Vascular development analysis: a study for tertiary anti-vascular endothelial growth factor therapy after second reactivation of retinopathy of prematurity.

Purpose: To observe the vascular development results of tertiary anti-vascular endothelial growth factor (anti-VEGF) therapy following spontaneous second reactivation of retinopathy of prematurity (ROP). Methods: This retrospective study included 22 infants (42 eyes) with Type 1 or aggressive ROP (A-ROP) who received three anti-VEGF drug treatments for ROP from January 2018 to December 2022. The vascular growth, possible associated risk factors, and the retinal vascularization (DB/DF ratio) were assessed. Results: The mean follow-up was 17.6 months. After the 3rd intravitreal injection, seven eyes showed complete vascularization (Group 1), while the remaining 35 eyes demonstrated persistent avascular retina (PAR) (Group 2). In Group 2, 17 eyes maintained a stable state and were classified in the regression subgroup. The other 18 eyes developed a 3rd reactivation (reactivation subgroup) and were treated with laser photocoagulation (LPC).Birth weight (BW) was significantly lower in Group 2 than in Group 1 (p < 0.001). The decision tree analysis shows that only infants weighing more than 1,250 g (17.50%) had a chance to achieve complete retinal vascularization. The possibility of PAR was higher in patients with BW <1,250 g than ≥1,250 g (70.00% vs. 12.50%). In addition, most infants with BW ≥ 1,290 g and initial ROP disease in Zone I or posterior Zone II developed PAR. Conclusion: Tertiary IVR can successfully treat a second ROP reactivation and improve peripheral retinal vascularization. BW is the most significant factor related to complete retinal vascularization. Our decision tree model may be helpful in predicting the prognosis of anti-VEGF drugs in the event of a second ROP reactivation.

Predictive Role of Fluorescein Angiography in Retinopathy of Prematurity.

BACKGROUND: Fluorescein angiography (FA) has been a pivotal tool for studying the pathophysiology of retinopathy of prematurity (ROP) in vivo. We examined the course of ROP using FA to assess the predictive value of angiographic features. METHODS: This is an observational retrospective cohort study of eyes screened for ROP with a binocular indirect ophthalmoscope and FA. RetCam fundus imaging and video digital fluorescein angiography were performed in the neonatal intensive care unit of Santa Maria Hospital of Perugia. The masked grading of the FA images was retrospectively conducted by two ROP expert ophthalmologists. RESULTS: A total of 80 eyes of 40 patients were included for this study. Among the angiographic features evaluated, leakage, shunts, and tangles were predictive of the development of treatment-requiring ROP (p < 0.05). CONCLUSIONS: FA can add to our understanding of the evolution of vascular abnormalities in the course of ROP and can help predict which eyes will go on to treatment.

An Interpretable System for Screening the Severity Level of Retinopathy in Premature Infants Using Deep Learning.

Accurate evaluation of retinopathy of prematurity (ROP) severity is vital for screening and proper treatment. Current deep-learning-based automated AI systems for assessing ROP severity do not follow clinical guidelines and are opaque. The aim of this study is to develop an interpretable AI system by mimicking the clinical screening process to determine ROP severity level. A total of 6100 RetCam Ⅲ wide-field digital retinal images were collected from Guangdong Women and Children Hospital at Panyu (PY) and Zhongshan Ophthalmic Center (ZOC). A total of 3330 images of 520 pediatric patients from PY were annotated to train an object detection model to detect lesion type and location. A total of 2770 images of 81 pediatric patients from ZOC were annotated for stage, zone, and the presence of plus disease. Integrating stage, zone, and the presence of plus disease according to clinical guidelines yields ROP severity such that an interpretable AI system was developed to provide the stage from the lesion type, the zone from the lesion location, and the presence of plus disease from a plus disease classification model. The ROP severity was calculated accordingly and compared with the assessment of a human expert. Our method achieved an area under the curve (AUC) of 0.95 (95% confidence interval [CI] 0.90-0.98) in assessing the severity level of ROP. Compared with clinical doctors, our method achieved the highest F1 score value of 0.76 in assessing the severity level of ROP. In conclusion, we developed an interpretable AI system for assessing the severity level of ROP that shows significant potential for use in clinical practice for ROP severity level screening.

