Introduction

Retinopathy of prematurity ranks among the leading preventable causes of blindness and visual impairment in infants and young children.1 ROP affects the normal development of retinal vascularization, which, if not detected and treated quickly, can lead to dreadful complications such as: macular folds, retinal detachment and even blindness.2 Over the years, medical progress has dually influenced ROP. On the one hand, the introduction of screening criteria, the detection of risk factors, the methods of diagnosis and treatment have contributed to a better management of this condition. On the other hand, neonatal intensive care units (NICU) have contributed to increasing the incidence of this disease by improving the survival rate of micro-premature babies who are much more likely to develop this condition.3 In developing countries, ROP continues to be a challenge, because the increasing survival rate of preterm infants and limited resources in monitoring the oxygen administration have significantly contributed to an increase in the number of preterm infants developing this disease.4 The influence of risk factors in the occurrence of this condition as well as its management have progressed to the same extent that medicine and technology have (Figure 1).5 Laser photocoagulation technique has highlighted a more optimistic future for visual acuity, and after demonstrating that VEGF upregulation is involved in the development of retinal neovascularization, extensive studies have focused on regulating the values of the vascular endothelial growth factor (VEGF).6

Figure 1 Schematic representation of the risk factors of ROP.

Abbreviation: IGF-1, insulin-like growth factor 1.

Materials and Methods

This review is based on an in-depth study of the literature available, which was conducted (starting from 2010 until January 2023) in databases such as Web of Science, PubMed, ScienceDirect Freedom Collection and Google Scholar, using MeSH terms such as: “retinopathy of prematurity”, “risk factors”, “anti-VEGV”, “micropreemie” “digital imaging”, “telescreening”, “artificial intelligence”, “OCT” or “IGF-1”. The articles that were not related to the retinopathy of prematurity were discarded according to their suitability to this review.

Etiology and New Perspectives on Risk Factors

Since the first description of this condition, many risk factors have been analyzed in several studies, but they have not been entirely understood yet.7 The two most important risk factors involved in the occurrence of ROP are birth weight (BW) <1500 g and gestational age (GA) <30 weeks of gestation, small gestational age being an accurate indicator of underdevelopment of the vascular and nervous systems.8 In a multicentric study including more than 4000 preterm infants weighing <1251 grams at birth, it has been demonstrated that for every extra 100 grams or every week of extra gestation, the risk of developing ROP decreases significantly. Thus, the chances of developing ROP decrease by approximately 27% for each weight gain of 100 grams and each 7-day increase in gestational age decreases the chances of developing ROP by approximately 19%.9 In several recent studies, in addition to birth weight, the low proportion of weight gain at 6 weeks postpartum below 50% of birth weight is an important predictor of the severity of ROP and is calculated by the formula: (Weight at 6 weeks – BW): BW.10

Oxygen therapy is essential for the survival of extremely young premature babies, but it can induce cerebral and pulmonary toxicity.11 Free postnatal administration of oxygen without careful monitoring is an important cause of ROP.12 At birth, premature babies, coming from a relatively hypoxic environment in the uterus, with incompletely vascularized retina, where oxygen saturation is about 50–70%, are exposed to high levels of oxygen either from the air or from oxygen therapy administration.13,14 Rapid increase in oxygen saturation immediately after birth to values between 80% and 100% induces a state of hyperoxia that suppresses the secretion of vascular endothelial growth factor and decreases the levels of Hypoxia-Inducible Factor (HIF)-1, generating a process of retinal vasoconstriction (Figure 2).15 Shortly after the publication of the SUPPORT study that attempted to determine the correct oxygen dose for preterm infants, the American Academy of Pediatrics (AAP) updated their recommendations for the oxygen saturation interval to indicate a target range greater than 85−89%. This update was made even though the oxygen saturation between 85% and 89% led to a decrease in severe forms of ROP, because the mortality rate was higher as compared to preterm infants who had a saturation range between 91% and 95%.16 In patients with associated cardiopulmonary pathology, oxygen saturation and the partial oxygen pressure (PaO2) may fluctuate outside the reference range even under close monitoring.17

Figure 2 Schematic representation of the interaction between oxygen, IGF-1, VEGF and the development of retinal vessels in ROP.

