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1.
  • Klevebro, S, et al. (author)
  • Cohort study of growth patterns by gestational age in preterm infants developing morbidity.
  • 2016
  • In: BMJ Open. - London, UK : BMJ. - 2044-6055. ; 6:11
  • Journal article (peer-reviewed)abstract
    • To examine differences in growth patterns in preterm infants developing major morbidities including retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotising enterocolitis (NEC) and intraventricular haemorrhage (IVH).Cohort study of 2521 infants born at a gestational age (GA) of 23-30weeks from 11 level III neonatal intensive care units in USA and Canada, and 3 Swedish population-based cohorts.Birth weight and postnatal weight gain were examined relative to birth GA and ROP, BPD, NEC and IVH development.Among infants with a birth GA of 25-30weeks, birth weight SD score and postnatal weight were lower in those developing ROP and BPD. Infants developing ROP showed lower growth rates during postnatal weeks 7-9 in the 23-24weeks GA group, during weeks 4-6 in the 25-26weeks GA group and during weeks 1-5 in the 27-30weeks GA group. Infants with BPD born at 27-30weeks GA showed lower growth rates during postnatal weeks 3-5. Infants with NEC had lower growth rates after postnatal week 6 in all GA groups, with no significant differences in birth weight SD score. IVH was not associated with prenatal or postnatal growth.In this cohort study of extremely preterm infants, we found that the postnatal growth pattern was associated with morbidities such as ROP, BPD and NEC as well as with gestational age at birth.
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2.
  • Cakir, B., et al. (author)
  • IGF1, serum glucose, and retinopathy of prematurity in extremely preterm infants
  • 2020
  • In: Jci Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 5:19
  • Journal article (peer-reviewed)abstract
    • BACKGROUND. Hyperglycemia, insulin insensitivity, and low IGF1 levels in extremely preterm infants are associated with an increased risk of retinopathy of prematurity (ROP), but the interactions are incompletely understood. METHODS. In 117 extremely preterm infants, serum glucose levels and parenteral glucose intake were recoded daily in the first postnatal week. Serum IGF1 levels were measured weekly. Mice with oxygen-induced retinopathy alone versus oxygen-induced retinopathy plus streptozotocin-induced hyperglycemia/hypoinsulinemia were assessed for glucose, insulin, IGF1, IGFBP1, and IGFBP3 in blood and liver. Recombinant human IGF1 was injected to assess the effect on glucose and retinopathy. RESULTS. The highest mean plasma glucose tertile of infants positively correlated with parenteral glucose intake [r (39) = 0.67, P < 0.0001]. IGF1 plasma levels were lower in the high tertile compared with those in low and intermediate tertiles at day 28 (P = 0.038 and P = 0.03). In high versus lower glucose tertiles, ROP was more prevalent (34 of 39 versus 19 of 39) and more severe (ROP stage 3 or higher; 71% versus 32%). In oxygen-induced retinopathy, hyperglycemia/hypoinsulinemia decreased liver IGF1 expression (P < 0.0001); rh-IGF1 treatment improved normal vascular regrowth (P = 0.027) and reduced neovascularization (P < 0.0001). CONCLUSION. In extremely preterm infants, high early postnatal plasma glucose levels and signs of insulin insensitivity were associated with lower IGF1 levels and increased ROP severity. In a hyperglycemia retinopathy mouse model, decreased insulin signaling suppressed liver IGF1 production, lowered serum IGF1 levels, and increased neovascularization. IGF1 supplementation improved retinal revascularization and decreased pathological neovascularization. The data support IGF1 as a potential treatment for prevention of ROP.
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3.
  • Cakir, B., et al. (author)
  • Thrombocytopenia is associated with severe retinopathy of prematurity
  • 2018
  • In: Jci Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 3:19
  • Journal article (peer-reviewed)abstract
    • Retinopathy of prematurity (ROP) is characterized by abnormal retinal neovascularization in response to vessel loss. Platelets regulate angiogenesis and may influence ROP progression. In preterm infants, we assessed ROP and correlated with longitudinal postnatal platelet counts (n = 202). Any episode of thrombocytopenia (< 100 x 10(9)/l) at >= 30 weeks postmenstrual age (at onset of ROP) was independently associated with severe ROP, requiring treatment. Infants with severe ROP also had a lower weekly median platelet count compared with infants with less severe ROP. In a mouse oxygen-induced retinopathy model of ROP, platelet counts were lower at P17 (peak neovascularization) versus controls. Platelet transfusions at P15 and P16 suppressed neovascularization, and platelet depletion increased neovascularization. Platelet transfusion decreased retinal of vascular endothelial growth factor A (VEGFA) mRNA and protein expression; platelet depletion increased retinal VEGFA mRNA and protein expression. Resting platelets with intact granules reduced neovascularization, while thrombin-activated degranulated platelets did not. These data suggest that platelet releasate has a local antiangiogenic effect on endothelial cells to exert a downstream suppression of VEGFA in neural retina. Low platelet counts during the neovascularization phase in ROP is significantly associated with the development of severe ROP in preterm infants. In a murine model of retinopathy, platelet transfusion during the period of neovascularization suppressed retinopathy.
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4.
  • Choi, J. H., et al. (author)
  • Efficacy of the Screening Algorithm WINROP in a Korean Population of Preterm Infants
  • 2013
  • In: Jama Ophthalmology. - 2168-6165. ; 131:1, s. 62-66
  • Journal article (peer-reviewed)abstract
    • Objective To investigate the efficacy of WINROP (https://winrop.com), an algorithm based on serial measurements of neonatal body weight to predict proliferative retinopathy of prematurity (ROP), in a Korean population of preterm infants. Methods The records of preterm infants with gestational age less than 32 weeks who were admitted to the neonatal intensive care unit at Chonnam National University Hospital, Gwangju, South Korea, from October 2006 to November 2010 were reviewed. The body weight of infants was measured weekly and entered into a computer-based surveillance system, WINROP, and the outcome was analyzed. Results A total of 314 preterm infants participated in the study. The mean gestational age was 29 weeks (range, 25-32 weeks). The mean body weight was 1263 g (range, 590-2260 g). For 166 of 314 infants (52.9%), a high-risk alarm was noted. In the high-risk alarm group, 36 infants developed type 1 ROP, according to the Early Treatment for Retinopathy of Prematurity criteria, and they were treated for ROP. The remaining 148 infants (47.1%) had a low-risk alarm. In the low-risk alarm group, 3 infants with bronchopulmonary dysplasia and intraventricular hemorrhage, a risk factor for ROP, and 1 infant without any risk factors for ROP developed type 1 ROP and were treated. Conclusions In a Korean population, the WINROP algorithm had a sensitivity of 90% for identifying infants with type 1 ROP. Although some limitations are present, adjustment to the WINROP algorithm for a specific population may improve the efficacy of predicting proliferative ROP and reduce the frequency of retinal examinations.
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5.
  • Connor, K. M., et al. (author)
  • Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis
  • 2007
  • In: Nat Med. - 1078-8956.
  • Journal article (peer-reviewed)abstract
    • Many sight-threatening diseases have two critical phases, vessel loss followed by hypoxia-driven destructive neovascularization. These diseases include retinopathy of prematurity and diabetic retinopathy, leading causes of blindness in childhood and middle age affecting over 4 million people in the United States. We studied the influence of omega-3- and omega-6-polyunsaturated fatty acids (PUFAs) on vascular loss, vascular regrowth after injury, and hypoxia-induced pathological neovascularization in a mouse model of oxygen-induced retinopathy. We show that increasing omega-3-PUFA tissue levels by dietary or genetic means decreased the avascular area of the retina by increasing vessel regrowth after injury, thereby reducing the hypoxic stimulus for neovascularization. The bioactive omega-3-PUFA-derived mediators neuroprotectinD1, resolvinD1 and resolvinE1 also potently protected against neovascularization. The protective effect of omega-3-PUFAs and their bioactive metabolites was mediated, in part, through suppression of tumor necrosis factor-alpha. This inflammatory cytokine was found in a subset of microglia that was closely associated with retinal vessels. These findings indicate that increasing the sources of omega-3-PUFA or their bioactive products reduces pathological angiogenesis. Western diets are often deficient in omega-3-PUFA, and premature infants lack the important transfer from the mother to the infant of omega-3-PUFA that normally occurs in the third trimester of pregnancy. Supplementing omega-3-PUFA intake may be of benefit in preventing retinopathy.
