Risk Of Retinopathy Of Prematurity Research Articles

Educational paper

Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease affecting the premature infant with an incompletely vascularized retina. The spectrum of ophthalmological findings in ROP exists from minimal sequelae, which do not affect vision, to bilateral retinal detachment and total blindness. With the increased survival of very small infants, retinopathy of prematurity has become one of the leading causes of childhood blindness. Over the past two decades, major advances have been made in understanding the pathogenesis of ROP, to a large extent as a result of changes in clinical risk factors (oxygen and non-oxygen related) and characteristics observed in ROP cases. This article provides a literature review on the evolution in clinical characteristics, classification and treatment modalities and indications of ROP. Special attention is hereby paid to the neonatal factors influencing the development of ROP and to the necessity for everyone caring for premature babies to have a well-defined screening and treatment protocol for ROP. Such screening protocol needs to be based on a unit-specific ROP risk profile and, consequently, may vary between different European regions. Retinopathy of prematurity is an important cause of ocular morbidity and blindness in children. With better understanding of the pathogenesis, screening and treatment guidelines have changed over time and are unit specific.

Placenta Microbiology and Histology and the Risk for Severe Retinopathy of Prematurity

To test the hypothesis that the presence of bacteria and/or histologic inflammation in the placenta of infants born preterm is associated with an increased risk for severe retinopathy of prematurity (ROP). This was a prospective cohort study. Exploratory and multivariable data analyses were used, including logistic regression models with interaction terms. Main outcomes were four definitions of severe ROP: stage 3 or higher, any ROP in zone I, prethreshold/threshold, and plus disease. Individually, placenta bacteria and histologic inflammation were not associated with severe ROP in univariable analyses among 1064 infants with gestational age <28 weeks or among 715 infants with gestational age <27 weeks (we excluded infants with a gestational age of 27 weeks because of the very small number of ROP cases). However, the co-occurrence of bacteria and inflammation was associated with an increased risk for ROP in zone I (odds ratio, 3.1; 95% confidence interval, 1.02-9.5). Among 339 infants with any placental bacteria, the co-occurrence of (1) inflammation and a gestational age of 23 to 24 weeks and (2) inflammation and hyperoxia were associated with prominent increases in risk for all definitions of severe ROP. While antenatal exposure to infection or inflammation alone does not appear to convey risk information for severe ROP, their co-occurrence does. This finding supports the hypothesis that a fetal inflammatory response to antenatal infection might be part of the etiology of severe ROP.

Evaluation of risk factors for retinopathy of prematurity

To evaluate the incidence and risk factors of ROP (retinopathy of prematurity) through a prospective multicenter study. Eleven children's or maternal & child hospitals participated in a collective network. All infants of birth weight < 2000 g, born in or transferred to one of the participating centers from January 1st 2005 to February 28th 2006 were recruited. Timely ophthalmologic examinations were performed. The relevant data at baseline and endpoints were collected at each unit. A total of 882 preterm infants fulfilled the screening criteria and 752 finished a followup. And 123 infants (16.4%) had some degree of ROP. Infants with ROP had a lower gestational age, birth weight and a longer duration of oxygen versus those without ROP [(30.82 +/- 0.20) weeks vs (32.56 +/- 0.09) weeks, (1430 +/- 25) g vs (1636 +/-10) g, (11.6 +/- 1.4) d vs (4.4 +/- 0.3) d]. Through a univariate analysis, birth weight, gestational age, asphyxia, oxygen duration > 5 days, apnea, surfactant usage, pneumonia, anemia, blood transfusion, acidosis and neonatal respiratory distress syndrome (NRDS) were associated with ROP (P < 0.05). Logistic regression analysis showed that birth weight (OR = 0.998), apnea (OR = 1.653) and blood transfusion (OR = 1.763) were independent risk factors for ROP. Asphyxia, oxygen duration > 5 days, surfactant usage, anemia, acidosis and NRDS, lower birth weight, apnea and blood transfusion may improve the risks of ROP.