Abbreviations: IGF-1, insulin-like growth factor 1; VEGF, vascular endothelial growth factor.

In addition, after birth, premature infants have low serum levels of insulin-like growth factor 1 (IGF-1), which plays an important role in the development of ROP.18,19 Low values of IGF-1 at birth inhibit the normal growth of retinal vascularization in the first phase of ROP, despite the presence of VEGF, because the action of VEGF on vascular endothelial cells is mediated by IGF-1.20 Simultaneously with increasing postmenstrual age (PMA), IGF-1 levels increase and allow VEGF to trigger angiogenesis.21 As a result, the neovascularization occurs, which is immature and incorrectly formed, thus leading to extraretinal fibrovascular proliferation, bleeding, retinal traction, and even retinal detachment (Figure 2).22 Pérez-Munuzuri et al demonstrated in a study that serum IGF-1 dosing at 3 weeks postpartum is a good predictor of ROP developing risk.23 In addition, IGF-binding protein 3 (IGFBP-3) helps to reduce retinal vascular loss and regrowth of retinal vascularization.24 Recent studies suggest that low plasma IGF-1 and IGFBP-3 levels are involved in the ROP development.25.

Although several studies have reported associations between changes in retinal vascularity and renal functional impairment, correlations between renal parameters and ROP have not been reported in literature until recently. In August 2022, Eroglu et al published a retrospective study analyzing the association between the retinopathy of prematurity and some parameters reflecting hepatic and renal function. They reported a new potential risk factor, namely proteinuria, finding a strong association between this renal parameter and ROP, highlighting the presence of proteinuria in 71.4% of the patients with type I or II retinopathy of prematurity and 91.7% of the patients with type I ROP. Moreover, premature babies with proteinuria and GA ≤ 32 weeks, have a fourfold risk of developing a severe form of ROP.26 Both the kidney and the retina share a similar embryological development.27 The stratigraphy of the glomerular basement membrane is similar to that of the outer retinal barrier, and both podocytes and EPR cells actively mediate the molecular exchange, playing the role of a metabolic barrier.28 Prematurity affects an important period in the process of nephrogenesis, as it is completed at 36 weeks of gestation and most nephrogenesis occurs towards the end of gestation. Taking into account that premature babies are born with a reduced number of nephrons, and they cannot regenerate, the compensatory nephron surface area increases, which leads to the risk of glomerulosclerosis.29 The immature glomeruli of premature babies have a filtering membrane with lower selectivity thus allowing larger amounts of proteins to pass into the Bowman’s space.30

The influence of the increased level of serum bilirubin on ROP is still a controversial subject in literature because of its double role, acting as a powerful antioxidant and at certain levels it can cause irreversible cellular damage.31,32 In a recent paper published, the serum value of total bilirubin was much lower among patients with type 1 ROP compared to the control group and to that of patients with ROP who did not require laser therapy. Therefore, a low level of total bilirubin seems to influence ROP but, taking into account the dual behavior, knowing the lower limit at which it plays an antioxidant role, it is as important as the limit above which induces toxic effects.26

Ji Woong and colleagues drew attention to the necessity of differentiating the risk factors involved in the development of ROP from those incriminated in the progression of ROP. Respiratory distress syndrome along with bronchopulmonary dysplasia are incriminated in the etiopathogenesis of ROP as a result of supplemental oxygen administration, but the way in which these risk factors intervene is different. In many studies, respiratory distress syndrome has been associated with the risk of developing ROP, as surfactant deficiency involves the administration of supplemental oxygen.33 Oxygen therapy may induce hyperoxia, leading to slowing the retinal vascular development and secondary hypoxia.34 On the other hand, bronchopulmonary dysplasia, which is a chronic condition in which alveolar and vascular development is disturbed, with the secondary reduction of pulmonary function, as a consequence of oxygen therapy or mechanical ventilation, has been associated with severe progression of ROP.35 There are many ways in which oxygen can be administered, but the duration of mechanical ventilation is a much more important risk factor for the development of ROP as compared to the total duration of oxygen therapy.36 In January 2023, Tiffany et al published a study that stratified the risk according to the gestational age, dividing preterm infants into three categories. For the second category, namely premature babies with GA between 24 and 26 weeks, the administration of corticosteroids for bronchopulmonary dysplasia represented an important risk factor for the development of severe forms of ROP.37

