The population of infants at risk for retinopathy of prematurity (ROP) varies by world region; in countries with well developed neonatal intensive care services, the highest risk infants are those ...born at less than 28 weeks gestational age (GA) and less than 1 kg at birth, while, in regions where many aspects of neonatal intensive and ophthalmological care are not routinely available, more mature infants up to 2000 g at birth and 37 weeks GA are also at risk for severe ROP. Treatment options for both groups of patients include standard retinal laser photocoagulation or, more recently, intravitreal anti-VEGF drugs. In addition to detection and treatment of ROP, this review highlights new opportunities created by telemedicine, where screening and diagnosis of ROP in remote locations can be undertaken by non-ophthalmologists using digital fundus cameras. The ophthalmological care of the ROP infant is undertaken in the wider context of neonatal care and general wellbeing of the infant. Because of this context, this review takes a multi-disciplinary perspective with contributions from retinal vascular biologists, pediatric ophthalmologists, an epidemiologist and a neonatologist. This review highlights the latest insights regarding cellular and molecular mechanisms in the formation of the retinal vasculature in the human infant, pathogenesis of ROP, detection and treatment of severe ROP, the risks and benefits of anti-VEGF therapy, the identification of new therapies over the horizon, and the optimal neonatal care regimen for best ROP outcomes, and the benefits and pitfalls of telemedicine in the remote screening and diagnosis of ROP, all of which have the potential to improve ROP outcomes.
•This review takes a multi-disciplinary perspective on ROP, bringing together contributions from retinal vascular biologists, pediatric ophthalmologists, epidemiologists and neonatologists.•With two distinct populations of infants with ROP in the developed and developing world, different approaches to the disease must be undertaken.•This review details the current understanding of the cellular and molecular mechanisms of human retinal vascular formation, detailing the mechanisms underlying the pathogenesis of the two phases of acute ROP.•We highlight the risks and benefits of anti-VEGF therapy in ROP. The potential harm from systemic exposure to anti-VEGF agents needs further study, given that VEGF has key roles in the development of many organs and also acts as a neuronal survival factor during embryonic development.•We recommend with the exception of certain key circumstances, use of anti-VEGF agents as a therapeutic intervention in ROP still needs to be approached with caution because of; 1) the risk of late recurrence of retinopathy due to incomplete peripheral retinal vascularization; 2) possible long term systemic side effects; and 3) the uncertainty about the correct dosage.•We identify new therapies over the horizon, and the optimal neonatal care regimen for best ROP outcomes, and the benefits and pitfalls of telemedicine in the remote screening and diagnosis of ROP, all of which have the potential to improve ROP outcomes.
IMPORTANCE: There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen. OBJECTIVE: To compare the effects of ...different target ranges for oxygen saturation as measured by pulse oximetry (Spo2) on death or major morbidity. DESIGN, SETTING, AND PARTICIPANTS: Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks’ gestation. EXPOSURES: Spo2 target range that was lower (85%-89%) vs higher (91%-95%). MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score <85) at a corrected age of 18 to 24 months. There were 16 secondary outcomes including the components of the primary outcome and other major morbidities. RESULTS: A total of 4965 infants were randomized (2480 to the lower Spo2 target range and 2485 to the higher Spo2 range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower Spo2 target group and 1150 of 2229 infants (51.6%) in the higher Spo2 target group (risk difference, 1.7% 95% CI, −1.3% to 4.6%; relative risk RR, 1.04 95% CI, 0.98 to 1.09, P = .21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower Spo2 target group, and 3 significantly favored the higher Spo2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower Spo2 target group and 418 of 2440 infants (17.1%) in the higher Spo2 target group (risk difference, 2.8% 95% CI, 0.6% to 5.0%; RR, 1.17 95% CI, 1.04 to 1.31, P = .01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower Spo2 target group and 308 of 2065 infants (14.9%) in the higher Spo2 target group (risk difference, −4.0% 95% CI, −6.1% to −2.0%; RR, 0.74 95% CI, 0.63 to 0.86, P < .001). Severe necrotizing enterocolitis occurred in 227 of 2464 infants (9.2%) in the lower Spo2 target group and 170 of 2465 infants (6.9%) in the higher Spo2 target group (risk difference, 2.3% 95% CI, 0.8% to 3.8%; RR, 1.33 95% CI, 1.10 to 1.61, P = .003). CONCLUSIONS AND RELEVANCE: In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower Spo2 target range compared with a higher Spo2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower Spo2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.
