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Inflammatory and Angiogenic Mediators in Amniotic Fluid Are Associated With the Development of Retinopathy of Prematurity in Preterm Infants.

ABSTRACT: Purpose:To investigate whether elevated levels of inflammatory/angiogenic and growth mediators in amniotic fluid (AF) and the presence of intra-amniotic infection are associated with the occurrence and progression of retinopathy of prematurity (ROP) in preterm infants. Methods:This retrospective cohort study included 175 premature singleton infants who were born between 23+0 and 32+0 weeks. AF obtained via amniocentesis was cultured, and endoglin, endostatin, insulin-like growth factor-binding protein (IGFBP)-2, IGFBP-3, IGFBP-4, IL-6, IL-8, matrix metalloproteinase-8, matrix metalloproteinase-9, and vascular endothelial growth factor receptor-1 levels were assayed by ELISA. The primary outcome measures included the occurrence of any stage ROP, severe ROP (stage ?3), and vision-threatening type 1 ROP requiring treatment. Results:Multiple logistic regression analyses revealed that there are significant associations between elevated AF endoglin levels and ROP occurrence; between elevated AF endoglin, endostatin, and IGFBP-2 levels and severe ROP; and between high AF endoglin, IL-6, and IL-8 levels and vision-threatening ROP requiring treatment, after adjusting for potential postnatal confounders. Using stepwise regression analyses, antenatal prediction models based on these AF biomarkers and prenatal factors were developed for the ROP outcomes, which had good discriminatory power (area under the curves, 0.731-0.863). However, we found that intra-amniotic infection is not associated with ROP occurrence and progression. Conclusions:Elevated levels of inflammatory (IL-6 and IL-8) and angiogenic (endoglin and IGFBP-2) mediators in the AF, but not the presence of intra-amniotic infection, are independently associated with the occurrence and progression of ROP in preterm infants. These findings suggest that the pathophysiologic events that predispose preterm neonates to ROP may begin before delivery.

SUBMITTER: Woo SJ

PROVIDER: S-EPMC7405804 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Inflammatory and Angiogenic Mediators in Amniotic Fluid Are Associated With the Development of Retinopathy of Prematurity in Preterm Infants.

Woo Se Joon SJ Park Jun Young JY Hong Subeen S Kim Yu Mi YM Park Ye Hyon YH Lee Young Eun YE Park Kyo Hoon KH

Investigative ophthalmology & visual science 20200501 5

<h4>Purpose</h4>To investigate whether elevated levels of inflammatory/angiogenic and growth mediators in amniotic fluid (AF) and the presence of intra-amniotic infection are associated with the occurrence and progression of retinopathy of prematurity (ROP) in preterm infants.<h4>Methods</h4>This retrospective cohort study included 175 premature singleton infants who were born between 23+0 and 32+0 weeks. AF obtained via amniocentesis was cultured, and endoglin, endostatin, insulin-like growth f ...[more]

PMID: 32446247

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Project description:IntroductionRetinopathy of prematurity (ROP) is a retinal vascular developmental disease associated with risks factors such as supplementary oxygen use or low birth weight/early gestational age. Multiple studies have reported associations between ROP and systemic inflammation. In this study, we investigated serum cytokines associated with ROP development and severity and assessed their applicability as potential biomarkers of ROP.MethodsThis prospective study was conducted at an institutional referral center between 2019 and 2021. To measure the serum levels of 40 inflammatory cytokines in eligible premature patients, we collected their serum samples during the enrollment of patients or the intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents and after 2 and 4 weeks.ResultsFifty patients were enrolled. In patients with type 1 ROP who received anti-VEGF agents (n = 22), the levels of serum intercellular adhesion molecule-1 decreased significantly (p < 0.05) at 4 weeks compared with the baseline level, whereas those of serum granulocyte-macrophage colony-stimulating factor increased significantly (p < 0.05). In patients with ROP who did not require any treatment (n = 14), no significant change was noted in the level of any of the 40 inflammatory cytokines. In control infants without ROP (n = 14), the serum levels of tumor necrosis factor-α, interleukin (IL)-15, and IL-12p40 increased significantly (p < 0.05) at 4 weeks. The changes in the levels of serum inflammatory cytokines did not vary significantly among the aforementioned three groups. A generalized estimating equation indicated that zone 1 ROP, stage 3 ROP, older postmenstrual age, respiratory distress syndrome, necrotizing enterocolitis, and sepsis were associated with the changes in serum cytokine levels.ConclusionsAlthough significant changes (compared with baseline) were observed in the serum levels of certain inflammatory cytokines in patients with type 1 ROP and infants without ROP, no significant difference in cytokine level fluctuations were noted among the three groups. Changes in serum inflammatory cytokine levels may not predict ROP development or severity. Additional comprehensive studies are warranted to establish their definitive role and significance in ROP, emphasizing the need for continued research in this area.

