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.

The prenatal phase of retinopathy of prematurity

“…Moreover, these investigators also report similar associations between high endoglin, interleukin (IL)-6 and IL-8 levels and vision-threatening ROP that required intervention. 29 Together with the above results on chorioamnionitis and ROP, these data can be explained in at least three ways. First, since maternal/foetal inflammation contributes to preterm birth, 30,31 it might be merely a marker of reduced gestational age without any independent effect on the process of ROP development.…”

Visuopathy of prematurity: is retinopathy just the tip of the iceberg?

“…Among preterm infants, inflammatory responses are common before and after birth 67 , 68 and are likely to be involved in ROP etiology and visual abnormalities among preterm infants 5 , 16 , 69 , 70 . These inflammatory responses may be a result of oxidative stress, and vice versa.…”

Effect of Probenecid on Endothelial Cell Growth Rate and Retinal Angiogenesis in an Oxygen-Induced Retinopathy Model

“…Notably, hepcidin production is also regulated by inflammatory cytokines, such as IL-6 ( Zlatanova et al, 2019 ). Increasing evidence suggests that the IL-6 pathway plays a prominent role in ROP pathogenesis and that interactions between IL-6 and endothelial cells regulate the recruitment of leukocytes and the expression of inflammatory proteins ( Bartkeviciene et al, 2020 ; Woo et al, 2020 ). Clinically, anemia is common in prematurity, and repeated red blood cell infusion and accompanying iron overload are risk factors for ROP ( Aher and Ohlsson, 2019 ).…”