Evaluation of the Retinopathy of Prematurity Activity Scale (ROP-ActS) in a randomised controlled trial aiming for prevention of severe ROP : A substudy of the Mega Donna Mega trial

Objective The current grading of retinopathy of prematurity (ROP) does not sufficiently discriminate disease severity for evaluation of trial interventions. The published ROP Activity Scales (original: ROP-ActS and modified: mROP-ActS), describing increasing severity of ROP, versus the categorical variables severe ROP, stage, zone and plus disease were evaluated as discriminators of the effect of an ROP preventive treatment. Methods and analysis The Mega Donna Mega trial investigated ROP in infants born <28-week gestational age (GA), randomised to arachidonic acid (AA) and docosahexaenoic acid (DHA) supplementation or no supplementation. Of 207 infants, 86% with finalised ROP screening were included in this substudy. ROP-ActS versus standard variables were evaluated using Fisher’s non-parametric permutation test, multivariable logistic and linear regression and marginal fractional response models. Results The AA:DHA group (n=84) and the control group (n=93) were well balanced. The maximum ROP-ActS measurement was numerically but not significantly lower in the AA:DHA group (mean: 4.0 (95% CI 2.9 to 5.0)) versus the control group (mean: 5.3 (95% CI 4.1 to 6.4)), p=0.11. In infants with any ROP, the corresponding scale measurements were 6.8 (95% CI 5.4 to 8.2) and 8.7 (95% CI 7.5 to 10.0), p=0.039. Longitudinal profiles of the scale were visually distinguished for the categories of sex and GA for the intervention versus control. Conclusions The preventive effect of AA:DHA supplementation versus no supplementation was better discriminated by the trial’s primary outcome, severe ROP, than by ROP-ActS. The sensitivity and the linear qualities of ROP-ActS require further validations on large data sets and perhaps modifications. Trial registration number NCT03201588

Low Birth Weight Is a Risk Factor for Severe Retinopathy of Prematurity Depending on Gestational Age

Objective: To evaluate the impact of low birth weight as a risk factor for retinopathy of prematurity (ROP) that will require treatment in correlation with gestational age at birth (GA). Study design In total, 2941 infants born <32 weeks GA were eligible from five cohorts of preterm infants previously collected for analysis in WINROP (Weight IGF-I Neonatal ROP) from the following locations: Sweden (EXPRESS) (n = 426), North America (n = 1772), Boston (n = 338), Lund (n = 52), and Gothenburg (n = 353). Data regarding GA at birth, birth weight (BW), gender, and need for ROP treatment were retrieved. Birth weight standard deviation scores (BWSDS) were calculated with Swedish as well as Canadian reference models. Small for gestational age (SGA) was defined as BWSDS less than −2.0 SDS using the Swedish reference and as BW below the 10th percentile using the Canadian reference charts. Results: Univariate analysis showed that low GA (p<0.001), low BW (p<0.001), male gender (p<0.05), low BWSDSCanada (p<0.001), and SGACanada (p<0.01) were risk factors for ROP that will require treatment. In multivariable logistic regression analysis, low GA (p<0.0001), male gender (p<0.01 and p<0.05), and an interaction term of BWSDS*GA group (p<0.001), regardless of reference chart, were risk factors. Low BWSDS was less important as a risk factor in infants born at GA <26 weeks compared with infants born at GA ≥26 weeks calculated with both reference charts (BWSDSSweden, OR = 0.80 vs 0.56; and BWSDSCanada, OR = 0.72 vs 0.41). Conclusions: Low BWSDS as a risk factor for vision-threatening ROP is dependent on the infant's degree of immaturity. In more mature infants (GA ≥26 weeks), low BWSDS becomes a major risk factor for developing ROP that will require treatment. These results persist even when calculating BW deficit with different well-established approaches

Insulin-like growth factor 1 has multisystem effects on foetal and preterm infant development.

