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DIABETIC RETINOPATHY IN PREGNANCY
DIABETES IN PREGNANCY
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DIABETIC RETINOPATHY IN PREGNANCY E. Albert Reece, MD, Carol J. Homko, RN, MS, CDE, and Zion Hagay, MD
Diabetic retinopathy is the most common chronic complication associated with diabetes mellitus. It affects 20% to 27% of diabetic women in the reproductive age group.ll, In the past, proliferative retinopathy had been considered a relative contraindication to pregnancy. However, as a result of advances in the treatment of diabetes itself, as well as of diabetic eye disease, more women with retinopathy and other forms of microvascular disease are choosing to become pregnant. This article reviews the course and treatment of pregnancy complicated by retinopathy. CLASSIFICATION OF RETINOPATHY
Diabetic retinopathy is a progressive disorder that has been traditionally classified as background, preproliferative, or proliferative retinopathy. The characteristic lesions of diabetic retinopathy are outlined in Table 1. Background retinopathy is characterized by the appearance of microaneurysms, exudates, and small dot or blot hemorrhages in the retina (Fig. 1).Unless these lesions occur in the perimacular area, they do not threaten vision, and the patient is generally asymptomatic. Background retinopathy is very common in diabetes and is found in 98% of individuals who have had diabetes for 15 years or On examination with an ophthalmoscope, retinal microaneurysms, an outpouching
From the Department of Obstetrics, Gynecology and Reproductive Sciences, Temple University School of Medicine, Philadelphia, Pennsylvania (EAR, CJH); and the Department of Obstetrics and Gynecology, Kaplan Hospital, Rehovot, Israel (ZH)
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Table 1. CHARACTERISTIC LESIONS OF DIABETIC RETINOPATHY Background diabetic retinopathy Microaneurysms Small-vessel obstruction, soft exudate, intraretinal microvascular abnormalities Venous abnormalities Retinal hemorrhages Hard exudate Disk edema Maculopathy Proliferative diabetic retinopathy Neovascularization Fibrous deposition Vitreous hemorrhage Retinal detachment From Hagay ZJ, Reece EA: Diabetes mellitus in pregnancy. In Reece EA, Hobbins JC, Mahoney MJ, Petrie RH (eds): Medicine of the Fetus and Mother. Philadelphia, JB Lippincott, 1992, p 1005; with permission.
of a retinal capillary, appear as a red dot. Hard exudates appear as spots of varying size with irregular margins and uneven densities. Exudates are collections of lipoproteins that leak from microaneurysms into the outer retinal layer. On examination, they appear yellow and can be found scattered or clumped in a circinate pattern around leaking microaneurysms.
Figure 1. Right fundus demonstrating background diabetic retinopathy. Optic disc (0)on far left. Dot-blot hemorrhages (DB) noted to the right of the fovea (F); microaneurysms (M) are brighter, smaller spots. Hard exudates (HE) are noted in a circular pattern just to right of the fovea.
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Figure 2. The same patient as in Figure 1 during the second trimester of pregnancy with proliferative diabetic retinopathy. Camera focused on the supratemporal retinal vascular arcade of the right eye. Neovascularization (N) of the retina is seen along the supratemporal vascular arcade. White and black dots are laser scars (LS) secondary to treatment. Whitish band along vascular arcade is a gliotic tissue (G) formed from proliferating Mueller fibers found within the retina. Gliotic tissue accompanies the neovascularization resulting from hypoxia of the retinal tissue.
Preproliferative retinopathy is considered to be a transitional stage toward proliferative retinopathy. This stage is characterized by the appearance of cotton-wool spots, which represent signs of ischemia. Cotton-wool spots are localized superficial swellings that result from an infarction in the nerve fiber layer. Clinically, they appear as grayish white lesions with feathery edges. Venous beading, or localized irregularities in venous caliber, and intraretinal microvascular abnormalities (IRMA) are also characteristic lesions found in the preproliferative stage. IRMA lesions are dilated capillaries and are strong predictors for progression of retinopathy. Proliferative diabetic retinopathy is characterized by neovascularization and the growth of abnormal blood vessels on the retinal surface (Fig. 2). These new vessels can extend into the vitreous cavity, leading to contraction and distortion of the vitreous gel, as well as detachment of the retina. In addition, these capillaries may rupture and hemorrhage into the vitreous cavity. The hemorrhages with or without traction detachment represent a serious threat to vision. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy, proliferative retinopathy was observed in 20% to 25% of patients with insulin-dependent diabetes mellitus (IDDM) of 15 years’ duration.18Hence, the severity of diabetic retinopathy is clearly related to the duration of diabetes.
