Retinopathy of prematurity (ROP) is a leading cause of preventable childhood blindness among low gestational age and low birth weight infants in the United States and is caused by the interruption of normal retinal angiogenesis.1 The landmark Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) and Early Treatment of Retinopathy of Prematurity (ETROP) clinical trials showed that vision loss and other adverse outcomes could be prevented with early detection and intervention.2,3 Currently, the gold standard of treatment for ROP is diode laser photocoagulation (DLP), which halts the continued development of abnormal vasculature in ROP.3
Angiogenic factors like vascular endothelial growth factor (VEGF) are critical to the retinal neovascularization process and thus play an important role in the pathogenesis of diseases like ROP. It follows that inhibitors of VEGF may therefore slow the progression of the disease. Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a recombinant humanized monoclonal antibody that suppresses angiogenesis by inhibiting VEGF. Originally developed as a therapeutic agent against metastatic colon cancer, its use has since expanded to other metastatic cancers as well as ophthalmic diseases, including age-related macular degeneration and diabetic retinopathy. Early case reports and retrospective studies showed promising results when using intravitreal bevacizumab to treat ROP.4–6 The Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) clinical trial found a lower rate of recurrence of ROP requiring additional treatment with bevacizumab as compared to diode laser photocoagulation.7 Despite its success, concerns regarding the long-term systemic and neurodevelopmental consequences of intravitreal bevacizumab have limited its widespread use.8,9
For this study, we hypothesize that initial treatment with intravitreal bevacizumab (IVB) does not lead to worse systemic morbidity as compared to initial treatment with diode laser photocoagulation in treatment-warranted ROP (TW-ROP). We retrospectively investigate the outcomes of the two interventions TW-ROP infants by comparing hospitalization outcomes including length of hospitalization, number of diagnoses pre- and post-treatment, oxygen requirements, cardiac procedures, and number of readmissions. We then investigate longer-term outcomes by assessing number of readmissions and neurodevelopmental progress during the first 20 months of life.
Patients and Methods
A retrospective review of all premature newborns with treatment-warranted ROP from January 1, 2013, to June 30, 2015, treated with either diode laser photocoagulation (DLP) under general anesthesia or 0.625 mg of IVB in the Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) database, as well as at Stanford Children's hospital, was performed. The database draws from six neonatal intensive care units (NICUs) from across Northern California. The study was approved prospectively by the institutional review board for review of patient records with information on neonatal characteristics, NICU course details, and neurodevelopmental status. All data were collected and handled in a manner compliant with the Health Insurance Portability and Accountability Act.
Records of each patient were reviewed, and the following data were collected. Baseline characteristics included gender, race, birth weight, and gestational age. Maternal age at birth, whether the birth was multiple, use of antenatal and postnatal steroids, and neonatal complications including patent ductus arteriosus (PDA) ligation, late-onset sepsis, intraventricular hemorrhage, and periventricular leukomalacia were also documented. Additionally, ROP classification and treatment modality were recorded for each infant. NICU course details included the length of hospitalization, the number of diagnoses noted at the time of treatment and discharge, the number of days an infant required oxygen support, the number of cardiac procedures performed, and the number of readmissions that occurred after discharge. Oxygen support ranged from intubation to continuous nasal cannula usage. Data on neurodevelopmental status were determined by reviewing the most recent documentation for high-risk infant follow-up (HRIF) in a behavior and development clinic. The HRIF program was established by California Children's Services (CCS) to identify infants who may develop CCS-eligible medical conditions after discharge from the NICU. As such, the program provides for various diagnostic services for children, including a standardized developmental assessment using the validated Bayley III Scales of Infant Development or an equivalent test like the Capute Scales. An infant was considered developmentally delayed if he or she scored below set cutoff points in any category, which have been previously validated.10,11
Infants were stratified into DLP or IVB groups based on their primary treatment, the initial treatment given to the infant at the time of ROP diagnosis. Neonatal characteristics, NICU course outcomes and neurodevelopmental outcome between the IVB and DLP groups were compared using the independent Student's t-test or Wilcoxon rank sums test for means and Fisher's exact test (two-tailed) for proportions. P values less than .05 were considered statistically significant. Univariate and multivariate logistic models were carried out by using Statistical Analysis Software University Edition (SAS Institute, Cary, NC).