Central nervous system injuries such as intraventricular hemorrhage and periventricular leukomalacia are considered to be risk factors for the progression of ROP.38,39 Both ROP and intraventricular hemorrhage develop due to vascular immaturity and inconsistent oxygen supply. The incrimination of this pathology in the progression of ROP has been demonstrated in numerous studies, this being correlated with stages 3 and 4 of ROP.33 In premature infants, the most common form of intracranial hemorrhage is represented by germinal matrix hemorrhage – intraventricular hemorrhage (GMH-IVH). In a study assessing the risk factors for GMH-IV in preterm infants with a GA <32 weeks, the incidence of ROP was significantly higher among patients who presented this form of hemorrhage.40 On the other hand, in the case of periventricular leukomalacia, insufficient myelination secondary to apoptosis of brain cells is caused by decreased systemic blood pressure and oxygen instability.41 Thus, both the progression of prematurity retinopathy and the progression of periventricular leukomalacia present a similar risk environment, namely oxygen imbalance.42

Blood transfusions are a risk factor for ROP because the transfused blood increases the level of adult hemoglobin at prematures, which has a lower affinity for oxygen and a higher concentration of iron.43,44 Due to the lower affinity, the transport of oxygen to the incompletely developed retina is higher and can induce a decrease in angiogenesis.45 Premature infants do not show effective protection against free iron because they have low levels of transferrin, and high levels of iron in adult hemoglobin, which can form free radicals that affect the developing retina.46

Future Directions on ROP Screening

Screening guidelines are vital in combating the potential complications of ROP.47 The screening complexity was the reason why many researchers proposed various algorithms to predict the risk of developing ROP.48 The multitude of screening algorithms is beneficial, but it clearly suggests that so far, no exclusive algorithm has been established to satisfy both the clinical need and, at the same time, some accepted values of sensitivity and specificity.49

Recently, in 2019, the DIGIROP algorithm was published for predicting the risk of developing ROP that requires treatment in case of premature babies with gestational age between 24 and 30 weeks. DIGIROP is a simplified version of the previous algorithms and is based only on the parameters at the time of birth: gestational age, birth weight and sex.50 The new algorithm seems to have a good potential, as it has been validated both internally and externally and its accuracy is comparable to that of previous prediction models.51

Due to geographical variations in socio-economic development, screening inclusion criteria vary by region, as there are no unanimous guidelines for ROP.52 At the last update, the American Academy of Ophthalmology (AAO) recommended the inclusion in the screening of all premature babies with a gestational age <30 weeks or a birth weight <1500 grams.53 In addition, older premature babies may be included in the screening, namely those with a birth weight of between 1500 and 2000 grams or those with a gestational age of more than 30 weeks but who have an additional risk of developing ROP. The additional risk is represented by oxygen therapy given for several consecutive days or given without monitoring oxygen saturation and inotropic drugs given for hypotension.54 In developed countries, such as New Zealand, where the incidence of ROP is low, premature infants with a GA <31 weeks or a BW <1250 grams are included in screening.55 In England, all premature babies with a GA <31 weeks or with a BW ≤1500 grams are examined.56 On the other hand, in developing countries, older babies are also included in screening. For example, in India, all infants with a GA ≤34 weeks and/or a BW ≤2000 g are examined, but also older infants with a GA ≤34 weeks who have had other associated risk factors.57

ROP ophthalmologic screening should begin at least 4 weeks postnatal age or at least 31 weeks postmenstrual age. The AAP recommends that ophthalmologic screening for ROP should be based on the postmenstrual age of the preterm infant, as it is more closely related to the onset of ROP as compared to postnatal age. Postmenstrual age is the sum of gestational age and postnatal age.58 Screening intervals for follow-up vary between 1 and 3 weeks depending on the results obtained and classified by the examining physician according to the international classification. Completion of examinations is based on postmenstrual age and the clinical status of the retina.59

