Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease that threatens the vision of premature infants. Various novel drugs have demonstrated therapeutic potential for ROP by targeting signaling pathways associated with vascular endothelial growth factor (VEGF) [such as PI3K/AKT, hypoxia-inducible factor (HIF)-1α/VEGF], oxidative stress, tumor necrosis factor (TNF)-α, and Notch pathways. Propranolol, insulin-like growth factor-1, and celecoxib attenuate pathological neovascularization via the PI3K/Akt signaling pathway. Tripterine and melatonin inhibit retinal neovascularization by modulating the HIF-1α/VEGF signaling axis. Adiponectin mitigates the damage caused by oxidative stress and preserves endothelial function by enhancing endothelial nitric oxide synthase activity. Omega-3 polyunsaturated fatty acids suppress TNF-α-mediated inflammatory responses, modulate retinal development and angiogenesis, and reduce retinal neovascular lesions. DAPT, a γ-secretase inhibitor, blocks Notch signaling to suppress abnormal vascular proliferation. These agents exhibit synergistic multi-pathway anti-angiogenic effects in preclinical models and early-phase clinical trials, offering critical insights for advancing drug development and clinical translation in ROP management.
Retinopathy of Prematurity/metabolism* ; Humans ; Signal Transduction/drug effects* ; Infant, Newborn ; Vascular Endothelial Growth Factor A/metabolism* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Oxidative Stress/drug effects* ; Fatty Acids, Omega-3/therapeutic use* ; Phosphatidylinositol 3-Kinases/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Receptors, Notch/metabolism* ; Angiogenesis Inhibitors/therapeutic use* ; Insulin-Like Growth Factor I/therapeutic use*

Retinopathy of prematurity (ROP) is a vision-threatening disorder that leads to pathological growth of the retinal vasculature due to hypoxia. Here, we investigated the potential effects of alamandine, a novel heptapeptide in the renin-angiotensin system (RAS), on hypoxia-induced retinal neovascularization and its underlying mechanisms. In vivo, the C57BL/6J mice with oxygen-induced retinopathy (OIR) were injected intravitreally with alamandine (1.0 μmol/kg per eye). In vitro, human retinal microvascular endothelial cells (HRMECs) were utilized to investigate the effects of alamandine (10 μg/mL) on proliferation, apoptosis, migration, and tubular formation under vascular endothelial growth factor (VEGF) stimulation. Single-cell RNA sequencing (scRNA-seq) matrix data from the Gene Expression Omnibus (GEO) database and RAS-related genes from the Molecular Signatures Database (MSigDB) were sourced for subsequent analyses. By integrating scRNA-seq data across multiple species, we identified that RAS-associated endothelial cell populations were highly related to retinal neovascularization. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed a significant decrease in alamandine levels in both the serum and retina of OIR mice compared to those in the control group. Next, alamandine ameliorated hypoxia-induced retinal pathological neovascularization and physiologic revascularization in OIR mice. In vitro, alamandine effectively mitigated VEGF-induced proliferation, scratch wound healing, and tube formation of HRMECs primarily by inhibiting the hypoxia-inducible factor-1α (HIF-1α)/VEGF pathway. Further, coincubation with D-Pro⁷ (Mas-related G protein-coupled receptor D (MrgD) antagonist) hindered the beneficial impacts of alamandine on hypoxia-induced pathological angiogenesis both in vivo and in vitro. Our findings suggested that alamandine could mitigate retinal neovascularization by targeting the MrgD-mediated HIF-1α/VEGF pathway, providing a potential therapeutic agent for OIR prevention and treatment.
Animals ; Retinal Neovascularization/prevention & control* ; Mice, Inbred C57BL ; Vascular Endothelial Growth Factor A/metabolism* ; Humans ; Mice ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Oligopeptides/therapeutic use* ; Signal Transduction/drug effects* ; Cell Proliferation/drug effects* ; Endothelial Cells/drug effects* ; Retinopathy of Prematurity/drug therapy* ; Apoptosis/drug effects* ; Cell Movement/drug effects* ; Renin-Angiotensin System/drug effects* ; Cells, Cultured

OBJECTIVE

This study determined the diagnostic accuracies of Growth and Retinopathy of Prematurity (GROP) criteria and a novel modified G-ROP criteria on identifying retinopathy of prematurity (ROP) in infants referred for screening at a tertiary hospital.