Current update on retinopathy of prematurity: screening and treatment

Despite current treatments, retinopathy of prematurity (ROP) remains a major cause of blindness in premature infants and the incidence is increasing with increased survival of infants born at very early gestational ages. This review summarizes the recent literature on ROP with a special focus on recent advances in treatment options as well as newly developed methods for disease screening. Genetic studies find a genetic predisposition to ROP-linking genes in the Wnt pathway with development of severe ROP. With regard to diagnosis, a new screening method has been developed that allows prediction of ROP risk based on postnatal body weight gain alone. Formerly weight gain postnatally in combination with insulin-like growth factor levels was found to predict treatable ROP. New treatment options for severe cases of ROP have been proposed targeting vascular endothelial growth factor (VEGF). Whether anti-VEGF treatment is well tolerated in preterm infants, however, has to be further evaluated in controlled clinical trials. Finally, new reports from the early treatment ROP group suggest that early laser treatment for type 1 but not type 2 high-risk prethreshold ROP improves visual acuity outcomes at 6 years of age. With the increasing survival of premature infants and increased incidence of ROP, it is important to screen for ROP risk and treat at-risk patients in a timely manner to preserve their visual function and reduce complications.

A Clinical Prediction Model to Stratify Retinopathy of Prematurity Risk Using Postnatal Weight Gain

To develop an efficient clinical prediction model that includes postnatal weight gain to identify infants at risk of developing severe retinopathy of prematurity (ROP). Under current birth weight (BW) and gestational age (GA) screening criteria, <5% of infants examined in countries with advanced neonatal care require treatment. This study was a secondary analysis of prospective data from the Premature Infants in Need of Transfusion Study, which enrolled 451 infants with a BW < 1000 g at 10 centers. There were 367 infants who remained after excluding deaths (82) and missing weights (2). Multivariate logistic regression was used to predict severe ROP (stage 3 or treatment). Median BW was 800 g (445-995). There were 67 (18.3%) infants who had severe ROP. The model included GA, BW, and daily weight gain rate. Run weekly, an alarm that indicated need for eye examinations occurred when the predicted probability of severe ROP was >0.085. This identified 66 of 67 severe ROP infants (sensitivity of 99% [95% confidence interval: 94%-100%]), and all 33 infants requiring treatment. Median alarm-to-outcome time was 10.8 weeks (range: 1.9-17.6). There were 110 (30%) infants who had no alarm. Nomograms were developed to determine risk of severe ROP by BW, GA, and postnatal weight gain. In a high-risk cohort, a BW-GA-weight-gain model could have reduced the need for examinations by 30%, while still identifying all infants requiring laser surgery. Additional studies are required to determine whether including larger-BW, lower-risk infants would reduce examinations further and to validate the prediction model and nomograms before clinical use.

A Clinical Prediction Model to Stratify Retinopathy of Prematurity Risk Using Postnatal Weight Gain

A Clinical Prediction Model to Stratify Retinopathy of Prematurity Risk Using Postnatal Weight Gain

Braille use among Norwegian children from 1967 to 2007: trends in the underlying causes

The aim of the study was to estimate the occurrence, diagnoses and time trends among Norwegian children that have received education in braille from 1967 to 2007. We used a retrospective population-based study design. The health care system is free for all inhabitants in Norway. We included all children that had received braille education the last four decades. From each student's record, we abstracted year born, country of birth, gender, year diagnosed, diagnosis, classification of visual impairment and type of reading media. We identified 287 children (137 girls and 150 boys) that had received braille education over the last 40 years. Of these, 262 (91.3%) children were born in Norway, 145 (53.7%) were diagnosed within the first year of life and 59 (20.6%) from age of one to five. The most frequent diagnoses were Retinopathy of Prematurity (ROP), Juvenile Ceroid Lipofuscinoses (JNCL), Lebers Congenital Amaurosis (LCA) and Retinitis Pigmentosa (RP). Among the children, 63% (N = 170) used braille only, 9% (N = 25) braille and print, but priority braille, and 27% (N = 73) braille and print, priority print. The number of children with ROP using braille had a peak in 1977, then the number declined. The number diagnosed with LCA increased from 1987 to 1992. The number of braille users among children diagnosed with JNCL tended to increase substantially after 1992. Braille education seemed to be dependent of trends in diagnoses as well as trends in recommendations from professional educators.