Currently, a new challenge is represented by micropreemies, defined as premature with a birth weight <750 grams. Berrocal et al draws attention to the fact that micropreemies require a customized screening algorithm as they have a higher aggressiveness of ROP, an increased incidence of the plus disease and more severe stages of disease. In a retrospective study conducted between 1990 and 2019 in a Neonatal Intensive Care Unit at Jackson Memorial Hospital, Berrocal et al highlighted the link between micropreemies and plus disease. Over the three decades of the study, the average birth weight of preterm infants with plus disease decreased from 721 to 604 grams, but both values fall into the micropreemie criteria. In the last decade of the study, all preterm infants with a confirmed plus disease had a birth weight <1000 grams.60 Taking into account the more aggressive disease encountered in micropreemies, the associated plus disease and the more severe stages, the initiation of screening among them is faster and subsequent re-examinations at shorter intervals compared to preterm infants with a birth weight >750 grams.61 This trend of early screening initiation, at 2–3 weeks postnatal, is also found in developing countries for preterm infants with a GA <28 weeks or a BW <1200 g who have a tendency to develop early aggressive posterior retinopathy.62,63

ROP screening is performed by a pediatric ophthalmologist or retina specialist through indirect binocular ophthalmoscopy along with concomitant scleral indentation for the assessment of retinal periphery.64 Recently, retinal examination methods have become more numerous and developed digital imaging techniques have offered new perspectives on the diagnosis and monitoring of retinopathy of prematurity.65

RetCam is a wide-angle computerized retinal imaging system that is commonly used in developed countries to examine preterm infants at risk of developing ROP.66 When it comes to diagnosing and monitoring ROP, the ability to store the images obtained and the possibility to dynamically compare the evolution of a patient are one of the important advantages of RetCam. On the other hand, these digital images of the retina can be analyzed by artificial intelligence techniques.67

Artificial intelligence (AI) is starting to play an increasingly important role in diagnosing medical conditions.68 Over time, many clinical studies have shown that there are significant fluctuations in the staging and clinical diagnosis of ROP, and these inconsistencies may lead to treatment discrepancies.69 In order to reduce the fluctuations of clinical reasoning, deep learning algorithms have been developed, which have shown good accuracy in detecting plus and pre-plus disease.70 Several studies have shown that artificial intelligence can reduce the variability between clinicians’ assessments.71 Moreover, AI is increasingly being used to create algorithms that help with stratifying the risk of premature babies that require treatment.72 Campbell et al compared a vascular severity score based on AI and ordinal disease severity labels performed by 34 experts from the ICROP3 committee for the accuracy of staging and identifying plus disease, leading to the conclusion that the results of the two methods were similar.73

Ramanathan et al recently published a systematic review on the diagnostic algorithms of ROP based on artificial intelligence, highlighting that the contribution of AI in the management of ROP is continuously increasing. In addition to diagnosing ROP, AI techniques are capable of identifying plus disease and of assessing its severity through a new automated score.74 In a study conducted with artificial intelligence, Brown et al managed to obtain for a set of 100 retinal photographic captures, which were previously evaluated by ophthalmologists, a sensitivity of 93% and 100% for plus disease, pre-plus disease, respectively, and a specificity of 94% for both cases.75 In 2021, Omneya proposed an automatic diagnostic tool based on deep learning techniques named DIAROP, that had an accuracy of about 93%. Thus, the diagnostic ability can be compared with recent tools for detecting retinopathy of prematurity, and the promising results suggest that DIAROP may be useful in detecting cases of ROP.76

