Maisa N. Feghali, MD Menachem Miodovnik, MD Jason G. Umans, MD, PhD
Of all the senses, sight must be the most delightful.
—Helen Keller
Key Points
• Diabetic retinopathy (DR) may progress during pregnancy and serial retinal examinations are essential
• Adequate glycemic control at conception significantly decreases the risk of retinopathy progression
• Retinal status at conception predicts the likelihood of retinopathy progression
• Longer duration of diabetes increases the risk for retinopathy progression
• Large improvement in glycemic control early in pregnancy may increase the risk of retinopathy
• Maternal and fetal outcomes can be optimized with adequate preconceptional glycemic control, blood pressure (BP) control, and evaluation of retinal disease
• Pregnancy has no long-term effects on the development or progression of DR
INTRODUCTION
Diabetic retinopathy (DR) is the leading cause of incident blindness among adults in the United States.1 Worldwide, there are approximately 93 million people with DR, including 28 million with advanced vision-threatening stages of the disease.2 DR is due primarily to vascular effects of chronic hyperglycemia, leading to retinal injury and ischemia. Therapy can both limit disease progression and improve visual defects. However, the majority of DR patients are asymptomatic until late stages of the disease, underlining the role of early screening and intervention to limit vision loss. The interaction between pregnancy and DR has long been a matter of controversy. Although there is evidence for progression of DR during pregnancy, most changes are transient and reversible. This chapter will review the natural history of DR and focus on its interplay with pregnancy, highlighting both short- and long-term outcomes.
PATHOGENESIS
Pathogenesis of DR is multifactorial, but ultimately due to the metabolic effects of chronic hyperglycemia.3 The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) found that intensive insulin therapy reduced the incidence of DR in subjects with type 1 and type 2 diabetes mellitus, respectively. In both studies, these improved outcomes were directly related to glycemic control, as assessed by glycosylated hemoglobin (HbA1c).4-6
DR is broadly classified as either proliferative or nonproliferative, based on the presence or absence of retinal neovascularization. Further stratification of disease severity, used more in research than in clinical practice, is based on objective retinal findings as outlined in Table 34-1.7 Early retinal lesions are often reversible, becoming fixed with more advanced and chronic DR. Nonproliferative abnormalities range from increased permeability and local edema to moderate and severe nonproliferative diabetic retinopathy (NPDR), characterized by vessel closure and ischemia. Loss of vision in NPDR is due primarily to macular edema. Proliferative diabetic retinopathy (PDR), with neovascularization of the retina and the posterior surface of the vitreous body, may progress to preretinal and vitreous hemorrhage, subsequent fibrosis, and possible retinal detachment. PDR may occur de novo or in the setting of prior or coexisting nonproliferative changes. Transient vision loss in PDR may result from acute hemorrhage; in most cases, vision will clear following reabsorption. More permanent visual loss is usually related to retinal detachment or to macular ischemia.
Within the retina, hyperglycemia mainly affects the microvascular endothelial cells (ECs).8,9 Animal models suggest that initial exposure of ECs to chronic hyperglycemia leads to the loss of capillary pericytes.10 This leads to the formation of microaneurysms and vascular closure due to the increased thrombogenicity of the endothelial surface.11,12 The ensuing retinal ischemia promotes angiogenesis and neovascularization. Several mechanisms may mediate these changes. Nonenzymatic glycosylation of serum or tissue proteins in the setting of hyperglycemia leads to irreversible formation of advanced glycosylation end products (AGEs),13 which can initiate a signaling cascade leading to oxidative stress and microvascular inflammation. The interaction between AGEs and tissue collagen has been implicated in the initiation of microvascular complications.14 Likewise, certain experimental and animal models of retinopathy have suggested a role for insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF), produced in response to tissue hypoxia, in mediating retinal neovascularization.15,16 Increased retinal blood flow in advanced DR, likely due to a loss of the retinal autoregulation,17 leads to increased shear stress which, in turn, promotes secretion of vasoactive factors and vascular leakage. In diabetes, vascular endothelium demonstrates an imbalance in hemostasis due to impaired synthesis of vasodilators, increased release of vasoconstrictors, and activation of the reninangiotensin system.18 In the retina, such changes facilitate ischemic injury and can lead to vascular leakage.17 Additionally, genetic and ethnic factors influence an individual's susceptibility to retinopathy, with a higher prevalence in individuals with a family history of DR, and those of African-American or Hispanic descent.6,19,20
TABLE 34-1 Classification of DR
|
Disease Severity Level |
Findings on Dilated Ophthalmoscopy |
|
No retinopathy |
No abnormalities |
|
Mild NDPR |
Microaneurysms only |
|
Moderate NDPR |
More than just microaneurysms but less severe than severe NPDR |
|
Severe NDPR |
Microaneurysms and any of the following: Extensive retinal hemorrhages in each quadrant Venous beading in two or more quadrants Prominent intravascular microvascular abnormalities in one or more quadrants And no signs of proliferative retinopathy |
|
PDR |
Neovascularization Vitreous/preretinal hemorrhage |
NATURAL HISTORY OF DR