UNLABELLED: Poor postnatal growth after preterm birth does not match the normal rapid growth in utero and is associated with preterm morbidities. Insulin-like growth factor 1 (IGF-1) axis is the major hormonal mediator of growth in utero, and levels of IGF-1 are often very low after preterm birth. We reviewed the role of IGF-1 in foetal development and the corresponding preterm perinatal period to highlight the potential clinical importance of IGF-1 deficiency in preterm morbidities. CONCLUSION: There is a rationale for clinical trials to evaluate the potential benefits of IGF-1 replacement in very preterm infants.This work was supported by a European Commission FP7 project 305485 PREVENT-ROP grant to all of the authors.This is the final version of the article. It first appeared from Wiley via https://doi.org/10.1111/apa.1335

Postnatal serum IGF-1 levels associate with brain volumes at term in extremely preterm infants

Background: Growth factors important for normal brain development are low in preterm infants. This study investigated the link between growth factors and preterm brain volumes at term. Material/methods: Infants born <28 weeks gestational age (GA) were included. Endogenous levels of insulin-like growth factor (IGF)−1, brain-derived growth factor, vascular endothelial growth factor, and platelet-derived growth factor (expressed as area under the curve [AUC] for serum samples from postnatal days 1, 7, 14, and 28) were utilized in a multivariable linear regression model. Brain volumes were determined by magnetic resonance imaging (MRI) at term equivalent age. Results: In total, 49 infants (median [range] GA 25.4 [22.9–27.9] weeks) were included following MRI segmentation quality assessment and AUC calculation. IGF-1 levels were independently positively associated with the total brain (p < 0.001, β = 0.90), white matter (p = 0.007, β = 0.33), cortical gray matter (p = 0.002, β = 0.43), deep gray matter (p = 0.008, β = 0.05), and cerebellar (p = 0.006, β = 0.08) volume adjusted for GA at birth and postmenstrual age at MRI. No associations were seen for other growth factors. Conclusions: Endogenous exposure to IGF-1 during the first 4 weeks of life was associated with total and regional brain volumes at term. Optimizing levels of IGF-1 might improve brain growth in extremely preterm infants. Impact: High serum levels of insulin-like growth factor (IGF)-1 during the first month of life were independently associated with increased total brain volume, white matter, gray matter, and cerebellar volume at term equivalent age in extremely preterm infants.IGF-1 is a critical regulator of neurodevelopment and postnatal levels are low in preterm infants. The effects of IGF-1 levels on brain development in extremely preterm infants are not fully understood.Optimizing levels of IGF-1 may benefit early brain growth in extremely preterm infants. The effects of systemically administered IGF-1/IGFBP3 in extremely preterm infants are now being investigated in a randomized controlled trial (Clinicaltrials.gov: NCT03253263)

Photoreceptor glucose metabolism determines normal retinal vascular growth

Abstract The neural cells and factors determining normal vascular growth are not well defined even though vision‐threatening neovessel growth, a major cause of blindness in retinopathy of prematurity (ROP) (and diabetic retinopathy), is driven by delayed normal vascular growth. We here examined whether hyperglycemia and low adiponectin (APN) levels delayed normal retinal vascularization, driven primarily by dysregulated photoreceptor metabolism. In premature infants, low APN levels correlated with hyperglycemia and delayed retinal vascular formation. Experimentally in a neonatal mouse model of postnatal hyperglycemia modeling early ROP, hyperglycemia caused photoreceptor dysfunction and delayed neurovascular maturation associated with changes in the APN pathway; recombinant mouse APN or APN receptor agonist AdipoRon treatment normalized vascular growth. APN deficiency decreased retinal mitochondrial metabolic enzyme levels particularly in photoreceptors, suppressed retinal vascular development, and decreased photoreceptor platelet‐derived growth factor (Pdgfb). APN pathway activation reversed these effects. Blockade of mitochondrial respiration abolished AdipoRon‐induced Pdgfb increase in photoreceptors. Photoreceptor knockdown of Pdgfb delayed retinal vascular formation. Stimulation of the APN pathway might prevent hyperglycemia‐associated retinal abnormalities and suppress phase I ROP in premature infants

GH Secretion in children. Methodological aspects of determining immunoreactive and bioactive isoforms