Retinopathy of prematurity – A world update Darlow, Brian A.; Gilbert, Clare
Seminars in perinatology,
October 2019, 2019-10-00, 20191001, Letnik:
43, Številka:
6
Journal Article
Recenzirano
This issue of Seminars in Perinatology reviews recent advances in ROP epidemiology, prevention, treatment and outcome. Chapters will have relevance for obstetricians, neonatologists, ophthalmologists ...and nurses practising in both high and middle-income countries where ROP is prevalent, and in many countries in Africa where ROP is an emerging problem.
Vitamin A is necessary for normal lung growth and the integrity of respiratory tract epithelial cells. Preterm infants have low vitamin A status at birth, and this has been associated with increased ...risk of developing chronic lung disease.
To evaluate vitamin A supplementation on the incidence of death and/or neonatal chronic lung disease and long-term neurodevelopmental disability in very low birthweight infants (VLBW); and to consider the effect of the supplementation route, dose, and timing.
In August 2011, the Cochrane Central Regsiter of Controlled Trials (Central, The Cochrane Library), MEDLINE, Science Citation Index and the Oxford Database of Perinatal Trials were searched. The reference lists of relevant trials, paediatric and nutrition journals, and conference abstracts and proceedings were handsearched up to 2007.
Randomised controlled trials comparing vitamin A supplementation with a control (placebo or no supplementation) or other dosage regimens in VLBW infants (birthweight ≤ 1500 g or < 32 weeks' gestation).
Both review authors screened the search results, extracted data, and assessed the trials' risk of bias. Results were reported as risk ratios (RR), risk differences (RD), and number needed to treat to benefit (NNTB), all with 95% confidence intervals (CI). Trialists were contacted for additional data.
Nine trials met the inclusion criteria, eight compared vitamin A supplementation with a control (1291 infants), and one compared different regimens (120 infants). Compared to the control group, vitamin A appears to be beneficial in reducing death or oxygen requirement at one month of age (RR 0.93, 95% CI 0.88 to 0.99; RD -0.05, 95% CI -0.10 to -0.01; NNTB 20, 95% CI 10 to 100; 1165 infants) and oxygen requirement at 36 weeks' postmenstrual age (RR 0.87, 95% CI 0.77 to 0.98; RD -0.08, 95% CI -0.14 to -0.01; NNTB 13, 95% CI 7 to 100; 824 infants). A trend towards a reduction in death or oxygen requirement at 36 weeks' postmenstrual age was also noted (RR 0.91, 95% CI 0.82 to 1.00; 1001 infants). Neurodevelopmental assessment of 88% of surviving infants in the largest trial showed no differences between the groups at 18 to 22 months of age, corrected for prematurity. The different dosage vitamin A regimens showed similar results.
Whether clinicians decide to utilise repeat intramuscular doses of vitamin A to prevent chronic lung disease may depend upon the local incidence of this outcome and the value attached to achieving a modest reduction in this outcome, balanced against the lack of other proven benefits and the acceptability of treatment. Information on long-term neurodevelopmental status suggests no evidence of either benefit or harm from the intervention.
There are significant international variations in chronic lung disease rates among very preterm infants yet there is little data on international variations in respiratory strategies.
To evaluate ...practice variations in the respiratory management of extremely preterm infants born at < 29 weeks' gestational age (GA) among 10 neonatal networks participating in the International Network for Evaluating Outcomes (iNeo) of Neonates collaboration.
A web-based survey was sent to the representatives of 390 neonatal intensive care units from Australia/New Zealand, Canada, Finland, Illinois (USA), Israel, Japan, Spain, Sweden, Switzerland, and Tuscany (Italy). Responses were based on practices in 2015.
