Validation of postnatal growth and retinopathy of prematurity (G-ROP) screening guidelines in a tertiary care hospital of Pakistan: A report from low-middle income country.

Retinopathy of Prematurity (ROP) significantly contributes to childhood blindness globally, with a disproportionately high burden in low- and middle-income countries (LMICs) due to improved neonatal care alongside inadequate ROP screening and treatment facilities. This study aims to validate the performance of Postnatal Growth and Retinopathy of Prematurity (G-ROP) screening criteria in a cohort of premature infants presenting at a tertiary care setting in Pakistan. This cross-sectional study utilized retrospective chart review of neonates admitted to the neonatal intensive care unit (NICU) at The Aga Khan University Hospital, Pakistan from January 2018 to February 2022. The complete G-ROP criteria were applied as prediction tool for infants with type 1 ROP, type 2 ROP, and no ROP outcomes. Out of the 166 cases, 125 cases were included in the final analysis, and remaining cases were excluded due to incomplete data. ROP of any stage developed in 83 infants (66.4%), of whom 55 (44%) developed type 1 ROP, 28 (22.4%) developed type 2 ROP, and 19 (15.2%) were treated for ROP. The median BW was 1060 gm (IQR = 910 to 1240 gm) and the median gestational age was 29 wk (IQR = 27 to 30 wk). The G-ROP criteria demonstrated a sensitivity of 98.18% (95% CI: 90.28-99.95%) for triggering an alarm for type 1 ROP. The G-ROP criteria achieved 100% sensitivity (95% CI: 87.66 to 100%) for type 2 ROP. The overall sensitivity of G-ROP criteria to trigger an alarm for any type of ROP was 98.8% (95% CI: 93.47 to 99.97%). Thus, the G-ROP screening model is highly sensitive in detecting at-risk infants for ROP in a Pakistani tertiary care setting, supporting its use in LMICs where standard screening criteria may not suffice.

Tear Proteomics in Infants at Risk of Retinopathy of Prematurity: A Feasibility Study.

Purpose: This feasibility study investigated the practicability of collecting and analyzing tear proteins from preterm infants at risk of retinopathy of prematurity (ROP). We sought to identify any tear proteins which might be implicated in the pathophysiology of ROP as well as prognostic markers. Methods: Schirmer's test was used to obtain tear samples from premature babies, scheduled for ROP screening, after parental informed consent. Mass spectrometry was used for proteomic analysis. Results: Samples were collected from 12 infants, which were all adequate for protein analysis. Gestational age ranged from 25 + 6 to 31 + 1 weeks. Postnatal age at sampling ranged from 19 to 66 days. One infant developed self-limiting ROP. Seven hundred one proteins were identified; 261 proteins identified in the majority of tear samples, including several common tear proteins, were used for analyses. Increased risk of ROP as determined by the postnatal growth ROP (G-ROP) criteria was associated with an increase in lactate dehydrogenase B chain in tears. Older infants demonstrated increased concentration of immunoglobulin complexes within their tear samples and two sets of twins in the cohort showed exceptionally similar proteomes, supporting validity of the analysis. Conclusions: Tear sampling by Schirmer test strips and subsequent proteomic analysis by mass spectrometry in preterm infants is feasible. A larger study is required to investigate the potential use of tear proteomics in identification of ROP. Translational Relevance: Tear sampling and subsequent mass spectrometry in preterm infants is feasible. Investigation of the premature tear proteome may increase our understanding of retinal development and provide noninvasive biomarkers for identification of treatment-warranted ROP.

Transient activation of retinopathy of prematurity secondary to erythrocyte suspension transfusion.