A total of 61 eyes from 32 patients had treatment-warranted ROP; 25 of these had complete medical records and were included in the study whereas the remaining patients were transferred from other hospitals and had missing information. Ten infants (20 eyes) were treated with DLP and 15 infants (29 eyes) were treated with IVB. The decision to treat with bevacizumab versus laser was made by the senior author (DMM) based on clinical presentation and whether the infant would be a candidate for the operating room. Of note, 14 out of the 15 IVB patients eventually required DLP for definitive ROP treatment about 19 weeks after the initial IVB treatment. One DLP infant received IVB 1 week after the initial laser treatment due to persistent plus disease.
Neonatal characteristics are summarized in Table 1. The average gestational age was approximately 25 weeks for both groups (IVB: 24.98 weeks vs. DLP: 24.62 weeks; P = .208). DLP infants were more likely to be male (80.0% vs. 46.7%; P = .211) and less likely to be a multiple (10.0% vs. 46.7%; P = .088) than IVB infants, though these did not reach statistical significance. All but one infant was in the extremely low birth weight category (< 1,000 grams [g]), with the IVB infants on average 25 g lighter than the DLP infants (662 g vs. 688 g; P = .890) and receiving their primary treatment approximately 1.5 weeks earlier than the DLP infants (34.71 weeks vs. 36.05 weeks; P = .244). The two groups were otherwise similar in race, maternal age at the time of birth, use of antenatal and postnatal steroids, and neonatal complications (Table 1).
The IVB infants had significantly fewer diagnoses at the time of discharge than the DLP infants (four vs. six diagnoses; P = .004), as well as fewer numbers of readmissions after initial hospital discharge (zero vs. one readmission; P = .038). The IVB infants also had fewer total days of hospitalization (117 days vs. 132 days; P = .114) and days of intubation after primary treatment (3 days vs. 9 days; P = .055) than the DLP infants, although statistical significance was not reached. There was no significant difference in the length of stay after primary treatment, number of diagnoses at the time of primary treatment, total days of oxygen requirement, total days of intubation, and number of cardiac procedures between the two groups (Table 2).
Comparison of Hospital Course Outcomes
The most recent HRIF neurodevelopmental evaluation using the Bayley III or Capute scales for all infants was conducted at an average of 20.4 months of corrected age. About half of the IVB infants, as compared to two-thirds of DLP infants, had testable neurodevelopmental delay at this time. Overall, IVB infants had lower odds of developing neurodevelopmental delay than DLP infants at approximately 20 months of corrected age (odds ratio [OR] = 0.92; 95% CI, 0.19–4.53). This held true even after adjusting for confounders including gestational age, birth weight, male gender, and neonatal complications (late onset sepsis, intraventricular hemorrhage, periventricular leukomalacia, PDA ligation), though statistical significance was not reached (adjusted OR = 0.87; 95% CI, 0.08–9.46). Of note, six out of 15 infants treated initially with bevacizumab had Zone 1 disease as compared to two out of 10 infants treated initially with DLP (40% vs. 20%); however, the overall difference in the severity of ROP at the time of treatment was not statistically significant (Table 1). One DLP infant did not have records of a neurodevelopmental evaluation available and was excluded from the analysis.
The findings of the Early Treatment of Retinopathy of Prematurity study helped solidify diode photocoagulation as the gold standard for the treatment of pre-threshold ROP.4 However, with the widespread adoption of intravitreal bevacizumab for neovascular conditions in adults, it was not long before bevacizumab was used in infants with retinopathy of prematurity. The results of the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) study lent support to this practice by showing higher and faster rates of regression in infants treated with intravitreal bevacizumab as compared to diode photocoagulation, without evidence of systemic toxicity at 54 weeks postmenstrual age in a cohort of 70 infants receiving bevacizumab.7
Despite these advantages, many practitioners are concerned with the theoretical consequences of systemic VEGF inhibition in a developing infant.8,12 These fears are not unfounded. VEGF-deficient mice show complete absence of vasculature, while perturbation of normal VEGF expression patterns permanently disrupts mouse retinal function and vascular patterns.13 Moreover, VEGF has been shown to be essential for organogenesis and skeletogensis.14 Despite these developmental consequences of VEGF dysregulation in animals, clinical studies in humans have largely been unable to identify systemic toxicity or effects on neurodevelopment in infants receiving bevacizumab.15,16 It is possible that intravitreal bevacizumab may not be absorbed systemically at levels sufficient enough or persist in the bloodstream long enough to cause deleterious developmental outcomes, though there is currently a lack of studies supporting either mechanism.