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6.
  • Eriksson, L., et al. (author)
  • WINROP can modify ROP screening praxis: a validation of WINROP in populations in Sormland and Vastmanland
  • 2014
  • In: British Journal of Ophthalmology. - : BMJ. - 0007-1161 .- 1468-2079. ; 98:7, s. 964-966
  • Journal article (peer-reviewed)abstract
    • Background This study validates the newly developed WINROP algorithm aimed at detecting retinopathy of prematurity (ROP) requiring treatment at an early stage. The study was conducted at two middle-sized hospitals in Sweden, prospectively and retrospectively. Methods A total of 104 children participated in this study. Their mean gestational age at birth was 28.7 weeks (range, 23.6-32.1 weeks), and their mean birth weight was 1208 g (range, 477-2340 g). Weekly weight measurements were used in WINROP to calculate the risk of developing ROP. Results 80% of infants (83/104) had no ROP, 15% (16/104) had mild ROP (stage 1 or 2), 5% (5/104) had severe ROP, and 2% (2/104) were treated for ROP. The alarm was registered at an average of 2 weeks postnatal age (range 1-6 weeks). Conclusions WINROP identified all the infants at risk for developing stage 3 ROP (100% sensitivity) and had a 59% specificity. The alarm was registered several weeks before screening for ROP began. WINROP can be used to complement conventional ROP screening.
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7.
  • Fluckiger, S., et al. (author)
  • [The early postnatal weight gain as a predictor of retinopathy of prematurity] : Der frühe postnatale Gewichtsverlauf als Prädiktor einer Frühgeborenenretinopathie
  • 2011
  • In: Klinische Monatsblätter für Augenheilkunde. - 1439-3999. ; 228:4, s. 306-10
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Premature infants are often stressed by the current retinopathy of prematurity (ROP) screening procedure. Additionally, only < 10 % of the screened infants will develop a ROP stadium requiring laser therapy. Therefore the present screening strategy is unsatisfactory. Furthermore, the current guidelines do not take into account postnatal factors. A new method considering postnatal factors is the weight, insulin-like growth factor, neonatal ROP (WINROP) algorithm. This approach is based on the early postnatal weight gain. The aim of this study was to assign the WINROP-algorithm to a preterm population in Switzerland and to analyze its ability for prediction. PATIENTS AND METHODS: In this retrospective study, all preterm infants with a gestational age (GA) < 32 weeks and/or a birth weight (BW)
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8.
  • Fu, Z. F., et al. (author)
  • Review: adiponectin in retinopathy
  • 2016
  • In: Biochimica Et Biophysica Acta-Molecular Basis of Disease. - : Elsevier BV. - 0925-4439. ; 1862:8, s. 1392-1400
  • Journal article (peer-reviewed)abstract
    • Neovascular eye diseases are a major cause of blindness including retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration in which new vessel formation is driven by hypoxia or metabolic abnormalities affecting the fuel supply. White-adipose-tissue derived adipokines such as adiponectin modulate metabolic responses. Increasing evidence shows that lack of adiponectin may result in retinal neovascularization. Activation of the adiponectin pathway may in turn restore energy metabolism, to suppress the drive for compensatory but ultimately pathological neovessels of retinopathy. In this review, we will summarize our current knowledge of the role of adiponectin in eye diseases of premature infants, diabetic patients as well as the elderly. Further investigations in this field are likely to lead to new preventative approaches for these diseases. (C) 2016 Elsevier B.V. All rights reserved.
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9.
  • Fu, Z. J., et al. (author)
  • Adiponectin Mediates Dietary Omega-3 Long-Chain Polyunsaturated Fatty Acid Protection Against Choroidal Neovascularization in Mice
  • 2017
  • In: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404 .- 1552-5783. ; 58:10, s. 3862-3870
  • Journal article (peer-reviewed)abstract
    • PURPOSE. Neovascular age-related macular degeneration (AMD) is a major cause of legal blindness in the elderly. Diets with omega3-long-chain-polyunsaturated-fatty-acid (omega 3-LCPUFA) correlate with a decreased risk of AMD. Dietary omega 3-LCPUFA versus omega 6-LCPUFA inhibits mouse ocular neovascularization, but the underlying mechanism needs further exploration. The aim of this study was to investigate if adiponectin (APN) mediated x omega 3-LCPUFA suppression of neovessels in AMD. METHODS. The mouse laser-induced choroidal neovascularization (CNV) model was used to mimic some of the inflammatory aspect of AMD. CNV was compared between wild-type (WT) and Apn(-/-) mice fed either otherwise matched diets with 2% x3 or 2% omega 6-LCPUFAs. Vldlr(-/-) mice were used to mimic some of the metabolic aspects of AMD. Choroid assay ex vivo and human retinal microvascular endothelial cell (HRMEC) proliferation assay in vitro was used to investigate the APN pathway in angiogenesis. Western blot for p-AMPK alpha/AMPK alpha and qPCR for Apn, Mmps, and IL-10 were used to define mechanism. RESULTS. omega 3-LCPUFA intake suppressed laser-induced CNV in WT mice; suppression was abolished with APN deficiency. omega 3-LCPUFA, mediated by APN, decreased mouse Mmps expression. APN deficiency decreased AMPK alpha phosphorylation in vivo and exacerbated choroid-sprouting ex vivo. APN pathway activation inhibited HRMEC proliferation and decreased Mmps. In Vldlr(-/-) mice, omega 3-LCPUFA increased retinal AdipoR1 and inhibited NV. omega 3-LCPUFA decreased IL-10 but did not affect Mmps in Vldlr(-/-) retinas. CONCLUSIONS. APN in part mediated omega 3-LCPUFA inhibition of neovascularization in two mouse models of AMD. Modulating the APN pathway in conjunction with a omega 3-LCPUFA-enriched-diet may augment the beneficial effects of omega 3-LCPUFA in AMD patients.
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10.
  • Fu, Z. J., et al. (author)
  • Dietary omega-3 polyunsaturated fatty acids decrease retinal neovascularization by adipose-endoplasmic reticulum stress reduction to increase adiponectin
  • 2015
  • In: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 101:4, s. 879-888
  • Journal article (peer-reviewed)abstract
    • Background: Retinopathy of prematurity (ROP) is a vision-threatening disease in premature infants. Serum adiponectin (APN) concentrations positively correlate with postnatal growth and gestational age, important risk factors for ROP development. Dietary omega-3 (n-3) long-chain polyunsaturated fatty acids (omega-3 LCPUFAs) suppress ROP and oxygen-induced retinopathy (OIR) in a mouse model of human ROP, but the mechanism is not fully understood. Objective: We examined the role of APN in ROP development and whether circulating APN concentrations are increased by dietary omega-3 LCPUFAs to mediate the protective effect in ROP. Design: Serum APN concentrations were correlated with ROP development and serum omega-3 LCPUFA concentrations in preterm infants. Mouse OIR was then used to determine whether omega-3 LCPUFA supplementation increases serum APN concentrations, which then suppress retinopathy. Results: We found that in preterm infants, low serum APN concentrations positively correlate with ROP, and serum APN concentrations positively correlate with serum omega-3 LCPUFA concentrations. In mouse OIR, serum total APN and bioactive high-molecular-weight APN concentrations are increased by omega-3 LCPUFA feed. White adipose tissue, where APN is produced and assembled in the endoplasmic reticulum, is the major source of serum APN. In mouse OIR, adipose endoplasmic reticulum stress is increased, and APN production is suppressed. omega-3 LCPUFA feed in mice increases APN production by reducing adipose endoplasmic reticulum stress markers. Dietary omega-3 LCPUFA suppression of neovascularization is reduced from 70% to 10% with APN deficiency. APN receptors localize in the retina, particularly to pathologic neovessels. Conclusion: Our findings suggest that increasing APN by omega-3 LCPUFA supplementation in total parental nutrition for preterm infants may suppress ROP.