Retinopathy of prematurity (ROP) is a serious retinal vascular disorder that needs prompt diagnosis, and treatment to prevent undesired visual outcomes. Due to its shorter period of disease progression, it is important to be hasty in treating ROP. Erythrocyte suspension (ES) aggravates the progression of ROP. However, this progression may be transient as in the present case reports. This case report aimed to present two cases that developed type 1 ROP after erythrocyte suspension transfusion. Clinical findings of the patients were resolved within a few days without any intervention. Premature infants receiving ES treatment can be observed for 24-48 hours, and the treatment can be planned after determining the persistence of the plus sign. Abbreviations: ES = Erythrocyte suspension, ROP = Retinopathy of prematurity, NICU = neonatal intensive care unit.

Early Single-Examination Optical Coherence Tomography Biomarkers for Treatment-Requiring Retinopathy of Prematurity.

Purpose: Optical coherence tomography (OCT) is an emerging adjunct imaging modality to evaluate retinopathy of prematurity (ROP). From an 11-year research database, we identify early OCT biomarkers that predict treatment-requiring ROP (TR-ROP). Methods: For preterm infants with acceptable OCT images at 32 ± 1 weeks postmenstrual age (PMA), we extracted the following measures: total retina, inner retinal layer (IRL), and outer retinal layer (ORL) thicknesses at the fovea and the parafovea, inner nuclear layer (INL) and choroidal thickness, parafovea/fovea (P/F) ratio, and presence of macular edema. Using univariable and multivariable logistic regression models, we evaluated the association between retinal and choroidal OCT measurements at 32 ± 1 weeks PMA and development of TR-ROP. Results: Of 277 eyes (145 infants) with usable OCT images, 67 eyes had TR-ROP. Lower P/F ratio (P < 0.0001), thicker foveal IRL (P = 0.0001), and thinner choroid (P = 0.03) were associated with TR-ROP in univariable analysis, but lost significance of association when adjusted for gestational age and race. Absence of macular edema was associated with TR-ROP when adjusted for gestational age and race (P = 0.01). In 185 eyes without macular edema, P/F ratio was associated with TR-ROP in both univariable analysis (P < 0.0001) and multivariable analysis (P = 0.02) with adjustment for gestational age and race. Conclusions: Presence of macular edema at 32 ± 1 weeks PMA in infants with lower gestational age may be protective against TR-ROP. In infants without macular edema, P/F ratio may be an early OCT biomarker for development of TR-ROP. Incorporation of early OCT biomarkers may be useful in prediction of TR-ROP.

Risk factor-based models to predict severe retinopathy of prematurity in preterm Thai infants.

PURPOSE: To develop prediction models for severe retinopathy of prematurity (ROP) based on risk factors in preterm Thai infants to reduce unnecessary eye examinations in low-risk infants. METHODS: This retrospective cohort study included preterm infants screened for ROP in a tertiary hospital in Bangkok, Thailand, between September 2009 and December 2020. A predictive score model and a risk factor-based algorithm were developed based on the risk factors identified by a multivariate logistic regression analysis. Validity scores, and corresponding 95% confidence intervals (CIs), were reported. RESULTS: The mean gestational age and birth weight (standard deviation) of 845 enrolled infants were 30.3 (2.6) weeks and 1264.9 (398.1) g, respectively. The prevalence of ROP was 26.2%. Independent risk factors across models included gestational age, birth weight, no antenatal steroid use, postnatal steroid use, duration of oxygen supplementation, and weight gain during the first 4 weeks of life. The predictive score had a sensitivity (95% CI) of 92.2% (83.0, 96.6), negative predictive value (NPV) of 99.2% (98.1, 99.6), and negative likelihood ratio (NLR) of 0.1. The risk factor-based algorithm revealed a sensitivity of 100% (94, 100), NPV of 100% (99, 100), and NLR of 0. Similar validity was observed when "any oxygen supplementation" replaced "duration of oxygen supplementation." Predictive score, unmodified, and modified algorithms reduced eye examinations by 71%, 43%, and 16%, respectively. CONCLUSIONS: Our risk factor-based algorithm offered an efficient approach to reducing unnecessary eye examinations while maintaining the safety of infants at risk of severe ROP. Prospective validation of the model is required.

Macular Curvature in Adults Born Preterm With and Without ROP: Results from the Gutenberg Prematurity Eye Study.