Risk factors for the time to development of retinopathy of prematurity in premature infants in Iran: a machine learning approach.

BACKGROUND: Retinopathy of prematurity (ROP), is a preventable leading cause of blindness in infants and is a condition in which the immature retina experiences abnormal blood vessel growth. The development of ROP is multifactorial; nevertheless, the risk factors are controversial. This study aimed to identify risk factors of time to development of ROP in Iran. METHODS: This historical cohort study utilized data from the hospital records of all newborns referred to the ROP department of Farabi Hospital (from 2017 to 2021) and the NICU records of infants referred from Mahdieh Hospital to Farabi Hospital. Preterm infants with birth weight (BW) ≤ 2000 g or gestational age (GA) < 34 wk, as well as selected infants with an unstable clinical course, as determined by their pediatricians or neonatologists, with BW > 2000 g or GA ≥ 34 wk. The outcome variable was the time to development of ROP (in weeks). Random survival forest was used to analyze the data. RESULTS: A total of 338 cases, including 676 eyes, were evaluated. The mean GA and BW of the study group were 31.59 ± 2.39 weeks and 1656.72 ± 453.80 g, respectively. According to the criteria of minimal depth and variable importance, the most significant predictors of the time to development of ROP were duration of ventilation, GA, duration of oxygen supplementation, bilirubin levels, duration of antibiotic administration, duration of Total Parenteral Nutrition (TPN), mother age, birth order, number of surfactant administration, and on time screening. The concordance index for predicting survival of the fitted model was 0.878. CONCLUSION: Our findings indicated that the duration of ventilation, GA, duration of oxygen supplementation, bilirubin levels, duration of antibiotic administration, duration of TPN, mother age, birth order, number of surfactant administrations, and on time screening are potential risk factors of prognosis of ROP. The associations between identified risk factors were mostly nonlinear. Therefore, it is recommended to consider the nature of these relationships in managing treatment and designing early interventions.

Oxygen in the neonatal ICU: a complicated history and where are we now?

Despite major advances in neonatal care, oxygen remains the most commonly used medication in the neonatal intensive care unit (NICU). Supplemental oxygen can be life-saving for term and preterm neonates in the resuscitation period and beyond, however use of oxygen in the neonatal period must be judicious as there can be toxic effects. Newborns experience substantial hemodynamic changes at birth, rapid energy consumption, and decreased antioxidant capacity, which requires a delicate balance of sufficient oxygen while mitigating reactive oxygen species causing oxidative stress. In this review, we will discuss the physiology of neonates in relation to hypoxia and hyperoxic injury, the history of supplemental oxygen in the delivery room and beyond, supporting clinical research guiding trends for oxygen therapy in neonatal care, current practices, and future directions.

Longitudinal analysis of carotenoid content in preterm human milk.

To describe the variability in carotenoid content of human milk (HM) in mothers of very to extremely low birth weight preterm infants throughout lactation and to explore the relationship between lutein in HM and the occurrence of retinopathy of prematurity (ROP) in preterm infants. We recruited healthy mothers along with their preterm infants that were born at gestational age 24 + 2 to 29 + 6 weeks or with a birth weight under 1500 g and were exclusively breastfed HM. Each participant provided up to 7 HM samples (2-10 ml) on day 0-3 and once a week until 6 weeks. Additionally, when possible, a blood sample was collected from the infant at week 6. Concentrations of the major carotenoids (lutein, zeaxanthin, beta-carotene, and lycopene) in all HM and blood samples were assessed and compared. Thirty-nine mother-infant dyads were included and 184 HM samples and 21 plasma samples were provided. Mean lutein, zeaxanthin, beta-carotene, and lycopene concentration decreased as lactation progressed, being at their highest in colostrum samples (156.9 vs. 66.9 vs. 363.9 vs. 426.8 ng/ml, respectively). Lycopene (41%) and beta-carotene (36%) were the predominant carotenoids in colostrum and up to 2 weeks post-delivery. Inversely, the proportion of lutein and zeaxanthin increased with lactation duration to account for 45% of the carotenoids in mature HM. Lutein accounted for 58% of the carotenoids in infant plasma and only 28% in HM. Lutein content of transition and mature HM did not differ between mothers of ROP and non-ROP infants.Conclusion Carotenoid content of HM was dynamic and varied between mothers and as lactation progressed. Infant plasma displayed a distinct distribution of carotenoids from HM.