The Wisconsin Epidemiologic Study of Diabetic Retinopathy first described the natural history of DR. Started in the 1980s, this effort included 99% of clinicians in an 11-county area of southern Wisconsin, who followed over 10,000 diabetic patients. It described the prevalence of diabetic complication in patients treated with then-conventional therapy.21,22 In patients with type 1 diabetes, the onset of DR followed diagnosis of type 1 diabetes mellitus (DM) by three to five years, occurring in almost all patients by 15-20 years. By contrast, patients with type 2 diabetes appeared to have developed retinopathy four to seven years before the clinical diagnosis of diabetes, perhaps due to prolonged antecedent prediabetes, or to comorbid vascular risk factors, as occurs in diabetic nephropathy. DR prevalence increased progressively with increasing duration of either type 1 or type 2 DM.21,22
More recent studies (DCCT and UKPDS), comparing more intensive to then-conventional glycemic targets, found that glycemic control was a major determinant for the development and progression of DR in patients with type 1 and type 2 diabetes.4,5 Follow-up cohorts from Wisconsin also revealed decreased prevalence of retinopathy 8-10 years after diagnosis with initiation of therapy and a lower rate of severe retinopathy with newer treatment strategies.23,24 The DCCT also concluded that intensive insulin therapy was associated with worsening retinopathy in the first year following initiation of therapy (Figure 34-1).4 However, there was no evidence that subjects with more rapid reduction of HbA1c had a greater risk of early worsening of retinopathy than those with more gradual reduction, when the reductions were of similar magnitude. In subjects with early worsening of DR, retinal examinations revealed an increased number of soft exudates.25 Interestingly, this effect was short-lived, with improved retinopathy at two years when compared with subjects receiving conventional therapy. The mechanisms that may contribute to early retinopathy progression are uncertain. Rapid normalization of hyperglycemia appears to increase EC apoptosis.26,27 In addition, narrowed vessels are thought to be more sensitive to a decreased plasma volume with correction of hyperglycemia, perhaps leading to small vessel collapse, superficial retinal infarcts and the soft exudates which are observed clinically.25
RISK FACTORS FOR RETINOPATHY DEVELOPMENT AND PROGRESSION
As noted previously, diabetes duration is closely associated with the presence and type of retinopathy. Background retinopathy is estimated to develop in 46% of type 1 diabetes patients within five years, and 75% within 10 years from the time of diagnosis. Proliferative retinopathy rarely develops in the first five years after diagnosis, but has been noted in 15% of patient by 15 years and in 55% by 20 years from the time of diagnosis.21,22 Similarly, the age at the time of retinal examination is related to the severity of retinopathy.28 Not surprisingly, the severity of retinopathy at the start of an observation period is predictive of subsequent progression.29 Hyperglycemia and elevated levels of HbA1c are also associated with an increased risk of retinopathy.4 Coexistent hypertension has also been linked to progression and severity of DR.30,31 Antihypertensive regimens meant to slow the progression of nephropathy appear to also delay the progression of retinopathy.32
DR IN PREGNANCY
The pathogenesis of DR during pregnancy is multifactorial. Pregnancy is a state of hyperdynamic circulation due to vasodilation occurring early in gestation. A higher cardiac output, increased plasma volume and blood flow are also typical.33 In the absence of diabetes, autoregulatory mechanisms are activated and retinal blood flow (RBF) is unchanged. However, in pregnancies complicated by diabetes, retinal autoregulation is lost34 and RBF is increased.35 Increased RBF is associated with a higher degree of DR severity during pregnancy.36 Pregnancy is also characterized by a gradual increase in BP starting at 20 weeks of gestation and approximately 10%-20% of women with diabetes have preexisting or new onset hypertension during pregnancy. Hypertension during pregnancy and preeclampsia are both associated with a higher risk of retinopathy progression.37,38 Changes in circulating hormones and growth factors during pregnancy may also have an effect on the progression of retinopathy. The placenta is a source of angiogenic factors that result in vessel proliferation. Human placental lactogen and insulin-like growth factors have growth hormone-like actions and may contribute to retinopathy progression.39-41 When secreted in very high levels during pregnancy, they may theoretically stimulate new vessel formation in the retina. Endocrine effects of the feto-placental unit play a particular role in the development of insulin resistance during pregnancy.42,43 Even in healthy women, insulin sensitivity decreases by 40%-50% during the third trimester.44 In women with pregestational diabetes, insulin requirements increase steadily throughout gestation, especially for subjects with type 2 diabetes.45,46 Faced with these metabolic changes, intensive glucose control is the cornerstone of diabetes management in pregnancy. Glycemic control is necessary to improve obstetric, fetal, and neonatal outcomes. Similar to nonpregnant populations, rapid institution of intensive glucose control may accelerate retinopathy progression transiently.25
Despite the hormonal, physiological, and metabolic changes that occur, careful review of the evidence is necessary before concluding that pregnancy per se acceleratess DR progression. Most of the research on DR in pregnancy was completed in cohort studies. Differing study design, control groups used for comparison, fundoscopic examination method, and, most importantly, length of follow-up following delivery may explain the large variability in conclusions on the effect of pregnancy on DR. Reported rates of retinopathy progression range between 5% and 70%.47-54 Although we acknowledge the limitations of this body of research, some findings emerged to shed light on the risk factors for progression of DR in pregnancy.