Purpose: This study investigated the effects of prematurity and retinopathy of prematurity (ROP) as well as the associations of the ocular geometry with macular curvature in adults. Methods: The Gutenberg Prematurity Eye Study is a retrospective cohort study of preterm and full-term participants aged 18 to 52 years with a prospective ophthalmologic examination. The main outcome measure was the macular curvature in the central foveal optical coherence tomography (OCT) scan and its associations with gestational age (GA), birth weight and birth weight percentile, ROP occurrence, ROP treatment, and other perinatal factors were evaluated in univariable and multivariable linear regression analyses. Furthermore, a second model assessed the association of ocular geometry with macular curvature. Results: In the present study, 550 eyes of 284 adults born preterm and 277 eyes of 139 adults born full-term were examined (aged = 28.7 ± 8.7 years, 240 female subjects). In multivariable analyses for perinatal parameters, ROP treatment (B = -52.44, P = 0.023) and maternal smoking during pregnancy (B = 26.41, P = 0.019) showed an association with macular curvature. Regarding ocular geometric parameters, posterior segment length (B = 9.07, P < 0.001) and subfoveal choroidal thickness (B = -0.26, P < 0.001) were associated with macular curvature, central corneal thickness, anterior chamber depth, lens thickness, and foveal retinal thickness were not associated. Conclusions: Adults treated for ROP had relatively more negative curvature values compared to the full-term group, indicating a macular protrusion toward the vitreous cave. A thicker subfoveal choroidal thickness was associated with a flatter macular curvature, whereas a longer posterior segment length was associated with a steeper macular curvature indicating the characteristics of the myopic elongation of the eye.

Multinational External Validation of Autonomous Retinopathy of Prematurity Screening.

Importance: Retinopathy of prematurity (ROP) is a leading cause of blindness in children, with significant disparities in outcomes between high-income and low-income countries, due in part to insufficient access to ROP screening. Objective: To evaluate how well autonomous artificial intelligence (AI)-based ROP screening can detect more-than-mild ROP (mtmROP) and type 1 ROP. Design, Setting, and Participants: This diagnostic study evaluated the performance of an AI algorithm, trained and calibrated using 2530 examinations from 843 infants in the Imaging and Informatics in Retinopathy of Prematurity (i-ROP) study, on 2 external datasets (6245 examinations from 1545 infants in the Stanford University Network for Diagnosis of ROP [SUNDROP] and 5635 examinations from 2699 infants in the Aravind Eye Care Systems [AECS] telemedicine programs). Data were taken from 11 and 48 neonatal care units in the US and India, respectively. Data were collected from January 2012 to July 2021, and data were analyzed from July to December 2023. Exposures: An imaging processing pipeline was created using deep learning to autonomously identify mtmROP and type 1 ROP in eye examinations performed via telemedicine. Main Outcomes and Measures: The area under the receiver operating characteristics curve (AUROC) as well as sensitivity and specificity for detection of mtmROP and type 1 ROP at the eye examination and patient levels. Results: The prevalence of mtmROP and type 1 ROP were 5.9% (91 of 1545) and 1.2% (18 of 1545), respectively, in the SUNDROP dataset and 6.2% (168 of 2699) and 2.5% (68 of 2699) in the AECS dataset. Examination-level AUROCs for mtmROP and type 1 ROP were 0.896 and 0.985, respectively, in the SUNDROP dataset and 0.920 and 0.982 in the AECS dataset. At the cross-sectional examination level, mtmROP detection had high sensitivity (SUNDROP: mtmROP, 83.5%; 95% CI, 76.6-87.7; type 1 ROP, 82.2%; 95% CI, 81.2-83.1; AECS: mtmROP, 80.8%; 95% CI, 76.2-84.9; type 1 ROP, 87.8%; 95% CI, 86.8-88.7). At the patient level, all infants who developed type 1 ROP screened positive (SUNDROP: 100%; 95% CI, 81.4-100; AECS: 100%; 95% CI, 94.7-100) prior to diagnosis. Conclusions and Relevance: Where and when ROP telemedicine programs can be implemented, autonomous ROP screening may be an effective force multiplier for secondary prevention of ROP.