A notable exception was a recently published retrospective review showing increased neurodevelopmental delay in infants receiving intravitreal bevacizumab versus diode laser photocoagulation.9 However, in this study, infants receiving bevacizumab had significantly worse stages of retinopathy of prematurity at the time of treatment, which has been shown to be independently associated with neurodevelopmental delay.17 Furthermore, 16% of infants treated with laser did not meet standard guidelines for early treatment of ROP. By not accounting for these key differences between study groups, it is possible that the increase in neurodevelopmental delay was not due to bevacizumab, as was concluded by the authors. The importance of accounting for ROP stage in assessing neurodevelopmental outcomes was further explored by Lien et al., who compared infants treated with monotherapy (either intravitreal bevacizumab or diode laser photocoagulation) or combination therapy when monotherapy failed.18 No difference in neurodevelopmental outcomes was found between intravitreal bevacizumab or diode laser photocoagulation, but in those infants with more severe ROP that failed monotherapy, a significant reduction in neurodevelopmental outcomes was noted, highlighting the importance of accounting for ROP severity when assessing neurodevelopment.
As our study was retrospective in nature, there were no specific criteria with which we used to decide which newborns received IVB versus laser. However, typically we routinely chose bevacizumab over laser in sicker newborns and those unable to go to the operating room at the time of treatment. This approach to treatment was manifested in our data which showed, a greater proportion of infants treated initially with bevacizumab had Zone 1 disease as compared to infants treated initially with diode laser photocoagulation (Table 1). Despite the fact that worse ROP at the time of treatment is associated with worse developmental outcomes, we found no evidence of increased neurodevelopmental delay in these infants at 20 months of corrected age. Instead, the diode laser group actually showed slightly worse outcomes than the bevacizumab group in terms of number of medical diagnoses at discharge, even with a similar number of diagnoses at the time of primary treatment, as well as rates of readmission (Table 2). Though the local risks of diode photocoagulation, such as loss of peripheral vision, myopia,19 and even phthsis,20 are well-established, deleterious short and long-term systemic effects may occur either from the noxious stimulus of the procedure or as a direct consequence of the anesthetics needed to prevent pain and bradycardia.21
There is a growing body of evidence that systemic anesthetics and prolonged exposure to pain can have detrimental developmental effects on the neonate. In the case of systemic anesthetics, animal studies have shown that exposure in early life induces neuronal cell death, and for both rodents and macaques can lead to cognitive and behavioral impairments later in life.22 In humans, retrospective studies examining anesthetic exposure during the neonatal period have been difficult to interpret due to challenges of confounding variables such as associated systemic illnesses.23 Current recommendations are that general anesthesia should be delayed for non-urgent procedures until 3 years of life.24 In the case of neonatal pain, human and animal studies have shown central nervous system remodeling and lasting effects on the hypothalamic-pituitary-adrenal axis, though the long-lasting effects on neurodevelopment remain unknown.25 It is clear from these animal and human studies that the potential impacts of systemic anesthesia or incomplete pain relief on neonates should not be completely ignored when considering treatment with diode laser photocoagulation.
In our study, all but one infant who initially received bevacizumab ultimately underwent laser treatment. However, the concomitant exposure to anesthesia occurred almost 5 months of age earlier in the laser group as compared to the bevacizumab group, which may contribute to the worse outcomes we observed in the former. Interestingly, of the three infants in the study who also received anesthesia for patent ductus arteriosus ligation in the perinatal period (Table 1), only one developed neurodevelopmental deficits by 20 months of corrected age.
