will depend on the findings at the time of this examination. Pregnant women with less than severe NPDR should be examined every 3 months, whereas those with more severe stages should be seen every 1–3 months according to current guidelines.

Other Systemic Risk Factors

Diabetic nephropathy, as measured by albuminuria, proteinuria, or renal failure, is found to be a risk factor associated with progression of retinopathy in some, but not all, studies (43, 67, 68). Anemia has also been reported to be associated with progression of diabetic retinopathy in two small case series and two epidemiologic studies (43, 69–71). There was a progressive increase in the risk of development of high-risk PDR with decreasing hematocrit in an adjusted multivariate model in the ETDRS. This may add substantially to the evidence supporting the importance of anemia as a risk factor for diabetic retinopathy. History of diabetic neuropathy and cardiovascular autonomic neuropathy have also been suggested to be associated with increased risk of progression of retinopathy (43, 72, 73).

MANAGEMENT OF NONPROLIFERATIVE DIABETIC RETINOPATHY

The treatment recommendations of diabetic retinopathy are based on the results of two major randomized clinical trials of laser photocoagulation, the Diabetic Retinopathy Study (DRS), and the Early Treatment Diabetic Retinopathy Study (ETDRS). The treatment of NPDR depends on the severity of retinopathy and the presence or absence of clinically significant macular edema, which may be present at any stage of NPDR.

Photocoagulation

The DRS enrolled patients with severe nonproliferative or proliferative diabetic retinopathy and visual acuity of 20/100 or better. The DRS results demonstrated a 50% reduction in severe visual loss (visual acuity of 5/200 or worse at two or more consecutively completed follow-up visits scheduled at 4-month intervals) in eyes that had received photocoagulation (scatter and focal photocoagulation), compared with eyes that did not. DRS reports also identify retinopathy features associated with a particularly high risk of severe visual loss (74–77). These “high-risk” characteristics seen in the proliferative phase, which can be summarized as either neovascularization accompanied by vitreous hemorrhage or obvious neovascularization on or near the optic disc, even in the absence of vitreous hemorrhage, are described in further detail in Chap. 2.

Patients in the DRS had severe nonproliferative or proliferative retinopathy and were randomly assigned to either immediate photocoagulation or no photocoagulation, regardless of retinopathy progression. Although that study identified a group of patients at high risk for visual loss, it could not assess the appropriate timing of scatter photocoagulation. However, the ETDRS was designed to address this clinical question, as well as to evaluate the effects of laser photocoagulation for diabetic macular edema (78). To be eligible for the ETDRS, patients had to have diabetic retinopathy in both eyes with less than high-risk proliferative retinopathy (allowing for mild, moderate, and severe nonproliferative and early proliferative retinopathy) with or without macular edema. One eye of each patient

was randomly assigned to early photocoagulation using one of several strategies, and the fellow eye was assigned to deferral of photocoagulation (79).

Scatter Photocoagulation for Nonproliferative Diabetic Retinopathy

The comparison of early photocoagulation vs. deferral in the ETDRS revealed a small reduction in the incidence of severe visual loss in the early-treated eyes, but 5-year rates were low in both the early treatment and deferral groups (2.6% and 3.7%, respectively) (80). For eyes with only mild-to-moderate NPDR, rates of severe visual loss were even lower, and any reductions in visual loss from early photocoagulation did not seem sufficient to compensate for the unwanted side effects of scatter photocoagulation. As the retinopathy advances to the severe or very severe nonproliferative or early proliferative stage, the risk–benefit ratio becomes more favorable, and it is reasonable to consider initiating scatter photocoagulation before the development of high-risk PDR. Recent analyses of ETDRS data suggested that early scatter treatment is particularly effective in reducing severe visual loss in patients with type 2 diabetes (81). While no studies have been performed evaluating intraocular VEGF levels after scatter photocoagulation for NPDR, successful panretinal photocoagulation for ocular neovascularization was found to reduce intraocular VEGF by 75% in one study (82). These data provide an additional reason to recommend early scatter photocoagulation in older patients with very severe nonproliferative or early proliferative diabetic retinopathy.

If patients with either type 1 or 2 diabetes present with both clinically significant macular edema and very severe nonproliferative or early proliferative diabetic retinopathy, the treatment of the macular edema should be considered first, if possible. Data from the ETDRS demonstrated that initial scatter photocoagulation in such patients can actually worsen the macular edema.

Scatter Photocoagulation for Proliferative Retinopathy

The technique of scatter photocoagulation for PDR is discussed in Chap. 2. This technique is used for some eyes that are approaching high-risk PDR, for example, eyes with severe nonproliferative or early proliferative retinopathy. A standard “full” scatter panretinal photocoagulation should be applied (1,200–1,600 moderate intensity burns of 500 m in diameter).

Focal Photocoagulation for Diabetic Macular Edema

The ETDRS results also provide clinically important information to guide the treatment of diabetic macular edema (42, 79, 83, 84). In the ETDRS, eyes with mild or moderate NPDR and macular edema were randomly assigned to early focal/grid photocoagulation or no photocoagulation unless high-risk PDR developed. The main outcome variable was a decrease of 3 lines on a logarithmic visual acuity chart. This 3-line decrease represents a doubling of the initial visual angle, for example, a change from 20/20 to 20/40 or from 20/100 to 20/200. After 3 years of follow-up, 24% of the control group experienced such a visual loss when compared with 12% of the treated eyes. Focal/grid photocoagulation reduced the risk of moderate visual acuity loss for all eyes with