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.

Figure.

(A) Receiver operating characteristic (ROC) curve for the best antenatal prediction model (including high AF endoglin and high AF IL-6) for ROP occurrence (AUC, 0.731; SE, 0.045). (B) ROC curve for the best antenatal prediction model (including high AF endoglin and high AF IL-6) for severe ROP (AUC, 0.736; SE, 0.058). (C) ROC curve for the best antenatal prediction model (including high AF endoglin, high AF IL-8, and low gestational age at sampling) for vision-threatening ROP requiring treatment (AUC, 0.863; SE, 0.055).