This was a single-center, cross-sectional, retrospective study. Medical records of infants referred for ROP screening from January 2012 to December 2021 were reviewed. Infants were labelled as “requiring ROP examination” if they met the 2020 Philippine Academy of Ophthalmology – ROP Working Group (PAO-ROPWG) screening consensus, G-ROP, or modified G-ROP criteria. We compared the accuracy of each criterion in predicting prethreshold ROP, evaluating sensitivity, specificity, and predictive values, as well as percentage of low-risk infants. Statistical analysis used Chi-square tests and one-way ANOVA with post hoc testing.

Of the 873 infants, 162 infants (18.6%) were noted to have ROP of any stage. Type 1 ROP developed in 15.4%, and type 2 ROP in 16.7%. The 2020 PAO-ROPWG consensus had 100% sensitivity (95% CI: 86.3%- 100%) in detecting type 1 and 2 ROP while 323 infants (37%) were low-risk. G-ROP criteria had 100% (95% CI: 86.3%-100%) sensitivity and 79.2% (95% CI: 76.4%-81.9%) specificity in predicting type 1 ROP, and 88.89% (95% CI: 70.84%-97.65%) sensitivity and 79.1% (95% CI: 76.2%-81.8%) specificity in predicting type 2 ROP, while 672 infants (77%) were classified as low-risk. Modified G-ROP criteria had a 100% (95% CI: 86.3%-100%) sensitivity in predicting type 1 and 2 ROP, 54.9% (95% CI: 51.5%-58.3%) and 55.1% (95% CI: 51.7%-58.5%) specificity in predicting type 1 and type 2 ROP, respectively, while 472 infants (54%) were classified as low-risk.

G-ROP and modified G-ROP criteria showed high sensitivity and better specificity compared to the 2020 PAO-ROPWG consensus. Their stricter criteria for gestational age and birth weight likely enhanced specificity. Further research is needed to confirm these findings in a broader population.

OBJECTIVE

To identify the current practices of ophthalmology subspecialists involved in the treatment of retinopathy of prematurity (ROP) in the Philippines.

A survey was conducted among members of the Vitreo-Retina Society of the Philippines (VRSP) and the Philippine Society of Pediatric Ophthalmology and Strabismus (PSPOS) who treat ROP. The electronic questionnaire covered treatment preferences and factors influencing these preferences regarding the use of anti-vascular endothelial growth factor (anti-VEGF), laser indirect ophthalmoscopy (LIO), cryotherapy, and surgical interventions. Questions about referral system and ROP recurrences encountered by the respondents were included.

A total of 73 out of 86 (85.00% response rate) possible respondents were included in the study, majority (80.82%) of whom were retina subspecialists. The initial treatment preference for type 1 ROP was laser indirect ophthalmoscopy (43.84%), while anti-VEGF injection (67.12%) was preferred for aggressive posterior ROP (APROP). Among the available anti-VEGF agents, bevacizumab was the most favored (68.11%). Most ROP consultations (59.79%) occurred through referrals, primarily from pediatricians or neonatologists (91.78%). Subspecialists reported encountering more recurrences with anti-VEGF injections compared to LIO. LIO was the most preferred treatment after failed initial anti-VEGF therapy, with most recurrences occurring in patients older than 50 weeks post-conceptual age.

This study underscored the diverse treatment practices for ROP in the Philippines, influenced by factors such as variable access to equipment or drugs, clinician experience with specific treatments, and ocular factors such as faster regression of neovascularization. LIO was preferred as the initial therapy for Type 1 ROP and for managing recurrences, while anti-VEGF injections were favored for APROP and as an alternative treatment for Type 1 ROP. Given the absence of an established standard for treating recurrent ROP cases, long-term monitoring is necessary to facilitate timely interventions and prevent blindness.