Taken in aggregate, the ophthalmologist must attempt to assess the potential systemic risks of temporary VEGF suppression against exposure to systemic anesthetics or prolonged procedural pain, all of which have shown neurodevelopmental consequences in animals, but not as of yet, convincingly in humans. The decision is not straightforward. Our retrospective analysis suffers from confounding effects inherent to many retrospective studies, and the small sample size limits any definitive conclusions about the systemic safety of intravitreal bevacizumab. For instance, no clear guideline was used to decide one treatment modality over the other for the study, though the senior author kept in line with practice patterns at the time by routinely choosing bevacizumab for sicker newborns who would be poor candidates for the operating room. Furthermore, though our results showed no testable neurodevelopmental delay at approximately 20 months of corrected age, we cannot exclude the possibility that other forms of cognitive or developmental delay may manifest at a later age, indicating the need for further studies with longer follow-up times. However, our results are consistent with other studies that have shown effectiveness of VEGF inhibitors in the treatment of retinopathy of prematurity, without an observed increased risk of systemic morbidity when compared to diode laser photocoagulation.7,15–16,18 Future prospective studies that monitor long-term visual and systemic outcomes are required with a larger sample size in order to more accurately determine the safety profile of intravitreal bevacizumab and better define indications for use. In the meantime, the present study suggests that intravitreal bevacizumab should continue to be considered as a treatment option for premature infants diagnosed with retinopathy of prematurity.
- Smith LEH. Pathogenesis of retinopathy of prematurity. Growth Horm IGF Res. 2004; 14Suppl A:S140–144. doi:10.1016/j.ghir.2004.03.030 [CrossRef]
- Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity. Snellen visual acuity and structural outcome at 5 ½ years after randomization. Arch Ophthalmol. 1996;114(4):417–424. doi:10.1001/archopht.1996.01100130413008 [CrossRef]
- 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(12):1684–1694. doi:10.1001/archopht.121.12.1684 [CrossRef]
- Mintz-Hittner HA, Kuffel RR. Intravitreal injection of bevacizumab (avastin) for treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II. Retina. 2008;28(6):831–838. doi:10.1097/IAE.0b013e318177f934 [CrossRef]
- Dorta P, Kychenthal A. Treatment of type 1 retinopathy of prematurity with intravitreal bevacizumab (Avastin). Retina. 2010;30(4 Suppl):S24–31. doi:10.1097/IAE.0b013e3181ca1457 [CrossRef]
- Wu WC, Yeh PT, Chen SN, Yang CM, Lai CC, Kuo HK. Effects and complications of bevacizumab use in patients with retinopathy of prematurity: A multicenter study in Taiwan. Ophthalmology. 2011;118(1):176–183. doi:10.1016/j.ophtha.2010.04.018 [CrossRef]
- Mintz-Hittner HA, Kennedy KA, Chuang AZBEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364(7):603–615. doi:10.1056/NEJMoa1007374 [CrossRef]
- Moshfeghi DM, Berrocal AM. Retinopathy of prematurity in the time of bevacizumab: incorporating the BEAT-ROP results into clinical practice. Ophthalmology. 2011;118(7):1227–1228.
- Morin J, Luu TM, Superstein R, et al. Neurodevelopmental outcomes following bevacizumab injections for retinopathy of prematurity. Pediatrics. 2016;137(4). pii: e20153218. doi: . Epub 2016 Mar 17. doi:10.1542/peds.2015-3218 [CrossRef]
- Bayley N. Bayley Scales of Infant and Toddler Development, 3rd ed. San Antonio, TX: PsychoCorp; 2005.
- Vincer MJ, Cake H, Graven M, Dodds L, McHugh S, Fraboni T. A population-based study to determine the performance of the Cognitive Adaptive Test/Clinical Linguistic and Auditory Milestone Scale to Predict the Mental Developmental Index at 18 Months on the Bayley Scales of Infant Development-II in very preterm infants. Pediatrics. 2005;116(6):e864–867. doi:10.1542/peds.2005-0447 [CrossRef]