Overall, 321 of the 390 units responded (82%). The majority of units within networks (40-92%) mechanically ventilate infants born at 23-24 weeks' GA on continuous positive airway pressure (CPAP) with 30-39% oxygen in respiratory distress within 48 h after birth, but the proportion of units that offer mechanical ventilation for infants born at 25-26 weeks' GA at similar settings varied significantly (20-85% of units within networks). The most common respiratory strategy for infants born at 27-28 weeks' GA on CPAP with 30-39% oxygen with respiratory distress within 48 h after birth used by units also varied significantly among networks: mechanical ventilation (0-60%), CPAP (3-82%), intubation and surfactant administration with immediate extubation (0-75%), and less invasive surfactant administration (0-68%).
There are marked variations but also similarities in respiratory management of extremely preterm infants between networks. Further collaboration and exploration is needed to better understand the association of these variations in practice with pulmonary outcomes.
Background
The use of supplemental oxygen in the care of extremely preterm infants has been common practice since the 1940s. Despite this, there is little agreement regarding which oxygen saturation ...(SpO₂) ranges to target to maximise short‐ or long‐term growth and development, while minimising harms. There are two opposing concerns. Lower oxygen levels (targeting SpO₂ at 90% or less) may impair neurodevelopment or result in death. Higher oxygen levels (targeting SpO₂ greater than 90%) may increase severe retinopathy of prematurity or chronic lung disease.
The use of pulse oximetry to non‐invasively assess neonatal SpO₂ levels has been widespread since the 1990s. Until recently there were no randomised controlled trials (RCTs) that had assessed whether it is better to target higher or lower oxygen saturation levels in extremely preterm infants, from birth or soon thereafter. As a result, there is significant international practice variation and uncertainty remains as to the most appropriate range to target oxygen saturation levels in preterm and low birth weight infants.
Objectives
1. What are the effects of targeting lower versus higher oxygen saturation ranges on death or major neonatal and infant morbidities, or both, in extremely preterm infants?
2. Do these effects differ in different types of infants, including those born at a very early gestational age, or in those who are outborn, without antenatal corticosteroid coverage, of male sex, small for gestational age or of multiple birth, or by mode of delivery?
Search methods
We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 4), MEDLINE via PubMed (1966 to 11 April 2016), Embase (1980 to 11 April 2016) and CINAHL (1982 to 11 April 2016). We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials.
Selection criteria
Randomised controlled trials that enrolled babies born at less than 28 weeks' gestation, at birth or soon thereafter, and targeted SpO₂ ranges of either 90% or below or above 90% via pulse oximetry, with the intention of maintaining such targets for at least the first two weeks of life.
Data collection and analysis
We used the standard methods of Cochrane Neonatal to extract data from the published reports of the included studies. We sought some additional aggregate data from the original investigators in order to align the definitions of two key outcomes. We conducted the meta‐analyses with Review Manager 5 software, using the Mantel‐Haenszel method for estimates of typical risk ratio (RR) and risk difference (RD) and a fixed‐effect model. We assessed the included studies using the Cochrane 'Risk of bias' and GRADE criteria in order to establish the quality of the evidence. We investigated heterogeneity of effects via pre‐specified subgroup and sensitivity analyses.
Main results
Five trials, which together enrolled 4965 infants, were eligible for inclusion. The investigators of these five trials had prospectively planned to combine their data as part of the NeOProM (Neonatal Oxygen Prospective Meta‐analysis) Collaboration. We graded the quality of evidence as high for the key outcomes of death, major disability, the composite of death or major disability, and necrotising enterocolitis; and as moderate for blindness and retinopathy of prematurity requiring treatment.
