Protective effect of maternal uteroplacental insufficiency on oxygen-induced retinopathy in offspring: removing bias of premature birth

Abstract

To address the hypothesis that maternal uteroplacental insufficiency (UPI) increases severity of retinopathy of prematurity, we developed a composite rat model of UPI and oxygen-fluctuations and removed premature birth as a confounding factor. Timed-pregnant Sprague-Dawley dams underwent bilateral uterine artery ligation or anesthesia (control) at e19.5. Full-term pups developed in room air (RA) or an oxygen-induced retinopathy (OIR) model. Isolectin-stained retinal flat-mounts were analyzed for percent of areas of avascular/total retina (AVA) and of intravitreal neovascular/total retina (IVNV). Pup weights and serum and mRNA of liver and kidney VEGF, IGF-1, and erythropoietin (EPO) were determined. Multivariable mixed effects linear regressions and Pearson correlations were performed using STATA14. Postnatal growth restriction occurred in pups in UPI/RA, but not in UPI/OIR. Weight gain was similar between UPI/OIR and control/OIR pups. AVA was reduced and a trend toward reduced IVNV was seen in UPI/OIR compared to control/OIR. No difference in birth weights of UPI/OIR vs. control/OIR pups occurred. Serum and renal IGF-1 and EPO were significantly increased in UPI/OIR compared to control/OIR pups. In the absence of prematurity, UPI increased angiogenic factors in association with reduced OIR severity, suggesting that ischemia from UPI could yield protective angiogenic effects by offspring.

Current evidence and outcomes for retinopathy of prematurity prevention: insight into novel maternal and placental contributions

“…This is supported by rodent studies from Becker et al [185], in which premature birth was uncoupled from uteroplacental insufficiency (UPI, a major component of preeclampsia) using a rat uterine artery ligation model. They found that in the setting of term gestation, uteroplacental insufficiency resulted in a significant decrease in avascular area and a trend towards reduced proliferative vascularization in the OIR model of ROP, supporting a relationship between placental insufficiency and ROP protection at the earliest stages of retinal vascular development [185]. If ROP protection in the setting of preeclampsia is actually the inverse effect-namely an empirically greater risk or ROP from non-preeclamptic spontaneous preterm births-it can still be argued that mechanisms underlying reduced likelihood of ROP development in the setting of preeclampsia will inform approaches toward normalizing retinal vascular development and ROP prevention.…”

“…preterm delivery [10,17]. This is supported by rodent studies from Becker et al [185], in which premature birth was uncoupled from uteroplacental insufficiency (UPI, a major component of preeclampsia) using a rat uterine artery ligation model. They found that in the setting of term gestation, uteroplacental insufficiency resulted in a significant decrease in avascular area and a trend towards reduced proliferative vascularization in the OIR model of ROP, supporting a relationship between placental insufficiency and ROP protection at the earliest stages of retinal vascular development [185].…”

“…Multiple lines of evidence in the literature suggest that placental pathobiology is an underlying factor in our current paradigm of ROP pathogenesis. For example, Becker et al [185], suggest that increased systemic angiogenic factors are the etiologic basis for ROP protection in their OIR rat model. Although this has been incompletely assessed in humans, preeclampsia in humans involves dysregulation of angiogeneic factors, particularly in the maternal circulation [187][188][189].…”

Discovering Mechanisms in the Changing and Diverse Pathology of Retinopathy of Prematurity: The Weisenfeld Award Lecture

“…Intravitreal anti-VEGF in infants with only mild ROP or too high a dose of anti-VEGF may be harmful to the retina and to physiologic vascularity, potentially stimulating recurrent intravitreal neovascularization. These data provide insight into the observation that not all extremely premature infants, those born less than 1000 g birth weight or under 28 weeks gestational age, develop severe ROP, and it may be that some infants are able to induce protective mechanisms for survival and to avoid severe ROP 21,57…”

“…Therefore, we and other labs have experimentally recreated some of these stresses to understand their role in causing ROP features. Some of these include fluctuations in oxygenation,17,18 poor postnatal growth,19 poor infant oxidative reserve under conditions of increased oxidative signaling,20 and reduced ability to express protective factors to offset events from extreme prematurity 21…”