ROP: 80 Years after Its Detection - Where Do We Stand and How Long Will We Continue to Laser?

BACKGROUND: Retinopathy of prematurity (ROP), a potentially blinding disease, is increasing worldwide because of the increased survival of extremely preterm and preterm infants born where oxygen monitoring and ROP screening programs are insufficient. Repeated retinal examinations are stressful for infants, and laser photocoagulation treatment for sight-threatening ROP is destructive. The use of anti-VEGF agents instead of lasers is widespread but requires a long-term follow-up because of late recurrence of the disease. In addition, the optimal anti-VEGF agent dosage and long-term systemic effects require further study. SUMMARY: Interventions preventing ROP would be far preferable, and systemic interventions might promote better development of the brain and other organs. Interventions such as improved oxygen control, provision of fresh maternal milk, supplementation with arachidonic acid and docosahexaenoic acid, and fetal hemoglobin preservation by reducing blood sample volumes may help prevent ROP and reduce the need for treatment. Free readily available online tools to predict severe ROP may reduce unnecessary eye examinations and select, for screening, those at a high risk of needing treatment. KEY MESSAGES: Treatment warranting ROP is a sign of impaired neurovascular development in the central nervous system. Preventative measures to improve the outcomes are available. Screening can be refined using tools that can predict severe ROP. Laser treatment and anti-VEGF agents are valuable treatment modalities that may complement each other in recurrent ROP.

Nutritional interventions to prevent retinopathy of prematurity.

Very preterm infants are at high risk of growth failure. Poor weight gain is a prominent risk factor for retinopathy of prematurity (ROP) and optimizing nutrition could potentially promote growth and reduce ROP. Most infants at risk of ROP need parenteral nutrition initially and studies of enhanced parenteral provision of lipids and amino acids have suggested a beneficial effect on ROP. Higher amino acid intake was associated with lower incidence of hyperglycemia, a risk factor for ROP. For very preterm infants, providing unpasteurized fortified raw maternal breast milk appears to have a dose-dependent preventive effect on ROP. These infants become deficient in arachidonic acid (ArA) and docosahexaenoic acid (DHA) after birth when the maternal supply is lost. Earlier studies have investigated the impact of omega-3 fatty acids on ROP with mixed results. In a recent study, early enteral supplementation of ArA 100 mg/kg/d and DHA 50 mg/kg/d until term equivalent age reduced the incidence of severe ROP by 50%. IMPACT: Previous reviews of nutritional interventions to prevent morbidities in preterm infants have mainly addressed bronchopulmonary dysplasia, brain lesions and neurodevelopmental outcome. This review focusses on ROP. Neonatal enteral supplementation with arachidonic acid and docosahexaenoic acid, at levels similar to the fetal accretion rate, has been found to reduce severe ROP by 50% in randomized controlled trials.

Visual outcome at 2.5 years of age in ω-3 and ω-6 long-chain polyunsaturated fatty acid supplemented preterm infants: a follow-up of a randomized controlled trial.

Background: We investigated ophthalmological outcomes at 2.5 years of corrected age in children born extremely preterm (EPT) to evaluate the effects of postnatal enteral supplementation with ω-3 and ω-6 long-chain polyunsaturated fatty acids. Methods: In the Mega Donna Mega clinical trial, EPT infants born at less than 28 weeks of gestation were randomized to receive an enteral supplementation of docosahexaenoic acid (DHA) and arachidonic acid (AA) from birth to 40 weeks postmenstrual age. In this exploratory follow-up at 2.5 years of corrected age, we assessed visual acuity (VA), refraction, manifest strabismus, and nystagmus. Satisfactory VA was defined as ≥20/63. Multiple imputation (MI) was used to address the issue of missing data. Findings: Of 178 children in the trial, 115 (with median gestational age (GA) of 25 + 4/7 weeks and median birth weights of 790 g) were ophthalmologically assessed at a median corrected age of 2.7 years (range 2.0-3.9 years). VA assessment was missing in 42.1% (75/178), in 41.7% (35/84) of the AA/DHA supplemented infants, and in 42.6% (40/94) of the control infants. After MI and adjustments for GA, study center, plurality, and corrected age at VA exam, no significant effect of AA/DHA supplementation was detected in VA outcome (≥20/63) (odds ratio 2.16, confidence interval 95% 0.99-4.69, p = 0.053). Interpretation: In this randomized controlled trial follow-up, postnatal supplementation with enteral AA/DHA to EPT children did not significantly alter VA at 2.5 years of corrected age. Due to the high loss to follow-up rate and the limited statistical power, additional studies are needed. Funding: The Swedish Medical Research Council #2020-01092, The Gothenburg Medical Society, Government grants under the ALF agreement ALFGBG-717971 and ALFGBG-971188, De Blindas Vänner, Knut and Alice Wallenberg Foundation - Wallenberg Clinical Scholars, NIHEY017017, EY030904BCHIDDRC (1U54HD090255 Massachusetts Lions Eye Foundation) supported the study.