The use of imaging systems based on smartphone technology to detect retinopathy of prematurity has recently been reported in the literature.77 In April 2022, Jui-Yen et al published a prospective study comparing the accuracy of retinal imaging using the RetCam system with images taken with a 20-diopter pan-retinal lens attached via a portable instrument to a smartphone. Although the use of smartphone technology has many advantages such as good image quality, wide accessibility, easy portability and relatively low costs, with the help of smartphones you can get images with a field angle of up to 65 degrees. Instead, the RetCam system is a device with a wide angle of up to 130 degrees, and this is essential for capturing the retinal periphery. Given that smartphone technology has low visibility on the retinal periphery, the zone and stage of ROP could not be established through this technology.78

With the development of digital retinal imaging techniques, the telescreening variant was also considered, through which the detection of this pathology could be possible in disadvantaged regions of developing countries.79 Thus, after the images are captured by medical staff specially trained to use these devices, the images can be sent for evaluation to ophthalmologists specializing in ROP.80 Daniel et al validated in a study that remote examination of digital images can reduce the consequences of this pathology and telescreening can be an optimal future strategy for disadvantaged areas.81,82

The emergence of the portable variant of spectral domain optical coherence tomography (SD-OCT) has managed to cross a large barrier imposed by previous, fixed, mass models, thus offering new perspectives on neonatal retinal imaging.83 Until recently, OCT examinations focused on changes in the posterior retina because peripheral examination was limited by the OCT angle. In order to increase the benefits of OCT on ROP, OCT systems with a higher angle and increased image capture speed are being developed.84,85 Scruggs et al recently published a study showing that the detection, staging and analysis of peripheral features of ROP can be performed if scleral indentation is also performed during wider-angle OCT catches. Stage one is characterized by an increased reflectivity of the inner layers of the retina. In the second stage, the inner retina becomes thicker, exceeds the retinal plane and thus appears the pathognomonic sign for this stage, namely the retinal ridge. In the third stage, the extraretinal fibrovascular proliferation is visualized on the images obtained with the help of OCT. The small bundles of neovessels located posterior to the ridge can be easily highlighted and are considered to be the first signs of proliferation.86

The third edition of International Classification of Retinopathy of Prematurity (ICROP3) also highlighted the importance of OCT in the assessment of lesions of retinopathy of prematurity, emphasizing that certain changes that are difficult to assess clinically can be easily detected through OCT imaging. Thus, the update also included examples of the characteristic changes in both images captured by cross-sectional B-scans and en-face images. Changes founded on OCT include the demarcation line between the vascularized retina and the avascular retina, the retinal ridge, extraretinal proliferation, intraretinal exudates, retinoschisis, peripheral retinal detachment and retinal detachment involving the fovea, characteristic of stage 4B.53

Current Therapies of ROP

Laser photocoagulation aims at destroying the avascular retina, which is the main source of neovascularization formation. Prior to photocoagulation, cryotherapy was the standard treatment for ROP, but due to the more significant side effects associated with general anesthesia, it was replaced by laser photocoagulation, which has been shown to be superior.87 The thermal reaction is the basis of the changes induced by photocoagulation, because when the temperature in a tissue reaches a high level, the proteins are denatured and thus the coagulation process occurs.88 There are several theories in the literature on how photocoagulation inhibits the development of neovascularization, but it is most commonly considered that the degradation of the retinal tissue by photocoagulation reduces tissue oxygen demand and at the same time decreases the stimulation of proangiogenic factor production.89 Laser spots are applied confluently to the entire avascular area of the retina between the anterior edge of the retinal ridge and the ora serrata. Spots of 200 µm, with a power between 100 and 300 mW and a duration of 200 ms are usually used.90

Although diode laser photocoagulation is the gold standard for ROP treatment worldwide, the suppression of pathological angiogenesis by inhibiting vascular endothelial growth factor is a promising new approach to the treatment of retinopathy of prematurity.91,92 Following the publication of the first prospective BEAT-ROP (Efficacy Study of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity), which demonstrated the efficiency of the monoclonal antibody bevacizumab, anti-VEGF agents have been increasingly used as first-line treatment or as second-line treatment at certain stages and locations of the ROP.93 The VEGF family plays a major role in angiogenesis, with VEGF-A having an important influence on this process.94 Among the agents that inhibit vascular endothelial growth factor are agents that partially block VEGF-A and agents that perform a pan-blockade of VEGF-A. Pegaptanib sodium was the first approved anti-VEGF agent for age-related macular degeneration by partial blockade of VEGF-A, and has been reported in several studies in the literature as a therapeutic option for patients with ROP.95 Aurata et al compared the effect of single laser therapy with the effect of laser therapy used in combination with intravitreal administration of Pegaptanib sodium for stage 3+ for posterior I and II zone and found that the results were significantly better when Pegaptanib sodium was used as adjuvant for laser therapy.96