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11.
  • Fu, Zhongjie, et al. (author)
  • Photoreceptor glucose metabolism determines normal retinal vascular growth
  • 2018
  • In: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 10:1, s. 76-90
  • Journal article (peer-reviewed)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.
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12.
  • Gyllensten, Hanna, 1979, et al. (author)
  • Costs associated with retinopathy of prematurity: a systematic review and meta-analysis.
  • 2022
  • In: BMJ open. - : BMJ. - 2044-6055. ; 12:11
  • Research review (peer-reviewed)abstract
    • To review and analyse evidence regarding costs for retinopathy of prematurity (ROP) screening, lifetime costs and resource use among infants born preterm who develop ROP, and how these costs have developed over time in different regions.Systematic review and meta-analysis DATA SOURCES: PubMed and Scopus from inception to 23 June 2021.Included studies presented costs for ROP screening and the lifetime costs (including laser treatment and follow-up costs) and resource use among people who develop ROP. Studies not reporting on cost calculation methods or ROP-specific costs were excluded.Two independent reviewers screened for inclusion and extracted data, including items from a published checklist for quality assessment used for bias assessment, summary and random-effects meta-analysis for treatment costs. Included studies were further searched to identify eligible references and citations.In total, 15 studies reported ROP screening costs, and 13 reported lifetime costs (either treatment and/or follow-up costs) for infants with ROP. The range for screening costs (10 studies) was US$5-US$253 per visit, or US$324-US$1072 per screened child (5 studies). Costs for treatment (11 studies) ranged from US$38 to US$6500 per child. Four studies reported healthcare follow-up costs (lifetime costs ranging from US$64 to US$2420, and 10-year costs of US$1695, respectively), and of these, three also reported lifetime costs for blindness (range US$26 686-US$224 295) using secondary cost data. Included papers largely followed the quality assessment checklist items, thus indicating a low risk of bias.The costs of screening for and treating ROP are small compared with the societal costs of resulting blindness. However, little evidence is available for predicting the effects of changes in patient population, screening schedule or ROP treatments.CRD42020208213.
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13.
  • Hansen-Pupp, Ingrid, et al. (author)
  • Postnatal Decrease in Circulating Insulin-Like Growth Factor-I and Low Brain Volumes in Very Preterm Infants.
  • 2011
  • In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 96:4, s. 1129-1135
  • Journal article (peer-reviewed)abstract
    • Context: IGF-I and IGF binding protein-3 (IGFBP-3) are essential for growth and maturation of the developing brain. Objective: The aim of this study was to evaluate the association between postnatal serum concentrations of IGF-I and IGFBP-3 and brain volumes at term in very preterm infants. Design: Fifty-one infants with a mean (sd) gestational age (GA) of 26.4 (1.9) wk and birth weight (BW) of 888 (288) g were studied, with weekly blood sampling of IGF-I and IGFBP-3 from birth until 35 gestational weeks (GW) and daily calculation of protein and caloric intake. Magnetic resonance images obtained at 40 GW were segmented into total brain, cerebellar, cerebrospinal fluid, gray matter, and unmyelinated white matter volumes. Main Outcome Measures: We evaluated brain growth by measuring brain volumes using magnetic resonance imaging. Results: Mean IGF-I concentrations from birth to 35 GW correlated with total brain volume, unmyelinated white matter volume, gray matter volume, and cerebellar volume [r = 0.55 (P < 0.001); r = 0.55 (P < 0.001); r = 0.44 (P = 0.002); and r = 0.58 (P < 0.001), respectively]. Similar correlations were observed for IGFBP-3 concentrations. Correlations remained after adjustment for GA, mean protein and caloric intakes, gender, severe brain damage, and steroid treatment. Protein and caloric intakes were not related to brain volumes. Infants with BW small for GA had lower mean concentrations of IGF-I (P = 0.006) and smaller brain volumes (P = 0.001-0.013) than infants with BW appropriate for GA. Conclusion: Postnatal IGF-I and IGFBP-3 concentrations are positively associated with brain volumes at 40 GW in very preterm infants. Normalization of the IGF-I axis, directly or indirectly, may support normal brain development in very preterm infants.
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15.
  • Hellgren, Gunnel, 1961, et al. (author)
  • Construction of a soluble human GH-receptor/EGF-receptor hybrid and its activation by GH
  • 2004
  • In: Cytokine. ; 25:6, s. 260-4
  • Journal article (peer-reviewed)abstract
    • To develop a cell-free system that can be used to measure cytokine bioactivity we have designed a soluble hybrid molecule consisting of the extracellular domain of the GH-receptor (GHR) and the intracellular domain of the epidermal growth factor receptor (EGFR). A DNA construct encoding this hybrid-receptor was inserted into a baculoviral expression vector and expressed in Sf9-cells. Activation of the hybrid-receptor by ligand-induced dimerization can be measured as the incorporation of radiolabeled phosphate into a biotinylated tyrosine kinase peptide substrate. The kinase activity in samples stimulated with GH (10 ng/ml) increased 5-fold compared to samples without addition of GH. This is the first example of a functional hybrid-receptor where the transmembrane domain has been deleted. Our results suggest that such hybrid-receptors may be used for detection of GH and other cytokine-receptor activating substances in biological fluids.
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16.
  • Hellgren, Gunnel, 1961, et al. (author)
  • Decreased Platelet Counts and Serum Levels of VEGF-A, PDGF-BB, and BDNF in Extremely Preterm Infants Developing Severe ROP
  • 2021
  • In: Neonatology. - : S. Karger AG. - 1661-7800 .- 1661-7819. ; 118, s. 18-27
  • Journal article (peer-reviewed)abstract
    • Introduction: Thrombocytopenia has been identified as an independent risk factor for retinopathy of prematurity (ROP), although underlying mechanisms are unknown. In this study, the association of platelet count and serum platelet-derived factors with ROP was investigated. Methods: Data for 78 infants born at gestational age (GA) <28 weeks were included. Infants were classified as having no/mild ROP or severe ROP. Serum levels of vascular endothelial growth factor A, platelet-derived growth factor BB, and brain-derived neurotrophic factor were measured in serum samples collected from birth until postmenstrual age (PMA) 40 weeks. Platelet counts were obtained from samples taken for clinical indication. Results: Postnatal platelet counts and serum concentrations of the 3 growth factors followed the same postnatal pattern, with lower levels in infants developing severe ROP at PMA 32 and 36 weeks (p < 0.05-0.001). With adjustment for GA, low platelet counts and low serum concentrations of all 3 factors at PMA 32 weeks were significantly associated with severe ROP. Serum concentrations of all 3 factors also strongly correlated with platelet count (p < 0.001). Conclusion: In this article, we show that ROP, platelet counts, and specific pro-angiogenic factors correlate. These data suggest that platelet-released factors might be involved in the regulation of retinal and systemic angiogenesis after extremely preterm birth. Further investigations are needed.
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17.
  • Hellgren, Gunnel, 1961, et al. (author)
  • Effect of Preterm Birth on Postnatal Apolipoprotein and Adipocytokine Profiles
  • 2015
  • In: Neonatology. - : S. Karger AG. - 1661-7800 .- 1661-7819. ; 108:1, s. 16-22
  • Journal article (peer-reviewed)abstract
    • 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. (C) 2015 S. Karger AG, Basel
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18.