Erythropoietin and retinopathy of prematurity

Erythropoietin (EPO) is a glycoprotein that regulates many functions of an organism: It stimulates the production of red blood cells and it has angiogenic and neuroprotective properties in newborn infants. Retinopathy of prematurity (ROP) is a frequent cause of visual impairment in preterm newborn infants and it has two distinct phases in which hypoxia-induced angiogenic factors are involved. The relationship between EPO and ROP is derived from the observation of studies done on the haematopoietic effect of EPO. The first observations suggested that a precocious treatment with EPO increases the risk of ROP, while the most recent reports suggested that the late treatment with high doses of rhEPO can increase the risk of ROP. All these studies were not designed to demonstrate the relationship between EPO and ROP. Further studies specifically designed should be performed. New ongoing studies on the neuroprotective role of EPO should consider this objective. In the mean time the use of EPO in the neonatal period should be cautious, mainly in very low birth weight infants.

Adopting western retinopathy of prematurity screening programs in eastern countries, are we screening properly?

Purpose:To describe retinopathy of prematurity (ROP) among Jordanian preterm infants and evaluate the efficacy of applying current Western screening guidelines for Jordanian preterms.Materials and Methods:In this retrospective, descriptive hospital-based study, we collected data on preterm infants who were referred by their neonatologist for ROP screening at King Abdullah University Hospital between July 2006 and June 2007. Guidelines suggested by the American Academy of Pediatrics were followed. Additionally, older preterms considered at risk for ROP by the neonatal intensive care unit were screened. Any neonate with stage 1 ROP or higher in either eye was considered a positive case of ROP.Results:Ninety-one preterms were included in the study. The median birth weight was 1390 gm (range,730-1980 gms) and the gestational age ranged from 26 to 35 weeks with 64.8% of preterms ≤ 32 weeks. ROP occurred in 28.6% of all patients, in 20% of infants with birth weight greater than 1500 gms and in 9.4% of preterms with gestational age ≥ 32 weeks. Six patients (6.6%) required laser treatment, two with low birth weight greater than 1250 gm and one was 33 weeks of age. Consanguinity was identified in 19.2% of infants with ROP while consanguinity in infants who did not develop ROP was 1.9%. This difference was statistically significant (P<0.05).Conclusion:ROP occurs in premature infants in Jordan with gestational age above 32 weeks and birth weight above 1250 gm. Future guidelines for screening should incorporate the current study outcomes. A prospective, population-based is required to set national guidelines for ROP screening in the Jordanian population and similarly for different populations worldwide. Consanguinity may play a role in ROP development and further genetic studies may aid in elucidating the pathogenesis of ROP.

Evaluation of modified retinopathy of prematurity screening guidelines using birth weight as the sole inclusion criterion

Purpose:The purpose was to determine if birth weight (BW) alone can be the sole criterion for screening infants at risk for retinopathy of prematurity (ROP).Materials and Methods:In this retrospective, observational case series, 208 infants were screened for ROP using the American Association for Pediatric Ophthalmology and Strabismus (AAPOS) Guidelines (1997). Variables examined included gestational age (GA), birth weight (BW), and a composite variable BWGA Index [(grams × weeks)/1000], which takes into consideration both the birth weight and gestational age of the infant. Infants were divided into two groups: Group 1, BW ≤1250 g, and Group 2, BW >1250 g. Multivariate analysis was performed to detect factors predictive of ROP. Receiver operator characteristic (ROC) curves were generated to determine the efficacy of screening using the BW, GA, and BWGA Index. Statistical analyses were performed with logistic regression with a P-value of 0.05 or less indicating statistical significance.Results:Varying stages of ROP were present in 116 of 416 eyes. Of the 105 eyes in Group 2, only 1 eye developed stage 1 ROP. Only Group 1 eyes developed stage 3 or higher ROP. The ROC curve for BW alone gave an area under the curve (AUC) of 0.797 (standard error [SE] = 0.0329, P < 0.0001); for GA, AUC was 0.801 (SE = 0.0340, P < 0.0001) and for the BWGA Index, the AUC was 0.808 (SE = 0.0324, P < 0.0001). Using 1250-g BW as a criterion for ROP screening would have decreased the number of screenings by 24%, and did not exclude any ROP higher than stage 1.Conclusion:Data from our neonatal intensive care unit suggest that birth weight ≤ 1250 g alone is an adequate parameter to identify premature infants at risk for ROP.