Objective To explore the role of the base mismatch repair gene Mutyh in retinopathy of prematurity(ROP). Methods Mutyh(-/-)and wild-type(WT)mice were used for the modeling of oxygen-induced retinopathy.The retinal oxidative stress was examined,and the ultrastructures of photoreceptors and mitochondria were observed.The biomarkers of photoreceptors and mitochondria were tested.Furthermore,the photoreceptor cell line 661W was treated with hydrogen peroxide for the modeling of oxidative stress.In the cell model,and the oxidative stress and photoreceptor functions in the cells were measured. Results In both the mouse and cell models,the expression of Mutyh was up-regulated.Mutyh knockout in mice and knockdown in cells exerted negative effects on photoreceptors and mitochondria.Mutyh overexpression showed protective functions in the cell model,indicating that Mutyh played a role in repairing photoreceptors and mitochondria. Conclusions Mutyh showed the potential to become a biomarker of ROP.Increasing Mutyh expression might have therapeutic effects on ROP,which needs further validation.
Oxidative Stress ; Animals ; Mice ; DNA Glycosylases/metabolism* ; Retinopathy of Prematurity/etiology* ; Mice, Knockout ; Disease Models, Animal ; Humans ; Mitochondria/metabolism*

OBJECTIVES: To study new biomarkers for the early diagnosis of retinopathy of prematurity (ROP) by analyzing the differences in blood metabolites based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) and metabolomics. METHODS: Dried blood spots were collected from 21 infants with ROP (ROP group) and 21 infants without ROP (non-ROP group) who were hospitalized in the Sixth Affiliated Hospital of Sun Yat-sen University from January 2013 to December 2016. LC-MS/MS was used to measure the metabolites, and orthogonal partial least squares-discriminant analysis was used to search for differentially expressed metabolites and biomarkers. RESULTS: There was a significant difference in blood metabolic profiles between the ROP and non-ROP groups. The pattern recognition analysis, Score-plot, and weight analysis obtained 10 amino acids with a relatively large difference. Further statistical analysis showed that the ROP group had significant increases in blood levels of glutamic acid, leucine, aspartic acid, ornithine, and glycine compared with the non-ROP group (P<0.05). The receiver operating characteristic curve analysis showed that glutamic acid and ornithine had the highest value in diagnosing ROP. CONCLUSIONS Blood metabolites in preterm infants with ROP are different from those without ROP. Glutamic acid and ornithine are the metabolic markers for diagnosing ROP. LC-MS/MS combined with metabolomics analysis has a potential application value in the early identification and diagnosis of ROP.
Infant, Newborn ; Infant ; Humans ; Tandem Mass Spectrometry ; Infant, Premature ; Chromatography, Liquid ; Retinopathy of Prematurity/diagnosis* ; Glutamic Acid ; Ornithine