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ETIOPATHOLOGY OF RETINOPATHY
Increasing evidence supports the notion that the consequences of hyperglycemia with or without insulin deficiency contribute significantly to the pathogenesis of diabetic retinopathy and other microvascular complications. This evidence is based on clinical and experimental studies which have demonstrated that, with increased duration of diabetes, there is an increase in the prevalence and severity of retinopathy.2,6, 14,28, 29 The recently completed Diabetes Control and Complications Trial: a 10-year multicenter, National Institutes of Health-funded trial, has finally ended the debate concerning the relationship between control and complications. This trial was designed to compare intensive management with conventional diabetes therapy with regard to their effects on the development and progression of the long-term complications of diabetes. Two cohorts of patients were studied. A total of 1441 patients with IDDM were randomly assigned to either intensive or conventional diabetes control. Seven hundred and twenty-six individuals were in the primary prevention cohort, which included patients with no retinopathy at base line, and 715 individuals in the secondary intervention cohort with mild retinopathy at baseline. In the primary prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76% (95% confidence interval, 62% to 85%) as compared with conventional therapy. In the secondary intervention cohort, intensive therapy slowed the progression of retinopathy by 54% (95% confidence interval, 39% to 66%) and reduced the development of proliferative or severe nonproliferative retinopathy by 47% (95% confidence interval, 14% to 67%). The precise mechanisms, however, by which hyperglycemia and the other metabolic derangements of diabetes contribute to the tissue damage that underlies retinopathy and the other vascular complications are still unclear. A possible interplay between hyperglycemia and other genetic and environmental factors has been proposed. High glucose levels have been postulated to decrease retinal blood flow and to induce ischemia and hypoxia through several different mechani~ms.'~ Much recent attention has been directed toward the sorbitol or polyol p a t h ~ a y .8,~9, ,30 This pathway converts excess nonphosphorylated intracellular glucose to sorbitol and then fructose through the enzymes aldose reductase and sorbitol dehydrogenase in various tissues including the retina, kidney, peripheral nerves, and vasculature. The accumulation of sorbitol and fructose in the tissues is believed to lead to alterations in tissue function by impairment in myo-inositol metabolism and capillary narrowing caused by basement membrane thickening. Platelets also appear to be integrally involved in the pathogenesis of retinopathy and other vascular complications.1° Platelet aggregates and thrombi have been demonstrated in the small vessels of the retinas and kidneys of patients with diabetes. As a result, there is decreased oxygen release from the red blood cells, which may lead to thickening of the retinal capillary walls. Diminished platelet responsiveness to
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prostacyclin, increased platelet sensitivity to aggregating agents, and decreased synthesis of prostaglandin E by platelets and of prostacyclin by vessel walls have all been demonstrated in diabetes. Hyperglycemia is also believed to induce the production of high levels of plasma proteins, fibrinogen, and alpha-globulin. High concentrations of these plasma proteins cause increased plasma viscosity and a subsequent decrease in retinal blood flow.I0 EFFECTS OF PREGNANCY ON RETINOPATHY
Studies of the effect of pregnancy on diabetic retinopathy have reported conflicting conclusions. In general, more recent studies have found a higher rate of progression of diabetic retinopathy in pregnant women than was found in older studies. However, some changes have proved to be reversible, and many women have experienced regression of lesions following delivery.21,26 Moloney and DruryZ1found that background retinopathy developed during pregnancy in 15% of women in their case-control study. This is a much higher rate than has been observed in nonpregnant controls. They also found that 29% of patients with background retinopathy that was present before conception experienced progression of the retinopathy during pregnancy. In addition, neovascularization developed in four patients for the first time during the index pregnancy. However, by 6 months after delivery, background changes and neovascularization demonstrated regression in all cases. Increased doses of insulin and hydramnios were risk factors for retinal hemorrhage in the study population. These findings are consistent with those in the Rigshospitalet which also reported regression in class D patients who were not treated with photocoagulation. Approximately half of the patients with retinopathy showed progression during pregnancy. All of the women improved to some extent during the postpartum period. In a few women with background retinopathy at the onset of pregnancy, proliferative retinopathy developed that commonly disappeared shortly after delivery. The results of the Diabetes in Early Pregnancy Study (DIEP)3demonstrated that women with mild or more severe retinopathy at conception were at high risk for progression of retinopathy during pregnancy. Progression rates from nonproliferative retinopathy to proliferative retinopathy were 6.76% and 30% in patients whose baseline retinopathy was mild and moderate, respectively. Elevated glycosylated hemoglobin levels greater than 4 standard deviations above the mean were associated with a statistically significant increased risk of progression. In the DIEP study, as in previous studies, rapid normalization of glucose levels may have been a major independent variable in the progression of retinopathy. Klein and associates16performed a prospective study of the progres-
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sion of diabetic retinopathy in a group of pregnant women with IDDM compared with a group of women with IDDM who were not pregnant. Women were evaluated on referral and again in the postpartum period. Retinopathy was graded on the basis of fundus photographs using seven standard photographic fields. The glycosylated hemoglobin, duration of diabetes, current age, diastolic blood pressure, number of past pregnancies, and current pregnancy status were evaluated as risk factors for the progression of diabetic retinopathy. After adjusting for the level of glycemic control, the current pregnancy was significantly associated with progression (P <0.005; adjusted odds ratio, 2.3). Women with elevated diastolic blood pressure also had a greater tendency to progress, although the effect was less marked than for metabolic control. It was concluded that pregnancy and the level of glycemia are associated with the progression of diabetic retinopathy (Table 2). An association between the progression of diabetic retinopathy in pregnancy and hypertension also has been demonstrated. In a prospective study, Rosenn and colleagues25examined the risk for retinopathic complications in women with IDDM with chronic or pregnancy-induced hypertensive disorders. Of the 154 women prospectively followed, 51 experienced progression of retinopathy during the index pregnancy. Chronic hypertension, pregnancy-induced hypertension, and changes in glycemic control were significantly associated with the progression of retinopathy. PREGNANCY OUTCOMES IN THE PRESENCE OF DIABETIC RETINOPATHY
Although pregnancy is associated with the progression of retinopathy, meticulous ophthalmic surveillance and appropriate photocoagulation therapy can sufficiently treat and control proliferative retinal changes to allow continuation of the pregnancy in most cases. However, the presence of retinopathy, representing vascular compromise, has an effect on pregnancy or perinatal outcomes. Earlier studies (1980s) reTable 2. ORDINAL MULTIVARIATE LOGISTIC MODEL FOR CHANGES IN RETINOPATHY BETWEEN VISITS
P
Ratio
95% CI
Progression of Retinopathy More Likely If
<0.0001
1.7 1.8
1.4, 2.2 1.1, 2.8
Higher Pregnant
Odds Variable* HbAj Group
<0.02
95% CI = 95% confidence interval; HbA, = glycosylated hemoglobin. 'Variables dropped by backward elimination: diastolic blood pressure, P = 0.07; number of previous pregnancies, P = 0.21; age, P = 0.50; duration of diabetes, P = 0.84. From Klein BEK, Moss SE, Klein R: Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care 13:34-40, 1990; with permission.