Analysis of risk factors in the development of retinopathy of prematurity

Retinopathy of prematurity (ROP) is a multifactorial disease that occurs most frequently in very small and very sick preterm infants, and it has been identified as the major cause of childhood blindness. The aim of this study was to evaluate ROP incidence and risk factors associated with varying degrees of illness. The study was conducted at the Centre for Neonatology, Paediatric Clinic of the Clinical Centre Kragujevac, Serbia, in the period from June 2006 to December 2008. Ophthalmologic screening was performed in all children with body weight lower than 2000 g or gestational age lower than 36 weeks. We analyzed eighteen postnatal and six perinatal risk factors and the group correlations for each of the risk factors. Out of 317 children that were screened, 56 (17.7%) developed a mild form of ROP, while 68 (21.5%) developed a severe form. Univariate analysis revealed a large number of statistically significant risk factors for the development of ROP, especially the severe form. Multivariate logistical analysis further separated two independent risk factors: small birth weight (p = 0.001) and damage of central nervous system (p = 0.01). Independent risk factors for transition from mild to severe forms of ROP were identified as: small birth weight (p = 0.05) and perinatal risk factors (p = 0.02). Small birth weight and central nervous system damage were risk factors for the development of ROP, perinatal risk factors were identified as significant for transition from mild to severe form of ROP.

A Clinical Prediction Model to Stratify Retinopathy of Prematurity Risk Using Postnatal Weight Gain

A Clinical Prediction Model to Stratify Retinopathy of Prematurity Risk Using Postnatal Weight Gain

Comparison of UK and US screening criteria for detection of retinopathy of prematurity in a developing nation

To determine the incidence, risk factors, and appropriateness of differing guidelines in developed nations for screening for retinopathy of prematurity (ROP) in a single nursery in a large urban city in southern Turkey. The records of 260 premature infants born ≤34 weeks in a single tertiary unit were retrospectively reviewed for ROP risk factors and diagnosis. Applicability of UK and US criteria were assessed by the use of receiver operating characteristic curves. ROP of any stage was present in 60 infants (23%); ROP requiring treatment was seen in 30 (11.5%). Univariate analysis showed a significant relationship among the following factors: gestational age, birth weight, total duration of supplemental oxygen, duration of mechanical ventilation, respiratory distress syndrome, anemia, and intraventricular hemorrhage (p < 0.0001). Multiple logistic regression analysis showed gestational age (p = 0.039), birth weight (p = 0.05), respiratory distress syndrome (p = 0.05), and anemia (p = 0.004) as independent predictors of ROP requiring treatment. Area under curve for gestational age alone for diagnosing stage 2 or greater ROP was 0.824 ± 0.03 (p = 0.0001) and for birth weight alone was 0.808 ± 0.03 (p = 0.0001). UK screening criteria detected all stage 2 and greater ROP; US screening criteria missed 2 infants with stage 2 ROP but detected all treatment-requiring disease. Adoption of these screening criteria would have reduced unnecessary examinations by either 21% (UK) or 37% (US). UK and US criteria improved the detection accuracy for ROP requiring treatment in Turkey and should be studied for other developing nations.

Possible roles of bilirubin and breast milk in protection against retinopathy of prematurity

To explore the association of serum bilirubin level and breast milk feeding with retinopathy of prematurity (ROP) in preterm infants. We conducted a case-control study to examine the independent and combined effects of serum bilirubin and breast milk feeding on ROP risk in infants <32 weeks gestation or with birth weight <1500 g. Cases (66 infants with ROP) were matched with controls (66 infants without ROP) based on factors known to affect ROP risk. When analysed using the paired t-test, the peak bilirubin levels were lower in ROP cases than in controls (mean 7.2 vs. 7.9 mg/dL; p = 0.045). Using conditional logistic regression, we found a negative association between highest serum bilirubin level and risk of ROP (OR = 0.82 per 1-mg/dL change in bilirubin; p = 0.06). There was no significant association between breast milk feeding and risk of ROP. Bilirubin may help to protect preterm infants against ROP.

