Abstract
Background: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective.Methods: A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial.Results: Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297– 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cut-off of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment.Conclusion: Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a β-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results.Clinical Trial Registration The trial was registered at ClinicalTrials.gov with Identifier NCT02504944 and with EudraCT Number 2014-005472-29.
Highlights
Despite remarkable progress in many areas of neonatal medicine, retinopathy of prematurity (ROP) remains a very common and disabling complication of premature birth [1]
In the period 2011–2015, 2,746 very low birth weight (VLBW) newborns were admitted to the seven Neonatal Intensive Care Units (NICU) participating in the trial
7 newborns were excluded: 5 newborns because they had developed aggressive posterior ROP (AP-ROP), 1 newborn for protocol deviation, and 1 newborn because their parents withdrew their consent to proceed with the treatment after 4 days after enrolment
Summary
Despite remarkable progress in many areas of neonatal medicine, retinopathy of prematurity (ROP) remains a very common and disabling complication of premature birth [1]. Even though ROP is currently considered a multi-factorial disease that involves both oxygen-dependent and oxygen-independent factors such as nutritional intakes [2], phenomena such as low gestational age (GA), low birthweight, and supplemental oxygen therapy are the main factors associated with it [3]. The possibility to prevent or slow down the progression of ROP is predominantly dependent on a controlled and careful use of oxygen, but the possibility of pharmacological interventions arouses great interest [4]. ROP is a typical oxygen-dependent biphasic disease, where what happens in the first phase, following oxygen exposure, apparently mirrors what happens during the second phase, when the retina becomes hypoxic [3]. Oral propranolol reduces retinopathy of prematurity (ROP) progression, not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective
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