Severe retinopathy of prematurity (ROP) is a marker for neurocognitive impairment.1 Even without unfavorable ocular outcomes, the relationship between severe ROP and non-visual disabilities persists.2 Infants with severe ROP have higher rates of developmental delay, and the same process that leads to severe ROP may simultaneously injure the developing brain.3,4
Since the publication of the BEAT-ROP study, use of intravitreal bevacizumab (IVB) (Avastin; Genentech, South San Francisco, CA) has become increasingly common in the treatment of ROP, with additional reports of superior structural and refractive outcomes compared to laser.5–7 Yet this therapeutic modality remains controversial, largely due to concerns about neurodevelopment.8,9
When used as systemic chemotherapy for glioblastoma, bevacizumab has been linked to neurocognitive decline among patients in the RTOG 0825 trial.10 However, this association was not reported in the AVAglio trial.11
Although vascular endothelial growth factor (VEGF) is suppressed following IVB injections in premature infants,12 the optimal VEGF level in neonates is unknown. Serum VEGF is also suppressed in adults after intravitreal injections, and treatment with IVB has been used in adults with ocular neovascular disorders for more than a decade.13,14 Safety studies have focused on thromboembolic events, but even in elderly patients, anti-VEGF injections have not been associated with systemic effects.15
Further complicating the issue, the U.S. Food and Drug Administration released a statement in December 2016 warning that lengthy general anesthesia for children younger than 3 years of age may affect neurodevelopment.16 Often requiring prolonged sedation or anesthesia, laser treatment is no longer exempt from consideration of potential adverse systemic effects.
Although caution regarding anti-VEGF agents in neonates is reasonable, additional safety data are necessary. The purpose of this study is to compare neurodevelopmental outcomes among infants with severe ROP at our institution, where eyes with posterior type 1 ROP received laser before and IVB after January 2011.
Patients and Methods
Ethics approval was obtained from the University of Chicago Institutional Review Board (IRB17-0023-AM003).
Based on a treatment shift after the publication of BEAT-ROP in January 2011, a before-and-after study was designed to evaluate neurodevelopmental outcomes comparing IVB to laser at our institution. Retrospective paper chart (prior to July 1, 2012) and electronic medical record (beginning July 1, 2012) reviews were conducted to identify infants treated between 2006 and 2016. Before January 2011, 40 infants received laser peripheral retinal ablation. After January 2011, 46 infants received primary IVB — 42 of whom later received planned, delayed laser completion of treatment around 60 weeks PMA to reduce the chance of ROP reactivation, as explained in detail elsewhere.17
Primary outcome measures were death, cerebral palsy (CP), hearing loss, and bilateral visual impairment (BVI). BVI was defined as vision worse than 20/200 in the better-seeing eye, absent visual fixation, or bilateral nystagmus. CP was determined either by a chart diagnosis of CP or based on the General Movement Assessment (GMA).18 With 98% sensitivity and 91% specificity for CP at 10 to 15 weeks post-term, GMA is the most valid and reliable method for detecting infants at risk of CP in the first 4 months.19 GMA also correlates with Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) scores and white matter abnormalities on MRI.20–23 Odds ratios (ORs) were calculated to determine predictors of CP.
To avoid overestimating the number of infants with normal primary outcome measures, infants were excluded if follow-up was insufficient to confirm a negative or positive result. For CP, infants were included only if they completed GMA testing or maintained follow-up with general pediatrics or behavioral pediatrics for 2 years. For hearing loss, infants were included only if they completed a screening evaluation by audiology. For vision loss, infants were included only if they completed at least one comprehensive ophthalmology exam to evaluate fixation after the acute phase ROP screening was terminated.
Secondary outcome measures included scores from the BSID-III scores, which were available for 22 infants with ROP who had participated in a previous larger study on neurodevelopment. Inclusion criteria for the larger NICU study were birth weight (BW) less than 1,500 g and gestational age (GA) less than 31 weeks. Exclusion criteria were significant congenital malformations, genetic syndromes, and initial oxygen index greater than 20.
Statistical analysis was performed using Stata version 15 (StataCorp LP, College Station, TX). Percentages and means with standard deviations were calculated for summary data. P values were calculated using Fisher's exact test for categorical variables, the Wilcoxon rank-sum test for continuous variables, and a logistic regression for ORs. To compare BSID-III scores, confidence intervals were calculated for the mean difference by treatment group. The noninferiority margin was set at 5 points based on a mean of 100 points, with a standard deviation of 15 points for the BSID-III test. An adverse outcome was defined as any component score (motor, cognitive, or language) below 85 or 70, or more than 1 or 2 standard deviations below the mean.