Prognostic Value of Parenteral Nutrition Duration on Risk of Retinopathy of Prematurity: Development and Validation of the Revised DIGIROP Clinical Decision Support Tool.

Importance: The prognostic impact of parenteral nutrition duration (PND) on retinopathy of prematurity (ROP) is not well studied. Safe prediction models can help optimize ROP screening by effectively discriminating high-risk from low-risk infants. Objective: To evaluate the prognostic value of PND on ROP; to update and validate the Digital ROP (DIGIROP) 2.0 birth into prescreen and screen prediction models to include all ROP-screened infants regardless of gestational age (GA) and incorporate PND; and to compare the DIGIROP model with the Weight, IGF-1, Neonatal, and ROP (WINROP) and Postnatal Growth and ROP (G-ROP) models. Design, Setting, and Participants: This retrospective study included 11 139 prematurely born infants from 2007 to 2020 from the Swedish National Registry for ROP. Extended Poisson and logistic models were applied. Data were analyzed from August 2022 to February 2023. Main Outcomes and Measures: Any ROP and ROP requiring treatment were studied in relation to PND. ROP treatment was the outcome in DIGIROP models. Sensitivity, specificity, area under the receiver operating characteristic curve, and adjusted OR (aOR) with 95% CI were the main measures. Internal and external validations were performed. Results: Of 11 139 screened infants, 5071 (45.5%) were girls, and the mean (SD) gestational age was 28.5 (2.4) weeks. ROP developed in 3179 infants (29%), treatment was given in 599 (5%), 7228 (65%) had PND less than 14 days, 2308 (21%) had PND for 14 days or more, and 1603 (14%) had unknown PND. PND was significantly correlated with ROP severity (Spearman r = 0.45; P < .001). Infants with 14 days or more of PND vs less than 14 days had faster progression from any ROP to ROP treatment (adjusted mean difference, -0.9 weeks; 95% CI, -1.5 to -0.3; P = .004). Infants with PND for 14 days or more vs less than 14 days had higher odds of any ROP (aOR, 1.84; 95% CI, 1.62-2.10; P < .001) and of severe ROP requiring treatment (aOR, 2.20; 95% CI, 1.73-2.80; P < .001). Among all 11 139 infants, the DIGIROP 2.0 models had 100% sensitivity (95% CI, 99.4-100). The specificity was 46.6% (95% CI, 45.6-47.5) for the prescreen model and 76.9% (95% CI, 76.1-77.7) for the screen model. G-ROP as well as the DIGIROP 2.0 prescreen and screen models showed 100% sensitivity on a validation subset (G-ROP: sensitivity, 100%; 95% CI, 93-100; DIGIROP prescreen: sensitivity, 100%; 95% CI, 93-100; DIGIROP screen: sensitivity, 100%; 95% CI, 93-100), whereas WINROP showed 89% sensitivity (95% CI, 77-96). Specificity for each prediction model was 29% (95% CI, 22-36) for G-ROP, 38% (95% CI, 32-46) for DIGIROP prescreen, 53% (95% CI, 46-60) for DIGIROP screen at 10 weeks, and 46% (95% CI, 39-53) for WINROP. Conclusion and Relevance: Based on more than 11 000 ROP-screened infants born in Sweden, PND of 14 days or more corresponded to a significantly higher risk of having any ROP and receiving ROP treatment. These findings provide evidence to support consideration of using the updated DIGIROP 2.0 models instead of the WINROP or G-ROP models in the management of ROP.