150 Incidence of and Risk Factors for Neonatal Morbidity After Active Perinatal Care: Extremely Preterm Infants Study in Sweden (Express)

Aims: To determine the incidence of neonatal morbidity in extremely preterm infants and to identify associated risk factors. Methods: Population based study of infants born before 27 gestational weeks and admitted for neonatal intensive care in Sweden during 2004-2007. Results: Of 638 admitted infants, 141 died. Among these, life support was withdrawn in 55 infants because of anticipation of poor long-term outcome. Of 497 surviving infants, 10% developed severe intraventricular haemorrhage (IVH), 5.7% cystic periventricular leucomalacia (cPVL), 41% septicaemia and 5.8% necrotising enterocolitis (NEC); 61% had patent ductus arteriosus (PDA) and 34% developed retinopathy of prematurity (ROP) stage ≥ 3. Eighty-five per cent needed mechanical ventilation and 25% developed severe bronchopulmonary dysplasia (BPD). Forty-seven per cent survived to one year of age without any severe IVH, cPVL, severe ROP, severe BPD or NEC. Tocolysis increased and prolonged mechanical ventilation decreased the chances of survival without these morbidities. Maternal smoking and higher gestational duration were associated with lower risk of severe ROP, whereas PDA and poor growth increased this risk. Conclusions: Half of the infants surviving extremely preterm birth suffered from severe neonatal morbidities. Studies on how to reduce these morbidities and on the long-term health of survivors are warranted.

Administración precoz de eritropoyetina en el prematuro extremo, ¿factor de riesgo de la retinopatía del prematuro?

Introduction Erythropoietin (EPO) stimulates angiogenesis and may favour the appearance of retinopathy of prematurity (ROP). The objective was to determine if EPO+Fe administered from the 5th day of life could be an independent risk factor for ROP appearance and its severity. Patients and method The study included 718 preterm newborns with a birth weight ≤1,500 g or a gestational age ≤32 weeks (and 6 days), admitted between 2001 and 2008. During these years, the target SaO 2 was between 88% and 93%. EPO treatment began at 5–7 days of life, with a dose of 250 UI/Kg, 3 times a week, subcutaneously, together with Fe, 5–6 mg/kg/day, both until 34 weeks of corrected age or discharge. Results A total of 493 preterms (68.7%) did not have ROP, 139 (19.4%) had a grade 1 ROP, 50 (7.0%) a grade 2 ROP and 36 (5.0%) a grade 3 ROP. Laser therapy was required by 27 severe ROP was associated with lower birth weight and gestational age, more neonatal morbidity and a more aggressive treatment (duration of oxygen supplements or mechanical ventilation, number of blood transfusions). Risk factors independently and significantly associated with any ROP grade were: lower birth weight, no caesarean section, EPO administration and need for blood transfusion. EPO administration increased the risk of ROP by 2.4, but this only happened in case of grade 1 ROP (OR: 5.50). Conclusions EPO+Fe administration is associated and perhaps stimulates the appearance of grade 1 ROP.

The clustering of disorders in infants born before the 28th week of gestation

To see whether disorders prevalent in infants born extremely preterm cluster. Observational cohort study. University-affiliated newborn intensive care nurseries. One thousand two hundred and twenty-three infants born before the 28th week of gestation who survived until 36 weeks postmenstrual age when the diagnosis of bronchopulmonary dysplasia (BPD) could be made. None. Cerebral white matter damage (an echolucent lesion, or moderate or severe ventriculomegaly on a protocol cranial ultrasound scan), BPD, retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC) and early and late bacteremia. After adjustment for gestational age, children who had severe NEC (Bell stage IIIb) were at increased risk of cerebral white matter damage, severe ROP (stage 3+), and severe BPD (defined as both oxygen and ventilator dependent). Children who had early bacteremia were at increased risk of late bacteremia and severe ROP. Those who had severe ROP were at increased risk of severe BPD and both early and late bacteremia. Necrotizing enterocolitis is the disorder common to most of the clusters, but we do not know if its onset occurred before the others. Organ-damage-promoting substances, however, have been found in the circulation of newborn animals with bowel inflammation, supporting the view that NEC contributes to the damage of other organs.