Baseline characteristics are reported in Table 1. Male gender was more common in the laser group. Otherwise, neonatal comorbidities and ROP severity were similar by treatment group, including the subset of patients with BSID-III testing.
Table 2 displays the primary outcome measures by treatment group. Excluding four infants in each group who expired, there were no differences in rates of CP or hearing loss. There was a trend toward increased visual impairment with laser (unadjusted OR = 8.5; P = .058) After controlling for gender, zone of ROP, and hydrocephalus, the odds of vision loss were 13.2-times higher for infants treated with laser (P = .038). Other variables were included in the model without a significant change in the coefficient or P value.
Primary Outcome Measures Among All Treated Infants
Factors associated with CP are shown in Table 3. Unadjusted ORs show that periventricular leukomalacia, severe intraventricular hemorrhage (IVH), and hydrocephalus are associated with CP. Adjusting for gender, zone of ROP, and treatment, the odds of CP was 6.3-times higher for infants with hydrocephalus. Other variables such as Apgar scores, BW, and GA were included in the model with no significant changes. Severe IVH was not included because hydrocephalus and severe IVH were highly correlated (P < .01).
Predictors of Cerebral Palsy Among Infants Treated for Severe ROP
In addition, BVI was also associated with CP. Of the six patients with BVI, five (83%) had CP. This was significantly different from the rate of CP among patients without BVI: seven of 59 (12%; P = .001). After adjusting for gender, zone of ROP, hydrocephalus, and treatment, the odds of having a diagnosis of CP were 21.5-times higher for infants with BVI compared to infants without BVI (P = .018).
BSID-III testing was available for 22 infants (Table 4). There were no differences in motor, language, or cognitive Bayley-III domain scores by treatment group. However, large confidence intervals preclude confirmation of noninferiority. An adverse outcome, defined as any Bayley-III component score of less than 85, was common in both groups: seven of nine (78%) with laser and nine of 13 (69%) with primary IVB (P = 1.00). Severe delay, with any component score less than 70, was five of nine (56%) with laser and six of 13 (46%) with primary IVB (P = 1.00). Four patients who completed BSID-III testing had CP, all of whom had at least one component (motor, language, or cognitive) below 70.
Secondary Outcomes Measures: BSID-III Domain Scores
Infants without BSID-III scores were not sicker than infants who completed BSID-III testing, as demonstrated in Tables 1 and 5. The relative numbers of patients excluded from BSID-III analysis are similar by treatment groups.
Neurodevelopmental Outcomes Comparing Infants With and Without Bayley Scores
Of the 46 infants who received primary therapy with IVB, four families deferred an exam under anesthesia with intravenous fluorescein angiography and delayed laser and have maintained close follow-up in clinic for dilated exams every 3 months. Two of the 4 patients completed BSID-III testing. Statistical analyses were repeated excluding these patients, and there were no significant differences in primary or secondary outcomes. Additionally, analyses were repeated comparing the four infants with IVB monotherapy to the 42 infants with IVB primary therapy and delayed laser. Although there were no statistically significant differences in primary or secondary outcomes, the numbers were likely too small to detect a meaningful change.
The results of this study are reassuring that IVB treatment does not increase developmental delays in high-risk preterm infants with severe ROP. Although the rate of CP is high in both groups, estimates fall within the expected range around 24% for infants with severe ROP.24 Consistent with other studies reporting BSID-III scores in ROP,25,26 mean BSID-III scores are low in both groups.
Other studies have also reported similar neurodevelopmental outcomes comparing IVB to laser.25–28 Although Lien et al. reported poorer outcomes among infants treated with both modalities, no difference was found comparing IVB to laser monotherapy.27 Similarly, the BEAT-ROP group found no differences from a small number of patients at a single study center (n = 16).26 More recently, Chen et al. found that infants treated with IVB had fewer diagnoses at the time of discharge and lower rates of readmission than infants treated with laser.28
These findings contrast with results from Morin et al., which found higher rates of severe delay with IVB.25 However, propensity to use IVB among sicker infants may have biased the results.29 Infants who received IVB had lower baseline neonatal mortality scores (SNAP-II scores) and more severe (zone 1) ROP. Rationale for treatment decisions was not provided. Given that many patients were treated prior to BEAT-ROP, IVB may have been used more often among infants whose systemic conditions made them poor candidates for general anesthesia or whose ROP was more severe.29 Since baseline ROP severity and other neonatal comorbidities independently predict neurodevelopment outcomes,30–33 selection bias makes these data difficult to interpret.
