Since the use of intravitreal vascular endothelial growth factor (VEGF) inhibitors for posterior retinopathy of prematurity (ROP) was first described in 2007,1,2 the use of intravitreal bevacizumab has shown significant benefit for zone I ROP, but controlled clinical trials have not established its safety.3 There remains concern about the consequences of systemic drug absorption and VEGF suppression on neonatal organ development.
Currently, the commonly favored dose of intravitreal bevacizumab used in neonates with ROP (0.625 mg) is derived from the standard adult dose (1.25 mg).3,4 We describe a case in which resolution of ROP was achieved using an ultra-low dose of bevacizumab (0.16 mg).
A male twin born at 24 weeks of gestation with a birth weight of 630 g required respiratory support and supplementary oxygen in the neonatal period. Routine ROP screening was commenced at 31 weeks of gestation, at which point no ROP was present and vascularization had extended to the border of zones I and II.
A further examination 2 weeks later (33 weeks of gestation) revealed progression to stage 2 ROP in both eyes at the junction of zones I and II (Figures 1A–1B). Vascular dilatation and tortuosity was evident in two quadrants in the right eye and all four quadrants in the left eye. The features were consistent with aggressive posterior ROP. After obtaining parental consent, intravitreal bevacizumab was administered bilaterally (0.16 mg to the right eye and 0.32 mg to the left eye).
(A) Stage 2 retinopathy of prematurity (ROP) in the right eye. Vascular dilatation and tortuosity in two quadrants. (B) Stage 2 ROP in the left eye. Vessel dilatation in four quadrants with pre-retinal hemorrhage temporally. (C) The right eye 2 days postoperatively showing less vessel dilatation and tortuosity. (D) The left eye 2 days postoperatively showing less vessel dilatation and tortuosity.
Two days following treatment, improvement in the extent and stage of retinopathy and vessel dilatation was noted bilaterally (Figures 1C–1D). Complete bilateral resolution of ROP was seen 12 days postoperatively (35 weeks of gestation). At the child’s most recent review, 43 weeks postpartum (67 weeks of gestation), no recurrence of ROP was observed and the retina was vascularized into zone III.
The beneficial effect of a 0.625 mg dose of bevacizumab in ROP has been demonstrated in the Bevacizumab Eliminates the Angiogenic Threat of ROP trial for posterior stage 3 ROP disease.3 Despite the increasing popularity of intravitreal bevacizumab treatment for ROP, there have been no dose finding studies and little is known about the pharmacokinetics of the drug in this vulnerable population.5 Successful resolution of ROP has been reported with doses of bevacizumab ranging from 0.25 to 1.25 mg.4,6
VEGF expression is found in the developing lungs, kidneys, and brain of human neonates.5 The potential effects of systemic VEGF suppression following intravitreal bevacizumab injection on organ development in the preterm infant remain unknown. Although the BEAT ROP study did not identify statistically significant increased mortality following bevacizumab treatment, the trial was not powered to ascertain drug safety.
Following intravitreal injection of bevacizumab in older adults, systemic VEGF suppression is known to occur.7 Circulating bevacizumab and corresponding decreased serum VEGF have been reported following intravitreal injection of 0.5 and 1 mg bevacizumab in preterm infants with ROP (a limitation of that study was that the infants had previously received laser treatment for ROP, potentially disrupting the blood retinal barrier and perhaps potentiating drug passage).6 Although bevacizumab is a relatively large molecule, increased vascular permeability in ROP may exacerbate absorption of the drug into the systemic circulation.
In vitro studies of bevacizumab suggest that levels of the drug needed to completely bind VEGF are 2.6:1, whereas a ratio of 10:1 is needed to prevent endothelial cell migration.8 It has been suggested that the current doses of bevacizumab used in ROP may significantly exceed that which is necessary to block VEGF in ROP.5,9
We have observed complete resolution of zone I stage 2 ROP with 0.16 mg of bevacizumab, an ultra-low dose that has not been previously reported in the literature. In this case, bilateral treatment was necessary, but there was asymmetry of ROP and we chose to administer the smaller drug dose to the eye with the least aggressive disease. This approach allowed us to limit the total patient dose of bevacizumab administered to less than 0.5 mg. Simultaneous treatment of the fellow eye introduces the possibility of a confounding treatment effect on the index eye, and remains an important consideration when considering the validity of our single observation. Despite this limitation, our case raises the paradigm of successful treatment of ROP with small doses of bevacizumab. Pharmacokinetic and clinical studies will be necessary to elucidate the optimal dose of intravitreal bevacizumab for use in neonates. However, in the absence of such data, and so long as concerns about serious systemic side effects persist, we believe that we must strive to use the smallest effective dose.
- Travassos A, Teixeira S, Ferreira P, et al. Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity. Ophthalmic Surg Lasers Imaging. 2007;38:233–237.
- Chung EJ, Kim JH, Ahn HS, Koh HJ. Combination of laser photocoagulation and intravitreal bevacizumab (Avastin) for aggressive zone I retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol. 2007;245:1727–1730. doi:10.1007/s00417-007-0661-y [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;17:603–615. doi:10.1056/NEJMoa1007374 [CrossRef]
- Micieli JA, Surkont M, Smith AF. A Systematic analysis of the off-label use of bevacizumab for severe retinopathy of prematurity. Am J Ophthalmol. 2009;148:536–543. doi:10.1016/j.ajo.2009.05.031 [CrossRef]
- Hård AL, Hellström A. On safety, pharmacokinetics and dosage of bevacizumab in ROP treatment: a review. Acta Paediatr. 2011;100:1523–1527. doi:10.1111/j.1651-2227.2011.02445.x [CrossRef]
- Sato T, Wada K, Arahori H, et al. Serum Concentrations of bevacizumab (Avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity. Am J Ophthalmol. 2012;153:327–333. doi:10.1016/j.ajo.2011.07.005 [CrossRef]
- Chakravarthy U, Harding SP, IVAN Study Investigators et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology. 2012;119:1399–1411. doi:10.1016/j.ophtha.2012.04.015 [CrossRef]
- Wang Y, Fei D, Vanderlaan M, Song A. Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro. Angiogenesis. 2004;7:335–345. doi:10.1007/s10456-004-8272-2 [CrossRef]
- Sonmez K, Drenser KA, Capone A Jr, Trese MT. Vitreous levels of stromal cell-derived factor 1 and vascular endothelial growth factor in patients with retinopathy of prematurity. Ophthalmology. 2008;115:1065–1070. doi:10.1016/j.ophtha.2007.08.050 [CrossRef]