Interexpert Agreement in the Identification of Macular Location in Infants at Risk for Retinopathy of Prematurity

To characterize variability in the identification of the macular center among retinopathy of prematurity (ROP) experts. A printed set of 25 wide-angle retinal images was compiled from infants at risk for ROP using a commercially available camera. Ten recognized ROP experts were asked to mark the macular center on each image. For each image, we measured the distance from the optic disc center to the marked macular center. Distances were standardized by normalizing the horizontal optic disc diameter in each image to 0.93 mm. In images with visible peripheral disease, interexpert agreement on the presence of zone I disease was also determined. For the image with the least variability among experts, mean (SD) distance from the optic disc to the macular center was 3.69 (0.21) mm (range, 3.13-3.81 mm). For the image with the greatest variability among experts, distance from the optic disc to the macular center was 4.32 (1.19) mm (range, 3.21-7.19 mm). In 7 of 21 images (33%) with visible peripheral disease, there would have been disagreement among experts in the diagnosis of zone I disease based on identification of the macular center. Among the 10 experts, in 17 of 25 images (68%), 1 expert identified the distance between the optic disc and macular center to be greater than 1 SD from the mean. Significant variability exists among experts in identification of the macular center from wide-angle images, which raises concerns about the reliability of zone I ROP diagnosis.

Infection, Oxygen, and Immaturity: Interacting Risk Factors for Retinopathy of Prematurity

Background: Interactions among known risk factors for retinopathy of prematurity (ROP) remain to be clarified. Objectives: The aim of this study was to identify risk factors associated with ROP and to explore the interrelationships between prominent risk factors for ROP. Methods: From an institutional cohort of 1,646 very preterm newborns with gestational age <30 weeks or birth weight <1,501 g, we selected infants with a gestational age <30 weeks who met the criteria for ROP screening (n = 622) for a nested case-control analysis. Results: Of the 622 eligible newborns, 293 (47%) were diagnosed with ROP. From multivariable analyses, gestational age <26 weeks (OR 2.9, CI 1.7–4.9), oxygen exposure at 28 days (OR 1.7, CI 1.0–2.7), and neonatal sepsis (OR 2.1, CI 1.4–3.2) emerged as prominent risk factors for ROP. Oxygen- associated ROP risk was more prominent among infants of 23–25 weeks’ gestational age, while infection-associated ROP risk was higher among infants born at 28–29 weeks. The OR for the joint effect of all 3 risk factors (23.5) was higher than would have been expected under the additive (8.6) and the multiplicative (16.5) patterns of interaction. Conclusions: Our study suggests that neonatal sepsis, oxygen exposure, and low gestational age are not only independently associated with a significantly increased risk of ROP, but also interact beyond additive and even multiplicative patterns.

Blood Gases and Retinopathy of Prematurity: The ELGAN Study

Objective: This study tested the hypothesis that preterm infants who had a blood gas derangement on at least 2 of the first 3 postnatal days are at increased risk for more severe retinopathy of prematurity (ROP). Method: 1,042 infants born before 28 weeks’ gestational age (GA) were included. An infant was considered to be exposed if his/her blood gas measure was in the highest or lowest quartile for GA on at least 2 of the first 3 postnatal days. Results: Multivariable models adjusting for confounders indicate that exposure to a PCO₂ in the highest quartile predicts ROP (stage 3, 4 or 5: OR = 1.6, 95% CI = 1.1–2.3); zone 1: 2.0, 1.1–3.6; prethreshold/threshold: 1.9, 1.2–3.0; plus disease: 1.8, 1.1–2.9). Estimates are similar for a low pH for zone 1 (2.1, 1.2–3.8), prethreshold/threshold (1.8, 1.1–2.8), but did not quite achieve statistical significance for ROP stage 3, 4, or 5 (1.4, 0.9–2.0) and plus disease (1.5, 0.9–2.4). A PaO₂ in the highest quartile for GA on at least 2 of the first 3 postnatal days was associated with a doubling of the risk of ROP in zone 1 (2.5, 1.4–4.4) and of prethreshold/threshold disease (2.1, 1.4–3.3), a 70% risk increase for plus disease (1.7, 1.04–2.8), while a 40% risk increase for ROP stage 3 or higher did not achieve statistical significance (1.4, 0.96–2.0). Conclusion: Infants exposed to high PCO₂, low pH and high PaO₂ appear to be at increased risk of more severe ROP.