A child's hormone-dependent growth is dependent on multiple factors, although linear growth is closely associated with levels of growth hormone (GH) secretion. As GH in serum exists in several isoforms, some of which may not be identified by immunoassay, possible alterations in the secretion of these different isoforms in childhood may influence growth and/or metabolism. Changes in GH sensitivity may also affect growth. These changes may be primary, i.e. caused by defects in the GH receptor (GHR) or defects further along the GH ? insulin-like growth factor 1 (IGF-I) axis, or secondary, resulting from a variety of illnesses or malnutrition affecting various steps in the pathway from GH binding to IGF-I action.The general aim of the work reported in this thesis was to improve the diagnostic tools available to evaluate GH secretion in children.This work attempted to characterise immunoreactive serum GH measurements. In addition, the proportion of non-22 kDa GH isoforms in children of short stature and in children of normal stature was evaluated. This indicated that GH measurements should indeed be standardised, and assays cross-reactivity patterns explored to provide well-defined methods that can be used for screening children. It was found that the ratio of the total amount of GH compared with the amount of the 22 kDa isoform differed significantly between children of short stature and children of normal stature. The use of ratios on an individual level might serve as a valid screening method for identifying children for further studies. However, it is important to stress that immunoassays detect GH-like molecules in biological samples that interact with the antibodies used in the particular assay rather than measuring the biological activity of GH.The second part of this work focuses on the possibility of developing a bioassay that involves the concept of ligand-induced receptor dimerization, which is necessary for GH receptor activation. As a first step in the development of a cell-free assay we have constructed a soluble hybrid receptor consisting of the extracellular domain of the GH receptor linked to the intracellular domain of epidermal growth factor (EGF), containing a tyrosine kinase domain. A fusion protein has been constructed and expressed in a baculovirus system. The protein had GH-binding capacity as well as tyrosine kinase activity, indicating that both the GHR and the EGF receptor (EGFR) domains were functional when expressed as a chimeric protein. Further development of an assay that measures biologically active GH and is simple enough to use in a large-scale clinical setting would be a considerable improvement on present assay methods. Finally, a model was constructed that converted the IGF-I level of a child into an SD score. The objective was to produce reference values to be used in clinical practice in a model that would explain the variation in IGF-I levels throughout a child's growth phases without including too many variables. The study clearly showed that correct interpretation of IGF-I measurements is highly dependent on the relationship between age, gender and puberty

Systematic review of the healthcare cost of bronchopulmonary dysplasia

To determine the costs directly or indirectly related to bronchopulmonary dysplasia (BPD) in preterm infants. The secondary objective was to stratify the costs based on gestational age and/or birth weight. Systematic literature review. PubMed and Scopus were searched on 3 February 2020. Studies were selected based on eligibility criteria by two independent reviewers. Included studies were further searched to identify eligible references and citations. Two independent reviewers extracted data with a prespecified data extraction sheet, including items from a published checklist for quality assessment. The costs in the included studies are reported descriptively. Costs of BPD. The 13 included studies reported the total costs or marginal costs of BPD. Most studies reported costs during birth hospitalisation (cost range: Int$21 392–Int$1 094 509 per child, equivalent to €19 103–€977 397, in 2019) and/or during the first year of life. One study reported costs during the first 2 years; two other studies reported costs later, during the preschool period and one study included a long-term follow-up. The highest mean costs were associated with infants born at extremely low gestational ages. The quality assessment indicated a low risk of bias in the reported findings of included studies. This study was the first systematic review of costs associated with BPD. We confirmed previous reports of high costs and described the long-term follow-up necessary for preterm infants with BPD, particularly infants of very low gestational age. Moreover, we identified a need for studies that estimate costs outside hospitals and after the first year of life. CRD42020173234

A systematic review and meta-analysis of preanalytical factors and methodological differences influencing the measurement of circulating vascular endothelial growth factor.