In addition to baseline differences, imbalance in exclusion criteria also may have influenced the results of Morin et al.; nine laser-treated patients but only one IVB-treated patient were missing BSID-III scores.25 Reasons for exclusion included severe developmental delay, blindness, deafness, and poor cooperation — all of which may indicate neurocognitive impairment.29 If the analysis is repeated assuming the excluded patients had severe developmental delays, the difference loses significance (15 of 28 vs. 37 of 107; P = .082). Given multiple confounding factors, this study should be interpreted with caution.
Although the present study adds to a number of previous studies that have not found adverse neurocognitive effects with IVB, the evidence at this time for long-term systemic safety of anti-VEGF agents remains insufficient. Given the frequency of developmental delays among patients with severe ROP, isolating the impact of IVB remains a challenge. Consistent with previous studies,24,31,32 severe IVH leading to hydrocephalus was associated with CP. Although bronchopulmonary dysplasia (BPD) has also been linked to neurocognitive impairment,24,33 the high rate of BPD among patients with severe ROP likely obscures this association in our study population.
As one of the defining criteria for severe developmental disability,34 blindness is an important aspect of neurodevelopment. In the CRYO-ROP cohort, favorable visual acuity predicted lower risk of developmental disabilities and lower chance of special education placement.1 In this study, the one patient with bilateral visual impairment in the IVB group had severe CP and cortical visual impairment. Cortical vision loss is common in patients with CP.35 However, vision loss in the laser group was related to progression of ROP after treatment in all five infants. Although the same process underlying CP likely contributes to severe ROP,4 the proportion of infants with zone 1 ROP or aggressive posterior ROP was similar in both treatment groups. The G-ROP study also found higher rates of ROP progression comparing laser to IVB.36 Even if the number of infants affected by vision loss is small, the impact on development for those patients may be profound. For patients who require treatment for severe ROP, the role of visual impairment should not be underestimated.
Even without unfavorable visual outcomes, there appears to be a powerful connection between the retina and the brain that deserves further exploration. In the adult literature, two recent studies have reported an association between a thinner retinal nerve fiber layer, increased foveal avascular zone, and increased inner foveal thickness and increased risk of dementia.37,38 In premature infants, Lofqvist et al. observed that inhibition of brain growth, as measured by low head circumference, strongly predicted severe ROP.39 Severe ROP has also been associated with delayed white matter maturation on MRI,3 and cystoid macular edema among premature infants has been correlated with neurocognitive impairment.40 These findings suggest that ROP is not merely a vasoproliferative disorder, but also a disorder of the neurosensory retina.4 In the future, a collaboration between ROP specialists, pediatric neurologists, and neonatologists might help to find commonalities in both developing vascular beds that may elucidate strategies to prevent adverse outcomes in both locations.
This study is limited by lack of randomization and a small number of patients. Similar to neurodevelopmental outcomes from the BEAT-ROP cohort,13 large confidence intervals around the mean differences in BSID-III scores preclude noninferiority confirmation. Nonetheless, our primary outcomes suggest that BSID-III results may generalize to the larger cohort, and the strict before-and-after study design minimizes selection bias.
The PEDIG assessment of lower doses of bevacizumab may offer an alternative with less systemic risk,41 although many eyes may need additional treatment. Similarly, ranibizumab (Lucentis; Genentech, South San Francisco, CA) offers another alternative with less systemic absorption,42,43 although nonresponse and reactivation requiring retreatment has also been reported.44 In the future, it may be that lower dose anti-VEGF agents combined with delayed prophylactic laser may provide the optimal balance of sight preservation while minimizing potential adverse systemic effects. Certainly, larger studies are necessary to confirm the hypothesis that IVB does not increase the risk of developmental delays.
In conclusion, although caution is reasonable with anti-VEGF agents in neonates, IVB may improve visual outcomes without a significant negative impact on neurodevelopment. The impact of preserving vision on childhood development should not be underestimated. Larger prospective studies measuring neurodevelopment are needed to confirm this relationship.