[Survival and prematurity-related neonatal diagnoses among children born before 24 gestational weeks in Sweden 2007-2018]. / Allt fler barn födda före vecka 24 överlever, men sjukligheten är hög.

Children born before 24 gestational weeks had high neonatal morbidity and a majority had one or more neurodevelopmental disorders in addition to somatic diagnoses in childhood. Active Swedish perinatal care of infants with gestational age <24 weeks has resulted in a survival rate of more than 50 percent. Resuscitation of these immature infants is controversial, and some countries offer comfort care only. In a retrospective review of medical files and registries of 399 Swedish infants born before 24 gestational weeks, a majority had severe prematurity-related neonatal diagnoses. In childhood (2-13 years), 75 percent had at least one neurodevelopmental disorder and 88 percent had one or more prematurity-related somatic diagnosis (permanent or transient) that was likely to affect their quality of life. Long-term consequences for surviving infants should be considered in general recommendations as well as in parental information.

Validation of DIGIROP models and decision support tool for prediction of treatment for retinopathy of prematurity on a contemporary Swedish cohort.

BACKGROUND/AIMS: Retinopathy of prematurity (ROP) is currently diagnosed through repeated eye examinations to find the low percentage of infants that fulfil treatment criteria to reduce vision loss. A prediction model for severe ROP requiring treatment that might sensitively and specifically identify infants that develop severe ROP, DIGIROP-Birth, was developed using birth characteristics. DIGIROP-Screen additionally incorporates first signs of ROP in different models over time. The aim was to validate DIGIROP-Birth, DIGIROP-Screen and their decision support tool on a contemporary Swedish cohort. METHODS: Data were retrieved from the Swedish national registry for ROP (2018-2019) and two Swedish regions (2020), including 1082 infants born at gestational age (GA) 24 to <31 weeks. The predictors were GA at birth, sex, standardised birth weight and age at the first sign of ROP. The outcome was ROP treatment. Sensitivity, specificity and area under the receiver operating characteristic curve (AUC) with 95% CI were described. RESULTS: For DIGIROP-Birth, the AUC was 0.93 (95% CI 0.90 to 0.95); for DIGIROP-Screen, it ranged between 0.93 and 0.97. The specificity was 49.9% (95% CI 46.7 to 53.0) and the sensitivity was 96.5% (95% CI 87.9 to 99.6) for the tool applied at birth. For DIGIROP-Screen, the cumulative specificity ranged between 50.0% and 78.7%. One infant with Beckwith-Wiedemann syndrome who fulfilled criteria for ROP treatment and had no missed/incomplete examinations was incorrectly flagged as not needing screening. CONCLUSIONS: DIGIROP-Birth and DIGIROP-Screen showed high predictive ability in a contemporary Swedish cohort. At birth, 50% of the infants born at 24 to <31 weeks of gestation were predicted to have low risk of severe ROP and could potentially be released from ROP screening examinations. All routinely screened treated infants, excluding those screened for clinical indications of severe illness, were correctly flagged as needing ROP screening.

Retrospective evaluation of ophthalmological and neurological outcomes for infants born before 24 weeks gestational age in a Swedish cohort.

OBJECTIVES: To retrospectively evaluate ophthalmological and neurological outcomes in a Swedish cohort of infants born before 24 weeks gestational age (GA) and explore risk factors for visual impairment. SETTING: Eye and paediatric clinics in Sweden. PARTICIPANTS: Infants screened for retinopathy of prematurity (ROP) (n=399), born before 24 weeks GA, 2007-2018. Cases were excluded if ophthalmological follow-up records could not be traced. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were ophthalmological, including visual acuity (VA), refractive error, strabismus, nystagmus and cerebral visual impairment (CVI). Secondary outcomes comprised neonatal and neurological morbidities. Data were retrospectively retrieved from medical records. RESULTS: The 355 assessed children had a median GA of 23 weeks and 2 days and a median birth weight of 565 g. At the last available ophthalmological examination, the median age was 4.8 years (range 0.5-13.2 years). Nystagmus was recorded in 21.1%, strabismus in 34.8%, and 51.0% wore spectacles. Seventy-three of 333 (21.9%) were visually impaired, defined as being referred to a low vision clinic and/or having a VA less than 20/60 at 3.5 years of age or older. ROP treatment was a significant risk factor for visual impairment (OR 2.244, p=0.003). Visually impaired children, compared with children without visual impairment, more often had neurological deficits such as intellectual disability 63.8% versus 33.3% (p<0.001), epilepsy 21.1% versus 7.5% (p=0.001) and autism spectrum disorders 32.8% versus 20.9% (p=0.043). Nine of the 355 children had been diagnosed with CVI. CONCLUSIONS: Children born before 24 weeks GA frequently had visual impairment in association with neurological deficits. CVI was rarely diagnosed. A multidisciplinary approach for the evaluation and habilitation of these vulnerable infants is warranted. National follow-up guidelines need to be developed and implemented.

