Review question: We reviewed the evidence for the effect of beta-blockers on retinopathy of prematurity (ROP) in preterm infants.
Background: Babies who are born early (preterm) are at risk of developing disordered growth of the blood vessels in the back of their eyes, a disease called retinopathy of prematurity. Severe stages of this condition may result in poor vision or even blindness. Early treatment of retinopathy may improve vision in the long term. Currently, laser therapy is the treatment of choice for severe stages of ROP. However, it is an invasive procedure requiring expert skills and anaesthesia, and is not available in all countries in the world. Safe and effective drugs to prevent the disease are thus desirable. Beta-blockers are believed to be able to stop disordered growth of blood vessels in various parts of the body including the eye. Beta-blockers are used in children to treat a variety of diseases and are generally well tolerated. Nevertheless, they also bear the risk of adverse effects like lowering heart rate and blood pressure. The main aim of this review was to find out whether beta-blockers compared to placebo (an inactive drug) or no drug offer important advantages to preterm babies either by preventing severe stages of ROP or by treating the disease (when critical stages of ROP are already present).
Study characteristics: We examined the research published to 7 August 2017. We found three clinical trials recruiting 366 preterm babies. All three studies reported on preventing severe stages of retinopathy.
Key results: We found that orally administered beta-blockers may offer short-term benefits such as lower risk of progression to a more severe stage of retinopathy and less need for additional treatment. However, there were no data on long-term vision; and studies did not show an effect of beta-blockers on the most severe stages of retinopathy. On the other hand, serious adverse effects of beta-blockers were reported in one of three studies.
Quality of evidence: The overall quality of evidence for outcomes in this review varied from low to moderate. Thus, our confidence in the results of this review is very limited. We cannot recommend routine use of beta-blockers for prevention or treatment of ROP in preterm infants. Future high-quality studies are necessary to determine whether benefits of beta-blockers outweigh their risks in preventing or treating ROP in preterm infants.
Limited evidence of low-to-moderate quality suggests that prophylactic administration of oral beta-blockers might reduce progression towards stage 3 ROP and decrease the need for anti-VEGF agents or laser therapy. The clinical relevance of those findings is unclear as no data on long-term visual impairment were reported. Adverse events attributed to oral propranolol at a dose of 2 mg/kg/d raise concerns regarding systemic administration of this drug for prevention of ROP at the given dose. There is insufficient evidence to determine the efficacy and safety of beta-blockers for prevention of ROP due to high risk of bias in two included trials and the lack of long-term functional outcomes. We would encourage researchers to conduct large, well-designed trials to confirm or refute the role of beta-blockers for prevention and treatment of ROP in preterm infants. Trials should report on long-term visual impairment. Researchers should consider dose-finding studies of systemic beta-blockers and topical administration of beta-blockers, in order to optimise drug delivery and minimise adverse events.
Retinopathy of prematurity (ROP) is a vision-threatening disease of preterm neonates. The use of beta-adrenergic blocking agents (beta-blockers), which modulate the vasoproliferative retinal process, may reduce the progression of ROP or even reverse established ROP.
To determine the effect of beta-blockers on short-term structural outcomes, long-term functional outcomes, and the need for additional treatment, when used either as prophylaxis in preterm infants without ROP, stage 1 ROP (zone I), or stage 2 ROP (zone II) without plus disease or as treatment in preterm infants with at least prethreshold ROP.
We searched the Cochrane Neonatal Review Group Specialized Register; CENTRAL (in the Cochrane Library Issue 7, 2017); Embase (January 1974 to 7 August 2017); PubMed (January 1966 to 7 August 2017); and CINAHL (January 1982 to 7 August 2017). We checked references and cross-references and handsearched abstracts from the proceedings of the Pediatric Academic Societies Meetings.
We considered for inclusion randomised or quasi-randomised clinical trials that used beta-blockers for prevention or treatment of ROP in preterm neonates of less than 37 weeks' gestational age.
We used the standard methods of Cochrane and the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence.
We included three randomised trials (N = 366) in this review. Two of these studies were at high risk of bias. All studies reported on prevention of ROP and compared oral propranolol with placebo or no treatment. We found no trials assessing beta-blockers in infants with established stage 2 or higher ROP with plus disease.
In one trial, study medication was started after one week of life, i.e. prior to the first ROP screening. The other two trials included preterm infants if they had stage 2 or lower ROP without plus disease. Based on the GRADE assessment, we considered evidence to be of low quality for the following outcomes: rescue treatment with anti-VEGF or laser therapy; and arterial hypotension or bradycardia requiring inotropic support. Evidence was of moderate quality for the following outcomes: progression to stage 2 with plus disease; progression to stage 3 ROP; and progression to stage 4 or 5 ROP.
Meta-analysis of three trials (N = 366) suggested beneficial effects of oral beta-blockers on the risk of requiring anti-VEGF agents (typical risk ratio (RR) 0.32, 95% confidence interval (CI) 0.12 to 0.86; I² = 0%; typical risk difference (RD) −0.06, 95% CI −0.10 to −0.01; I² = 75%; number needed to treat for an additional beneficial outcome (NNTB) 18, 95% CI 14 to 84) and laser therapy (typical RR 0.54, 95% CI 0.32 to 0.89; typical RD −0.09, 95% CI −0.16 to −0.02; I² = 31%; NNTB 12, 95% CI 8 to 47). Meta-analysis of two trials (N = 161) demonstrated a beneficial effect of oral beta-blockers on progression to stage 3 ROP (typical RR 0.60, 95% CI 0.37 to 0.96; I² = 0%; typical RD −0.15, 95% CI −0.28 to −0.02; I² = 73%; NNTB 7, 95% CI 5 to 67). There was no significant effect of oral beta-blockers on progression to stage 2 ROP with plus disease or to stage 4 or 5 ROP. Although meta-analysis did not indicate a significant effect of beta-blockers on arterial hypotension or bradycardia, propranolol dosage in one study was reduced by 50% in infants of less than 26 weeks' gestational age due to severe hypotension, bradycardia, and apnoea in several participants. Analyses did not indicate significant effects of beta-blockers on complications of prematurity or mortality. None of the trials reported on long-term visual impairment.