- Avery RL. Extrapolating anti-vascular endothelial growth factor therapy into pediatric ophthalmology: Promise and concern. J AAPOS. 2009;13(4):329–331. doi:10.1016/j.jaapos.2009.06.003 [CrossRef]
- Pierce EA, Foley ED, Smith LE. Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch Ophthalmol. 1996;114(10):1219–1228. doi:10.1001/archopht.1996.01100140419009 [CrossRef]
- Haigh JJ. Role of VEGF in organogenesis. Organogenesis. 2008;4(4):247–256. doi:10.4161/org.4.4.7415 [CrossRef]
- Martínez-Castellanos MA, Schwartz S, Hernández-Rojas ML, et al. Long-term effect of antiangiogenic therapy for retinopathy of prematurity up to 5 years of follow-up. Retina. 2013;33(2):329–338. doi:10.1097/IAE.0b013e318275394a [CrossRef]
- Jalali S, Balakrishnan D, Zeynalova Z, Padhi TR, Rani PK. Serious adverse events and visual outcomes of rescue therapy using adjunct bevacizumab to laser and surgery for retinopathy of prematurity. The Indian Twin Cities Retinopathy of Prematurity Screening database Report number 5. Arch Dis Child Fetal Neonatal Ed. 2013;98(4):F327–333. doi:10.1136/archdischild-2012-302365 [CrossRef]
- Beligere N, Perumalswamy V, Tandon M, et al. Retinopathy of prematurity and neurodevelopmental disabilities in premature infants. Semin Fetal Neonatal Med. 2015;20(5):346–353. doi:10.1016/j.siny.2015.06.004 [CrossRef]
- Lien R, Yu MH, Hsu KH, et al. Neurodevelopmental outcomes in infants with retinopathy of prematurity and bevacizumab treatment. PLoS ONE. 2016;11(1):e0148019. doi:10.1371/journal.pone.0148019 [CrossRef]
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|Characteristic||IVB (n = 15)||DLP (n = 10)||P Value|
|Gestational Age, Weeks (Mean ± SD)||24.98 ± 1.14||24.62 ± 1.21||.208|
|Birth Weight, Grams (Mean ± SD)||662.33 ± 132.73||688.30 ± 181.78||.890|
|Male Gender, n (%)||7 (46.7)||8 (80.0)||.211|
|Multiple, n (%)||7 (46.7)||1 (10.0)||.088|
|Race, n (%)||.912|
| White||4 (26.7)||2 (20.0)|
| Hispanic||6 (40.0)||4 (40.0)|
| Asian||5 (33.3)||4 (40.0)|
|Maternal Age, Years (Mean ± SD)||31.92 ± 5.06||30.30 ± 5.54||.399|
|Antenatal Steroids, n (%)||12 (80.0)||5 (50.0)||.284|
|Postnatal Steroid Use, n (%)||9 (60.0)||7 (70.0)||.691|
|Patent Ductus Arteriosus Ligation, n (%)||3 (20.0)||0 (0.0)||.250|
|Late-Onset Sepsis, n (%)||3 (20.0)||3 (30.0)||.653|
|Intraventricular Hemorrhage, n (%)||.924|
| Grade 1–2||4 (26.7)||2 (20.0)|
| Grade 3–4||3 (20.0)||2 (20.0)|
|Periventricular Leukomalacia, n (%)||2 (13.3)||1 (10.0)||1.000|
|Retinopathy of Prematurity, n (%)||.244|
| Zone I plus with stage 1, 2, 3; no plus stage 3||6 (40.0)||2 (20.0)|
| Zone II no plus with stage 1, 2, 3||2 (13.3)||0 (0.0)|
| Zone II plus with stage 1, 2, 3||7 (46.7)||7 (70.0)|
| Zone III plus||0 (0.0)||1 (10.0)|
|Age at Initial Treatment, Weeks (Mean ± SD)||34.71 ± 1.73||36.05 ± 2.84||.244|
Comparison of Hospital Course Outcomes
|Outcome||IVB (n = 15)||DLP (n = 10)||P Value|
|Hospitalization, Days (Mean ± SD)|
| Total length of stay||117.21 ± 25.20||131.70 ± 22.73||.114|
| Length of stay after primary treatment||52.79 ± 23.44||53.10 ± 22.12||.682|
|Diagnoses, Number (Mean ± SD)|
| At time of primary treatment||5.13 ± 1.64||6.10 ± 1.45||.151|
| At time of discharge||4.40 ± 1.18||6.40 ± 1.71||.004|
|Oxygen Requirement, Days (Mean ± SD)|
| Duration of hospitalization||108.79 ± 30.05||109.00 ± 38.05||.907|
| After initial treatment||42.14 ± 28.48||37.10 ± 29.48||.792|
|Intubation, Days (Mean ± SD)|
| Duration of hospitalization||39.50 ± 18.73||41.10 ± 18.07||.792|
| After initial treatment||2.71 ± 4.98||9.00 ± 10.06||.055|
| Cardiac procedures, number (mean ± SD)||0.20 ± 0.41||0.20 ± 0.63||.602|
| Readmissions, number (mean ± SD)||0.27 ± 0.46||1.10 ± 1.37||.038|