Project description:BACKGROUNDHyperglycemia, 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.METHODSIn 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.RESULTSThe 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).CONCLUSIONIn 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.TRIAL REGISTRATIONClinicalTrials.gov NCT02760472 (Donna Mega).FUNDINGThis study has been supported by the Swedish Medical Research Council (14940, 4732, 20144-01-3, and 21144-01-3), a Swedish government grant (ALFGB2770), Lund medical faculty grants (ALFL, 11615 and 11601), the Skåne Council Foundation for Research and Development, the Linnéa and Josef Carlsson Foundation, the Knut and Alice Wallenberg Foundation, the NIH/National Eye Institute (EY022275, EY017017, EY017017-13S1, and P01 HD18655), European Commission FP7 project 305485 PREVENT-ROP, Deutsche Forschungsgemeinschaft (CA-1940/1-1), and Stiftelsen De Blindas Vänner.

Project description:Among extremely preterm infants, we evaluated whether bevacizumab therapy compared with surgery for retinopathy of prematurity (ROP) is associated with adverse outcomes in early childhood. This study was a retrospective analysis of prospectively collected data on preterm (22-26 + 6/7 weeks' gestational age) infants admitted to the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers who received bevacizumab or surgery exclusively for ROP. The primary outcome was death or severe neurodevelopmental impairment (NDI) at 18 to 26 months' corrected age (Bayley Scales of Infant and Toddler Development, Third Edition cognitive or motor composite score <70, Gross Motor Functional Classification Scale level ≥2, bilateral blindness or hearing impairment). The cohort (N = 405; 214 [53%] boys; median [interquartile range] gestational age: 24.6 [23.9-25.3] weeks) included 181 (45%) infants who received bevacizumab and 224 (55%) who underwent ROP surgery. Infants treated with bevacizumab had a lower median (interquartile range) birth weight (640 [541-709] vs 660 [572.5-750] g; P = .02) and longer durations of conventional ventilation (35 [21-58] vs 33 [18-49] days; P = .04) and supplemental oxygen (112 [94-120] vs 105 [84.5-120] days; P = .01). Death or severe NDI (adjusted odds ratio [aOR] 1.42; 95% confidence interval [CI] 0.94 to 2.14) and severe NDI (aOR 1.14; 95% CI 0.76 to 1.70) did not differ between groups. Odds of death (aOR 2.54 [95% CI 1.42 to 4.55]; P = .002), a cognitive score <85 (aOR 1.78 [95% CI 1.09 to 2.91]; P = .02), and a Gross Motor Functional Classification Scale level ≥2 (aOR 1.73 [95% CI 1.04 to 2.88]; P = .04) were significantly higher with bevacizumab therapy. In this multicenter cohort of preterm infants, ROP treatment modality was not associated with differences in death or NDI, but the bevacizumab group had higher mortality and poor cognitive outcomes in early childhood. These data reveal the need for a rigorous appraisal of ROP therapy.

Dataset Information

Inflammatory and Angiogenic Mediators in Amniotic Fluid Are Associated With the Development of Retinopathy of Prematurity in Preterm Infants.

Publications

Inflammatory and Angiogenic Mediators in Amniotic Fluid Are Associated With the Development of Retinopathy of Prematurity in Preterm Infants.

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