  • Hellgren, Gunnel, 1961, et al. (author)
  • Increased postnatal concentrations of pro-inflammatory cytokines are associated with reduced IGF-I levels and retinopathy of prematurity
  • 2018
  • In: Growth Hormone & Igf Research. - : Elsevier BV. - 1096-6374. ; 39, s. 19-24
  • Journal article (peer-reviewed)abstract
    • Objective: Retinopathy of prematurity (ROP) is a multifactorial disease linked to low insulin-like growth factor (IGF)-I levels and perhaps to postnatal inflammation. Here, we investigated the longitudinal postnatal serum concentrations of pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha in relation to IGF-I levels and ROP. Design: The study cohort included 52 infants born before 31 gestational weeks. The infants were screened for ROP and classified as non-ROP (n = 33), non-proliferative ROP (stages 1 and 2; n = 10), or proliferative ROP (stage 3, all treated for ROP; n = 9). Blood samples were collected at birth, 24 h after birth, and then weekly until at least 36 weeks postmenstrual age (PMA) (i.e., up to 13 weeks after birth). Circulating levels of IL-6 and TNF-alpha were evaluated in relation to circulating IGF-I levels and ROP. Results: IL-6 levels negatively correlated with IGF-I levels between 5 and 8 weeks after birth, (p < 0.01 to p < 0.05). At birth, the IL-6 and TNF-alpha levels were similar independent of later ROP. Twenty-four hours after birth, both IL-6 and TNF-alpha levels had increased in infants later treated for ROP (p < 0.05). Postnatal, infants treated for ROP had higher IL-6 levels than infants without ROP. Conclusions: The pro-inflammatory response is associated with low IGF-I levels and the development of ROP.
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19.
  • Hellgren, Gunnel, 1961, et al. (author)
  • Proliferative Retinopathy Is Associated with Impaired Increase in BDNF and RANTES Expression Levels after Preterm Birth.
  • 2010
  • In: Neonatology. - : S. Karger AG. - 1661-7819 .- 1661-7800. ; 98:4, s. 409-418
  • Journal article (peer-reviewed)abstract
    • Background: Extremely preterm delivery is, amongst other complications, associated with retinopathy of prematurity (ROP). Untreated, ROP can progress to visual impairment and blindness due to an overgrowth of new vessels in the retina and vitreous cavity. Objective: The aim of this study was to identify cytokine markers within the first weeks of life that could be used to predict the risk for development of ROP later in life. Methods: Serum levels of 27 different cytokines in infants born at gestational weeks 23-30 were analyzed using a multiplex immunoassay method and compared between infants who did not develop ROP and infants who later developed proliferative ROP. In addition, mRNA levels of brain-derived neurotrophic factor (BDNF) in retinas from mice exposed to hyperoxia were analyzed using quantitative real-time PCR. Results: At birth, serum levels of IL-5 were higher in infants with no ROP compared to infants with proliferative ROP. 10-14 days after birth, serum levels of BDNF and RANTES were lower in infants who later developed proliferative ROP compared to infants who did not develop ROP. Furthermore, mRNA expression levels of BDNF in retinas from mice exposed to hyperoxia were significantly lower at postnatal day 15 compared to retinas from mice in room air. Conclusions: These results indicate that BDNF and RANTES may be important factors in the selective vulnerability of ROP development in preterm infants.
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20.
  • Hellgren, Gunnel, 1961, et al. (author)
  • Safety aspects of longitudinal administration of IGF-I/IGFBP-3 complex in neonatal mice.
  • 2011
  • In: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. - : Elsevier BV. - 1532-2238. ; 21:4, s. 205-11
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: Very preterm birth is associated with a high risk of morbidity. Infants born very preterm have low serum levels of insulin-like growth factor I (IGF-I), that further decrease after birth. IGF-I is essential for brain development and low serum levels have been associated with retinopathy of prematurity. The present study aimed to investigate the effects of prolonged administration of a low dose of rhIGF-I/rhIGFBP-3 on glucose levels and total body weight, as well as liver, spleen and brain weights, and gray and subcortical white matter in newborn mice. DESIGN: The study was performed as three different trials. In all experiments C57BL/6N mice were injected with a rhIGF-I/rhIGFBP-3 complex or saline. In the first experimental trial, blood glucose levels were assessed 30min, 1h, 1.5h, 3h, 6h, 24h and 48h after the rhIGF-I/rhIGFBP-3 or saline injection on postnatal day (PND) 6. In the second trial, mice were injected daily from PND 3 to 11 and sacrificed on PND 12 for analysis of IGF-I serum levels. In the third trial, body and organ weights and effects on gray and white matter were assessed on PND 18 after PND 3-11 treatments as above. Effects on gray and white matter were measured using immunoreactivity for microtubule-associated protein-2 (MAP-2), myelin basic protein (MBP), 2',3'-cyclic nucleotide 3' phosphodiesterase (CNPase), neurofilament and oligodendrocyte lineage transcription factor 2 (Olig2). RESULTS: Blood glucose levels were unchanged in the rhIGF-I/rhIGFBP-3-treated group compared to baseline. In the control group glucose levels increased 30min after the second saline injection; levels were not elevated at the subsequent time point. Three hours after the rhIGF-I/rhIGFBP-3 or saline, glucose levels were lower in rhIGF-I/rhIGFBP-3-treated animals than in saline treated (p=0.026). At PND 18, total body weight was higher in rhIGF-I/rhIGFBP-3-treated mice compared with controls (p<0.05), but there were no differences between groups in brain, liver or spleen weights. No differences in gray matter area were found between groups. Analyses of white matter markers showed an increased number of Olig2-positive cells in rhIGF-I/rhIGFBP-3-treated mice compared with controls (p<0.001). There were no differences between groups in terms of MBP, CNPase or neurofilament immunoreactivity. CONCLUSIONS: Prolonged administration of rhIGF-I/rhIGFBP-3 did not have a negative impact on blood glucose levels and was beneficial for total body growth.
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21.
  • Hellgren, Gunnel, 1961, et al. (author)
  • Serum concentrations of vascular endothelial growth factor in relation to retinopathy of prematurity.
  • 2016
  • In: Pediatric research. - : Springer Science and Business Media LLC. - 1530-0447 .- 0031-3998. ; 79, s. 70-75
  • Journal article (peer-reviewed)abstract
    • The role of vascular endothelial growth factor (VEGF) in the pathogenesis of retinopathy of prematurity (ROP) has been clearly established. However, little is known about temporal changes in circulating VEGF concentrations in the preterm infant. The objective was to determine the longitudinal serum concentrations of VEGF in relation to ROP.
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22.
  • Hellström, Ann, 1959, et al. (author)
  • Association of Docosahexaenoic Acid and Arachidonic Acid Serum Levels With Retinopathy of Prematurity in Preterm Infants
  • 2021
  • In: Jama Network Open. - : American Medical Association (AMA). - 2574-3805. ; 4:10
  • Journal article (peer-reviewed)abstract
    • 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.
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23.
  • Hellström, Ann, 1959, et al. (author)
  • Early weight gain predicts retinopathy in preterm infants: new, simple, efficient approach to screening
  • 2009
  • In: Pediatrics. - 1098-4275. ; 123:4, s. 638-645
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: The risk for sight-threatening retinopathy of prematurity is predicted by using gestational age and/or weight at birth. All infants below a threshold undergo serial ophthalmologic examinations for identification of those who would benefit from treatment (approximately 10%). We hypothesized that factoring in postnatal weight gain could identify children at risk for sight-threatening retinopathy of prematurity more specifically and earlier. METHODS: Weekly weights from birth to postmenstrual week 36 were retrospectively entered into a surveillance system that gave an alarm when the rate of weight gain decreased to a certain level. For all children (N = 354) screened and/or treated for retinopathy of prematurity at Sahlgrenska University Hospital in 2004-2007, weekly weights were recorded. One child was excluded because of known nonphysiologic weight gain (hydrocephalus). RESULTS: For 127 (36%) of 353 children, no alarm was given; for 40%, alarm at low risk was given after postmenstrual week 32. None of those children developed retinopathy of prematurity requiring treatment. Of the remaining 24% of children who received alarm at high or low risk before 32 postmenstrual weeks, 41% developed proliferative retinopathy of prematurity and 29% were treated because of sight-threatening disease. The median time from alarm to treatment was 9 weeks. CONCLUSIONS: The weight, insulin-like growth factor, neonatal retinopathy of prematurity algorithm detected early 100% of infants who developed retinopathy of prematurity requiring treatment and correctly predicted the majority who did not require treatment. With this simple postnatal evaluation, costly stressful eye examinations can be markedly reduced (approximately 75% of infants). In addition, early identification of children at risk may lead to the initiation of interventions and possibly prevent sight-threatening retinopathy of prematurity.