National cohort of infants born before 24 gestational weeks showed increased survival rates but no improvement in neonatal morbidity.

AIM: To describe survival and neonatal morbidities in infants born before 24 weeks of gestation during a 12-year period. METHODS: Data were retrieved from national registries and validated in medical files of infants born before 24 weeks of gestation 2007-2018 in Sweden. Temporal changes were evaluated. RESULTS: In 2007-2018, 282 live births were recorded at 22 weeks and 460 at 23 weeks of gestation. Survival to discharge from hospital of infants born alive at 22 and 23 weeks increased from 20% to 38% (p = 0.006) and from 45% to 67% (p < 0.001) respectively. Caesarean section increased from 12% to 22% (p = 0.038) for infants born at 22 weeks. Neonatal morbidity rates in infants alive at 40 weeks of postmenstrual age (n = 399) were unchanged except for an increase in necrotising enterocolitis from 0 to 33% (p = 0.017) in infants born at 22 weeks of gestation. Bronchopulmonary dysplasia was more common in boys than girls, 90% versus 82% (p = 0.044). The number of infants surviving to 40 weeks doubled over time. CONCLUSION: Increased survival of infants born before 24 weeks of gestation resulted in increasing numbers of very immature infants with severe neonatal morbidities likely to have a negative impact on long-term outcome.

Neurodevelopmental disorders and somatic diagnoses in a national cohort of children born before 24 weeks of gestation.

AIM: This study investigated childhood diagnoses in children born extremely preterm before 24 weeks of gestation. METHODS: Diagnoses of neurodevelopmental disorders and selected somatic diagnoses were retrospectively retrieved from national Swedish registries for children born before 24 weeks from 2007 to 2018. Their individual medical files were also examined. RESULTS: We studied 383 children born at a median of 23.3 (range 21.9-23.9) weeks, with a median birthweight of 565 (range 340-874) grams. Three-quarters (75%) had neurodevelopmental disorders, including speech disorders (52%), intellectual disabilities (40%), attention deficit hyperactivity disorder (30%), autism spectrum disorders (24%), visual impairment (22%), cerebral palsy (17%), epilepsy (10%) and hearing impairment (5%). More boys than girls born at 23 weeks had intellectual disabilities (45% vs. 27%, p < 0.01) and visual impairment (25% vs. 14%, p < 0.01). Just over half of the cohort (55%) received habilitation care. The majority (88%) had somatic diagnoses, including asthma (63%) and failure to thrive/short stature (39%). CONCLUSION: Most children born before 24 weeks had neurodevelopmental disorders and/or additional somatic diagnoses in childhood and were referred to habilitation services. Clinicians should be aware of the multiple health and developmental problems affecting these children. Resources are needed to identify their long-term support needs at an early stage.

Blood protein profiles related to preterm birth and retinopathy of prematurity.