- Msall ME, Phelps DL, DiGaudio KM, et al. Severity of neonatal retinopathy of prematurity is predictive of neurodevelopmental functional outcome at age 5.5 years. Pediatrics. 2000;106(5):998–1005. doi:10.1542/peds.106.5.998 [CrossRef]
- Schmidt B, Davis PG, Asztalos EV, Solimano A, Roberts RS. Association between severe retinopathy of prematurity and nonvisual disabilities at age 5 years. JAMA. 2014;311(5):523–525. doi:10.1001/jama.2013.282153 [CrossRef]
- Glass TJA, Chau V, Gardiner J, et al. Severe retinopathy of prematurity predicts delayed white matter maturation and poorer neurodevelopment. Arch Dis Child Fetal Neonatal Ed. 2017;102(6):F532–F537. doi:10.1136/archdischild-2016-312533 [CrossRef]
- Msall ME. The retina as a window to the brain in vulnerable neonates. Pediatrics. 2006;117(6):2287–2289. doi:10.1542/peds.2006-0385 [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]
- Geloneck MM, Chuang AZ, Clark WL, et al. Refractive outcomes following bevacizumab monotherapy compared with conventional laser treatment: A randomized clinical trial. JAMA Ophthalmol. 2014;132(11):1327–1333. doi:10.1001/jamaophthalmol.2014.2772 [CrossRef]
- Hwang CK, Hubbard GB, Hutchinson AK, Lambert SR. Outcomes after intravitreal bevacizumab versus laser photocoagulation for retinopathy of prematurity: A 5-year retrospective analysis. Ophthalmology. 2015;122(5):1008–1015. doi:10.1016/j.ophtha.2014.12.017 [CrossRef]
- Good WV. Bevacizumab for retinopathy of prematurity: Treatment when pathology is embedded in a normally developing vascular system. Ophthalmology. 2016;123(9):1843–1844. doi:10.1016/j.ophtha.2016.06.054 [CrossRef]
- Quinn GE, Darlow BA. Concerns for development after bevacizumab treatment of ROP. Pediatrics. 2016;137(4). pii: e20160057. doi:. Epub 2016 Mar 17. doi:10.1542/peds.2016-0057 [CrossRef]
- Latzer P, Schlegel U, Theiss C. Morphological changes of cortical and hippocampal neurons after treatment with VEGF and bevacizumab. CNS Neurosci Ther. 2016;22(6):440–450. doi:10.1111/cns.12516 [CrossRef]
- Fathpour P, Obad N, Espedal H, et al. Bevacizumab treatment for human glioblastoma. Can it induce cognitive impairment?Neuro Oncol. 2014;16(5):754–756. doi:10.1093/neuonc/nou013 [CrossRef]
- Lynch SS, Cheng CM. Bevacizumab for neovascular ocular diseases. Ann Pharmacother. 2007;41(4):614–625. doi:10.1345/aph.1H316 [CrossRef]
- Wu WC, Lien R, Liao PJ, et al. Serum levels of vascular endothelial growth factor and related factors after intravitreous bevacizumab injection for retinopathy of prematurity. JAMA Ophthalmol. 2015;133(4):391–397. doi:10.1001/jamaophthalmol.2014.5373 [CrossRef]
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- Thulliez M, Angoulvant D, Pisella P, Bejan-Angoulvant T. Overview of systematic reviews and meta-analyses on systemic adverse events associated with intravitreal anti–vascular endothelial growth factor medication use. JAMA Ophthalmol. 2018;136(5):557–566. doi:10.1001/jamaophthalmol.2018.0002 [CrossRef]
- Center for Drug Evaluation and Research. Drug Safety and Availability - FDA Drug Safety Communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. U.S Food and Drug Administration website. https://www.fda.gov/Drugs/DrugSafety/ucm532356.htm. Published December 14, 2016. Accessed April 7, 2017.