When an aligned definition of major disability was used, there was no significant difference in the composite primary outcome of death or major disability in extremely preterm infants when targeting a lower (SpO₂ 85% to 89%) versus a higher (SpO₂ 91% to 95%) oxygen saturation range (typical RR 1.04, 95% confidence interval (CI) 0.98 to 1.10; typical RD 0.02, 95% CI ‐0.01 to 0.05; 5 trials, 4754 infants) (high‐quality evidence). Compared with a higher target range, a lower target range significantly increased the incidence of death at 18 to 24 months corrected age (typical RR 1.16, 95% CI 1.03 to 1.31; typical RD 0.03, 95% CI 0.01 to 0.05; 5 trials, 4873 infants) (high‐quality evidence) and necrotising enterocolitis (typical RR 1.24, 95% 1.05 to 1.47; typical RD 0.02, 95% CI 0.01 to 0.04; 5 trials, 4929 infants; I² = 0%) (high‐quality evidence). Targeting the lower range significantly decreased the incidence of retinopathy of prematurity requiring treatment (typical RR 0.72, 95% CI 0.61 to 0.85; typical RD ‐0.04, 95% CI ‐0.06 to ‐0.02; 5 trials, 4089 infants; I² = 69%) (moderate‐quality evidence). There were no significant differences between the two treatment groups for major disability including blindness, severe hearing loss, cerebral palsy, or other important neonatal morbidities.
A subgroup analysis of major outcomes by type of oximeter calibration software (original versus revised) found a significant difference in the treatment effect between the two software types for death (interaction P = 0.03), with a significantly larger treatment effect seen for those infants using the revised algorithm (typical RR 1.38, 95% CI 1.13 to 1.68; typical RD 0.06, 95% CI 0.01 to 0.10; 3 trials, 1716 infants). There were no other important differences in treatment effect shown by the subgroup analyses using the currently available data.
Authors' conclusions
In extremely preterm infants, targeting lower (85% to 89%) SpO₂ compared to higher (91% to 95%) SpO₂ had no significant effect on the composite outcome of death or major disability or on major disability alone, including blindness, but increased the average risk of mortality by 28 per 1000 infants treated. The trade‐offs between the benefits and harms of the different oxygen saturation target ranges may need to be assessed within local settings (e.g. alarm limit settings, staffing, baseline outcome risks) when deciding on oxygen saturation targeting policies.
To compare survival rates and age at death among very preterm infants in 10 national and regional neonatal networks.
A cohort study of very preterm infants, born between 24 and 29 weeks' gestation ...and weighing <1500 g, admitted to participating neonatal units between 2007 and 2013 in the International Network for Evaluating Outcomes of Neonates. Survival was compared by using standardized ratios (SRs) comparing survival in each network to the survival estimate of the whole population.
Network populations differed with respect to rates of cesarean birth, exposure to antenatal steroids and birth in nontertiary hospitals. Network SRs for survival were highest in Japan (SR: 1.10; 99% confidence interval: 1.08-1.13) and lowest in Spain (SR: 0.88; 99% confidence interval: 0.85-0.90). The overall survival differed from 78% to 93% among networks, the difference being highest at 24 weeks' gestation (range 35%-84%). Survival rates increased and differences between networks diminished with increasing gestational age (GA) (range 92%-98% at 29 weeks' gestation); yet, relative differences in survival followed a similar pattern at all GAs. The median age at death varied from 4 days to 13 days across networks.
The network ranking of survival rates for very preterm infants remained largely unchanged as GA increased; however, survival rates showed marked variations at lower GAs. The median age at death also varied among networks. These findings warrant further assessment of the representativeness of the study populations, organization of perinatal services, national guidelines, philosophy of care at extreme GAs, and resources used for decision-making.
Background
Vitamin A is necessary for normal lung growth and the integrity of respiratory tract epithelial cells. Preterm infants have low vitamin A status at birth and this has been associated with ...an increased risk of developing chronic lung disease.
Objectives
To evaluate supplementation with vitamin A on the incidence of death or neonatal chronic lung disease and long‐term neurodevelopmental disability in very low birth weight (VLBW) infants compared with a control (placebo or no supplementation), and to consider the effect of the supplementation route, dose, and timing.
Search methods
For the original review and subsequent updates, we searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, Science Citation Index, and the Oxford Database of Perinatal Trials. The reference lists of relevant trials, paediatric and nutrition journals, and conference s and proceedings were handsearched up to 2010.