On the other hand, the agents that perform a pan-blockade of VEGF-A, namely bevacizumab, ranibizumab and aflibercept, are more frequently described in studies concerning the therapy of retinopathy of prematurity.97 Bevacizumab is a recombinant humanized monoclonal antibody, being the most widely used anti-VEGF agent for the treatment of ROP. However, recent studies have focused on ranibizumab and aflibercept as they appear to be safer and more effective therapeutic alternatives.98

Regarding the affinity of the VEGF receptor, special attention has recently been paid to aflibercept as its affinity is approximately 100 times higher (Dissociation constant = 0.49 pmol/L) compared to ranibizumab (Dissociation constant = 46 pmol/L) and bevacizumab (Dissociation constant = 58 pmol/L). In addition to inhibiting VEGF-A, aflibercept inhibits other incriminating factors in pathological vascularization such as VEGF-B and placental growth factors 1 and 2.99 In 2021, Chen et al published an article in which they systematically analyzed all studies on the effectiveness of aflibercept on ROP. After analyzing six series of cases that included 218 eyes treated with this therapeutic agent, they found that this anti-VEGF is promising for the treatment of ROP as the average regression rate of ROP was approximately 97%, and the average recurrence rate of about 16%, thus being comparable to previously available anti-VEGF agents.100

Although the three agents perform a pan-blockade of VEGF-A, their molecular weights are different: bevacizumab – 148 kDa, ranibizumab – 48 kDa and aflibercept – 115 kDa. The intermediate molecular weight of aflibercept is not only an advantage for the intravitreal half life, which is about 7.1 days, but also an advantage for the clinical period action that possibly extends up to about 2 and a half months. The duration of action of aflibercept is approximately twice that of ranibizumab, but ranibizumab is currently the first and only authorized therapeutic agent for this indication.101 Ranibizumab approval is based on the study RAINBOW (Ranibizumab Compared With Laser Therapy for the Treatment of Infants Born Prematurely With Retinopathy of Prematurity), which demonstrated the effectiveness and safety of this drug.102

Dual-diode laser photocoagulation therapy with intravitreal anti-VEGF injections is a new therapeutic trend today for ROP. Although the side effects of ablative laser therapy have not been found in injections of anti-VEGF agents, several clinical trials have drawn attention to the risk of entering the systemic circulation and may affect serum VEGF values that may interact with neurodevelopment of premature babies.103 Furthermore, it is believed that the combined therapy of these anti-VEGF agents together with laser photocoagulation reduces the required doses of anti-VEGF, and thus reduces the risk of systemic penetration.104,105

Chiang et al recently published a study in which they analyzed the effects of anti-VEGF treatment on neurodevelopment in patients with ROP. A number of 2090 premature infants were included in their study, being divided into four groups: without ROP, ROP without therapeutic intervention, ROP associated with laser therapy and ROP associated with anti-VEGF agents. The neurodevelopment of premature infants was evaluated until the corrected ages of 24 months using the third edition of the Bayley scale, leading to the conclusion that anti-VEGF agents apparently do not influence neurodevelopment.106

In the literature, low plasma levels of IGF-1 and IGFBP-3 are involved in the development of ROP, and recent studies suggest that intravenous administration of Recombinant Human Insulin-Like Growth Factor (rhIGF-1) together with its binding protein-3 (rhIGFBP-3) is a promising method for the normalization of IGF-1 plasma concentrations in the first phase of ROP.107,108