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Table 3. NEONATAL OUTCOME Outcome Pregnancy Spontaneous abortion Stillbirth Live birth* Neonatal growth status Appropriate-for-gestational-age(5th to 95th percentile) Small-for-gestational-age( 4 t h percentile) Large-for-gestational-age(>95th percentile) Neonatal complications None Congenital anomalies Hypoglycemia Hyperbilirubinemia Perinatal survival rate
Number
2 (1 OYO) 1 (5%) 17 (85%) 11 (64%) 4 (24%)
2 (1 2%) 9 (53%) 3 (1 8%) 4 (23%) 1 (6%)
17 (94%)
*Mean birth weight, 2.620 g (-834 SD). From Reece €A, Lockwood CJ,Tuck S, et al: Retinal and pregnancy outcomes in the presence of diabetic proliferative retinopathy. J Reprod Med 39:799-804, 1994; with permission.
ported a relatively high incidence of adverse outcomes. Price and colleaguesz3reported on five patients with proliferative retinopathy during pregnancy. Preeclampsia developed in all five women; three (60%) required cesarean section, and only two (40%) neonates had uncomplicated outcomes. Horvat and colleagues'l reported similar outcomes in their series of seven pregnancies complicated by diabetic proliferative retinopathy: one stillbirth, one termination because of hypertension, one neonatal demise, one infant death, and only three normal outcomes. A more recent report, however, has demonstrated significantly better perinatal outcomes. Reece and colleaguesz4reported on the outcomes of 20 pregnancies complicated by advanced diabetic retinopathy. Spontaneous abortion occurred in two (10%) and stillbirth in one (5%); the remaining 17 pregnancies culminated in live births (Table 3). The perinatal survival rate was 94%. Photocoagulation therapy was necessary before pregnancy in 45%, during pregnancy in 6O%, and postpartum in 65%. Klein and colleague^'^ reported the outcomes in 179 pregnant diabetic women. Twenty-eight of these pregnancies were complicated by proliferative retinopathy. Logistic regression analysis was used to evaluate significant predictors of pregnancy outcome. Adverse outcomes were defined as abortions, perinatal death, and severe congenital anomalies. Of the variables of maternal age, duration of diabetes, glycosylated hemoglobin, proteinuria, cigarette smoking status, and severity of diabetic retinopathy, only diabetic retinopathy significantly predicted an adverse outcome. Thirteen percent of women with mild retinopathy had infants with adverse outcomes as compared with adverse outcomes in 43% of the offspring of women with severe retinopathy ( P < 0.001).
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TIGHT METABOLIC CONTROL AND THE PROGRESSION OF RETINOPATHY
Studies in nonpregnant patients with IDDM investigated the effect of glycemic control on the progression of diabetic retinopathy. Progression of diabetic retinopathy was significantly higher over an 8-month period in comparison with a control group with proper metabolic control.20After 2 years of follow-up, no statistical significance was found between the rates of progression of retinopathy in the two groups. It was suggested that one should avoid achieving good glycemic control too rapidly in patients with IDDM with retinopathy and poor glycemic control. Phelps and colleagues2*have reported similar findings in pregnant patients with IDDM. Fifty-five percent of retinal abnormalities worsened following the initiation of intensive therapy to normalize maternal blood glucose levels. Deterioration of background retinopathy correlated significantly with the level of glucose control at entry into the study and with the degree of improvement achieved. It was emphasized that retinal changes were relatively minor, and that the benefits of careful diabetic control during gestation outweighed the retinal changes noted. The conclusion must be that the increased risk for progression of diabetic retinopathy by rapid glycemic control should not suggest that less rigid control is appropriate.
OTHER OCULAR COMPLICATIONS
Two other ocular complications can occur in women of childbearing age-acute optic disk edema (pseudopapilledema) and macular edema. They have been reported to occur in association with preeclampsia in diabetic women.14 Physical findings in acute optic disk edema include edema of the optic disk and visual field defects. Although pregnancy may be an inciting factor, the condition is relatively benign, and pregnancy is not ~ontraindicated.~~ Macular edema can be associated with any stage of retinopathy. It encompasses a number of characteristic lesions, including a collection of fluid or thickening in the macula, hard exudates within the macular area, nonperfusion of the retina inside the temporal vessel arcades, or any combination of these findings. Sinclair and colleagues27have reported the development of severe macular edema associated with preproliferative or proliferative retinopathy in seven women with IDDM during pregnancy with minimal or no retinopathy before conception. Women in whom macular edema develops should be referred to an experienced retinologist or general ophthalmologist for treatment. Patients with clinically significant macular edema are candidates for focal laser photocoagulation.
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MANAGEMENT OF DIABETIC RETINOPATHY DURING PREGNANCY
Diabetic retinopathy occurring during pregnancy should be treated in essentially the same manner as in the nonpregnant state. Fundus photography and laser treatment can be used safely during pregnancy when indicated. Despite evidence that retinopathy often spontaneously regresses following delivery, most experts still recommend laser photocoagulation during gestation. Ideally, diabetic women contemplating pregnancy should undergo careful retinal examination before conception and treatment with laser photocoagulation, if necessary. Fluorescein angiography is not recommended during pregnancy because of uncertainty of the effect and possible toxicity in the fetus. We perform ophthalmoscopy every trimester in pregnant women with IDDM and even more frequently in patients with documented prepregnancy retinopathy. The preferred mode of delivery in patients with active proliferative retinopathy remains controversial. In the past, the performance of cesarean section was suggested to avoid the Valsalva maneuver and the risk for vitreous hemorrhage. Today, however, most investigators including our group do not recommend cesarean delivery in patients with active neovascularization because it has been found that vitreous hemorrhages during childbirth are extremely rare.1° Furthermore, there are no data to show any advantage of cesarean section over vaginal delivery in patients with proliferative retinopathy.
