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Neurodevelopmental Outcomes of Preterm Infants With Retinopathy of Prematurity by Treatment.

ABSTRACT: OBJECTIVE: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. METHODS: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). RESULTS: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. CONCLUSIONS: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.

SUBMITTER: Natarajan G

PROVIDER: S-EPMC6855825 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Neurodevelopmental Outcomes of Preterm Infants With Retinopathy of Prematurity by Treatment.

Natarajan Girija G Shankaran Seetha S Nolen Tracy L TL Sridhar Amaanti A Kennedy Kathleen A KA Hintz Susan R SR Phelps Dale L DL DeMauro Sara B SB Carlo Waldemar A WA Gantz Marie G MG Das Abhik A Greenberg Rachel G RG Younge Noelle E NE Bliss Joseph M JM Seabrook Ruth R Sánchez Pablo J PJ Wyckoff Myra H MH Bell Edward F EF Vohr Betty R BR Higgins Rosemary D RD

Pediatrics 20190723 2

<h4>Objective</h4>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.<h4>Methods</h4>This study was a retrospective analysis of prospectively collected data on preterm (22-26 + 6/7 weeks' gestational age) infants admitted to the <i>Eunice Kennedy Shriver</i> National Institute of Child Health and Human Development Neonatal Research Network centers who received ...[more]

PMID: 31337693

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Project description:ImportanceCirculating levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) are important in the course of brain injury in adults, but longitudinal postnatal circulating levels in preterm infants have not been investigated.ObjectivesTo examine postnatal longitudinal serum levels of NfL and GFAP in preterm infants during the first 15 weeks of life and to explore possible associations between these biomarkers, neonatal morbidities, and neurodevelopmental outcomes at 2 years.Design, setting, and participantsThis cohort study used data from 3 clinical studies, including 221 infants born before 32 weeks gestational age (GA) from 1999 to 2015; neurodevelopmental outcomes were evaluated in 120 infants. Data were collected at tertiary-level neonatal intensive care units in Gothenburg, Lund, and Uppsala, Sweden. Data analysis was conducted from January to October 2020.ExposurePreterm birth.Main outcomes and measuresSerum NfL and GFAP levels, retinopathy of prematurity (ROP), intraventricular hemorrhage, and Bayley Scales of Infant Development II and III at 2 years of age, analyzed by multivariate logistic regression measured by odds ratio (OR), and receiver operating characteristic curve (ROC) analysis. Area under the curve (AUC) was also measured.ResultsThe 221 included infants (108 [48.9%] girls) had a mean (SD) GA at birth of 26.5 (2.1) weeks and a mean (SD) birth weight of 896 (301) grams. NfL levels increased after birth, remaining high during the first 4 weeks of life before declining to continuously low levels by postnatal age 12 weeks (median [range] NfL level at birth: 58.8 [11.5-1371.3] ng/L; 1 wk: 83.5 [14.1-952.2] ng/L; 4 wk: 24.4 [7.0-306.0] ng/L; 12 wk: 9.1 [3.7-57.0] ng/L). In a binary logistic regression model adjusted for GA at birth, birth weight SD score, Apgar status at 5 minutes, and mode of delivery, the NfL AUC at weeks 2 to 4 was independently associated with any ROP (OR, 4.79; 95% CI, 2.17-10.56; P < .001). In an exploratory analysis adjusted for GA at birth and sex, NfL AUC at weeks 2 to 4 was independently associated with unfavorable neurodevelopmental outcomes at 2 years corrected age (OR per 10-unit NfL increase, 1.07; 95% CI, 1.02-1.13; P = .01). Longitudinal GFAP levels were not significantly associated with neonatal morbidity or neurodevelopmental outcome.Conclusions and relevanceIn this study, high NfL levels during the first weeks of life were associated with ROP and poor neurodevelopmental outcomes at 2 years of age. Associations between NfL and later neurovascular development in infants born prematurely should be investigated further.

Project description:Purpose: To evaluate the relationship between retinopathy of prematurity (ROP) severity and neurodevelopmental outcomes in premature neonates at 0-36 months corrected age. Methods: A retrospective chart review was performed on 228 neonates screened for ROP at the UCLA Mattel Children's Hospital between 2011 and 2018. Demographic information, clinical outcomes, ROP severity (no ROP, type 1 ROP, type 2 ROP), and Bayley-III neurodevelopmental scores were collected. Infants were grouped into corrected age cohorts (0-12, 12-24, and 24-36 months) to assess neurodevelopmental outcomes with increasing age. Within each age cohort, ANOVA and Chi-Square testing were used to detect differences in birth characteristics and neurodevelopmental scores between infants with type 1 ROP, type 2 ROP, or no ROP. Univariable analyses assessed the relationship between ROP severity and neurodevelopmental outcomes within each age cohort. A multivariable analysis was then performed to determine if ROP severity remained significantly associated with worse neurodevelopmental scores after controlling for birth weight (BW), intraventricular hemorrhage grade (IVH), health insurance type, male sex, and age at Bayley testing. Results: Without controlling for factors associated with prematurity, neonates with type 1 ROP had poorer cognition (p = 0.001) and motor (p = 0.006) scores at ages 0-12 months and poorer cognition (p = 0.01), language (p = 0.04) and motor (p = 0.04) scores at ages 12-24 months than infants without ROP, but no significant differences were detected at ages 24-36 months. After adjusting for BW, IVH, insurance type, male sex, and age at Bayley testing, ROP severity was no longer associated with worse neurodevelopmental scores in any domain. Conclusion: This study emphasizes that poorer neurodevelopmental outcomes in preterm neonates are most likely related to lower birthweight, associated co-morbidities of prematurity, and socioeconomic factors such as health insurance, not severity of ROP itself.

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: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.

Dataset Information

Neurodevelopmental Outcomes of Preterm Infants With Retinopathy of Prematurity by Treatment.

Publications

Neurodevelopmental Outcomes of Preterm Infants With Retinopathy of Prematurity by Treatment.

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