Insulin-like growth factor-1 for the prevention or treatment of retinopathy of prematurity

Retinopathy of prematurity (ROP) is a disorder of the developing retina in which abnormal proliferation of retinal blood vessels may lead to severe visual compromise or retinal detachment in infants born preterm. Insulin-like growth factor-1 (IGF-1) promotes normal retinal vessel growth in utero; however, IGF-1 levels fall substantially following preterm birth. By returning IGF-1 to in utero levels, postnatal treatment with IGF-1 may interrupt ROP pathogenesis, preventing disease or reducing its severity.

To compare treatment with IGF-1 to standard care or placebo for the prevention of retinopathy of prematurity or treatment of early retinopathy of prematurity.

We used CENTRAL, MEDLINE, Embase, Cochrane Database of Systematic Reviews, Issue 3, 2025, in the Cochrane Library, CINAHL Plus with Full Text (EBSCOhost), Epistemonikos, clinical trials registries (US National Library of Medicine Clinicaltrials.gov, World Health Organization's International Trials Registry Platform, and ISRCTN Registry), together with reference checking and citation searching to identify studies that are included in this review. The latest search date was 10 March 2025.

We considered all randomized controlled trials (RCTs), cluster-RCTs, and quasi-RCTs comparing IGF-1 with standard care or placebo for the prevention of ROP or treatment of early ROP in preterm infants. We planned to exclude cross-over randomized trials.

Our outcomes of interest were: • Development of Type 1 ROP, defined as ROP requiring treatment at any time during the birth hospitalization or outpatient follow-up • Development of ROP ≥ stage 3 at any time during the birth hospitalization or outpatient follow-up • Development of ROP of any severity at any time during the birth hospitalization or outpatient follow-up • Occurrence of one or more serious adverse events (SAEs) at any time during the birth hospitalization • Mortality during the birth hospitalization • Hypoglycemia during the birth hospitalization RISK OF BIAS: We used the original Cochrane Risk of Bias 1 tool (RoB 1) to assess possible bias in the included studies.

Dichotomous data were reported using risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CIs). Where possible, we synthesized results for each outcome using meta-analysis with fixed-effect models. We used GRADE to assess the certainty of evidence for each outcome.

We included two studies totaling 140 participants. Both included studies were parallel-group RCTs performed between 2011 and 2016 enrolling extremely preterm infants in well-resourced settings in Europe and North America. The two published primary study references describe a two-center RCT (n = 19) and a 20-center RCT (n = 121) comparing treatment starting on the first day of life with intravenous IGF-1 (as mecasermin rinfabate) to standard care for prevention of ROP in newborn infants at 23 weeks' to 27 weeks plus six days' gestational age with follow-up through 40 weeks' postmenstrual age.

Type 1 ROP/ROP requiring treatment Evidence is very uncertain regarding the effect of treatment with IGF-1 as compared to standard care/placebo for preventing development of Type 1 ROP/ROP requiring treatment (RR 0.94, 95% CI 0.38 to 2.35; P = 0.90; I² = 0%; 2 RCTs, 116 infants; very low-certainty evidence). ROP ≥ stage 3 Evidence is very uncertain regarding the effect of treatment with IGF-1 as compared to standard care/placebo for preventing development of severe ROP (RR 1.27, 95% CI 0.61 to 2.65; P = 0.52; I² = 0%; 2 RCTs, 116 infants; very low-certainty evidence). ROP of any severity Evidence is very uncertain regarding the effect of treatment with IGF-1 as compared to standard care/placebo for preventing development of ROP of any severity (RR 1.30, 95% CI 0.94 to 1.80; P = 0.12; I² = 0%; 2 RCTs, 116 infants; very low-certainty evidence). SAEs during the birth hospitalization Evidence is very uncertain regarding the safety of treatment with IGF-1 as compared to standard care/placebo as reflected by the occurrence of one or more SAEs during the birth hospitalization in preterm infants (RR 1.18, 95% CI 0.94 to 1.47; P = 0.15; I² = 65%; 2 studies, 140 infants; very low-certainty evidence). Post-hoc sensitivity analysis including only the larger RCT demonstrated an increased risk of experiencing one or more SAEs with IGF-1 compared to controls (RR 1.28, 95% CI 1.01 to 1.62, P = 0.05; RD 0.17, 95% CI 0.01 to 0.33, P = 0.04; number needed to treat for an additional harmful outcome (NNTH) 5.9; I² = not applicable; 1 RCT, 121 infants; very low-certainty evidence). All-cause mortality during the birth hospitalization Evidence is very uncertain regarding the effect of treatment with IGF-1 as compared to standard care/placebo on all-cause mortality during the birth hospitalization in preterm infants (RR 1.69, 95% CI 0.71 to 3.99; P = 0.23; I² = not applicable; 1 RCT, 121 infants; very low-certainty evidence). Hypoglycemia during the birth hospitalization Evidence is very uncertain regarding the safety of treatment with IGF-1 as compared to standard care/placebo as reflected by the incidence of hypoglycemia in preterm infants during the birth hospitalization (RR 1.00, 95% CI 0.62 to 1.63; P = 0.99; I² = 0%; 2 RCTs, 140 infants; very low-certainty evidence). We assessed all results to be of very low certainty due to small total enrollment and substantial risk of bias. Both included studies had a high risk of bias in two domains. In addition, both were funded by industry.

The available data are of very low certainty, and so we are not able to draw conclusions about the effects of treatment with IGF-1 in preterm infants for preventing or treating ROP, or about its effects on risk of serious adverse events, mortality, or hypoglycemia in this population.

This Cochrane review had no dedicated funding.

Protocol available via DOI: 10.1002/14651858.CD013216.