Due to a higher complication rate, increased postoperative inflammation, and an unfavorable structural and functional outcome in patients treated with cryotherapy, the diode laser photocoagulation is currently regarded as the standard of treatment for the management of ROP. Despite the superior results from this procedure, complications may also arise from the use of laser treatment in the management of ROP. These complications include the absorption of laser energy in the anterior segment, lens, and the retina. Deciding on the amount of energy to use is challenging since direct laser-causing damage such as retinal breaks or retinal detachment could arise if excessive energy is used, but insufficient laser treatment could also result in skip areas and lead to reactivation of ROP (Figs. 11.3, 11.4 and 11.5) [10]. In addition, laser-induced complications also cause the peripheral retinal damage and cause strabismus, visual field constriction, and refractive errors. Possible complications associated with laser photocoagulation are shown in Table 11.2.

Because VEGF concentrations are highly elevated in advanced ROP, a growing body of evidence supports the rationale of pharmacologic targeting of VEGF in the treatment of ROP [11–13]. Bevacizumab (Avastin; Genentech Inc., South San Francisco, CA) and ranibizumab (Lucentis; Genentech Inc., South San Francisco, CA) are two monoclonal anti-VEGF agents, with different molecular sizes, structures, and half-lives [14, 15], that have demonstrated efficacy in the treatment of type-1 ROP [16–21].

Treatment techniques with intravitreal anti-VEGF agents, such as dose, injection site, depth, and angle are modified for the pediatric population. The injection is performed with a 30-gauge needle that is initially directed along an angle that is perpendicular to the globe and then redirected slightly toward the center of the eyeball after the needle had passed the equator of the lens. These modifications mitigate or avoid damaging either the lens or the retina [21]. The injected dosages (0.625 mg/0.025 ml for bevacizumab and 0.25 mg/0.025 ml for ranibizumab) are half dose of those used in the adults. To avoid unintended complications, physicians should be familiar with the various injection techniques before applying this treatment to the newborns [21, 22]. Post injection, infants are closely monitored for potential complications, including cataract, endophthalmitis, and retinal detachment.

Another complication with intravitreal injection of bevacizumab (IVB) in ROP is a longer recurrence time compared with conventional laser therapy. The BEAT-ROP study [18] observed a late recurrence of disease in 2 of 62 eyes in infants with zone 1 disease and in 4 of 78 eyes in infants with a posterior zone 2 disease after treatment with IVB. Considering all recurrences together, the time to recurrence was 16.0 ± 4.6 weeks in 6 eyes that received IVB injection, compared with 6.2 ± 5.7 weeks in 32 eyes that received conventional laser therapy. Additional laser photocoagulation may be necessary in these patients.

IVB may neutralize the VEGF concentration that is present in the vitreous cavity, but has no role in inhibiting continual production of VEGF in the avascular area. Thus, a late recurrence is possible if VEGF is continually produced in the avascular retina after degradation of bevacizumab and the subsequent loss of its therapeutic effects. Thus, laser therapy may still be necessary for nonresponders to IVB [21].

It has been noted that a small proportion of bevacizumab could leak into the systemic circulation following IVB injection [23, 24]. The inhibition of systemic VEGF raises concerns that these important physiological effects associated with VEGF in development [25–27] may lead to abnormal organogenesis or neurodevelopment. Sato et al. [23] found that the serum VEGF was suppressed for up to 2 weeks after IVB injection. However, Martínez-Castellanos et al. [28] did not find any abnormality in neuro-developments 5 years after the use of IVB in a longitudinal study. Banker et al. [29] also did not report signs of developmental delay 6 years following the use of IVB. However, both of these studies were limited by a modest number of patients and of a non-randomized study design. The long-term safety and systemic effects of anti-VEGF agents in the treatment of ROP remain to be clarified [30].

Another concern from treatment-induced complication is the development of myopia and worsening of refractive error in ROP patients. Harder et al. [31] reported an incidence of high myopia in 9% of patients treated with bevacizumab compared with 42% in the laser group. This relatively favorable outcomes in refractive status with anti-VEGF agents [21, 31] compared to laser-treated patients may be due to the fact that a better preserved peripheral retina in the anti-VEGF treated eyes helps the emmetropization process. The peripheral retina has been demonstrated to be important in the regulation of emmetropization in animal models, possibly due to its visual feedback [32]. Possible complications associated with anti-vascular endothelial growth factor agents are listed in Table 11.3 and Figs. 11.6 and 11.7.