CONCLUSION
Taken together, the available studies would seem to indicate that pregnancy is an independent risk factor for diabetic retinopathy. Hypertension, poor control early in pregnancy, and rapid normalization all seem to be associated with the potential to accelerate the retinal deterioration. Furthermore, women with more advanced forms of retinopathy and a longer duration of diabetes are at highest risk for progression of the retinopathy during gestation.
References 1. Berk MA, Miodovnik M, Mimouni F Impact of pregnancy on complications of insulindependent diabetes mellitus. Am J Perinatol5:359-367, 1988 2. Cahill GF Jr, Etzwiler DD, Freinkel N "Control" and diabetes. N Engl J Med 294:14331438, 1976 3. Chang S, Fuhrmann M, Jovanovic L The diabetes in early pregnancy study group (DIEP): Pregnancy, retinopathy normoglycemia. A preliminary analysis. Diabetes 35(suppl):3A, 1985
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4. DCCT Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977-986, 1993 5. Elman KD, Welch RA, Frank RN, et al: Diabetic retinopathy in pregnancy: A review. Obstet Gynecol 75:119-127, 1990 6. Engerman RL, Bloodworth JMB, Nelson S: Relationship of microvascular disease in diabetes to metabolic control. Diabetes 26:760, 1977 7. Frank RN: On the pathogenesis of diabetic retinopathy. Ophthalmology 91:626, 1984 8. Gabbay K The sorbitol pathway and the complications of diabetes. N Engl J Med 288:831-836, 1973 9. Green DA, Lattimer SA, Sima AAF: Sorbitol, phosphoinositides, and sodium-potassium ATPase in the pathogenesis of diabetic complications. N Engl J Med 316599606, 1987 10. Hagay ZJ, Reece EA: Diabetes mellitus in pregnancy. In Reece EA, Hobbins JC, Mahoney MJ, et a1 (eds): Medicine of the Fetus and Mother. Philadelphia, JB Lippincott, 1992 11. Hollingsworth DR Pregnancy, Diabetes and Birth A Management Guide, ed 2. Baltimore, Williams & Wilkins, 1992, p p 15-19 12. Horvat M, MacLean H, Boldberg L, et al: Diabetic retinopathy in pregnancy: A 12year prospective survey. Br J Ophthalmol 64398-403, 1980 13. Johnston GP: Pregnancy and diabetic retinopathy. Am J Ophthalmol90519-524, 1980 14. Jovanovic-Peterson L, Peterson CM: Diabetic retinopathy. In Reece EA, Coustan DR (eds): Diabetes in Pregnancy. New York, Churchill Livingstone, 1995 15. Klein BEK, Klein R, Meuer SM, et a 1 Does the severity of retinopathy predict pregnancy outcome? J Diabetic Complications 2:179-184, 1988 16. Klein BEK, Moss SE, Klein R Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care 13:34-40, 1990 17. Klein R Recent developments in the understanding and management of diabetic retinopathy. Med Clin North Am 721415,1988 18. KIein R, KIein BEK, Moss S, et al: The Wisconsin epidemiologic study of diabetic retinopathy. 111. Prevalence and risk of diabetic retinopathy when the age at diagnosis is less than thirty years. Arch Ophthalmol 102:520, 1984 19. Klein R, Klein BEK, Moss S, et al: The Wisconsin epidemiologic study of diabetic retinopathy. 111. Prevalence and risk of diabetic retinopathy when the age at diagnosis is greater than thirty years. Arch Ophthalmol 102:527, 1984 20. The Kroc Collaborative Study Group: Diabetic retinopathy after two years of intensified insulin treatment: Follow-up of the Kroc Collaborative Study. JAMA 260:37-41, 1988 21. Moloney JBM, Drury MI: The effect of pregnancy on the natural course of diabetic retinopathy. Am J Ophthalmol93745,1982 22. Phelps RL, Sakol P, Metzger BE, et al: Changes in diabetic retinopathy during pregnancy: Correlations with regulation of hyperglycemia. Arch Ophthalmol 104:180& 1810, 1986 23. Price JH, Hadden DR, Archer DB, et al: Diabetic retinopathy in pregnancy. Br J Obstet Gynaecol91:ll-17, 1984 24. Reece EA, Lockwood CJ, Tuck S, et al: Retinal and pregnancy outcomes in the presence of diabetic proliferative retinopathy. J Reprod Med 39:799-804, 1994 25. Rosenn B, Miodovnik M, Kranias G, et al: Progression of diabetic retinopathy in pregnancy: Association with hypertension in pregnancy. Am J Obstet Gynecol 166:1214-1218, 1992 26. Serup L: Influence of pregnancy on diabetic retinopathy. Acta Endocrinol 112(~~ppl):122-124, 1986 27. Sinclair SH, Nesler C, Foxman B, et al: Macular edema and pregnancy in insulindependent diabetes. Am J Ophthalmol97:154-167, 1984 28. Sinclair S, Nesler C, Schwartz S: Retinopathy in the pregnant diabetic. Clm Obstet Gynecol 28:536, 1985 29. Skyler J S Complications of diabetes mellitus: Relationship to metabolic dysfunction. Diabetes Care 2499, 1977
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30. Sorbinil Retinopathy Trial Research Group: A randomized trial of sorbinil, and aldose reductase inhibitor, in diabetic retinopathy. Arch Ophthalmol 108:12341244, 1990 31. Ward SC, Woods DR, Gilstrap LC 111, et al: Pregnancy and acute optic disc edema of juvenile-onset diabetes. Obstet Gynecol 64:816-818, 1984 Address reprint requests to E. Albert Reece, MD Department of Obstetrics, Gynecology and Reproductive Sciences Temple University School of Medicine 3401 North Broad Street, 7-OPB Philadelphia, PA 19140