Genetic discoveries are revolutionizing today’s medicine, but although there are several studies that have looked at the influence of different signaling pathways, the genetics of ROP is not yet elucidated.49 Several studies have implicated the theory that the G protein-coupled receptor kinase 5 (GRK5) has an important polymorphism that can desensitize beta-adrenoceptors and thus create resistance to noradrenergic factors.109 Blockade of beta-adrenoceptors by GRK5 polymorphism suggests that a similar pharmacologically induced blockade of these receptors may contribute to the reduction of neovascularization and thereby reduce the progression of retinopathy of prematurity.110 In addition, mutations in three genes involved in the etiology of familial exudative vitreoretinopathy by acting on the Wnt receptor signaling pathway (Frizzled-4, Low-density lipoprotein receptor-related protein 5, Norrin) have also recently been associated with an increased risk of developing severe forms of ROP.111–113 Genetic therapy aimed at targeting the expression and modulation of certain growth factors and cytokines incriminated in the development of ROP appears to be a promising therapeutic method for the future.114,115

Conclusion

These particularly vulnerable premature babies face a life in the dark with all the associated emotional, social and economic consequences should they not be diagnosed and treated in a timely manner. Since the first description of ROP, research on this pathology has been in a continuous dynamic with a view to preventing all these unfortunate repercussions. This motivation for research has brought major contributions to the management of ROP. Apart from BW, GA and oxygen therapy, certain biological parameters can indicate the risk of ROP occurrence. IGF-1 plays an important part in the development of this pathology, and several studies have been sustaining lately that the intravenous therapy with Recombinant Human Insulin-Like Growth Factor (rhIGF-1) together with its binding protein −3 (rhIGFBP-3) is a promising solution to normalize the plasmatic value of IGF-1 from the first phase of ROP. Starting from the idea that the kidneys and the retina have a similar embryological development, there have been recent reports to indicate a new potential risk factor, ie proteinuria.

The discovery of anti-VEGF agents that suppress pathological angiogenesis, has tipped the scales in favour of a better visual prognosis and new research rules out concerns about the interaction between these agents and the neurodevelopment of premature babies. Laser photocoagulation together with anti-VEGF agents have revolutionized the treatment of this pathology, currently being an important weapon against retinal neovascularization. In the aftermath of the implementation of digital imaging techniques, telescreening seems to be a promising option for diagnosing premature babies in disadvantaged areas. Also, the portable version of optical coherence tomography offers new perspectives on neonatal retinal imaging and artificial intelligence makes its presence increasingly felt among the ROP diagnostic methods.

Abbreviations

ROP, retinopathy of prematurity; OCT, optical coherence tomography; VEGF, vascular endothelial growth factor; NICU, neonatal intensive care unit; BW, birth weight; GA, gestational age GA; HIF-1, hypoxia-inducible factor-1; AAP, American Academy of Pediatrics; PaO2, partial oxygen pressure; IGF-1, insulin-like growth factor 1; PMA, postmenstrual age; IGFBP-3, IGF-binding protein 3; GMH-IVH, germinal matrix hemorrhage – intraventricular hemorrhage; AAO, American Academy of Ophthalmology; AI, artificial intelligence; DIAROP, Automated Deep Learning-Based Diagnostic Tool for Retinopathy of Prematurity; SD-OCT, spectral domain optical coherence tomography; ICROP, International Classification of Retinopathy of Prematurity; BEAT-ROP, Efficacy Study of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity; VEGF-A, vascular endothelial growth factor A; VEGF-B, vascular endothelial growth factor B; kDa, kilodaltons; rhIGF-1, recombinant human insulin-like growth factor 1; RAINBOW, Ranibizumab Compared With Laser Therapy for the Treatment of Infants Born Prematurely With Retinopathy of Prematurity; rhIGFBP-3, recombinant human insulin-like growth factor binding protein-3; GRK5, G protein-coupled receptor kinase 5.

Acknowledgments

The authors wish to acknowledge that the present article was supported by ‘Dunarea de Jos’ University of Galati, Romania.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The present study was supported by the Doctoral School of Biomedical Sciences, ‘Dunarea de Jos’ University of Galati, Romania.

Disclosure

The authors declare no conflicts of interest.

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