Postnatal Growth Trajectories Outcomes shows no differences Following Bevacizumab Treatment for ROP
Retinopathy of prematurity (ROP) is a leading cause of childhood blindness characterized by neovascularization of the immature retina that can progressively lead to retinal detachment. The pathogenesis of ROP is thought to involve two phases, a hyperoxic phase followed by a hypoxic phase. In phase one, excess oxygen exposure due to the extrauterine environment or supplemental oxygen causes downregulation of growth factors and termination of retinal blood vessel growth. During this phase, vascular endothelial growth factor (VEGF), an essential factor in angiogenesis, is suppressed. In phase two, increasing metabolic demands of the maturing retina cause hypoxic ischemia, upregulated VEGF, and subsequent vasoproliferation.
The current most widely accepted treatment for ROP is peripheral laser ablation, which has shown to improve visual, structural, and refractive outcomes. However, laser photocoagulation is destructive to the retina, and more recent studies on the use of anti-VEGF agents have shown that intravitreal bevacizumab (IVB) monotherapy is an effective treatment for ROP. The use of IVB as a primary treatment has quickly gained popularity because it does not require general anesthesia, is more easily tolerated by sicker babies, and allows further development of peripheral retinal vessels before possible laser treatment is needed.
However, due to the anti-angiogenic effects of anti-VEGF agents, concern has risen regarding the systemic effects of IVB injection in premature infants. The presence of bevacizumab in the systemic circulation after intravitreal injection has been observed for as long as 8 weeks after injection, while serum levels of VEGF were suppressed for the same duration.
Systemic VEGF plays a key role in organogenesis and neural tube development and may have a neuroprotective effect during periods of hypoxic cerebral injury, the most common known cause of cerebral palsy. VEGF-mediated angiogenesis has also been shown to affect adipose tissue growth and function, contributing to weight gain and insulin resistance. Furthermore, the interplay between VEGF and IGF-1 has prompted interest in postnatal growth rate as a prognostic factor in developing ROP. The potential consequences of anti-VEGF therapy on these physiological processes are not completely understood. The goal of this study by Zhang et al was to investigate the postnatal growth and neurodevelopment of preterm infants treated with IVB for ROP. Comparison of postnatal growth curves from the time of treatment to 50 weeks PMA showed no significant differences in growth trajectories between groups after adjusting for the corresponding growth parameters at birth.
This was a retrospective comparative study. A total of 262 infants were divided among three study groups: 22 treated with intravitreal bevacizumab, 55 treated with laser, and 185 with ROP that resolved without treatment. Infants with nonviable course or hydrocephalus, a source of non-physiologic weight gain, were excluded. Neurodevelopment was assessed with Bayley III scores at 17–28 months if available and presence of hearing loss or cerebral palsy. Weekly weight, height, and head circumference from birth through 50 weeks postmenstrual age (PMA) were modeled to determine differences in growth trajectories following treatment.
Comparison of postnatal growth curves from the time of treatment to 50 weeks PMA showed no significant differences in growth trajectories between groups after adjusting for the corresponding growth parameters at birth. Comparison of Bayley scores in patients with available data (n = 120) showed no significant differences. There was an increased risk of cerebral palsy in the IVB group after logistic regression adjusting for baseline confounders, but this did not retain statistical significance after applying the false discovery rate correction for multiple testing.
The purpose of this study was to analyze postnatal growth and neurodevelopmental outcomes in a large single-center cohort of premature babies treated with IVB for ROP. The findings in this study were two-fold: the analysis of growth outcomes shows no difference in growth rates in weight, height, and head circumference over time in the IVB-treated group; in addition, study found no significant differences in Bayley III scores at 17–28 months between treatment groups.
It has been suggested that cerebral palsy is a movement disorder that is present from birth rather than a postnatal developmental disorder. However, even in the absence of a genetic component, postnatal neurologic insults such as infection, trauma, sepsis, kernicterus, or hypoxia-ischemia can precipitate CP. VEGF suppression could also theoretically fall into this category, as VEGF has been suggested to have a neuroprotective effect in hypoxic-ischemic brain injury. Despite the high probability of a false-positive result in study evidenced by the statistical correction, authors ultimately could not fully exclude the possibility of cerebral palsy risk with IVB treatment, and further studies are needed to better understand their association.
Growth rate, the change in growth over time, is a more sensitive indicator of growth than a single measurement and absolute growth rate during the first year of life is not significantly different between the two sexes. Comparison of growth trajectories in the weeks prior to treatment showed similar growth rates between groups, supporting the consistent growth trends among all preterm infants in this retrospective study. There were additionally no overall differences in PMA at the time of treatment between the IVB and laser groups.
Intravitreal bevacizumab can escape from the eye into the systemic circulation and has been detected within serum as early as one to two days after intravitreal injection, with correspondingly suppressed serum VEGF levels up to eight weeks after treatment. Comparison of growth trends between treatment groups shows no significant differences in weight, height, or head circumference changes in the bevacizumab group compared to the laser and untreated groups up to 50 weeks PMA, which is up to 18 weeks after the earliest time of treatment in the sample.
In all, anti-VEGF treatment for ROP has been shown to have comparable short-term efficacy to laser photocoagulation and has increased in usage due to greater ease of administration, decreased destruction of the peripheral retina, and lower risk of myopia. Studies on the systemic effects of these agents have been largely reassuring, but the lower quality of available evidence still warrants caution and investigation regarding their longterm effects on developing infants. The results show no significant differences in postnatal growth, Bayley scores, hearing loss, and cerebral palsy compared to ROP infants receiving laser or no treatment. Further prospective, randomized studies will be needed to determine if anti-VEGF treatment for ROP indeed has clinically significant systemic consequences.
Source: Zhang et al; Clinical Ophthalmology 2022:16 2713–2722 https://doi.org/10.2147/OPTH.S378520