Outcomes of Modified Limbal Lensectomy-Vitrectomy in Stages 4B and 5 Retinopathy of Prematurity with Extended Retrolental Fibroplasia.

PURPOSE: To report on the anatomical and functional outcomes of a modified limbal lensectomy-vitrectomy (LV) approach for stages 4B and 5 retinopathy of prematurity (ROP) as defined in the International Classification of Retinopathy of Prematurity, 3rd Edition (ICROP 3). DESIGN: Retrospective, monocentric, consecutive case series. PATIENTS: Infants with ROP that underwent limbal LV for diffuse retrolental fibroplasia. METHODS: Clinical charts and Retcam photographs were reviewed. Surgical approach consisted of a limbal LV through peripheral iridectomies with centripetal dissection of the preretinal fibrosis. MAIN OUTCOME MEASURES: Anatomical success and visual function at last follow-up were evaluated. Multivariate logistic regression was used to explore potential prognostic factors affecting the anatomical outcome. RESULTS: A total of 128 eyes of 81 patients with a mean gestational age of 28.7 ± 3.0 weeks and a mean birthweight of 1244 ± 429 g were included. Eighteen eyes (14.1%) had a stage 4B, 24 (18.8%) a stage 5B, and 86 a stage 5C (67.2%) ROP. Mean age at surgery was 57.4 ± 36.3 weeks and mean postoperative follow-up was 22.7 ± 20.4 months. Only 5 eyes (3.9%) had prior peripheral retinal ablation. Macular reattachment was achieved in 74 eyes (57.8%). Controlling for other baseline factors, a stage 5C (versus stage 4B, odds ratio [OR] = 6.9 [1.5-32.1], P = 0.01 and versus stage 5B, OR = 7.4 [1.5-37.1], P = 0.02), the presence of vascular activity (OR = 6.4 [2.3-18.1], P < 0.001), and the presence of Schlieren sign (OR = 13.0 [2.1-82.2], P = 0.006) were associated with a failure of macular reattachment. Visual acuity was assessed in 92 eyes (71.9%), among which 59 eyes (64.1%) had light perception or better. CONCLUSIONS: Modified limbal LV resulted in macular reattachment in more than half of eyes with ROP-related retinal detachment and diffuse retrolental fibrosis. A stage 5C based on ICROP 3, the presence of vascular activity, and a Schlieren sign were significantly associated with a failure of macular reattachment. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Image-free recognition of moderate ROP from mild with machine learning algorithm on plasma Raman spectrum.

The retinopathy of prematurity (ROP) can cause serious clinical consequences and, fortunately, it is remediable while the time window for treatment is relatively narrow. Therefore, it is urgent to screen all premature infants and diagnose ROP degree timely, which has become a large workload for pediatric ophthalmologists. We developed a retinal image-free procedure using small amount of blood samples based on the plasma Raman spectrum with the machine learning model to automatically classify ROP cases before medical intervention was performed. Statistical differences in infrared Raman spectra of plasma samples were found among the control, mild (ZIIIS1), moderate (ZIIIS2 & ZIIS1), and advanced (ZIIS2) ROP groups. With the different wave points of Raman spectra as the inputs, the outputs of our support vector machine showed that the area under the curves in the receiver operating characteristic (AUC) were 0.763 for the pair comparisons of the control with the mild groups, 0.821 between moderate and advanced groups (ZIIS2), while more than 90% in comparisons of the other four pairs: control vs. moderate (0.981), control vs. advanced (0.963), mild vs. moderate (0.936), and mild vs. advanced (0.953), respectively. Our study could advance principally the ROP diagnosis in two dimensions: the moderate ROPs have been classified remarkably from the mild ones, which leaves more time for the medical treatments, and the procedure of Raman spectrum with a machine learning model based on blood samples can be conveniently promoted to those hospitals lacking of the pediatric ophthalmologists with experience in reading retinal images.