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24.
  • Hellström, Ann, 1959, et al. (author)
  • Effect of Enteral Lipid Supplement on Severe Retinopathy of Prematurity A Randomized Clinical Trial
  • 2021
  • In: JAMA Pediatrics. - : American Medical Association (AMA). - 2168-6203 .- 2168-6211. ; 175:4, s. 359-367
  • Journal article (peer-reviewed)abstract
    • 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 27 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 (100mg/kg/d) and DHA (50mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age. MAIN OUTCOMES AND MEASURES The primary outcomewas 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.
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25.
  • Hellström, Ann, 1959, et al. (author)
  • IGF-1 as a Drug for Preterm Infants : A Step-Wise Clinical Development
  • 2017
  • In: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 23:38, s. 5964-5970
  • Research review (peer-reviewed)abstract
    • BACKGROUND: Insulin-like growth factor 1 (IGF-1) is a mitogenic hormone involved in many processes such as growth, metabolism, angiogenesis and differentiation. After very preterm birth, energy demands increase while maternal supplies of nutrients and other factors are lost and the infant may become dependent on parenteral nutrition for weeks. Low postnatal IGF-1 concentrations in preterm infants are associated with poor weight gain, retinopathy of prematurity (ROP) and other morbidities. We will describe the process by which we aim to develop supplementation with recombinant human (rh) IGF-1 and its binding protein rhIGFBP-3 as a possible therapy to promote growth and maturation and reduce morbidities in extremely preterm infants.METHODS: In order to calculate a dose of IGF-1 tolerated by neonates, a pharmacokinetic study of transfusion with fresh frozen plasma was performed, which provided a relatively low dose of IGF-1, (on average 1.4 µg/kg), that increased serum IGF-1 to levels close to those observed in fetuses and preterm infants of similar GAs. Thereafter, a Phase I 3 hours IV infusion of rhIGF-1/rhIGFBP-3 was conducted in 5 infants, followed by a Phase II study with four sections (A-D). In the Phase II, sections A-D studies, time on infusion increased and younger gestational ages were included.RESULTS: IV infusion increased IGF-1 but with short half-life (0.5h) implying a need for continuous infusion. In order to obtain in utero levels of IGF-I, the dose was increased from 100 to 250 µg/kg/24 h and the infusion was prolonged from 3 weeks postnatal age until a postmenstrual age of 29 weeks and 6 days.CONCLUSION: The purpose has been to ensure high-quality research into the development of a new drug for preterm infants. We hope that our work will help to establish a new standard for the testing of medications for preterm infants.
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26.
  • Hellström, Ann, 1959, et al. (author)
  • IGF-I in the clinics: Use in retinopathy of prematurity
  • 2016
  • In: Growth Hormone & Igf Research. - : Elsevier BV. - 1096-6374. ; 30-31, s. 75-80
  • Journal article (peer-reviewed)abstract
    • Retinopathy of prematurity is a potentially blinding disease, which is associated with low neonatal IGF-I serum concentrations and poor growth. In severe cases impaired retinal vessel growth is followed by pathologic neovascularization, which may lead to retinal detachment. IGF-I may promote growth even in catabolic states. Treating preterm infants with recombinant human (rh) IGF-I to concentrations normally found during gestation has been suggested to have a preventative effect on ROP. A recent phase 2 study treating infants (gestational age between 23 weeks + 0 days and 27 weeks +6 days) with rhIGF-I/IGF binding protein-3 until 30 postmenstrual weeks showed no effect on ROP but a 53% reduction in severe bronchopulmonary dysplasia and 44% reduction in severe intraventricular hemorrhage. Oxygen is a major risk factor for ROP and during the phase 2 study oxygen saturation targets were increased to 90-95%, due to national guidelines, which might have affected ROP rate and severity making increased IGF-I a weaker preventative factor for ROP.
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27.
  • Hellström, Ann, 1959, et al. (author)
  • Insulin-like growth factor 1 has multisystem effects on foetal and preterm infant development.
  • 2016
  • In: Acta paediatrica (Oslo, Norway : 1992). - : Wiley. - 1651-2227 .- 0803-5253. ; 105:6, s. 576-86
  • Journal article (peer-reviewed)abstract
    • 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.
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28.
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29.
  • Hellström, Ann, 1959, et al. (author)
  • Role of Insulinlike Growth Factor 1 in Fetal Development and in the Early Postnatal Life of Premature Infants
  • 2016
  • In: American Journal of Perinatology. - : Georg Thieme Verlag KG. - 0735-1631 .- 1098-8785. ; 33:11, s. 1067-1071
  • Journal article (peer-reviewed)abstract
    • The neonatal period of very preterm infants is often characterized by a difficult adjustment to extrauterine life, with an inadequate nutrient supply and insufficient levels of growth factors, resulting in poor growth and a high morbidity rate. Long-term multisystem complications include cognitive, behavioral, and motor dysfunction as a result of brain damage as well as visual and hearing deficits and metabolic disorders that persist into adulthood. Insulinlike growth factor 1 (IGF-1) is a major regulator of fetal growth and, development of most organs especially the central nervous system including the retina. Glucose metabolism in the developing brain is controlled by IGF-1 which also stimulates differentiation and prevents apoptosis. Serum concentrations of IGF-1 decrease to very low levels after very preterm birth and remain low for most of the perinatal development. Strong correlations have been found between low neonatal serum concentrations of IGF-1 and poor brain and retinal growth as well as poor general growth with multiorgan morbidities, such as intraventricular hemorrhage, retinopathy of prematurity, bronchopulmonary dysplasia, and necrotizing enterocolitis. Experimental and clinical studies indicate that early supplementation with IGF-1 can improve growth in catabolic states and reduce brain injury after hypoxic/ischemic events. A multicenter phase II study is currently underway to determine whether intravenous replacement of human recombinant IGF-1 up to normal intrauterine serum concentrations can improve growth and development and reduce prematurity-associated morbidities.
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30.