BACKGROUND: Nearly one in ten children is born preterm. The degree of immaturity is a determinant of the infant's health. Extremely preterm infants have higher morbidity and mortality than term infants. One disease affecting extremely preterm infants is retinopathy of prematurity (ROP), a multifactorial neurovascular disease that can lead to retinal detachment and blindness. The advances in omics technology have opened up possibilities to study protein expressions thoroughly with clinical accuracy, here used to increase the understanding of protein expression in relation to immaturity and ROP. METHODS: Longitudinal serum protein profiles the first months after birth in 14 extremely preterm infants were integrated with perinatal and ROP data. In total, 448 unique protein targets were analyzed using Proximity Extension Assays. RESULTS: We found 20 serum proteins associated with gestational age and/or ROP functioning within mainly angiogenesis, hematopoiesis, bone regulation, immune function, and lipid metabolism. Infants with severe ROP had persistent lower levels of several identified proteins during the first postnatal months. CONCLUSIONS: The study contributes to the understanding of the relationship between longitudinal serum protein levels and immaturity and abnormal retinal neurovascular development. This is essential for understanding pathophysiological mechanisms and to optimize diagnosis, treatment and prevention for ROP. IMPACT: Longitudinal protein profiles of 14 extremely preterm infants were analyzed using a novel multiplex protein analysis platform combined with perinatal data. Proteins associated with gestational age at birth and the neurovascular disease ROP were identified. Among infants with ROP, longitudinal levels of the identified proteins remained largely unchanged during the first postnatal months. The main functions of the proteins identified were angiogenesis, hematopoiesis, immune function, bone regulation, lipid metabolism, and central nervous system development. The study contributes to the understanding of longitudinal serum protein patterns related to gestational age and their association with abnormal retinal neuro-vascular development.

Development and validation of a new clinical decision support tool to optimize screening for retinopathy of prematurity.

BACKGROUND/AIMS: Prematurely born infants undergo costly, stressful eye examinations to uncover the small fraction with retinopathy of prematurity (ROP) that needs treatment to prevent blindness. The aim was to develop a prediction tool (DIGIROP-Screen) with 100% sensitivity and high specificity to safely reduce screening of those infants not needing treatment. DIGIROP-Screen was compared with four other ROP models based on longitudinal weights. METHODS: Data, including infants born at 24-30 weeks of gestational age (GA), for DIGIROP-Screen development (DevGroup, N=6991) originate from the Swedish National Registry for ROP. Three international cohorts comprised the external validation groups (ValGroups, N=1241). Multivariable logistic regressions, over postnatal ages (PNAs) 6-14 weeks, were validated. Predictors were birth characteristics, status and age at first diagnosed ROP and essential interactions. RESULTS: ROP treatment was required in 287 (4.1%)/6991 infants in DevGroup and 49 (3.9%)/1241 in ValGroups. To allow 100% sensitivity in DevGroup, specificity at birth was 53.1% and cumulatively 60.5% at PNA 8 weeks. Applying the same cut-offs in ValGroups, specificities were similar (46.3% and 53.5%). One infant with severe malformations in ValGroups was incorrectly classified as not needing screening. For all other infants, at PNA 6-14 weeks, sensitivity was 100%. In other published models, sensitivity ranged from 88.5% to 100% and specificity ranged from 9.6% to 45.2%. CONCLUSIONS: DIGIROP-Screen, a clinical decision support tool using readily available birth and ROP screening data for infants born GA 24-30 weeks, in the European and North American populations tested can safely identify infants not needing ROP screening. DIGIROP-Screen had equal or higher sensitivity and specificity compared with other models. DIGIROP-Screen should be tested in any new cohort for validation and if not validated it can be modified using the same statistical approaches applied to a specific clinical setting.

Association of Docosahexaenoic Acid and Arachidonic Acid Serum Levels With Retinopathy of Prematurity in Preterm Infants.