BackgroundIntraocular treatment with antibodies targeting vascular endothelial growth factor (anti-VEGF) inhibits pathological vessel growth in adults and preterm infants. Recently, concerns regarding the impact of anti-VEGF treatment on systemic VEGF levels in preterm infants have been raised. Earlier studies suggest that preanalytical and methodological parameters impact analytical VEGF concentrations, but we have not found a comprehensive systematic review covering preanalytical procedures and methods for VEGF measurements.ObjectiveThis review aimed to evaluate the most critical factors during sample collection, sample handling, and the analytical methods that influence VEGF levels and therefore should be considered when planning a prospective collection of samples to get reproducible, comparable results.Material and methodsPubMed and Scopus databases were searched 2021/Nov/11. In addition, identification of records via other methods included reference, citation, and Google Scholar searches. Rayyan QCRI was used to handle duplicates and the selection process. Publications reporting preanalytical handling and/or methodological comparisons using human blood samples were included. Exclusion criteria were biological, environmental, genetic, or physiological factors affecting VEGF. The data extraction sheets included bias assessment using the QUADAS-2 tool, evaluating patient selection, index-test, reference standard, and flow and timing. Concentrations of VEGF and results from statistical comparisons of analytical methods and/or preanalytical sample handling and/or different sample systems were extracted. The publications covering preanalytical procedures were further categorized based on the stage of the preanalytical procedure. Meta-analysis was used to visualize VEGF concentrations among healthy individuals. The quality of evidence was rated according to GRADE.ResultsWe identified 1596 publications, and, after the screening process, 43 were considered eligible for this systematic review. The risk of bias estimation was difficult for 2/4 domains due to non-reported information. Four critical steps in the preanalytical process that impacted VEGF quantification were identified: blood drawing and the handling before, during, and after centrifugation. Sub-categorization of those elements resulted in nine findings, rated from moderate to very low evidence grade. The choice of sample system was the most reported factor. VEGF levels (mean [95% CI]) in serum (n = 906, 20 publications), (252.5 [213.1-291.9] pg/mL), were approximated to ninefold higher than in plasma (n = 1122, 23 publications), (27.8 [23.6-32.1] pg/mL), based on summarized VEGF levels with meta-analysis. Notably, most reported plasma levels were below the calibration range of the used method.ConclusionWhen measuring circulating VEGF levels, choice of sample system and sample handling are important factors to consider for ensuring high reproducibility and allowing study comparisons. Protocol: CRD42020192433

Effect of Preterm Birth on Postnatal Apolipoprotein and Adipocytokine Profiles

BACKGROUND: Critical metabolic changes preparing for ex utero life may occur at the fetal age of approximately 28-32 weeks, and preterm birth <28 weeks postmenstrual age (PMA) may affect these pathways. Children born <28 weeks often have poorer outcomes possibly due to a major shift in metabolism, including nutritional supply and a shift in lipid-transporting particles and lipid profile. This shift may occur in apolipoprotein and adipocytokine levels, which may influence metabolism. OBJECTIVE: To determine whether there is a shift in apolipoprotein and adipocytokine levels in neonates born at a gestational age (GA) of 28 and 32 weeks, respectively. METHODS: Blood samples from 47 infants (GA 32 weeks, n = 30 and GA 28 weeks, n = 17) were collected at birth and, in the GA28 group, also at PMA 32 weeks. Apolipoproteins A-1, A-2, B, C-2, C-3, and E were analyzed, as well as adiponectin and leptin levels. RESULTS: Serum levels of apolipoproteins A-1, C-2, C-3, and E were lower at birth in the GA28 group compared to the GA32 group. Adiponectin and leptin levels were low at birth in the GA28 group. In the GA28 group 4 weeks after birth, leptin levels were still low, whereas adiponectin levels had increased to levels similar to those found at birth in the GA32 group. Apolipoprotein A-1, C-2, C-3, and E levels were negatively correlated with days receiving total parenteral nutrition. CONCLUSION: There are significant differences in apolipoprotein and adipocytokine levels, which can be associated with GA and birth weight. The impact of these changes on neonatal and future morbidity remains to be determined

Low Postnatal Serum IGF-I levels is Associated with Bronchopulmonary Dysplasia (BPD).

Aim: To characterize postnatal changes in serum IGF-I in relation to development of bronchopulmonary dysplasia (BPD) in very preterm infants. Methods: Longitudinal study of 108 infants with mean (SD) gestational age 27.2 (2.2) weeks. Weekly serum samples of IGF-I were analyzed from birth until postmenstrual age 36 weeks. Multivariate models were developed to identify independent predictors of BPD. Results: Postnatal mean IGF-I levels at postnatal day 3 to 21 were lower in infants with BPD compared to infants with no BPD (16 vs. 26 ug/L, p<0.001). Longitudinal postnatal change in IGF-I levels (IGF-I regression coefficient (β), postnatal days 3 to 21, was lower in infants with BPD compared to infants with no BPD (0.28 vs. 0.97, p=0.002) and mean IGF-I during postmenstrual age 30-33 weeks was lower in infants with BPD as compared to infants without BPD (22 vs. 29 ug/L, p<0.001). In a binomial multiple regression model lower gestational age, male gender and lower mean serum IGF-I levels during postnatal day 3-21 were the most predictive risk factors associated with BPD (r(2) =0.634, p<0.001). Conclusion: Lower IGF-I concentrations during the first weeks after very preterm birth are associated with later development of BPD. © 2012 The Author(s)/Acta Paediatrica © 2012 Foundation Acta Paediatrica