0889-8545/96 $0.00
+ .20
DIABETIC RETINOPATHY IN PREGNANCY E. Albert Reece, MD, Carol J. Homko, RN, MS, CDE, and Zion Hagay, MD
Diabetic retinopathy is the most common chronic complication associated with diabetes mellitus. It affects 20% to 27% of diabetic women in the reproductive age group.ll, In the past, proliferative retinopathy had been considered a relative contraindication to pregnancy. However, as a result of advances in the treatment of diabetes itself, as well as of diabetic eye disease, more women with retinopathy and other forms of microvascular disease are choosing to become pregnant. This article reviews the course and treatment of pregnancy complicated by retinopathy. CLASSIFICATION OF RETINOPATHY
Diabetic retinopathy is a progressive disorder that has been traditionally classified as background, preproliferative, or proliferative retinopathy. The characteristic lesions of diabetic retinopathy are outlined in Table 1. Background retinopathy is characterized by the appearance of microaneurysms, exudates, and small dot or blot hemorrhages in the retina (Fig. 1).Unless these lesions occur in the perimacular area, they do not threaten vision, and the patient is generally asymptomatic. Background retinopathy is very common in diabetes and is found in 98% of individuals who have had diabetes for 15 years or On examination with an ophthalmoscope, retinal microaneurysms, an outpouching
From the Department of Obstetrics, Gynecology and Reproductive Sciences, Temple University School of Medicine, Philadelphia, Pennsylvania (EAR, CJH); and the Department of Obstetrics and Gynecology, Kaplan Hospital, Rehovot, Israel (ZH)
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Table 1. CHARACTERISTIC LESIONS OF DIABETIC RETINOPATHY Background diabetic retinopathy Microaneurysms Small-vessel obstruction, soft exudate, intraretinal microvascular abnormalities Venous abnormalities Retinal hemorrhages Hard exudate Disk edema Maculopathy Proliferative diabetic retinopathy Neovascularization Fibrous deposition Vitreous hemorrhage Retinal detachment From Hagay ZJ, Reece EA: Diabetes mellitus in pregnancy. In Reece EA, Hobbins JC, Mahoney MJ, Petrie RH (eds): Medicine of the Fetus and Mother. Philadelphia, JB Lippincott, 1992, p 1005; with permission.
of a retinal capillary, appear as a red dot. Hard exudates appear as spots of varying size with irregular margins and uneven densities. Exudates are collections of lipoproteins that leak from microaneurysms into the outer retinal layer. On examination, they appear yellow and can be found scattered or clumped in a circinate pattern around leaking microaneurysms.
Figure 1. Right fundus demonstrating background diabetic retinopathy. Optic disc (0)on far left. Dot-blot hemorrhages (DB) noted to the right of the fovea (F); microaneurysms (M) are brighter, smaller spots. Hard exudates (HE) are noted in a circular pattern just to right of the fovea.
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Figure 2. The same patient as in Figure 1 during the second trimester of pregnancy with proliferative diabetic retinopathy. Camera focused on the supratemporal retinal vascular arcade of the right eye. Neovascularization (N) of the retina is seen along the supratemporal vascular arcade. White and black dots are laser scars (LS) secondary to treatment. Whitish band along vascular arcade is a gliotic tissue (G) formed from proliferating Mueller fibers found within the retina. Gliotic tissue accompanies the neovascularization resulting from hypoxia of the retinal tissue.
Preproliferative retinopathy is considered to be a transitional stage toward proliferative retinopathy. This stage is characterized by the appearance of cotton-wool spots, which represent signs of ischemia. Cotton-wool spots are localized superficial swellings that result from an infarction in the nerve fiber layer. Clinically, they appear as grayish white lesions with feathery edges. Venous beading, or localized irregularities in venous caliber, and intraretinal microvascular abnormalities (IRMA) are also characteristic lesions found in the preproliferative stage. IRMA lesions are dilated capillaries and are strong predictors for progression of retinopathy. Proliferative diabetic retinopathy is characterized by neovascularization and the growth of abnormal blood vessels on the retinal surface (Fig. 2). These new vessels can extend into the vitreous cavity, leading to contraction and distortion of the vitreous gel, as well as detachment of the retina. In addition, these capillaries may rupture and hemorrhage into the vitreous cavity. The hemorrhages with or without traction detachment represent a serious threat to vision. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy, proliferative retinopathy was observed in 20% to 25% of patients with insulin-dependent diabetes mellitus (IDDM) of 15 years’ duration.18Hence, the severity of diabetic retinopathy is clearly related to the duration of diabetes.