Importance: Supplementing preterm infants with long-chain polyunsaturated fatty acids (LC-PUFA) has been inconsistent in reducing the severity and incidence of retinopathy of prematurity (ROP). Furthermore, few studies have measured the long-term serum lipid levels after supplementation. Objective: To assess whether ROP severity is associated with serum levels of LC-PUFA, especially docosahexaenoic acid (DHA) and arachidonic acid (AA), during the first 28 postnatal days. Design, Setting, and Participants: This cohort study analyzed the Mega Donna Mega study, a randomized clinical trial that provided enteral fatty acid supplementation at 3 neonatal intensive care units in Sweden. Infants included in this cohort study were born at a gestational age of less than 28 weeks between December 20, 2016, and August 6, 2019. Main Outcomes and Measures: Severity of ROP was classified as no ROP, mild or moderate ROP (stage 1-2), or severe ROP (stage 3 and type 1). Serum phospholipid fatty acids were measured through gas chromatography-mass spectrometry. Ordinal logistic regression, with a description of unadjusted odds ratio (OR) as well as gestational age- and birth weight-adjusted ORs and 95% CIs, was used. Areas under the curve were used to calculate mean daily levels of fatty acids during postnatal days 1 to 28. Blood samples were obtained at the postnatal ages of 1, 3, 7, 14, and 28 days. Results: A total of 175 infants were included in analysis. Of these infants, 99 were boys (56.6%); the median (IQR) gestational age was 25 weeks 5 days (24 weeks 3 days to 26 weeks 6 days), and the median (IQR) birth weight was 785 (650-945) grams. A higher DHA proportion was seen in infants with no ROP compared with those with mild or moderate ROP or severe ROP (OR per 0.5-molar percentage increase, 0.49 [95% CI, 0.36-0.68]; gestational age- and birth weight-adjusted OR, 0.66 [95% CI, 0.46-0.93]). The corresponding adjusted OR for AA levels per 1-molar percentage increase was 0.83 (95% CI, 0.66-1.05). The association between DHA levels and ROP severity appeared only in infants with sufficient AA levels, suggesting that a mean daily minimum level of 7.8 to 8.3 molar percentage of AA was necessary for a detectable association between DHA level and less severe ROP. Conclusions and Relevance: This cohort study found that higher mean daily serum levels of DHA during the first 28 postnatal days were associated with less severe ROP even after adjustment for known risk factors, but only in infants with sufficiently high AA levels. Further studies are needed to identify LC-PUFA supplementation strategies that may prevent ROP and other morbidities.

High rate and large intercentre variability in retreatment of retinopathy of prematurity in infants born <24 gestational weeks.

OBJECTIVE: Prematurity is a major risk factor for retinopathy of prematurity (ROP). We aimed to elucidate ROP prevalence, treatment and retreatment in infants born before 24 gestational age (GA) weeks in a Swedish cohort. METHODS AND ANALYSIS: Infants with completed ROP screening, born at <24 GA weeks, 2007-2018 in Sweden were included. Data of GA, birth weight (BW), sex, neonatal morbidities, maximal ROP stage, aggressive posterior ROP (APROP), ROP treatments, treatment modality and treatment centre were retrieved. RESULTS: In total, 399 infants, with a mean GA of 23.2 weeks (range 21.9-23.9) and a mean BW of 567 g (range 340-874), were included. ROP was detected in 365 (91.5%) infants, 173 (43.4%) were treated for ROP and 68 of 173 (39.3%) were treated more than once. As the first treatment, 142 (82.0%) received laser and 29 (16.1%) received intravitreal injection of antivascular endothelial growth factor (anti-VEGF). Retreatment was performed after first laser in 46 of 142 (32.4%) and in 20 of 29 (69.0%) after first anti-VEGF treatment. Retreatment rate was not associated with GA, BW or sex but with APROP, treatment method (anti-VEGF) and treatment centre where the laser was performed (p<0.001). Twenty eyes progressed to retinal detachment, and two infants developed unilateral endophthalmitis after anti-VEGF treatment. CONCLUSION: Infants, born at <24 weeks' GA, had high rates of treatment-warranting ROP and retreatments. Treatment centre highly influenced the retreatment rate after laser indicating that laser treatment could be improved in some settings.

Effect of Enteral Lipid Supplement on Severe Retinopathy of Prematurity: A Randomized Clinical Trial.

Importance: Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP). Objective: To determine whether enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants. Design, Setting, and Participants: The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks' gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020. Interventions: Infants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth. Results: A total of 101 infants (58 boys [57.4%]; mean [SD] gestational age, 25.5 [1.5] weeks) were included in the AA:DHA group, and 105 infants (59 boys [56.2%]; mean [SD] gestational age, 25.5 [1.4] weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 [15.8%] in the AA:DHA group vs 35 of 105 [33.3%] in the control group; adjusted relative risk, 0.50 [95% CI, 0.28-0.91]; P = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% [95% CI, 0.46-1.18 mol%]; P < .001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%]; P = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 [47.5%] vs 48 of 105 [45.7%]) and of any grade of intraventricular hemorrhage (43 of 101 [42.6%] vs 42 of 105 [40.0%]). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died. Conclusions and Relevance: This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT03201588.

Unpasteurised maternal breast milk is positively associated with growth outcomes in extremely preterm infants.