- Garcia Gonzalez JM, Snyder L, Blair M, Rohr A, Shapiro M, Greenwald M. Prophylactic peripheral laser and fluorescein angiography after bevacizumab for retinopathy of prematurity. Retina. 2018;38(4):764–772. doi:10.1097/IAE.0000000000001581 [CrossRef]
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|All Treated Infants||Treated Infants With BSID-III|
|Laser (n = 40)||IVB (n = 46)||P Value*||Laser (n = 9)||IVB (n = 13)||P Value*|
|Gestational Age, Weeks (Mean + SD)||25.4 ± 2.3||24.7 ± 1.3||.50||25.4 + 2.0||25.1 + 1.3||.95|
|Birth Weight, Grams (Mean + SD)||729 ± 207||665 ± 131||.25||676 + 112||698 + 103||.81|
|Black Race, n (%)||17 (41)||15 (33)||.51||5 (56)||7 (54)||1.00|
|Male Gender, n (%)||29 (73)||23 (50)||.03||5 (56)||6 (46)||1.00|
|Apgar 1 Minute (Mean + SD)||3.8 ± 2.1||3.4 ± 2.3||.39||4.0 + 1.2||3.4 + 2.0||.50|
|Apgar 5 Minute (Mean + SD)||6.5 ± 1.9||5.9 ± 2.0||.25||7.1 + 1.1||5.9 + 1.8||.18|
|Bronchopulmonary Dysplasia, n (%)||27 (69)||26 (57)||.27||6 (67)||9 (69)||1.00|
|Severe Intraventricular Hemorrhage||9 (22)||11 (24)||1.00||3 (33)||4 (31)||1.00|
|Periventricular Leukomalacia, n (%)||9 (22)||5 (11)||.24||0 (9)||2 (15)||.49|
|Hydrocephalus, n (%)||8 (20)||6 (13)||0.56||2 (22)||4 (31)||1.00|
|Necrotizing Enterocolitis, n (%)||13 (32)||15 (33)||1.00||1 (11)||1 (8)||1.00|
|Patent Ductus Arteriosis Ligation, n (%)||11 (28)||8 (17)||.30||3 (33)||2 (15)||.61|
|Sepsis, n (%)||24 (62)||26 (58)||0.83||6 (67)||8 (62)||1.00|
|Length of Stay, n (%)||148 ± 75||143 ± 54||.89||132 + 30||143 + 59||.92|
|Zone 1 ROP, n (%)||14 (36)||17 (37)||1.00||2 (22)||5 (38)||.65|
|APROP, n (%)||7 (18)||10 (22)||.79||1 (11)||2 (15)||1.00|
Primary Outcome Measures Among All Treated Infants
|Laser (n = 40)||IVB (n = 46)||P Value*|
|Death, n (%)||4/40 (10)||4/46 (9)||1.00|
|Cerebral Palsy, n (%)||9/35 (26)||6/41 (15)||.26|
|Hearing Loss, n (%)||8/35 (23)||7/39 (18)||.77|
|Bilateral Vision Loss, n (%)†||5/28 (18)||1/40 (2.5)||.07|
Predictors of Cerebral Palsy Among Infants Treated for Severe ROP
|OR||P Value*||Adjusted OR||P Value*|
|Gestational Age, Weeks||0.96||.84||0.94||.78|
|Birth Weight, Grams||1.00||.63||1.00||.68|
|Apgars at 1 Minute||0.98||.06||0.99||.17|
|Apgars at 5 Minutes||0.98||.07||0.99||.19|
|Severe Intraventricular Hemorrhage||3.57||.04||1.89||.45|
|Patent Ductus Arteriosis Ligation||0.84||.80||0.95||.74|
|Length of Stay||0.99||.94||1.00||.96|
|Zone 1 ROP||1.71||.37||1.54||.50|
Secondary Outcomes Measures: BSID-III Domain Scores
|Laser (n = 9)||IVB (n = 13)||Mean Difference (95% CI)||P Value*|
|Motor, Mean + SD||77.3 + 18.8||81.2 + 25.5||3.9 (−17.0, 24.8)||.74|
|Language, Mean + SD||84.5 + 9.7||83.8 +17.3||−0.7 (−14.1, 12.6)||.68|
|Cognitive, Mean + SD||76.7 + 19.2||77.0 + 20.3||0.3 (−17.6, 18.3)||.95|
Neurodevelopmental Outcomes Comparing Infants With and Without Bayley Scores
|All Treated Infants|
|Has BSID-III||No BSID-III||P Value*|
|Death, n (%)||1/22 (5%)||7/64 (11%)||.67|
|Cerebral Palsy, n (%)||4/22 (18%)||11/54 (20%)||1.00|
|Hearing Loss, n (%)||7/22 (32%)||8/52 (15%)||.12|
|Bilateral Vision Loss, n (%)†||2/22 (11%)||4/45 (8%)||.66|