Objective: To analyze the prevalence and the risk factors of fungal sepsis in 25 neonatal intensive care units (NICU) among preterm infants in China, and to provide a basis for preventive strategies of fungal sepsis. Methods: This was a second-analysis of the data from the "reduction of infection in neonatal intensive care units using the evidence-based practice for improving quality" study. The current status of fungal sepsis of the 24 731 preterm infants with the gestational age of <34⁺⁰ weeks, who were admitted to 25 participating NICU within 7 days of birth between May 2015 and April 2018 were retrospectively analyzed. These preterm infants were divided into the fungal sepsis group and the without fungal sepsis group according to whether they developed fungal sepsis to analyze the incidences and the microbiology of fungal sepsis. Chi-square test was used to compare the incidences of fungal sepsis in preterm infants with different gestational ages and birth weights and in different NICU. Multivariate Logistic regression analysis was used to study the outcomes of preterm infants with fungal sepsis, which were further compared with those of preterm infants without fungal sepsis. The 144 preterm infants in the fungal sepsis group were matched with 288 preterm infants in the non-fungal sepsis group by propensity score-matched method. Univariate and multivariate Logistic regression analysis were used to analyze the risk factors of fungal sepsis. Results: In all, 166 (0.7%) of the 24 731 preterm infants developed fungal sepsis, with the gestational age of (29.7±2.0) weeks and the birth weight of (1 300±293) g. The incidence of fungal sepsis increased with decreasing gestational age and birth weight (both P<0.001). The preterm infants with gestational age of <32 weeks accounted for 87.3% (145/166). The incidence of fungal sepsis was 1.0% (117/11 438) in very preterm infants and 2.0% (28/1 401) in extremely preterm infants, and was 1.3% (103/8 060) in very low birth weight infants and 1.7% (21/1 211) in extremely low birth weight infants, respectively. There was no fungal sepsis in 3 NICU, and the incidences in the other 22 NICU ranged from 0.7% (10/1 397) to 2.9% (21/724), with significant statistical difference (P<0.001). The pathogens were mainly Candida (150/166, 90.4%), including 59 cases of Candida albicans and 91 cases of non-Candida albicans, of which Candida parapsilosis was the most common (41 cases). Fungal sepsis was independently associated with increased risk of moderate to severe bronchopulmonary dysplasia (BPD) (adjusted OR 1.52, 95%CI 1.04-2.22, P=0.030) and severe retinopathy of prematurity (ROP) (adjusted OR 2.55, 95%CI 1.12-5.80, P=0.025). Previous broad spectrum antibiotics exposure (adjusted OR=2.50, 95%CI 1.50-4.17, P<0.001), prolonged use of central line (adjusted OR=1.05, 95%CI 1.03-1.08, P<0.001) and previous total parenteral nutrition (TPN) duration (adjusted OR=1.04, 95%CI 1.02-1.06, P<0.001) were all independently associated with increasing risk of fungal sepsis. Conclusions: Candida albicans and Candida parapsilosis are the main pathogens of fungal sepsis among preterm infants in Chinese NICU. Preterm infants with fungal sepsis are at increased risk of moderate to severe BPD and severe ROP. Previous broad spectrum antibiotics exposure, prolonged use of central line and prolonged duration of TPN will increase the risk of fungal sepsis. Ongoing initiatives are needed to reduce fungal sepsis based on these risk factors.
Infant ; Infant, Newborn ; Humans ; Birth Weight ; Intensive Care Units, Neonatal ; Retrospective Studies ; Tertiary Care Centers ; Infant, Extremely Low Birth Weight ; Gestational Age ; Infant, Extremely Premature ; Sepsis/epidemiology* ; Retinopathy of Prematurity/epidemiology* ; Bronchopulmonary Dysplasia/epidemiology*

Objectives. To determine the safety and efficacy of three different mydriatic regimens in premature infants referred for retinopathy of prematurity (ROP) screening using (1) multiple alternate instillations of 0.5% cyclopentolate hydrochloride and 2.5% phenylephrine (MAI), (2) single instillation of 0.5%/0.5% tropicamide + phenylephrine (SI) and (3) single instillation of 0.5%/0.5% tropicamide + phenylephrine with a cotton wick placed in the inferior fornix (SIW) in a Philippine tertiary hospital.

Methods. A randomized, double-blind, clinical trial included preterm infants for ROP screening at a Philippine tertiary hospital. After instillations via MAI, SI, and SIW, systolic blood pressure (SBP), diastolic pressure (DBP), mean arterial pressure (MAP), heart rate, and oxygen saturation were monitored. Pupillary dilation was also measured.

Results. Sixty preterm infants, 20 to each intervention, were included. The MAI group did not have significant changes relative to its baseline vital signs. The use of SI produced lower DBP (p<0.0106) and MAP (p<0.0027) compared to MAI. The use of SI produced lower DBP (p<0.01) and MAP (p<0.003) compared to MAI. The SIW group exhibited significant increases in SBP (p<0.002) and in MAP (p<0.04) compared to MAI. This increase in SBP exceeded the clinical normal values for <37 weeks old infants. Pupillary dilation did not have significant differences among groups (p=0.24).

Conclusion. Due to significant increase in SBP, it is recommended to discontinue SIW in preterm infants for ROP screening since it may promote the mydriatic's systemic absorption. Except for the clinically increased heart rate in infants aged ?37 weeks at examination, SI was found to be at par with the recommendation of the UK ROP Guidelines of May 2008.