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ETIOPATHOLOGY OF RETINOPATHY
Increasing evidence supports the notion that the consequences of hyperglycemia with or without insulin deficiency contribute significantly to the pathogenesis of diabetic retinopathy and other microvascular complications. This evidence is based on clinical and experimental studies which have demonstrated that, with increased duration of diabetes, there is an increase in the prevalence and severity of retinopathy.2,6, 14,28, 29 The recently completed Diabetes Control and Complications Trial: a 10-year multicenter, National Institutes of Health-funded trial, has finally ended the debate concerning the relationship between control and complications. This trial was designed to compare intensive management with conventional diabetes therapy with regard to their effects on the development and progression of the long-term complications of diabetes. Two cohorts of patients were studied. A total of 1441 patients with IDDM were randomly assigned to either intensive or conventional diabetes control. Seven hundred and twenty-six individuals were in the primary prevention cohort, which included patients with no retinopathy at base line, and 715 individuals in the secondary intervention cohort with mild retinopathy at baseline. In the primary prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76% (95% confidence interval, 62% to 85%) as compared with conventional therapy. In the secondary intervention cohort, intensive therapy slowed the progression of retinopathy by 54% (95% confidence interval, 39% to 66%) and reduced the development of proliferative or severe nonproliferative retinopathy by 47% (95% confidence interval, 14% to 67%). The precise mechanisms, however, by which hyperglycemia and the other metabolic derangements of diabetes contribute to the tissue damage that underlies retinopathy and the other vascular complications are still unclear. A possible interplay between hyperglycemia and other genetic and environmental factors has been proposed. High glucose levels have been postulated to decrease retinal blood flow and to induce ischemia and hypoxia through several different mechani~ms.'~ Much recent attention has been directed toward the sorbitol or polyol p a t h ~ a y .8,~9, ,30 This pathway converts excess nonphosphorylated intracellular glucose to sorbitol and then fructose through the enzymes aldose reductase and sorbitol dehydrogenase in various tissues including the retina, kidney, peripheral nerves, and vasculature. The accumulation of sorbitol and fructose in the tissues is believed to lead to alterations in tissue function by impairment in myo-inositol metabolism and capillary narrowing caused by basement membrane thickening. Platelets also appear to be integrally involved in the pathogenesis of retinopathy and other vascular complications.1° Platelet aggregates and thrombi have been demonstrated in the small vessels of the retinas and kidneys of patients with diabetes. As a result, there is decreased oxygen release from the red blood cells, which may lead to thickening of the retinal capillary walls. Diminished platelet responsiveness to
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prostacyclin, increased platelet sensitivity to aggregating agents, and decreased synthesis of prostaglandin E by platelets and of prostacyclin by vessel walls have all been demonstrated in diabetes. Hyperglycemia is also believed to induce the production of high levels of plasma proteins, fibrinogen, and alpha-globulin. High concentrations of these plasma proteins cause increased plasma viscosity and a subsequent decrease in retinal blood flow.I0 EFFECTS OF PREGNANCY ON RETINOPATHY
Studies of the effect of pregnancy on diabetic retinopathy have reported conflicting conclusions. In general, more recent studies have found a higher rate of progression of diabetic retinopathy in pregnant women than was found in older studies. However, some changes have proved to be reversible, and many women have experienced regression of lesions following delivery.21,26 Moloney and DruryZ1found that background retinopathy developed during pregnancy in 15% of women in their case-control study. This is a much higher rate than has been observed in nonpregnant controls. They also found that 29% of patients with background retinopathy that was present before conception experienced progression of the retinopathy during pregnancy. In addition, neovascularization developed in four patients for the first time during the index pregnancy. However, by 6 months after delivery, background changes and neovascularization demonstrated regression in all cases. Increased doses of insulin and hydramnios were risk factors for retinal hemorrhage in the study population. These findings are consistent with those in the Rigshospitalet which also reported regression in class D patients who were not treated with photocoagulation. Approximately half of the patients with retinopathy showed progression during pregnancy. All of the women improved to some extent during the postpartum period. In a few women with background retinopathy at the onset of pregnancy, proliferative retinopathy developed that commonly disappeared shortly after delivery. The results of the Diabetes in Early Pregnancy Study (DIEP)3demonstrated that women with mild or more severe retinopathy at conception were at high risk for progression of retinopathy during pregnancy. Progression rates from nonproliferative retinopathy to proliferative retinopathy were 6.76% and 30% in patients whose baseline retinopathy was mild and moderate, respectively. Elevated glycosylated hemoglobin levels greater than 4 standard deviations above the mean were associated with a statistically significant increased risk of progression. In the DIEP study, as in previous studies, rapid normalization of glucose levels may have been a major independent variable in the progression of retinopathy. Klein and associates16performed a prospective study of the progres-
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sion of diabetic retinopathy in a group of pregnant women with IDDM compared with a group of women with IDDM who were not pregnant. Women were evaluated on referral and again in the postpartum period. Retinopathy was graded on the basis of fundus photographs using seven standard photographic fields. The glycosylated hemoglobin, duration of diabetes, current age, diastolic blood pressure, number of past pregnancies, and current pregnancy status were evaluated as risk factors for the progression of diabetic retinopathy. After adjusting for the level of glycemic control, the current pregnancy was significantly associated with progression (P <0.005; adjusted odds ratio, 2.3). Women with elevated diastolic blood pressure also had a greater tendency to progress, although the effect was less marked than for metabolic control. It was concluded that pregnancy and the level of glycemia are associated with the progression of diabetic retinopathy (Table 2). An association between the progression of diabetic retinopathy in pregnancy and hypertension also has been demonstrated. In a prospective study, Rosenn and colleagues25examined the risk for retinopathic complications in women with IDDM with chronic or pregnancy-induced hypertensive disorders. Of the 154 women prospectively followed, 51 experienced progression of retinopathy during the index pregnancy. Chronic hypertension, pregnancy-induced hypertension, and changes in glycemic control were significantly associated with the progression of retinopathy. PREGNANCY OUTCOMES IN THE PRESENCE OF DIABETIC RETINOPATHY
Although pregnancy is associated with the progression of retinopathy, meticulous ophthalmic surveillance and appropriate photocoagulation therapy can sufficiently treat and control proliferative retinal changes to allow continuation of the pregnancy in most cases. However, the presence of retinopathy, representing vascular compromise, has an effect on pregnancy or perinatal outcomes. Earlier studies (1980s) reTable 2. ORDINAL MULTIVARIATE LOGISTIC MODEL FOR CHANGES IN RETINOPATHY BETWEEN VISITS
P
Ratio
95% CI
Progression of Retinopathy More Likely If
<0.0001
1.7 1.8
1.4, 2.2 1.1, 2.8
Higher Pregnant
Odds Variable* HbAj Group
<0.02
95% CI = 95% confidence interval; HbA, = glycosylated hemoglobin. 'Variables dropped by backward elimination: diastolic blood pressure, P = 0.07; number of previous pregnancies, P = 0.21; age, P = 0.50; duration of diabetes, P = 0.84. From Klein BEK, Moss SE, Klein R: Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care 13:34-40, 1990; with permission.