For the 2016 update, we used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 4), MEDLINE via PubMed (1 May 2016), EMBASE (1 May 2016), and CINAHL (1 May 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi‐randomised trials.
Selection criteria
Randomised controlled trials comparing vitamin A supplementation with a control (placebo or no supplementation) or other dosage regimens in VLBW infants (birth weight ≤ 1500 grams or less than 32 weeks' gestation).
Data collection and analysis
Two review authors screened the search results, extracted data, and assessed the trials for risk of bias. Results were reported as risk ratios (RR), risk differences (RD), and number needed to treat to benefit (NNTB), all with 95% confidence intervals (CI). Trialists were contacted for additional data.
Main results
Eleven trials met the inclusion criteria. Ten trials (1460 infants) compared vitamin A supplementation with a control and one (120 infants) compared different regimens of vitamin A supplementation. Compared to the control group, vitamin A appeared to have a small benefit in reducing the risk of death or oxygen requirement at one month of age (typical RR 0.93, 95% CI 0.88 to 0.99; typical RD −0.05, 95% CI −0.10 to −0.01; NNTB 20, 95% CI 10 to 100; 6 studies, 1165 infants) and the risk of chronic lung disease (oxygen requirement) at 36 weeks' postmenstrual age (typical RR 0.87, 95% CI 0.77 to 0.99; typical RD −0.07, 95% CI −0.13 to −0.01; NNTB 11, 95% CI 6 to 100; 5 studies, 986 infants) (moderate‐quality evidence). There was a marginal reduction of the combined outcome of death or chronic lung disease (typical RR 0.92, 95% CI 0.84 to 1.01; typical RD −0.05, 95% CI −0.11 to 0.01; 4 studies, 1089 infants). Neurodevelopmental assessment of 88% of the surviving infants in the largest trial showed no difference between the groups at 18 to 22 months of age, corrected for prematurity (low‐quality evidence). There is no evidence to support different vitamin A dosing regimens. No adverse effects of vitamin A supplementation were reported, but it was noted that intramuscular injections of vitamin A were painful.
Authors' conclusions
Whether clinicians decide to utilise repeat intramuscular doses of vitamin A to prevent chronic lung disease may depend upon the local incidence of this outcome and the value attached to achieving a modest reduction in the outcome balanced against the lack of other proven benefits and the acceptability of the treatment. Information on long‐term neurodevelopmental status suggests no evidence of either benefit or harm from the intervention.
To assess the physical well-being and components of the metabolic syndrome in a national cohort of very low birth weight (VLBW) young adults and same age controls.
The New Zealand VLBW Study cohort ...prospectively included all infants with birth weight <1500 g born in 1986, with 338 (82%) surviving to discharge home. Height and weight were measured at age 7-8 years. The VLBW cohort (n = 229; 71% alive) and term-born controls (n = 100) aged 27-29 years were clinically assessed in a single center over 2 days, including assessment for components of the metabolic syndrome.
Compared with controls, both male and female VLBW adults were significantly shorter (P < .001), but only females were lighter (P < .001) and had lower mean body mass index (P = .044), fat mass, and body fat percentage. Males, but not females, had significantly higher systolic blood pressure (P = .028), but there were no significant differences in other components of the metabolic syndrome. There was no difference in the prevalence of the metabolic syndrome in VLBW adults compared with controls (males, 22.2% vs 11.1%; P = .15: females, 12.8% vs 13.1%; P = .95). Examining the VLBW cohort with logistic regression, male sex, gestational age <28 weeks, Māori/Pacific Island ethnicity, and body mass index >90th percentile at age 7-8 years were significant predictors for the metabolic syndrome at age 27-29 years, with ORs of 2-4.
Systolic blood pressure in males was the only component of the metabolic syndrome that was significantly elevated in VLBW adults compared with controls. Extreme prematurity (<28 weeks) and body mass index >90th percentile at age 7-8 years were significant predictors of the metabolic syndrome at age 27-29 years.
Registered at the Australian Clinical Trials Registry: ACTRN12612000995875.
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