  • Hellström, Ann, 1959, et al. (author)
  • The IGF system and longitudinal growth in preterm infants in relation to gestational age, birth weight and gender
  • 2020
  • In: Growth Hormone & Igf Research. - : Elsevier BV. - 1096-6374. ; 51, s. 46-57
  • Journal article (peer-reviewed)abstract
    • Objective: Growth factors in the blood of very preterm infants may reflect growth and contribute to the understanding of early development. We investigated postnatal levels of insulin-like growth factors (IGFs) in infants born very preterm and related them to early growth development. Design: Blood samples were analyzed weekly for IGF-I, IGF-II, IGF binding protein (BP)-1, IGFBP-3, and acid-label subunit (ALS). Methods: 73 children born very preterm (gestational age (GA) < 32 weeks) were divided according to their gender-specific birth weight standard deviation score (SDS) into either appropriate for GA (AGA) or small for GA (SGA). Fifty-two (71%) and forty-three (59%) infants completed follow-up with anthropometry at approximately 3 years and at 5 years of age respectively. Thirty-six subjects (49%) had blood sampling for IGF-I and IGFBP-3 measurements up to 3 years of age. Results: IGF-I, IGFBP-3, and ALS levels increased in all groups from week 31 to week 36, with generally lower levels in the SGAs, with a concomitant lower growth velocity. Postnatal ALS was strongly associated with IGF-I and IGFBP-3 in boys, girls and AGA infants. IGF-II was higher in earlier born preterms (GA < 27 weeks) at postmenstrual ages 27.5-29.9 weeks compared with SGAs and late GA (GA >= 27 weeks) preterms (p <.0001). IGF-II, in contrast to IGF-I, did not differ between SGAs and AGAs at weeks 31-36. Mean IGFBP-1 was highest in the SGAs compared to AGAs at mean week 28,5 and 31 (p=.001) and IGFBP-1 levels were elevated in relation to IGF-I in the SGAs at that period. At follow-up, the increase in IGF-I between week 31 and 33.5 was a significant positive determinant of height SDS at 3 and 5 years of age in forward multiple regression analysis, independent of target height. Conclusion: This is the first study to investigate postnatal ALS levels in preterm infants. In very preterm infants, IGF-II is less affected by size at birth during early postnatal weeks compared with IGF-I. Early elevated IGFBP-1 might protect the SGA infants from an intense metabolic rate. Our results indicate that anabolic and metabolic processes during weeks 31-36 predicts later height.
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31.
  • Hellström, William, et al. (author)
  • C-Peptide Suppression during Insulin Infusion in the Extremely Preterm Infant Is Associated with Insulin Sensitivity
  • 2019
  • In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 104:9, s. 3902-3910
  • Journal article (peer-reviewed)abstract
    • Context: Little is known about the individual response of glucose-regulating factors to administration of exogenous insulin infusion in extremely preterm infants. Objective: To evaluate longitudinal serum concentrations of insulin, C-peptide, and plasma glucose levels in a high-frequency sampling regimen in extremely preterm infants treated with insulin because of hyperglycemia. Design: Prospective longitudinal cohort study. Setting: Two university hospitals in Sweden between December 2015 and September 2016. Patients and Intervention: Serum samples were obtained from nine extremely preterm infants, gestational age between 22 (+3) and 26 (+5) weeks (+ days), with hyperglycemia (plasma-glucose >10 mmol/L) at the start of insulin infusion, at 12, 24, and every 24 hours thereafter during ongoing infusion, and 12, 24, and 72 hours after the end of insulin infusion. Main outcome measures: Longitudinal serum concentrations of insulin and C-peptide and plasma glucose levels. Results: During insulin infusion, the serum C-peptide concentrations decreased compared with at start of infusion (P = 0.036), and then increased after ending the infusion. Individual insulin sensitivity based on the nonfasting plasma glucose/insulin ratio at the start of insulin infusion correlated with the initial decrease in serum ΔC-peptide[after 12h] (P = 0.007) and the degree of lasting decrease in serum ΔC-peptide[after end of infusion] (P = 0.015). Conclusion: Exogenous insulin infusion suppressed the C-peptide concentration to individually different degrees. In addition, the effect of insulin infusion on β cells may be linked to individual insulin sensitivity, where a low insulin sensitivity resulted in a more pronounced decrease in C-peptide during insulin infusion.
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32.
  • Hellström, William, et al. (author)
  • Postnatal serum IGF-1 levels associate with brain volumes at term in extremely preterm infants
  • 2023
  • In: Pediatric Research. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 93:3, s. 666-674
  • Journal article (peer-reviewed)abstract
    • 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, beta = 0.90), white matter (p = 0.007, beta = 0.33), cortical gray matter (p = 0.002, beta = 0.43), deep gray matter (p = 0.008, beta = 0.05), and cerebellar (p = 0.006, beta = 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).
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33.
  • Humayun, Jhangir, et al. (author)
  • Systematic review of the healthcare cost of bronchopulmonary dysplasia.
  • 2021
  • In: BMJ open. - : BMJ. - 2044-6055. ; 11:8
  • Journal article (peer-reviewed)abstract
    • 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$21392-Int$1 094509 per child, equivalent to €19103-€977397, in 2019) and/or during the first year of life. One study reported costs during the first 2years; 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.
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34.
  • Hård, Anna-Lena, 1949, et al. (author)
  • Predicting proliferative retinopathy in a Brazilian population of preterm infants with the screening algorithm WINROP
  • 2010
  • In: Archives of Ophthalmology. - : American Medical Association (AMA). - 0003-9950. ; 128:11, s. 1432-1436
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: To retrospectively validate the WINROP (weight, insulinlike growth factor I, neonatal, retinopathy of prematurity [ROP]) algorithm in a Brazilian population. WINROP aims to predict ROP and is based on longitudinal weight measurements from birth until postmenstrual age 36 weeks. WINROP has predicted 100% of severe ROP in 3 neonatal intensive care unit settings in the United States and Sweden. METHODS: In children admitted to the neonatal intensive care unit at Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil, from April 2002 to October 2008, weight measurements had been recorded once a week for children screened for ROP, 366 of whom had a gestational age of 32 weeks or less. The participating children had a median gestational age of 30 weeks (range, 24-32 weeks) at birth and their median birth weight was 1215 g (range, 505-2000 g). RESULTS: For 192 of 366 children (53%), no alarm or low-risk alarm after postmenstrual age 32 weeks occurred. Of these, 190 of 192 did not develop proliferative disease. Two boys with severe sepsis who were treated for ROP received low-risk alarms at postmenstrual age 33 and 34 weeks, respectively. The remaining 174 children (47%) received high- or low-risk alarms before or at 32 weeks. Of these infants, 21 (12%) developed proliferative ROP. CONCLUSIONS: In this Brazilian population, WINROP, with limited information on specific gestational age and date of weight measurement, detected early 90.5% of infants who developed stage 3 ROP and correctly predicted the majority who did not. Adjustments to the algorithm for specific neonatal intensive care unit populations may improve the results for specific preterm populations.
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35.
  • Hök Wikstrand, Margareta, 1946, et al. (author)
  • Maternal and neonatal factors associated with poor early weight gain and later retinopathy of prematurity.
  • 2011
  • In: Acta paediatrica (Oslo, Norway : 1992). - : Wiley. - 1651-2227 .- 0803-5253.
  • Journal article (peer-reviewed)abstract
    • Aim: To identify factors associated with poor early weight gain as reflected in an alarm system, WINROP and risk of later proliferative ROP in infants with gestational age <28 weeks. Methods: Infants with a WINROP alarm and proliferative ROP, the "alarm group" (n=23) were matched to gestational age and gender to a "no alarm group" (n=23) with no WINROP alarm and no or mild ROP. Retrospectively maternal variables, birth characteristics and neonatal factors, during the first three postnatal weeks, were compared. Results: The "alarm group" had lower birth weight and birth weight standard deviation score, longer stay in ventilator, more insulin and corticosteroid treatments, and lower white blood cell count. In a logistic regression model birth weight standard deviation score, insulin, low white blood cell count, absence of both elevated C- reactive protein and premature rupture of membranes were associated with proliferative ROP and WINROP alarm (p=0.000, r(2) = 0.704). Conclusions: This study shows that prenatal factors resulting in low birth weight have persisting effects on early postnatal growth, metabolism and inflammatory response. Future prospective studies will focus on the link between these factors and pathological retinal vessel development in the early postnatal period to find possible preventive strategies.
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36.
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37.
  • Ley, David, et al. (author)
  • Longitudinal infusion of a complex of insulin-like growth factor-I and IGF-binding protein-3 in five preterm infants : pharmacokinetics and short-term safety.