AIM: Extrauterine growth restriction is common among extremely preterm infants. We explored whether intake of unpasteurised maternal milk (MM) and pasteurised donor milk (DM) was associated with longitudinal growth outcomes and neonatal morbidities in extremely preterm infants. METHODS: Observational study of 90 preterm infants born between 2013 and 2015 in Gothenburg, Sweden. Data were prospectively collected on nutritional and breast milk intakes during the first 28 days. RESULTS: Ninety infants (39 girls and 51 boys) with a median gestational age of 25.3 (22.7-27.9) weeks were evaluated. MM intake (mL/kg/d) correlated positively with almost all z-scores for weight, length and head circumference at 28 postnatal days and at postmenstrual age (PMA) 32 and 36 weeks. After multivariable adjustment, MM intake and weight z-score at 28 postnatal days and at PMA 32 and 36 weeks remained significantly associated. Infants consuming ≥80% MM had more favourable weight z-scores at PMA 32 and 36 weeks. Intake of DM did not correlate with any growth outcomes. Infants without retinopathy of prematurity had a significantly higher intake of MM (mL/kg/d). CONCLUSION: Unpasteurised MM was positively associated with longitudinal growth outcomes. Motivating mothers to provide their infants with their own milk after preterm birth should be emphasised.

Individual Risk Prediction for Sight-Threatening Retinopathy of Prematurity Using Birth Characteristics.

Importance: To prevent blindness, repeated infant eye examinations are performed to detect severe retinopathy of prematurity (ROP), yet only a small fraction of those screened need treatment. Early individual risk stratification would improve screening timing and efficiency and potentially reduce the risk of blindness. Objectives: To create and validate an easy-to-use prediction model using only birth characteristics and to describe a continuous hazard function for ROP treatment. Design, Setting, and Participants: In this retrospective cohort study, Swedish National Patient Registry data from infants screened for ROP (born between January 1, 2007, and August 7, 2018) were analyzed with Poisson regression for time-varying data (postnatal age, gestational age [GA], sex, birth weight, and important interactions) to develop an individualized predictive model for ROP treatment (called DIGIROP-Birth [Digital ROP]). The model was validated internally and externally (in US and European cohorts) and compared with 4 published prediction models. Main Outcomes and Measures: The study outcome was ROP treatment. The measures were estimated momentary and cumulative risks, hazard ratios with 95% CIs, area under the receiver operating characteristic curve (hereinafter referred to as AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Among 7609 infants (54.6% boys; mean [SD] GA, 28.1 [2.1] weeks; mean [SD] birth weight, 1119 [353] g), 442 (5.8%) were treated for ROP, including 142 (40.1%) treated of 354 born at less than 24 gestational weeks. Irrespective of GA, the risk for receiving ROP treatment increased during postnatal weeks 8 through 12 and decreased thereafter. Validations of DIGIROP-Birth for 24 to 30 weeks' GA showed high predictive ability for the model overall (AUC, 0.90 [95% CI, 0.89-0.92] for internal validation, 0.94 [95% CI, 0.90-0.98] for temporal validation, 0.87 [95% CI, 0.84-0.89] for US external validation, and 0.90 [95% CI, 0.85-0.95] for European external validation) by calendar periods and by race/ethnicity. The sensitivity, specificity, PPV, and NPV were numerically at least as high as those obtained from CHOP-ROP (Children's Hospital of Philadelphia-ROP), OMA-ROP (Omaha-ROP), WINROP (weight, insulinlike growth factor 1, neonatal, ROP), and CO-ROP (Colorado-ROP), models requiring more complex postnatal data. Conclusions and Relevance: This study validated an individualized prediction model for infants born at 24 to 30 weeks' GA, enabling early risk prediction of ROP treatment based on birth characteristics data. Postnatal age rather than postmenstrual age was a better predictive variable for the temporal risk of ROP treatment. The model is an accessible online application that appears to be generalizable and to have at least as good test statistics as other models requiring longitudinal neonatal data not always readily available to ophthalmologists.

Screening and novel therapies for retinopathy of prematurity - A review.