Automated diagnosis of plus disease in retinopathy of prematurity using quantification of vessels characteristics.

The condition known as Plus disease is distinguished by atypical alterations in the retinal vasculature of neonates born prematurely. It has been demonstrated that the diagnosis of Plus disease is subjective and qualitative in nature. The utilization of quantitative methods and computer-based image analysis to enhance the objectivity of Plus disease diagnosis has been extensively established in the literature. This study presents the development of a computer-based image analysis method aimed at automatically distinguishing Plus images from non-Plus images. The proposed methodology conducts a quantitative analysis of the vascular characteristics linked to Plus disease, thereby aiding physicians in making informed judgments. A collection of 76 posterior retinal images from a diverse group of infants who underwent screening for Retinopathy of Prematurity (ROP) was obtained. A reference standard diagnosis was established as the majority of the labeling performed by three experts in ROP during two separate sessions. The process of segmenting retinal vessels was carried out using a semi-automatic methodology. Computer algorithms were developed to compute the tortuosity, dilation, and density of vessels in various retinal regions as potential discriminative characteristics. A classifier was provided with a set of selected features in order to distinguish between Plus images and non-Plus images. This study included 76 infants (49 [64.5%] boys) with mean birth weight of 1305 ± 427 g and mean gestational age of 29.3 ± 3 weeks. The average level of agreement among experts for the diagnosis of plus disease was found to be 79% with a standard deviation of 5.3%. In terms of intra-expert agreement, the average was 85% with a standard deviation of 3%. Furthermore, the average tortuosity of the five most tortuous vessels was significantly higher in Plus images compared to non-Plus images (p ≤ 0.0001). The curvature values based on points were found to be significantly higher in Plus images compared to non-Plus images (p ≤ 0.0001). The maximum diameter of vessels within a region extending 5-disc diameters away from the border of the optic disc (referred to as 5DD) exhibited a statistically significant increase in Plus images compared to non-Plus images (p ≤ 0.0001). The density of vessels in Plus images was found to be significantly higher compared to non-Plus images (p ≤ 0.0001). The classifier's accuracy in distinguishing between Plus and non-Plus images, as determined through tenfold cross-validation, was found to be 0.86 ± 0.01. This accuracy was observed to be higher than the diagnostic accuracy of one out of three experts when compared to the reference standard. The implemented algorithm in the current study demonstrated a commendable level of accuracy in detecting Plus disease in cases of retinopathy of prematurity, exhibiting comparable performance to that of expert diagnoses. By engaging in an objective analysis of the characteristics of vessels, there exists the possibility of conducting a quantitative assessment of the disease progression's features. The utilization of this automated system has the potential to enhance physicians' ability to diagnose Plus disease, thereby offering valuable contributions to the management of ROP through the integration of traditional ophthalmoscopy and image-based telemedicine methodologies.

Ophthalmic sequelae of prematurity in late childhood and adulthood: A review.

Advances in the care of premature infants have resulted in unprecedented rates of survival of these infants into adulthood, including those born at very low gestational ages. Ophthalmologists have historically followed premature infants to assess for the presence of and potential need for treatment of retinopathy of prematurity. However, a growing body of literature suggests that the ophthalmic consequences of prematurity extended beyond retinopathy of prematurity and that ophthalmic sequelae of prematurity can endure through adulthood even among formerly preterm adults who were never diagnosed with retinopathy of prematurity. These abnormalities can include a range of both anterior segment and posterior segment sequelae, including higher rates of corneal aberrations, ocular hypertension, strabismus, foveal anomalies, and retinal tears and detachments. This review aims to summarise this literature, underscoring the importance of lifelong examinations and regular monitoring for these complications among adults who were born prematurely.

The impact of blood lactic acid levels on retinopathy of prematurity morbidity.

