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Severe retinopathy of prematurity (ROP) occurs in the smallest and sickest of premature infants. We hypothesized that, in a rat model of oxygen induced retinopathy, abnormal neovascularization would occur more frequently in larger litters where the pups are subject to postnatal growth retardation. Four litters of newborn Sprague-Dawley rats were studied; rats were randomly mixed to form two large litters (n = 25 each) and two small litters (n = 10 each). All litters were exposed to 7 days cyclic hyperoxia and hypoxia followed by 5 days in room air. ADPase stained retinae were evaluated in a masked manner for the presence and severity of abnormal neovascularization. Fluorescein perfused retinae were digitized and the ratios of vascularized:total retinal area were calculated using computer assisted image analysis. As expected, final weight in the large litters was less than in the small litters (15.3 +/- 3.8g vs. 23.4 +/- 2.1g, p < 0.001). Neovascularization occurred in 53% of rats in the large litters vs. 15% in the small litters (p = 0.009). Rats with retinae demonstrating neovascularization were smaller than those without (16.2 +/- 4.7g vs. 19.6 +/- 5.0g, p = 0.016). The severity of neovascularization in clock h was inversely correlated with final weight (rs = -0.35, p = 0.01) and ratio of vascularized:total retina area (rs = -0.46, p < 0.001). Smaller rat pups raised in larger litters, with resultant growth retardation, develop more frequent and more severe abnormal retinal neovascularization. Our results correlate with clinical experience in the premature infant.

Many animal models of retinal disease use the neonatal rat. Raising rat pups in large litters has been shown to result in postnatal growth retardation. We investigated the effect of litter size on the normal postnatal vascularization of the neonatal rat retina. Sixty-six newborn rat pups were divided among 5 nursing mothers into 3 small litters (n = 10) and 2 large litters (n = 18). On day 6 of life the rats were sacrificed and total retinal and vascularized retinal areas analyzed. The total retinal area was reduced in the rats raised in larger litters (28.6 mm2 vs. 25.9 mm2 p < 0.001) but there was a more pronounced reduction in vascularized retinal area (67% vascularized vs. 54% vascularized, p < 0.001). Postnatal vascularization of the normal rat retina may be influenced by litter size.

Hyperoxia is a risk factor for retinopathy of prematurity (ROP), a blinding disease in infants. However, ROP develops in human infants without raised arterial oxygen levels, such as in cyanotic congenital heart disease. In these infants raised pCO2 may be a risk factor. We investigated the effect of inspired CO2 on oxygen induced retinopathy in the rat. 56 newborn Sprague-Dawley rats were exposed to high cyclical O2 for seven days. In a control group, 27 rats were exposed to negligible CO2 by the use of soda lime. In the high CO2 group, 29 rats were exposed to elevated CO2 by omitting soda lime from their chambers. Rats in both groups had a recovery period of three days in room air following cyclical O2 exposure. On the eleventh day all rats were sacrificed after intracardiac injections of fluorescein under deep anesthesia and the retinae were dissected and flat mounted for fluorescent microscopy. The ratio of vascularized:total retinal area was calculated using computer assisted image analysis. In the high CO2 group 62% +/- 7% SD of the retina was vascularized vs. 81% +/- 7% in low CO2 group (p < 0.001). Elevated inspired CO2 results in pronounced retardation of retinal vascular development in neonatal rats exposed to fluctuating raised oxygen.