  • 2013
  • In: Pediatric Research. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 73:1, s. 68-74
  • Journal article (peer-reviewed)abstract
    • Background:In preterm infants, low levels of insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) are associated with impaired brain growth and retinopathy of prematurity (ROP). Treatment with IGF-I/IGFBP-3 may be beneficial for brain development and may decrease the prevalence of ROP.Methods:In a phase II pharmacokinetics and safety study, five infants (three girls) with a median (range) gestational age (GA) of 26 wk + 6 d (26 wk + 0 d to 27 wk + 2 d) and birth weight of 990 (900-1,212) g received continuous intravenous infusion of recombinant human (rh)IGF-I/rhIGFBP-3. Treatment was initiated during the first postnatal day and continued for a median (range) duration of 168 (47-168) h in dosages between 21 and 111 µg/kg/24 h.Results:Treatment with rhIGF-I/rhIGFBP-3 was associated with higher serum IGF-I and IGFBP-3 concentrations (P < 0.001) than model-predicted endogenous levels. Of 74 IGF-I samples measured during study drug infusion, 37 (50%) were within the target range, 4 (5%) were above, and 33 (45%) were below. The predicted dose of rhIGF-I/rhIGFBP-3 required to establish circulating levels of IGF-I within the intrauterine range in a 1,000 g infant was 75-100 µg/kg/24 h. No hypoglycemia or other adverse effects were recorded.Conclusion:In this study, continuous intravenous infusion of rhIGF-I/rhIGFBP-3 was effective in increasing serum concentrations of IGF-I and IGFBP-3, and was found to be safe.
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38.
  • Ley, David, et al. (author)
  • Longitudinal infusion of insulin-like growth factor-I and IGF-binding protein-3 complex to five preterm infants: pharmacokinetics and short term safety.
  • 2013
  • In: Pediatric Research. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 63:1, s. 68-74
  • Journal article (peer-reviewed)abstract
    • Background:In preterm infants, low levels of insulin like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) are associated with impaired brain growth and retinopathy of prematurity (ROP).Treatment with IGF-I/IGFBP-3 may be beneficial for brain development and decrease prevalence of ROP.Methods:In a phase II pharmacokinetic and safety study, five infants (3 girls) with a median (range) gestational age (GA) of 26+6 (26+0 - 27+2) weeks and birth weight (BW) of 990 (900-1212) g received continuous intravenous infusion of rhIGF-I/rhIGFBP-3. Treatment was initiated during the first postnatal day and continued for median (range) 168h (47-168) in doses between 21 - 111 µg/kg/24h.Results:Treatment with rhIGF-I/rhIGFBP-3 was associated with higher serum IGF-I and IGFBP-3 concentrations (p<0.001) than model-predicted endogenous levels. Out of 74 IGF-I samples measured during study drug infusion, 37 (50%) were within target range, 4 (5%) above and 33 (45%) were below. Predicted dose of rhIGF-I/rhIGFBP-3 to establish circulating levels of IGF-I within the intrauterine range in a 1000g infant was 75-100 µg/kg/24h. No hypoglycemia or other adverse effects were recorded.Conclusion:Continuous intravenous infusion of rhIGF-I/rhIGFBP-3 was effective in increasing serum concentrations of IGF-I and IGFBP-3. Administration during study was safe.Pediatric Research (2012); doi:10.1038/pr.2012.146.
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39.
  • Liegl, R., et al. (author)
  • IGF-1 in retinopathy of prematurity, a CNS neurovascular disease
  • 2016
  • In: Early Human Development. - : Elsevier BV. - 0378-3782. ; 102, s. 13-19
  • Journal article (peer-reviewed)abstract
    • The retina is part of the central nervous system and both the retina as well as the brain can suffer from severe damage after very preterm birth. Retinopathy of prematurity is one of the major causes of blindness in these children and brain neuronal impairments including cognitive defects, cerebral palsy and intraventricular hemorrhage (IVH) are also complications of very preterm birth. Insulin-like growth factor 1 (IGF-1) acts to promote proliferation, maturation, growth and survival of neural cells. Low levels of circulating IGF-1 are associated with ROP and defects in the IGF-1 gene are associated with CNS disorders including learning deficits and brain growth restriction. Treatment of preterm infants with recombinant IGF-1 may potentially prevent ROP and CNS disorders. This review compares the role of IGF-1 in ROP and CNS disorders. A recent phase 2 study showed a positive effect of IGF-1 on the severity of IVH but no effect on ROP. A phase 3 trial is planned. © 2016 Elsevier Ireland Ltd
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40.
  • Lund, Anna My, et al. (author)
  • Unpasteurised maternal breast milk is positively associated with growth outcomes in extremely preterm infants
  • 2020
  • In: Acta Paediatrica. - Oxford, UK : Wiley. - 0803-5253 .- 1651-2227. ; 109:6
  • Journal article (peer-reviewed)abstract
    • 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.
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41.
  • Lundgren, Pia, 1967-, et al. (author)
  • Implementing Higher Oxygen Saturation Targets Reduced the Impact of Poor Weight Gain as a Predictor for Retinopathy of Prematurity
  • 2018
  • In: Acta Paediatrica. - Oxford, UK : Wiley-Blackwell. - 0803-5253 .- 1651-2227. ; 107:5, s. 767-773
  • Journal article (peer-reviewed)abstract
    • Aim: This study evaluated poor weight gain as a risk factor for infants who required treatment for retinopathy of prematurity (ROP), by comparing those born before and after the implementation of higher oxygen saturation (SpO2 ) targets at the Queen Silvia Children's Hospital, Gothenburg, Sweden. Methods: We compared infants born at less than 31 weeks, who were screened and, or, treated for ROP: 127 in 2011-2012 when SpO2 targets were 88-92% and 142 in 2015-2016 when they were 91-95%. The subjects were reviewed for birth characteristics, weekly weight and ROP treatment. Data were analysed using the weight, insulin-like growth factor 1, neonatal, ROP (WINROP) prediction tool. Results: The 2011-2012 infants who needed ROP treatment (12.6%) had significantly poorer postnatal weight gain than those who did not, but this was not seen in the treated (17.6%) and nontreated ROP groups in 2015-2016. WINROP sensitivity decreased from 87.5% in 2011-12 to 48% in 2015-2016. Conclusion: After the SpO2 target range was increased from 88-92% to 91-95%, postnatal weight gain was no longer a significant risk factor and WINROP lost its ability to predict ROP requiring treatment. Risk factors clearly change as neonatal care develops.
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42.
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43.
  • Lundgren, Pia, 1967-, et al. (author)
  • Weight at first detection of retinopathy of prematurity predicts disease severity
  • 2014
  • In: British Journal of Ophthalmology. - London, UK : BMJ Publishing Group Ltd. - 0007-1161 .- 1468-2079. ; 98:11, s. 1565-1569
  • Journal article (peer-reviewed)abstract
    • Objective: To investigate whether postnatal weight at first detection of retinopathy of prematurity (ROP) can predict preterm infants who will develop severe ROP warranting treatment.Design: This modern, population-based cohort included 147 infants born at gestational age (GA) <32 weeks in the Gothenburg region during 2011–2012 and screened for ROP at Sahlgrenska University hospital. GA, birth weight (BW), and weekly postnatal weight from birth until postmenstrual age (PMA) 40 weeks data were retrospectively retrieved. Birth weight SD scores (BWSDS) were calculated. ROP data, including first detected ROP stage, maximal ROP stage, ROP treatment, and PMA at first detected sign of ROP were also retrieved. Weight SDS (WSDS) at first ROP detection was calculated.Results: Stepwise multivariate logistic regression analysis revealed that the best fit-model of risk factors for developing severe ROP warranting treatment included; GA (OR=0.28, CI 95% 0.12 to 0.66, p<0.01) and WSDS at first ROP detection (OR=0.22, CI 95% 0.05 to 0.89, p<0.05).Conclusions: Low weight and low WSDS at first ROP detection can be useful predictors for ROP warranting treatment.
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44.