BACKGROUND: Retinopathy of prematurity (ROP) is a common disease in premature infants. In recent years, most researchers have used lactic acid as poor prognosis marker in premature infants. This study aims to explore investigate the impact of blood lactic acid levels on ROP. METHODS: A retrospective case-control study was conducted, and infants with severe ROP born with birth weight (BW) ≤ 1500 g and gestational age (GA) ≤ 32 weeks were enrolled from November 2016 to November 2021. Infants without any stage ROP were included as controls and were matched with ROP infants (1:2) by GA and BW. All selected preterm infants were tested for heel terminal trace blood gas analysis within two weeks of life. Changes in blood lactic acid levels in the two groups were compared and analyzed by using multivariate logistic regression analysis. Sensitivity and specificity were analyzed by receiver operating characteristic (ROC) curve. RESULTS: There were 79 infants in ROP group, and 158 infants in control group. The levels of blood lactic acid were significantly higher in the ROP group on days 1, 3, 5, and 7 compared with control group (all p < 0.05). The blood lactic acid levels on day 5 was an independent risk factor for ROP (p = 0.017). The area under the curve (AUC), sensitivity and specificity were highest on day 5 (AUC 0.716, sensitivity 77.2% and specificity 62.0%, respectively, p < 0.001), and higher on days 1, 3, and 7. CONCLUSION: A high blood lactic acid level in the first seven days of life may be associated with increases ROP occurrence in very preterm infants, and suggest blood lactic acid level may impact the occurrence of ROP.

Prevalence and causes of ocular disorders and visual impairment among preterm children in Ethiopia.

OBJECTIVE: The aim of this study was to determine the prevalence, causes of ocular disorders and visual impairment among preterm children previously admitted to neonatal intensive care units in Addis Ababa, Ethiopia. METHODS AND ANALYSIS: A prospective screening survey was conducted from February to June 2019 at the paediatric eye clinic of Menelik II Hospital. Children who were preterm at birth and who attended the eye clinic were included in the study. Data on demographic and neonatal characteristics, neonatal and maternal comorbidities and ocular disorders were collected. OR and univariate analysis were used to identify predictors of ocular diseases and visual impairment. RESULTS: There were 222 children included in the study with a mean age at presentation of 2.62 years (range 2.08-6.38 years), mean gestational age 34.11 weeks (range 30-36) weeks and mean birth weight 1941.72 g (range 953-3500 g). Nearly two-thirds had ocular disorders with refractive error (51.8%), strabismus (11.3%) and a history of retinopathy of prematurity (ROP) (7.2%) being more common. One-fourth of the children had visual impairment, and the prevalence of amblyopia was 40.1%. Uncorrected refractive errors, strabismus and ROP were causes for visual impairment. CONCLUSION: Visual impairment and amblyopia are common in Ethiopia. There is a need to develop a screening protocol for ocular disorders for preterm children to enhance early detection and prevention of childhood visual impairment.

Lensectomy as treatment for refractory or progressive retinopathy of prematurity narrow-angle glaucoma.

We present the case of a patient with a history of laser-treated retinopathy of prematurity (ROP) who developed narrow angles and intermittent angle closure. Despite laser peripheral iridotomy/iridoplasty, 1 year later, the patient had recurrent narrowing that resolved following clear lens extraction with intraocular lens placement. This case highlights the importance of continued monitoring for narrow angles in patients with ROP history.

Unilateral Retinopathy in a Preterm Infant With 4q Duplication: Description and Management.

A 33-5/7, 1570 g dichorionic diamniotic twin presented with cryptorchidism, failed hearing examination (both ears), poor feeding, profound hypoglycemia, coagulopathy, conjugated hyper-bilirubinemia, hydronephrosis, and hypotension. Microarray sent with results of whole genome SNP microgray analysis detected an interstitial duplication of the chromosomal segment 4q35 1q35.2. On this basis, telemedicine screening was performed to evaluate for ocular abnormalities in association with abnormal gene testing. Unilateral advanced retinopathy was noted affecting the right eye, with mature vascularization in the left eye. This infant was managed in concordance with retinopathy of prematurity guidelines, despite not making screening criteria. Off-label intravitreal bevacizumab injection (0.625 mg in 0.025 mL) resulted in full vascular maturation assessed by fluorescein angiography 6 months later. This represents the first description and management of retinopathy in 4q duplication syndrome. [Ophthalmic Surg Lasers Imaging Retina 2024;55:228-230.].