With current screening for sight threatening retinopathy of prematurity (ROP) <10% of screened infants need treatment. Prediction models based on birth characteristics, postnatal weight gain and other factors have been developed to reduce examinations in low-risk infants. A model based on advanced statistics using data from >7000 infants registered in the Swedish ROP registry is being developed. Based on birth characteristics only, it appears to predict total risk of ROP-treatment as well as models including weight measurements. Treatment risk peaked at 12 weeks of age. Laser therapy is the method of choice for severe ROP. Anti-VEGF therapies are implemented worldwide despite insufficient knowledge of choice of drug, dosage and long term systemic effects. Prevention of ROP may be achieved through oxygen control and provision of the mother's breastmilk. Other interventions such as supplementation with long chain polyunsaturated fatty acids and preservation of fetal haemoglobin are investigated.

Review shows that donor milk does not promote the growth and development of preterm infants as well as maternal milk.

AIM: This nonsystematic review examined differences in the composition of raw maternal breastmilk and pasteurised donor milk and possible health effects on preterm infants. METHODS: We searched PubMed up to July 2018 for studies published in English that focused on four comparisons as follows: raw maternal milk versus donor milk, human milk before and after Holder pasteurisation, milk from mothers who delivered preterm and at term and milk collected during early and late lactation. We also searched for possible effects of the milk components, as well as the effects of maternal and donor milk on preterm infants' health. RESULTS: Raw maternal milk contained factors involved in antioxidant and anti-inflammatory defence, gut microbiome establishment and the maturation of immune defences, food tolerability and metabolism. Many of these factors were reduced or abolished in processed donor milk. Both maternal milk and donor milk have been associated with a reduced incidence of necrotising enterocolitis. High-dose feeding with maternal milk during the neonatal period reportedly reduced the risk of other morbidities and promoted growth and neurodevelopment. CONCLUSION: Many of the components in raw maternal breastmilk were lacking in pasteurised donor milk, which was inferior in promoting the growth and development of very preterm infants.

Association of Retinopathy of Prematurity With Low Levels of Arachidonic Acid: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Mice with oxygen-induced retinopathy fed matched diets except for ω-3 long-chain polyunsaturated fatty acids (LC-PUFAs) vs ω-6 LC-PUFAs demonstrate relative antiangiogenic and neuroprotective associations of ω-3 LC-PUFAs. However, supplementing preterm infants with LC-PUFAs has been inconsistent in reducing major preterm morbidities. However, few studies measured serum lipid levels after supplementation. Objective: To examine the associated risk of retinopathy of prematurity (ROP) from the levels of circulating ω-3 and ω-6 LC-PUFAs. Design, Setting, and Participants: This longitudinal clinical study was a further analysis of serum lipid levels from a randomized controlled trial cohort of 90 infants born at gestational age (GA) less than 28 weeks. From April 4, 2013, to September 22, 2015, cord blood samples, followed by venous blood samples, were obtained at birth and at 1, 7, 14, and 28 days after birth and then at postmenstrual age (PMA) 32, 36, and 40 weeks at the neonatal intensive care unit at Sahlgrenska University Hospital in Göteborg, Sweden. Main Outcomes and Measures: Serum phospholipid fatty acids were transmethylated and measured by gas chromatography-mass spectrometry. Mann-Whitney test, logistic regression Spearman rank correlation, and receiver operating characteristic curve analysis were used to compare differences between infants with no ROP and infants who developed ROP. Results: Serum levels from 78 infants (43 male [55%]; mean [SD] GA, 25.5 [1.4] weeks) with a known ROP outcome were evaluated. Lower area under the curve (AUC) of arachidonic acid (AA) (20:4 ω-6) was seen in infants with a later diagnosis of ROP compared with infants with no ROP in the first month of life (mean, 34.05 [95% CI, 32.10-36.00] vs 37.15 [95% CI, 34.85-39.46]; P < .05). In addition, lower levels of AA at 32 weeks' PMA were seen in infants with later severe ROP compared with in those without ROP (mean, 7.06 [95% CI, 6.60-7.52] vs 8.74 [95% CI, 7.80-9.67]; P < .001). In logistic modeling, low postnatal serum levels of AA and GA at birth identified with a sensitivity greater than 90% of infants who developed ROP. Conclusions and Relevance: Low postnatal levels of the ω-6 LC-PUFAs (AA) are strongly associated with ROP development. Evaluating postnatal AA fraction after birth in addition to GA may be useful for ROP prediction. Trial Registration: clinicaltrials.gov Identifier: NCT02760472.