The Effects of Early Enteral and Parental Nutrition on Retinopathy of Prematurity: A Systematic Review.

The management of preterm newborns must consider the severe problem of retinopathy of prematurity (ROP). A systematic review has been conducted to effectively acknowledge how enteral and parenteral early nutrition affect the growth and progression of ROP. The study summarizes recent findings from various sources to give insight into the relationship between dietary practices and ROP risks. When untreated, retinopathy of prematurity (ROP) may cause severe vision loss or blindness in premature newborns. The latter two phases of ROP progression are the most serious. A child's early nutrition, both orally and intravenously, significantly impacts the severity and progression of ROP. This systematic review aims to examine the evidence linking early nutrition to ROP in premature infants. The study used Embase, Scopus, and PubMed to conduct our search. ROP, premature newborns, and nutrition were keywords used to find relevant papers. Nine research studies made it through the screening process and offered important information on the impact of diet on ROP. These studies support the idea that poor nutrition is a driving force behind the onset of ROP. The risk of ROP has been associated with postnatal development, hyperglycemia, polyunsaturated fatty acid levels, and the presence of breast milk. The outlook for ROP has also been discovered to be affected by the length of time the patient has received parenteral feeding. The incidence and severity of ROP may be mitigated by providing better nutrition to premature newborns. This comprehensive study concludes that early nutrition, both enteral and parenteral, substantially influences the development and progression of ROP in premature newborns. The significance of nutrition in newborn care is highlighted by the possibility that improved dietary methods might aid in preventing and treating this vision-threatening illness.

Central macular morphology and optic nerve fibre layer thickness in young adults born premature and screened for retinopathy of prematurity.

PURPOSE: To investigate central retinal morphology and optic retinal nerve fibre layer (RNFL) in prematurely born young adults and compare to term born controls. MATERIALS AND METHODS: The participants were 59 prematurely born individuals, with a birthweight ≤1.500 g, and 44 term born controls, all 25-29 years of age. Visual acuity (VA) and contrast sensitivity (CS) were assessed. The retinal macular thickness, ganglion cell-inner plexiform layer (GC-IPL) thickness and RNFL thickness were assessed with Cirrus optical coherence tomography (OCT). RESULTS: Central macular thickness was increased (mean 26.7 µm) in prematurely born individuals compared to controls. The macular GC-IPL was thinner (mean 3.84 µm), also when excluding those with previous retinopathy of prematurity (ROP) and those with neurological complications. Gestational age at birth and previous treatment of ROP were risk factors for a thicker macula, however, not for reduced GC-IPL. The average peripapillary RNFL was thinner (mean 4.61 µm) in the prematurely born individuals, also when excluding those with previous ROP and/or neurological complications. Within the prematurely born group, treated ROP was correlated with increased average RNFL. Further, both better VA and CS were associated with thinner optic nerve RNFL and thicker average GC-IPL. CONCLUSION: Macular and optic nerve morphology were influenced by premature birth as assessed with OCT in adult individuals. Gestational age at birth and treatment for ROP seemed to affect central macular thickness, and treated ROP affected the peripapillary RNFL. Thus, retinal sequelae remained in adulthood.

ROP-GAN: an image synthesis method for retinopathy of prematurity based on generative adversarial network.

