Retinopathy of prematurity and neurodevelopmental outcomes in preterm infants: A systematic review and meta-analysis

Abstract

BackgroundRetinopathy of prematurity (ROP) and abnormal brain development share similar risk factors and mechanisms. There has been contrasting evidence on the association of ROP with adverse neurodevelopmental outcomes.ObjectiveWe analysed the association between ROP at levels of severity and treatment with all neurodevelopmental outcomes until adolescence.Data sourceWe followed PRISMA guidelines and searched Medline and Embase between 1 August 1990 and 31 March 2022.Study selection and participantsRandomised or quasi-randomised clinical trials and observational studies on preterm infants (<37 weeks) with ROP [type 1 or severe ROP, type 2 or milder ROP, laser or anti-vascular endothelial growth factor (VEGF) treated] were included.Data extraction and synthesisWe included studies on ROP and any neurocognitive or neuropsychiatric outcomes.OutcomesThe primary outcomes were as follows: cognitive composite scores evaluated between the ages of 18 and 48 months by the Bayley Scales of Infant and Toddler Development (BSID) or equivalent; neurodevelopmental impairment (NDI; moderate to severe NDI or severe NDI), cerebral palsy, cognitive impairment; and neuropsychiatric or behavioural problems. The secondary outcomes were as follows: motor and language composite scores evaluated between the ages of 18 and 48 months by BSID or equivalent; motor/language impairment; and moderate/severe NDI as defined by the authors.ResultsIn preterm infants, “any ROP” was associated with an increased risk of cognitive impairment or intellectual disability [n = 83,506; odds ratio (OR): 2.56; 95% CI: 1.40–4.69; p = 0.002], cerebral palsy (n = 3,706; OR: 2.26; 95% CI: 1.72–2.96; p < 0.001), behavioural problems (n = 81,439; OR: 2.45; 95% CI: 1.03–5.83; p = 0.04), or NDI as defined by authors (n = 1,930; OR: 3.83; 95% CI: 1.61–9.12; p = 0.002). Type 1 or severe ROP increased the risk of cerebral palsy (OR: 2.19; 95% CI: 1.23–3.88; p = 0.07), cognitive impairment or intellectual disability (n = 5,167; OR: 3.56; 95% CI: 2.6–4.86; p < 0.001), and behavioural problems (n = 5,500; OR: 2.76; 95% CI: 2.11–3.60; p < 0.001) more than type 2 ROP at 18–24 months. Infants treated with anti-VEGF had higher odds of moderate cognitive impairment than the laser surgery group if adjusted data (gestational age, sex severe intraventricular haemorrhage, bronchopulmonary dysplasia, sepsis, surgical necrotising enterocolitis, and maternal education) were analysed [adjusted OR (aOR): 1.93; 95% CI: 1.23–3.03; p = 0.04], but not for cerebral palsy (aOR: 1.29; 95% CI: 0.65–2.56; p = 0.45). All outcomes were adjudged with a “very low” certainty of evidence.Conclusion and relevanceInfants with “any ROP” had higher risks of cognitive impairment or intellectual disability, cerebral palsy, and behavioural problems. Anti-VEGF treatment increased the risk of moderate cognitive impairment. These results support the association of ROP and anti-VEGF treatment with adverse neurodevelopmental outcomes.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42022326009.

Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): five-year outcomes of a randomised trial

“…Two recent systematic reviews concluded that there was an association between bevacizumab and adverse neurodevelopmental outcomes, such that new safety studies were required including long term follow up. 10 , 11 All anti-VEGF agents move quickly into the systemic circulation after intravitreal injection, but bevacizumab and aflibercept appear to be cleared more slowly from the circulation with resultant suppression of VEGF levels. 28 We have confirmed the rapid clearance of ranibizumab and lack of effect on VEGF levels in the RAINBOW population.…”

“…Such data are important as there remains concern that the suppression of systemic VEGF levels after intravitreal treatment might produce remote effects on somatic or neurological development. 6 For example, recent reports, 7 , 8 , 9 including two systematic reviews with meta-analysis, 10 , 11 have suggested that neuromorbidity may be more frequent after bevacizumab treatment. The two largest non-randomised studies 7 , 8 comprise the majority of included infants and may have been biased because anti-VEGF treatment was preferred in sicker and less mature infants, who would be expected to have higher rates of neurodevelopmental impairment.…”

Association of Fortification with Human Milk versus Bovine Milk-Based Fortifiers on Short-Term Outcomes in Preterm Infants—A Meta-Analysis

“…Premature delivery invariably results in very different neurodevelopment with effects lasting into adulthood [ 2 ]. Multiple complications such as necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), late-onset sepsis (LOS), and retinopathy of prematurity (ROP), are independently associated with adverse neurological outcomes [ 3 , 4 , 5 , 6 , 7 ]. Preterm infants must adjust to extrauterine life without the caloric and nutritional supply from the placenta.…”

Efficacy of supplemental oxygen in reducing the need for laser or intravitreal bevacizumab in preterm infants with stage 2 retinopathy of prematurity

“…ROP deemed high risk for disease progression that could result in a poor visual or anatomic outcome (Type 1 ROP) is treated with laser photocoagulation and/or intravitreal anti-VEGF antibody (bevacizumab) [6]. Several studies have reported an association between laser photocoagulation and decreased visual acuity and a higher rate of myopia and astigmatism during childhood [7,8]. Infants received intravitreal bevacizumab treatment may experience reactivation of ROP [9].…”