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Table 3. NEONATAL OUTCOME Outcome Pregnancy Spontaneous abortion Stillbirth Live birth* Neonatal growth status Appropriate-for-gestational-age(5th to 95th percentile) Small-for-gestational-age( 4 t h percentile) Large-for-gestational-age(>95th percentile) Neonatal complications None Congenital anomalies Hypoglycemia Hyperbilirubinemia Perinatal survival rate
Number
2 (1 OYO) 1 (5%) 17 (85%) 11 (64%) 4 (24%)
2 (1 2%) 9 (53%) 3 (1 8%) 4 (23%) 1 (6%)
17 (94%)
*Mean birth weight, 2.620 g (-834 SD). From Reece €A, Lockwood CJ,Tuck S, et al: Retinal and pregnancy outcomes in the presence of diabetic proliferative retinopathy. J Reprod Med 39:799-804, 1994; with permission.
ported a relatively high incidence of adverse outcomes. Price and colleaguesz3reported on five patients with proliferative retinopathy during pregnancy. Preeclampsia developed in all five women; three (60%) required cesarean section, and only two (40%) neonates had uncomplicated outcomes. Horvat and colleagues'l reported similar outcomes in their series of seven pregnancies complicated by diabetic proliferative retinopathy: one stillbirth, one termination because of hypertension, one neonatal demise, one infant death, and only three normal outcomes. A more recent report, however, has demonstrated significantly better perinatal outcomes. Reece and colleaguesz4reported on the outcomes of 20 pregnancies complicated by advanced diabetic retinopathy. Spontaneous abortion occurred in two (10%) and stillbirth in one (5%); the remaining 17 pregnancies culminated in live births (Table 3). The perinatal survival rate was 94%. Photocoagulation therapy was necessary before pregnancy in 45%, during pregnancy in 6O%, and postpartum in 65%. Klein and colleague^'^ reported the outcomes in 179 pregnant diabetic women. Twenty-eight of these pregnancies were complicated by proliferative retinopathy. Logistic regression analysis was used to evaluate significant predictors of pregnancy outcome. Adverse outcomes were defined as abortions, perinatal death, and severe congenital anomalies. Of the variables of maternal age, duration of diabetes, glycosylated hemoglobin, proteinuria, cigarette smoking status, and severity of diabetic retinopathy, only diabetic retinopathy significantly predicted an adverse outcome. Thirteen percent of women with mild retinopathy had infants with adverse outcomes as compared with adverse outcomes in 43% of the offspring of women with severe retinopathy ( P < 0.001).
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TIGHT METABOLIC CONTROL AND THE PROGRESSION OF RETINOPATHY
Studies in nonpregnant patients with IDDM investigated the effect of glycemic control on the progression of diabetic retinopathy. Progression of diabetic retinopathy was significantly higher over an 8-month period in comparison with a control group with proper metabolic control.20After 2 years of follow-up, no statistical significance was found between the rates of progression of retinopathy in the two groups. It was suggested that one should avoid achieving good glycemic control too rapidly in patients with IDDM with retinopathy and poor glycemic control. Phelps and colleagues2*have reported similar findings in pregnant patients with IDDM. Fifty-five percent of retinal abnormalities worsened following the initiation of intensive therapy to normalize maternal blood glucose levels. Deterioration of background retinopathy correlated significantly with the level of glucose control at entry into the study and with the degree of improvement achieved. It was emphasized that retinal changes were relatively minor, and that the benefits of careful diabetic control during gestation outweighed the retinal changes noted. The conclusion must be that the increased risk for progression of diabetic retinopathy by rapid glycemic control should not suggest that less rigid control is appropriate.
OTHER OCULAR COMPLICATIONS
Two other ocular complications can occur in women of childbearing age-acute optic disk edema (pseudopapilledema) and macular edema. They have been reported to occur in association with preeclampsia in diabetic women.14 Physical findings in acute optic disk edema include edema of the optic disk and visual field defects. Although pregnancy may be an inciting factor, the condition is relatively benign, and pregnancy is not ~ontraindicated.~~ Macular edema can be associated with any stage of retinopathy. It encompasses a number of characteristic lesions, including a collection of fluid or thickening in the macula, hard exudates within the macular area, nonperfusion of the retina inside the temporal vessel arcades, or any combination of these findings. Sinclair and colleagues27have reported the development of severe macular edema associated with preproliferative or proliferative retinopathy in seven women with IDDM during pregnancy with minimal or no retinopathy before conception. Women in whom macular edema develops should be referred to an experienced retinologist or general ophthalmologist for treatment. Patients with clinically significant macular edema are candidates for focal laser photocoagulation.
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MANAGEMENT OF DIABETIC RETINOPATHY DURING PREGNANCY
Diabetic retinopathy occurring during pregnancy should be treated in essentially the same manner as in the nonpregnant state. Fundus photography and laser treatment can be used safely during pregnancy when indicated. Despite evidence that retinopathy often spontaneously regresses following delivery, most experts still recommend laser photocoagulation during gestation. Ideally, diabetic women contemplating pregnancy should undergo careful retinal examination before conception and treatment with laser photocoagulation, if necessary. Fluorescein angiography is not recommended during pregnancy because of uncertainty of the effect and possible toxicity in the fetus. We perform ophthalmoscopy every trimester in pregnant women with IDDM and even more frequently in patients with documented prepregnancy retinopathy. The preferred mode of delivery in patients with active proliferative retinopathy remains controversial. In the past, the performance of cesarean section was suggested to avoid the Valsalva maneuver and the risk for vitreous hemorrhage. Today, however, most investigators including our group do not recommend cesarean delivery in patients with active neovascularization because it has been found that vitreous hemorrhages during childbirth are extremely rare.1° Furthermore, there are no data to show any advantage of cesarean section over vaginal delivery in patients with proliferative retinopathy.