Objective. Training data with annotations are scarce in the intelligent diagnosis of retinopathy of prematurity (ROP), and existing typical data augmentation methods cannot generate data with a high degree of diversity. In order to increase the sample size and the generalization ability of the classification model, we propose a method called ROP-GAN for image synthesis of ROP based on a generative adversarial network.Approach. To generate a binary vascular network from color fundus images, we first design an image segmentation model based on U2-Net that can extract multi-scale features without reducing the resolution of the feature map. The vascular network is then fed into an adversarial autoencoder for reconstruction, which increases the diversity of the vascular network diagram. Then, we design an ROP image synthesis algorithm based on a generative adversarial network, in which paired color fundus images and binarized vascular networks are input into the image generation model to train the generator and discriminator, and attention mechanism modules are added to the generator to improve its detail synthesis ability.Main results. Qualitative and quantitative evaluation indicators are applied to evaluate the proposed method, and experiments demonstrate that the proposed method is superior to the existing ROP image synthesis methods, as it can synthesize realistic ROP fundus images.Significance. Our method effectively alleviates the problem of data imbalance in ROP intelligent diagnosis, contributes to the implementation of ROP staging tasks, and lays the foundation for further research. In addition to classification tasks, our synthesized images can facilitate tasks that require large amounts of medical data, such as detecting lesions and segmenting medical images.

Congenital Cataracts in Preterm Infants: A Review.

A congenital cataract is one of the most treatable causes of visual impairment during infancy. Preterm infants who are born alive before 37 weeks of pregnancy need special care, including proper age documentation, preoperative assessment, and monitoring postoperatively for at least 24 hours. Management of cataracts in preterm infants is critical as regards the timing of cataract surgery and the challenges associated with cataract surgery and posterior segment management for retinopathy of prematurity (ROP). This narrative review aims to provide comprehensive insight and up-to-date clinical research findings regarding the pathophysiology and management of congenital cataracts in preterm infants.

Twelve-year outcomes of bedside laser photocoagulation for severe retinopathy of prematurity.

Purpose: The purpose of this study is to evaluate the 12-year outcomes of bedside laser photocoagulation (LP) for severe retinopathy of prematurity (ROP) under sedation combined with ocular surface anesthesia in neonatal intensive care units (NICU). Design: The study is a retrospective case series. Methods: Infants treated with bedside LP for severe ROP from April 2009 to September 2021 were included. All LP treatments were performed under sedation and surface anesthesia at the bedside in NICU. Data were recorded for clinical and demographic characteristics, total laser spots, duration of treatment, proportion of total regression of ROP, proportion of recurrence, and adverse events. Results: A total of 364 infants (715 eyes) were included, with a mean gestational age of 28.6 ± 2.4 weeks (range: 22.6-36.6 weeks) and a mean birth weight of 1,156.0 ± 339.0 g (range: 480-2,200 g). The mean number of laser spots was 832 ± 469, and the mean duration of treatment was 23.5 ± 5.3 min per eye. Of all the eyes, 98.3% responded to LP with complete regression of ROP. ROP recurred in 15 (2.1%) eyes after the initial LP. Additional LP was performed in seven (1.0%) eyes. No patient exhibited mistaken LP of other ocular tissues, and there were no serious ocular adverse effects. None of them needed endotracheal intubation. Conclusions: Bedside LP treatment is effective and safe for premature infants with severe ROP under sedation and surface anesthesia in NICU, especially for infants whose general condition is unstable and not suitable for transport.

Vitreoretinal biomarkers of retinopathy of prematurity using handheld optical coherence tomography: a review.

Retinopathy of prematurity (ROP) is caused by abnormal retinal vascularization in premature infants that has the potential for severe long-term vision impairment. Recent advancements in handheld optical coherence tomography (OCT) have enabled noninvasive, high-resolution, cross-sectional imaging of the infant eye at the bedside. The use of handheld OCT devices in the diagnosis of ROP in premature infants has furthered our understanding of disease state and progression. This review discusses the known and novel biomarkers of ROP severity in premature infants identified through handheld OCT and potential for future directions.

