Table 3:

Comparison of Neurodevelopmental Outcomes of IVB+DLP and DLP-Only Groups

Discussion

The high rate of NDD in infants who have required treatment for ROP is quite striking but is consistent with previously reported rates in extremely premature infants; extreme prematurity and ROP are both independently associated with NDD. Factors including early gestational age, low birth weight, prolonged ventilator dependence, general anesthesia for non-ocular surgeries, and other medical comorbidities are associated with higher rates of NDD.24–27 For these reasons, and due to lack of large prospective studies with extended follow-up, refuting or confirming concerns about IVB adversely affecting neurodevelopment has proven challenging.

In this study, the addition of IVB to DLP was not associated with an increased risk of NDD in infants with TW-ROP. Several other studies have found no differences in NDD in infants receiving IVB compared to DLP or untreated infants. As part of the Bevacizumab Eliminates the Angiogenic Threat for Retinopathy of Prematurity (BEAT-ROP) study, a randomized trial comparing IVB to DLP with a primary endpoint at 54 weeks, a 2-year prospective extension study was performed. There were 16 infants included in the extension study (seven treated with IVB and nine with DLP) followed out to between 18 and 28 months corrected age. BSID-III developmental scores in these infants were low relative to norms expected for healthy infants, but there was no significant difference between the two groups.17 Similarly, Chen et al. reported retrospective results of 10 infants who received IVB and 15 infants who received DLP. At 20 months corrected age, the authors noted no significant difference in NDD between these two groups.18 Araz-Ersan et al. reported 13 infants treated with IVB as adjunctive treatment for type 1 ROP had no significant difference in BSID scores compared to 13 birth weight- and gestational age-matched infants treated with laser therapy alone.19 In a prospective, case-control study of 148 patients by Fan et al., no significant differences were found in BSID-III neurodevelopmental outcomes at a mean age of 1.5 years in infants with untreated ROP and infants treated with a single dose of IVB for ROP.20

However, some authors have reported higher rates of NDD in infants receiving IVB. Morin et al. reported that in 27 infants treated with IVB and 98 treated with DLP, median BSID-III motor scores in the bevacizumab group were lower than in the laser group, but this statistical significance disappeared after adjusting for other risk factors known to be associated with NDD. There was an odds ratio of 3.1 of severe neurodevelopmental disabilities in infants treated with bevacizumab even after adjusting for NDD risk factors.14

Several important critiques of this study were raised by Blair and Shapiro, including that infants in the IVB group had worse systemic illnesses than in the laser group. Additionally, 11 infants in the laser group had such mild retinopathy that they “did not fulfill current recommendations for ROP treatment,” whereas none of the infants who were treated with IVB had such mild retinopathy. This difference in disease severity is important because retinopathy severity is associated with neurodevelopmental outcomes. Finally, due to developmental delay, uncooperative behavior, blindness, and deafness, BSID-III assessment could not be performed in nine infants in the laser group but in only one in the IVB group, and these infants were excluded from the results of the study.28 These shortcomings have raised doubts about the conclusions of Morin et al.

Lien et al. evaluated 61 infants who received laser, IVB, or IVB and laser. Although the authors found no difference in motor developmental index and psychomotor developmental index scores between the IVB and laser groups, there was an odds ratio of 5.3 of mental and psychomotor impairment in infants treated with IVB and laser treatment.16 Importantly, infants that received both IVB and DLP in this study were younger, had lower birth weight, and more had zone I disease, which may have biased these results.28

A major shortcoming of all nonrandomized studies examining this subject is that the treating physician's selection of IVB or DLP may be driven by infant-specific factors that also could increase or decrease the risk of NDD. At our institution, IVB is frequently used to treat infants with more tenuous systemic medical status at the time of development of TW-ROP and inability to perform DLP safely under general anesthesia, as well as more posterior ROP, as evidenced by the data presented herein. Although not significant in this small study, there is a trend toward the use of IVB in younger gestational age and lower birth weight infants at our institution. These factors would be expected to bias retrospective studies including the present study, toward artificially high rates of NDD in infants receiving IVB. Despite these confounders, no significant differences in NDD were identified in this cohort.

Aside from the retrospective design of the present study, several other weaknesses must be addressed. The small number of patients included in this analysis may disguise any significant differences between the two groups by not providing enough power to identify an association. The prolonged study period of 2010 to 2017 may introduce other types of bias; medical advances in neonatal care over the last decade may impact rates of NDD. Additionally, the IVB+DLP group had a younger average age at follow up of 24 months, and the DLP group had a follow up age of 27.7 months. This was statistically significant and could impact the relative scoring of NDD.

Despite these shortcomings, this study did not identify an increased risk of NDD in infants receiving IVB in addition to DLP compared with DLP alone. As this small study underscores, very high rates of NDD occur in infants who have required treatment for ROP. Further study is warranted to identify modifiable risk factors for NDD in these extremely premature infants.

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Characteristics of Infants Treated With IVB+DLP Versus DLP Only

IVB+DLP (n = 18)DLP (n = 48)P Value
Gestational Age (Weeks)24.525.3.08
Birth Weight (kg)0.650.70.44
Female Gender, n (%)8 (44)23 (48).93
Ventilator Dependence, n (%)16 (89)41 (87).99
Additional Surgeries Involving General Anesthesia, n (%)11 (61)29 (60).99
Presence of Intracranial Hemorrhage, n (%)10 (56)23 (48).93
Presence of Necrotizing Enterocolitis, n (%)4 (22)7 (15).89
Oxygen Requirement at Discharge From NICU, n (%)5 (28)25 (52).78

Treatment Characteristics of Infants Treated for TW-ROP

ROP TreatmentIVB+DLP (n = 18)DLP (n = 48)P Value
Average Corrected Age at Primary Treatment (Weeks)36.737.8.28
Presence of Plus Disease Documented at Primary Treatment, n (%)17 (94)37 (77).88
Average Time Between IVB and Delayed DLP Days (Range in Days)71 (5 – 244)

Comparison of Neurodevelopmental Outcomes of IVB+DLP and DLP-Only Groups

IVB+DLP (n = 18)DLP (n = 48)P Value
Diagnosis of Developmental Delay, n (%)14 (78)39 (81).98
Average Corrected Age at Follow-Up (Months)24.027.7.01
BSID-III Scores, MeanIVB+DLP (n = 6)DLP (n = 25)
Cognition8282.99
Language Composite7686.22
Motor Composite7985.35
Authors

From the Department of Ophthalmology, Wake Forest University School of Medicine, Winston-Salem, North Carolina (KA, ND, MAG); and the Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina (ASA).

Presented at the Association for Research in Vision and Ophthalmology meeting in March 2019 in Vancouver, Canada.

The authors report no relevant financial disclosures.

Address correspondence to Margaret A. Greven, MD, Department of Ophthalmology, Wake Forest University School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC 27157; email: mgreven@wakehealth.edu.

Received: June 05, 2019
Accepted: February 25, 2020

10.3928/23258160-20200326-03

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