OBJECTIVES: To investigate the efficacy of intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection in the treatment of retinopathy of prematurity (ROP) and the risk factors for recurrence. METHODS: A retrospective analysis was performed on the medical data of 159 infants with ROP who were born in the First Affiliated Hospital of Zhengzhou University and underwent anti-VEGF treatment from January 2016 to December 2021. According to the presence or absence of recurrence within the follow-up period after initial anti-VEGF treatment, they were divided into a recurrence group with 24 infants and a non-recurrence group with 135 infants. The medical data were compared between the two groups, and a multivariate logistic regression analysis was used to investigate the risk factors for the recurrence of ROP after anti-VEGF treatment. RESULTS: After one-time anti-VEGF treatment, all 159 infants showed regression of plus disease. Recurrence was observed in 24 infants (15.1%) after anti-VEGF treatment, with a mean interval of (8.4±2.6) weeks from treatment to recurrence. The multivariate logistic regression analysis showed that preoperative fundus hemorrhage and prolonged total oxygen supply time were risk factors for the recurrence of ROP (P<0.05), while gestational hypertension was a protective factor (P<0.05). CONCLUSIONS Intravitreal anti-VEGF injection is effective for ROP. Preoperative fundus hemorrhage and long duration of oxygen therapy may increase the risk of ROP recurrence, and further studies are needed to investigate the influence of gestational hypertension on the recurrence of ROP.
Female ; Humans ; Infant ; Infant, Newborn ; Pregnancy ; Angiogenesis Inhibitors/therapeutic use* ; Endothelial Growth Factors/therapeutic use* ; Hemorrhage ; Hypertension, Pregnancy-Induced ; Oxygen/therapeutic use* ; Retinopathy of Prematurity/drug therapy* ; Retrospective Studies ; Risk Factors ; Vascular Endothelial Growth Factor A

Objective: To investigate the incidence and trend of short-term outcomes among preterm infants born <34 weeks' gestation. Methods: A secondary analysis of data from the standardized database established by a multicenter cluster-randomized controlled study "reduction of infection in neonatal intensive care units (NICU) using the evidence-based practice for improving quality (REIN-EPIQ) study". This study was conducted in 25 tertiary NICU. A total of 27 192 infants with gestational age <34 weeks at birth and admitted to NICU within the first 7 days of life from May 2015 to April 2018 were enrolled. Infants with severe congenital malformation were excluded. Descriptive analyses were used to describe the mortality and major morbidities of preterm infants by gestational age groups and different admission year groups. Cochran-Armitage test and Jonckheere-Terpstra test were used to analyze the trend of incidences of mortality and morbidities in 3 study-years. Multiple Logistic regression model was constructed to analyze the differences of outcomes in 3 study-years adjusting for confounders. Results: A total of 27 192 preterm infants were enrolled with gestational age of (31.3±2.0) weeks at birth and weight of (1 617±415) g at birth. Overall, 9.5% (2 594/27 192) of infants were discharged against medical advice, and the overall mortality rate was 10.7% (2 907/27 192). Mortality for infants who received complete care was 4.7% (1 147/24 598), and mortality or any major morbidity was 26.2% (6 452/24 598). The incidences of moderate to severe bronchopulmonary dysplasia, sepsis, severe intraventricular hemorrhage or periventricular leukomalacia, proven necrotizing enterocolitis, and severe retinopathy of prematurity were 16.0% (4 342/27 192), 11.9% (3 225/27 192), 6.8% (1 641/24 206), 3.6% (939/25 762) and 1.5% (214/13 868), respectively. There was a decreasing of the overall mortality (P<0.001) during the 3 years. Also, the incidences for sepsis and severe retinopathy of prematurity both decreased (both P<0.001). However, there were no significant differences in the major morbidity in preterm infants who received complete care during the 3-year study period (P=0.230). After adjusting for confounders, infants admitted during the third study year showed significantly lower risk of overall mortality (adjust OR=0.62, 95%CI 0.55-0.69, P<0.001), mortality or major morbidity, moderate to severe bronchopulmonary dysplasia, sepsis and severe retinopathy of prematurity, compared to those admitted in the first study year (all P<0.05). Conclusions: From 2015 to 2018, the mortality and major morbidities among preterm infants in Chinese NICU decreased, but there is still space for further efforts. Further targeted quality improvement is needed to improve the overall outcome of preterm infants.
Bronchopulmonary Dysplasia/epidemiology* ; Gestational Age ; Humans ; Infant ; Infant Mortality/trends* ; Infant, Newborn ; Infant, Premature ; Infant, Premature, Diseases/epidemiology* ; Patient Discharge ; Retinopathy of Prematurity/epidemiology* ; Sepsis/epidemiology*