Most Up-to-Date Analysis of Epidemiological Data on the Screening Guidelines and Incidence of Retinopathy of Prematurity in Europe-A Literature Review.

INTRODUCTION: Global predictions indicate that the incidence of retinopathy of prematurity (ROP) is increasing, but the lack of current epidemiological data on the occurrence of ROP in Europe prompted the authors to update these data. METHODS: European studies related to the presence of ROP were analyzed, and the reason for the differences in the percentage of ROP and different screening criteria were checked. RESULTS: The study presents results from individual and multiple centers. Current ROP incidence data varies from a low of 9.3% in Switzerland to the highest values of 64.1% in Portugal and 39.5% in Norway. The national screening criteria are used in the Netherlands, Germany, Norway, Poland, Portugal, Switzerland, and Sweden. Uniform criteria-Royal College of Paediatrics and Child Health guidelines are used in England and Greece. American Academy of Pediatrics screening guidelines are used in France and Italy. CONCLUSIONS: The epidemiology of ROP in European countries varies significantly. The increase in the diagnosis and treatment rate of ROP in recent years correlates with the narrowing of diagnostic criteria in newly issued guidelines (which include the WINROP and G-ROP algorithms), a higher number of less developed preterm infants, and a lower percentage of live births.

GabROP: Gabor Wavelets-Based CAD for Retinopathy of Prematurity Diagnosis via Convolutional Neural Networks.

One of the most serious and dangerous ocular problems in premature infants is retinopathy of prematurity (ROP), a proliferative vascular disease. Ophthalmologists can use automatic computer-assisted diagnostic (CAD) tools to help them make a safe, accurate, and low-cost diagnosis of ROP. All previous CAD tools for ROP diagnosis use the original fundus images. Unfortunately, learning the discriminative representation from ROP-related fundus images is difficult. Textural analysis techniques, such as Gabor wavelets (GW), can demonstrate significant texture information that can help artificial intelligence (AI) based models to improve diagnostic accuracy. In this paper, an effective and automated CAD tool, namely GabROP, based on GW and multiple deep learning (DL) models is proposed. Initially, GabROP analyzes fundus images using GW and generates several sets of GW images. Next, these sets of images are used to train three convolutional neural networks (CNNs) models independently. Additionally, the actual fundus pictures are used to build these networks. Using the discrete wavelet transform (DWT), texture features retrieved from every CNN trained with various sets of GW images are combined to create a textural-spectral-temporal demonstration. Afterward, for each CNN, these features are concatenated with spatial deep features obtained from the original fundus images. Finally, the previous concatenated features of all three CNN are incorporated using the discrete cosine transform (DCT) to lessen the size of features caused by the fusion process. The outcomes of GabROP show that it is accurate and efficient for ophthalmologists. Additionally, the effectiveness of GabROP is compared to recently developed ROP diagnostic techniques. Due to GabROP's superior performance compared to competing tools, ophthalmologists may be able to identify ROP more reliably and precisely, which could result in a reduction in diagnostic effort and examination time.

The role of hepatic and renal functions in the development of retinopathy of prematurity: Is proteinuria a new risk factor?

PURPOSE: To investigate the association of hepatic and renal parameters with the development of retinopathy of prematurity (ROP) in premature infants with a gestational age ≤ 32 weeks. METHODS: Medical records of 240 preterm infants were reviewed retrospectively, 85 of them were grouped as type 1, type 2 ROP, and control group. The 4th week hepatic and renal function test results of the groups, on the day of their first ROP examinations, were compared for the risk of development of ROP and the development of type 1 ROP. RESULTS: In this study, 12, 35, and 38 infants were enrolled in the type 1, type 2 ROP, and control group, respectively. The average gestational age and birth weight were higher; however, the duration of oxygen treatment was lower in the control group (p < 0.001). The blood glucose level was significantly higher in the type 1 ROP group than in the other groups (p = 0.023). The mean of total serum bilirubin of the type 1 ROP group was significantly lower than those of the type 2 ROP and control group (p = 0.032). Proteinuria was present in 85.7% of preterms with treatment-requiring ROP and proteinuria increased the risk of ROP by 3.9 times (OR with 95% CI 3.9 (1.19-12.75), p = 0.042). CONCLUSION: We found significantly higher blood glucose and lower total bilirubin level in the type 1 ROP group. Moreover, our findings suggest that proteinuria may not be only a comorbidity factor but also related to a higher frequency of ROP and type 1 ROP in preterm infants.