Determinants of compliance with outpatient examinations for infants at risk for retinopathy of prematurity.

PURPOSE: To assess the level and the determinants of compliance with outpatient retinopathy of prematurity (ROP) examination appointments at a tertiary academic center. METHODS: The medical records of babies scheduled for outpatient ROP examination between January 1, 2022, and December 31, 2022, were reviewed retrospectively. Data collected included appointments scheduled and attended, birth weight, gestational age, ROP staging at discharge, maternal ethnicity (self-identified), household type, proximity to hospital and median family income (US Census based on home zip codes). Univariate and multivariable analyses were performed. A P value of <0.05 was considered significant. RESULTS: The records of 66 babies were analyzed. Forty-nine babies (74%) attended all scheduled ROP examination appointments (fully compliant). The mean appointment compliance rate was 86%, with a 1.5% no-show rate. Seven children (11%) required the intervention of Child Protective Services. One baby was never seen in the clinic. In unadjusted analysis, maternal ethnicity (P = 0.028) and median family income lower than the national average (P = 0.049) were sociodemographic factors associated with lower compliance. Clinical factors associated with lower compliance were lower gestational ages (P = 0.005) and lower birth weight (P = 0.006). In multivariable logistic regression adjusting for all candidate predictors, only birth weight remained significantly associated with lower compliance (P = 0.036). CONCLUSIONS: Clinical and sociodemographic factors may be associated with compliance with outpatient ROP examination recommendations. Extremely low-birth-weight babies were at the greatest risk for noncompliance.

Implementation of optical coherence tomography in retinopathy of prematurity screening.

PURPOSE OF REVIEW: In this review, we explore the investigational applications of optical coherence tomography (OCT) in retinopathy of prematurity (ROP), the insights they have delivered thus far, and key milestones for its integration into the standard of care. RECENT FINDINGS: While OCT has been widely integrated into clinical management of common retinal diseases, its use in pediatric contexts has been undermined by limitations in ergonomics, image acquisition time, and field of view. Recently, investigational handheld OCT devices have been reported with advancements including ultra-widefield view, noncontact use, and high-speed image capture permitting real-time en face visualization. These developments are compelling for OCT as a more objective alternative with reduced neonatal stress compared to indirect ophthalmoscopy and/or fundus photography as a means of classifying and monitoring ROP. SUMMARY: OCT may become a viable modality in management of ROP. Ongoing innovation surrounding handheld devices should aim to optimize patient comfort and image resolution in the retinal periphery. Future clinical investigations may seek to objectively characterize features of peripheral stage and explore novel biomarkers of disease activity.

Management of Icteric Vitreous, Retinal Opacification, and Atypical Retinopathy of Prematurity.

A dichorionic, diamniotic twin born at 24-0/7 weeks and 740 g developed hyperbilirubinemia, necrotizing enterocolitis, and sepsis. Photographic imaging documented vitreous opacification, which was absent in the fellow twin. Retinal opacification was presumed secondary to embolic sepsis and responded to systemic antibiotics. Subsequent dropout of vascularized retina corresponded to areas of retinal opacification. Type 1 retinopathy of prematurity (ROP)-Zone I, Stage 3 ROP bilateral-demonstrated a rapid and durable response to off-label intravitreal bevacizumab 0.625 mg. Retinal opacification resolved between 39 and 40 weeks postmenstrual age. Systemic comorbidities may alter the appearance, course, and management of ROP. [Ophthalmic Surg Lasers Imaging Retina 2024;55:164-167.].