  • Lundgren, Pia, 1967-, et al. (author)
  • WINROP identifies severe retinopathy of prematurity at an early stage in a nation-based cohort of extremely preterm infants
  • 2013
  • In: PLOS ONE. - San Francisco : Public Library of Science, PLoS. - 1932-6203. ; 8:9
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: To evaluate the ability of a postnatal weight-gain algorithm (WINROP) to identify sight-threatening retinopathy of prematurity (ROP type 1) in a nation-based extremely preterm infant cohort.METHODS: This study enrolled all 707 live-born extremely preterm (gestational age [GA] <27 weeks) infants, born 2004-2007 in Sweden; the Extremely preterm Infants in Sweden Study (EXPRESS). WINROP analysis was performed retrospectively in 407 of the infants using weekly weight gain to assess the preterm infant's risk of developing ROP type 1 requiring treatment. GA, birthweight (BW), and weekly postnatal weight measurements were entered into WINROP. WINROP signals with an alarm to indicate if the preterm infant is at risk for ROP type 1.RESULTS: In this extremely preterm population, WINROP correctly identified 96% (45/47) of the infants who required treatment for ROP type 1. The median time from alarm to treatment was 9 weeks (range, 4-20 weeks).CONCLUSIONS: WINROP, an online surveillance system using weekly weight gain, identified extremely preterm infants at risk for ROP type 1 requiring treatment at an early stage and with high sensitivity in a Swedish nation-based cohort.
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45.
  • Löfqvist, Chatarina, 1964, et al. (author)
  • A pharmacokinetic and dosing study of intravenous insulin-like growth factor-I and IGF-binding protein-3 complex to preterm infants
  • 2009
  • In: Pediatric Research. - 1530-0447 .- 0031-3998. ; 65:5, s. 574-9
  • Journal article (peer-reviewed)abstract
    • In preterm infants, low levels of insulin like growth factor 1 (IGF-I) have been associated with impaired growth and retinopathy of prematurity. Our objective was to study safety and pharmacokinetics of i.v. administered rhIGF-I with its binding protein 3 (rhIGFBP-3) to preterm infants. At 3 d chronological age, an i.v. 3 h infusion of rhIGF-I/rhIGFBP-3 was administered followed by serial measurements of IGF-I and IGFBP-3. Infants were evaluated for physiologic safety measurements. The individual dose of rhIGF-I ranged from 1 to 12 microg/kg. The study was conducted at Queen Silvia Children's Hospital, Gothenburg, Sweden, between January and November 2007. Five patients (3 F) with mean (range) post menstrual age 27 wk (26-29) and birth weight 1022 g (810-1310) participated. IGF-I and IGFBP-3 levels before infusion were median (range) 18 (12-28) and 771 (651-1047) ng/mL, respectively. Immediately after study drug infusion, serum IGF-I and IGFBP-3 levels were 38 (25-59) and 838 (754-1182) ng/mL, respectively. Median (range) half-life for IGF-I and IGFBP-3 was 0.79 (0.59-1.42) and 0.87 (0.85-0.94) hours, respectively. Blood glucose, insulin, sodium, potassium, and physiologic safety measures were within normal ranges. The rhIGF-I/rhIGFBP-3 equimolar proportion was effective in increasing serum IGF-I levels and administration under these study conditions was safe and well tolerated.
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46.
  • Löfqvist, Chatarina, 1964, et al. (author)
  • Association of Retinopathy of Prematurity With Low Levels of Arachidonic Acid A Secondary Analysis of a Randomized Clinical Trial
  • 2018
  • In: Jama Ophthalmology. - : American Medical Association (AMA). - 2168-6165. ; 136:3, s. 271-277
  • Journal article (peer-reviewed)abstract
    • IMPORTANCE Mice with oxygen-induced retinopathy fed matched diets except for omega-3 long-chain polyunsaturated fatty acids (LC-PUFAs) vs omega-6 LC-PUFAs demonstrate relative antiangiogenic and neuroprotective associations of omega-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 omega-3 and omega-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 Goteborg, 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 omega-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 omega-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.
  •  
47.
  • Löfqvist, Chatarina, 1964 (author)
  • GH Secretion in children. Methodological aspects of determining immunoreactive and bioactive isoforms
  • 2001
  • Doctoral thesis (other academic/artistic)abstract
    • 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.
  •  
48.
  • Löfqvist, Chatarina, 1964, et al. (author)
  • IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth
  • 2007
  • In: Proc Natl Acad Sci U S A. - 0027-8424. ; 104:25, s. 10589-94
  • Journal article (peer-reviewed)abstract
    • Vessel loss precipitates many diseases. In particular, vessel loss resulting in hypoxia induces retinal neovascularization in diabetic retinopathy and in retinopathy of prematurity (ROP), major causes of blindness. Here we define insulin-like growth factor binding protein-3 (IGFBP3) as a new modulator of vascular survival and regrowth in oxygen-induced retinopathy. In IGFBP3-deficient mice, there was a dose-dependent increase in oxygen-induced retinal vessel loss. Subsequent to oxygen-induced retinal vessel loss, Igfbp3(-/-) mice had a 31% decrease in retinal vessel regrowth versus controls after returning to room air. No difference in serum insulin-like growth factor 1 (IGF1) levels was observed among groups. Wild-type mice treated with exogenous IGFBP3 had a significant increase in vessel regrowth. This correlated with a 30% increase in endothelial progenitor cells in the retina at postnatal day 15, indicating that IGFBP3 could be serving as a progenitor cell chemoattractant. In a prospective clinical study, we measured IGFBP3 (and IGF1) plasma levels weekly and examined retinas in all premature infants born at gestational ages <32 weeks at high risk for ROP. The mean level of IGFBP3 at 30-35 weeks postmenstrual age (PMA) for infants with proliferative ROP (ROP stages 3>, n = 13) was 802 microg/liter, and for infants with no ROP (ROP stage 0, n = 38) the mean level was 974 microg/liter (P < 0.03). These results suggest that IGFBP3, acting independently of IGF1, helps to prevent oxygen-induced vessel loss and to promote vascular regrowth after vascular destruction in vivo in a dose-dependent manner, resulting in less retinal neovascularization.
  •  
49.
  • Löfqvist, Chatarina, 1964, et al. (author)
  • Longitudinal Postnatal Weight and Insulin-like Growth Factor I Measurements in the Prediction of Retinopathy of Prematurity
  • 2006
  • In: Arch Ophthalmol. - : American Medical Association (AMA). ; 124:12, s. 1711-1718
  • Journal article (peer-reviewed)abstract
    • Objective To investigate whether postnatal growth and development influence retinopathy of prematurity (ROP) and may be included in screening for ROP. Design We developed an algorithm to predict for individual infants the risk of later ROP development requiring treatment based on the postnatal longitudinal systemic factors of insulin-like growth factor I (IGF-I) level, IGF binding protein 3 level, and postnatal weight gain. We developed the algorithm based on 79 preterm infants considered at risk for ROP by standard criteria (gestational age, 23.6-31.7 weeks) in a longitudinal study measuring weight gain and serum IGF-I and IGF binding protein 3 levels weekly from birth until discharge from the hospital. We monitored deviations from reference models for weight and IGF-I level (preterm children who developed no or minimal ROP) to detect indications for treatable ROP by Early Treatment for Retinopathy of Prematurity study criteria. Results This monitoring method detected 6 (100%) of 6 infants in this cohort who required treatment for ROP with a warning signal at least 5 weeks before requiring treatment and at least 3 weeks before the onset of stage 3 ROP. The majority of infants (61/73 infants) requiring no treatment were also correctly identified. Conclusions Monitoring the postnatal factors of weight, IGF-I level, and IGF binding protein 3 level substantially enhances the clinician's ability to identify patients who will require treatment for ROP.
  •  
50.
  • Löfqvist, Chatarina, 1964, et al. (author)
  • Low Postnatal Serum IGF-I levels is Associated with Bronchopulmonary Dysplasia (BPD).
  • 2012
  • In: Acta paediatrica. - : Wiley. - 1651-2227 .- 0803-5253. ; 101:12, s. 1211-1216
  • Journal article (peer-reviewed)abstract
    • 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.
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