CONCLUSION
Taken together, the available studies would seem to indicate that pregnancy is an independent risk factor for diabetic retinopathy. Hypertension, poor control early in pregnancy, and rapid normalization all seem to be associated with the potential to accelerate the retinal deterioration. Furthermore, women with more advanced forms of retinopathy and a longer duration of diabetes are at highest risk for progression of the retinopathy during gestation.
References 1. Berk MA, Miodovnik M, Mimouni F Impact of pregnancy on complications of insulindependent diabetes mellitus. Am J Perinatol5:359-367, 1988 2. Cahill GF Jr, Etzwiler DD, Freinkel N "Control" and diabetes. N Engl J Med 294:14331438, 1976 3. Chang S, Fuhrmann M, Jovanovic L The diabetes in early pregnancy study group (DIEP): Pregnancy, retinopathy normoglycemia. A preliminary analysis. Diabetes 35(suppl):3A, 1985
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4. DCCT Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977-986, 1993 5. Elman KD, Welch RA, Frank RN, et al: Diabetic retinopathy in pregnancy: A review. Obstet Gynecol 75:119-127, 1990 6. Engerman RL, Bloodworth JMB, Nelson S: Relationship of microvascular disease in diabetes to metabolic control. Diabetes 26:760, 1977 7. Frank RN: On the pathogenesis of diabetic retinopathy. Ophthalmology 91:626, 1984 8. Gabbay K The sorbitol pathway and the complications of diabetes. N Engl J Med 288:831-836, 1973 9. Green DA, Lattimer SA, Sima AAF: Sorbitol, phosphoinositides, and sodium-potassium ATPase in the pathogenesis of diabetic complications. N Engl J Med 316599606, 1987 10. Hagay ZJ, Reece EA: Diabetes mellitus in pregnancy. In Reece EA, Hobbins JC, Mahoney MJ, et a1 (eds): Medicine of the Fetus and Mother. Philadelphia, JB Lippincott, 1992 11. Hollingsworth DR Pregnancy, Diabetes and Birth A Management Guide, ed 2. Baltimore, Williams & Wilkins, 1992, p p 15-19 12. Horvat M, MacLean H, Boldberg L, et al: Diabetic retinopathy in pregnancy: A 12year prospective survey. Br J Ophthalmol 64398-403, 1980 13. Johnston GP: Pregnancy and diabetic retinopathy. Am J Ophthalmol90519-524, 1980 14. Jovanovic-Peterson L, Peterson CM: Diabetic retinopathy. In Reece EA, Coustan DR (eds): Diabetes in Pregnancy. New York, Churchill Livingstone, 1995 15. Klein BEK, Klein R, Meuer SM, et a 1 Does the severity of retinopathy predict pregnancy outcome? J Diabetic Complications 2:179-184, 1988 16. Klein BEK, Moss SE, Klein R Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care 13:34-40, 1990 17. Klein R Recent developments in the understanding and management of diabetic retinopathy. Med Clin North Am 721415,1988 18. KIein R, KIein BEK, Moss S, et al: The Wisconsin epidemiologic study of diabetic retinopathy. 111. Prevalence and risk of diabetic retinopathy when the age at diagnosis is less than thirty years. Arch Ophthalmol 102:520, 1984 19. Klein R, Klein BEK, Moss S, et al: The Wisconsin epidemiologic study of diabetic retinopathy. 111. Prevalence and risk of diabetic retinopathy when the age at diagnosis is greater than thirty years. Arch Ophthalmol 102:527, 1984 20. The Kroc Collaborative Study Group: Diabetic retinopathy after two years of intensified insulin treatment: Follow-up of the Kroc Collaborative Study. JAMA 260:37-41, 1988 21. Moloney JBM, Drury MI: The effect of pregnancy on the natural course of diabetic retinopathy. Am J Ophthalmol93745,1982 22. Phelps RL, Sakol P, Metzger BE, et al: Changes in diabetic retinopathy during pregnancy: Correlations with regulation of hyperglycemia. Arch Ophthalmol 104:180& 1810, 1986 23. Price JH, Hadden DR, Archer DB, et al: Diabetic retinopathy in pregnancy. Br J Obstet Gynaecol91:ll-17, 1984 24. Reece EA, Lockwood CJ, Tuck S, et al: Retinal and pregnancy outcomes in the presence of diabetic proliferative retinopathy. J Reprod Med 39:799-804, 1994 25. Rosenn B, Miodovnik M, Kranias G, et al: Progression of diabetic retinopathy in pregnancy: Association with hypertension in pregnancy. Am J Obstet Gynecol 166:1214-1218, 1992 26. Serup L: Influence of pregnancy on diabetic retinopathy. Acta Endocrinol 112(~~ppl):122-124, 1986 27. Sinclair SH, Nesler C, Foxman B, et al: Macular edema and pregnancy in insulindependent diabetes. Am J Ophthalmol97:154-167, 1984 28. Sinclair S, Nesler C, Schwartz S: Retinopathy in the pregnant diabetic. Clm Obstet Gynecol 28:536, 1985 29. Skyler J S Complications of diabetes mellitus: Relationship to metabolic dysfunction. Diabetes Care 2499, 1977
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30. Sorbinil Retinopathy Trial Research Group: A randomized trial of sorbinil, and aldose reductase inhibitor, in diabetic retinopathy. Arch Ophthalmol 108:12341244, 1990 31. Ward SC, Woods DR, Gilstrap LC 111, et al: Pregnancy and acute optic disc edema of juvenile-onset diabetes. Obstet Gynecol 64:816-818, 1984 Address reprint requests to E. Albert Reece, MD Department of Obstetrics, Gynecology and Reproductive Sciences Temple University School of Medicine 3401 North Broad Street, 7-OPB Philadelphia, PA 19140