Potential Role of Bilirubin in Preventing Retinopathy of Prematurity.

BACKGROUND: One of the most common problems in preterm neonates is retinopathy of prematurity (ROP). It has been shown antioxidants may be effective in preventing the development and progression of ROP. Considering the antioxidant properties of bilirubin, we decided to investigate the bilirubin level in neonates with ROP and compare it with healthy neonates. METHODS: This case-control study was performed on VLBW neonates admitted to the NICU of Ghaem Hospital in Mashhad between 2014 and 2020 for a Jaundice evaluation. Complete neonate's characteristics, maternal history and laboratory results were collected in a questionnaire. Then the neonates were examined for ROP by a fellowship of the retina of an ophthalmologist at 32 weeks or four weeks after birth. The highest bilirubin levels during their hospitalization were also recorded. RESULTS: Of 427 neonates examined, 121 (37.7%) had a normal eye examination, and 266 (62.3%) had ROP. The mean weight, gestational age and bilirubin were 1455.8 ± 431.4 grams, 31.6 ± 2.3 weeks and 8.8 ± 2.4 mg/dl, respectively. There was a significant difference between controls and neonates with ROP with regard to birth weight, duration of intermittent positive pressure ventilation (IPPV), duration of oxygen therapy, first and fifth minute Apgar scores, the maximum level of bilirubin and gestational age (P < 0.05). It was observed that the maximum level of bilirubin was lower in neonates with higher stages of ROP. CONCLUSION: According to the results of this study, higher levels of bilirubin in neonates may be a protective factor against ROP. Moreover, increased levels of bilirubin are associated with reduced severity of ROP. Therefore, prophylaxis phototherapy in premature infants may need to be reconsidered.

Autonomic measures identify stress, pain, and instability associated with retinopathy of prematurity ophthalmologic examinations.

Background: Retinopathy of prematurity (ROP) ophthalmologic examinations cause stress and pain. Infants' stress and pain can be measured non-invasively using skin conductance (SC) and high frequency heart rate variability (HF-HRV), reflecting sympathetic-mediated sweating and parasympathetic activity, respectively. Objectives: To test the utility of SC to detect sympathetic activation during ROP examination, and the contribution of HF-HRV to predict stability post-examination. Methods: In this prospective, single center study, we measured SC continuously pre-, during, and post-examination, and HRV at 24 h pre-ROP examination. Clinical data included stability [apneas, bradycardias, and desaturations (A/B/Ds)], and interventions post-examination. Results: SC increased 56% above baseline during ROP examination (p = 0.001) and remained elevated post-examination (p = 0.02). Post-hoc analysis showed higher illness acuity, represented by need for respiratory support, was associated with lower HF-HRV at 24 h pre-ROP examination (p = 0.001). Linear regression indicated lower HF-HRV at 24 h pre-examination contributed to the need for higher intervention (i.e., stimulation to breathe, oxygen support) particularly among infants with higher illness acuity [F(1, 15) = 5.05, p = 0.04; ß = -1.33, p = 0.04]. Conclusion: ROP examination induced a 2-fold increase in sympathetic activation which remained above baseline in recovery. Also, we propose that the low parasympathetic tone associated with autonomic imbalance contributes to instability and need for higher intervention to assure stabilization with A/B/D events. Our findings provide insight into the underestimation of adverse events associated with ROP examination and identification of infants who may be more vulnerable to potential sequelae following ROP examinations.