RISK FACTORS FOR DEVELOPMENT AND PROGRESSION OF RETINOPATHY DURING PREGNANCY
Severity of Preexisting Retinal Disease
DR progression was related to the severity of preexisting retinopathy before conception in the Diabetes in Early Pregnancy Study.55 Ten percent of women without DR at baseline progressed to NPDR, but none progressed to PDR. In women with baseline minimal DR (i.e., microaneurysms), 20% experienced worsening of NPDR and 3% developed PDR. By contrast, 50% of women with moderate NPDR at baseline progressed to more severe NPDR during pregnancy and 25% developed PDR. A summary of other studies supporting the association between DR progression in pregnancy and severity of retinopathy is presented in Table 34-2. Due to their observational design and the lack of control groups, these studies do not enable us to ascertain whether progression would have occurred without pregnancy. In a prospective controlled study, Klein et al. found no difference in DR prevalence comparing early pregnant women (43%) and nonpregnant controls (39%), despite better glycemic and BP control in the pregnant women.50 However, their results were not stratified by initial retinal disease. Regression analysis controlling for baseline HbA1c, but not for baseline DR, suggested a twofold increased risk of DR progression in the pregnant group, with a follow-up at approximately nine weeks postpartum.
Since several studies have described regression of retinal changes in the postpartum period,37,48,53,56 duration of follow-up postpartum may significantly impact our interpretation of studies aimed at assessment of DR progression due to pregnancy. In women with mild DR, the rates of both microaneurysm formation and disappearance increase during pregnancy. The microaneurysm count is greatest at three months postpartum, but the rate of disappearance exceeds that of formation six months postpartum,57 suggesting that effects of pregnancy on DR may be short-lived.
Duration of Diabetes
Not surprisingly, risk factors for DR progression in nonpregnant individuals also apply in the setting of pregnancy. The Diabetes in Early Pregnancy Study demonstrated a gradual increase in the risk of DR progression with longer duration of diabetes with a peak at 15-20 years.55 Women with disease duration of 0-5 years, 6-10 years, 11-15 years, 16-20 years, and more than 20 years had risks of progression of 5%, 14%, 34%, 45%, and 36%, respectively. By comparison, PDR occurred in only 18% of women with diabetes for less than 15 years compared with 39% of women with diabetes for over 15 years. Conversely, women who experienced DR progression in pregnancy had longer duration of diabetes compared to women without progression.53 A recent cohort study also found that DR progression was significantly greater in women with diabetes for 10-19 years compared to those with the disease for less than 10 years (10% vs. 0%, P = 0.007).47 The study also included 20 pregnancies in women with diabetes for more than 20 years, who had no or mild retinopathy at the time of conception. Only one of these women experienced DR progression, highlighting the importance of retinal status at the time of conception in predicting DR progression during pregnancy.
Glycemic Control
Several studies have determined that poor glycemic control before pregnancy and rapid control early in pregnancy are associated with a higher risk of DR progression.55,58 In the Diabetes in Early Pregnancy Study, elevated HbA1c early in pregnancy was associated with a higher risk for DR progression.55 Women with an HbA1c level 6 standard deviations above the control group's mean had double the odds of worsening DR (CI 1.1-7.2; P = 0.039). The study also concluded that DR progression was associated with the largest improvement in HbA1c between baseline and 14 weeks. In other studies, pregnant women with good preconceptional glycemic control have a lower risk of DR progression (5%-6.3%).47,59 A nested analysis of the DCCT, which focused on the effect of pregnancy, also evaluated the effect of pregnancy in 94 women treated with intensive therapy compared to 86 women who were assigned conventional therapy.54 Upon confirmation of pregnancy, subjects were all treated with an intensive regimen. The study demonstrated more frequent worsening of DR in women who had been on conventional therapy before pregnancy compared to those who had received preconcep- tional intensive therapy (19.6% vs. 7.2%). These findings parallel the paradoxical worsening of retinopathy in the intensive therapy group during the first of the DCCT and emphasize the importance of tight preconceptional glycemic control.
TABLE 34-2 Progression of DR in Pregnancy Stratified by Initial Retinal Status
|
Number and % With Progression by Initial Status Number of No Retinopathy Background Retinopathy Proliferative Retinopathy Pregnancies |
|||||||
|
Horvat69 (1980) |
160 |
13/118 |
11% |
11/35 |
31% |
1/7 |
14% |
|
Moloney48 (1982) |
53 |
8/20 |
40% |
15/30 |
50% |
1/3 |
33% |
|
Dibble51 (1982) |
55 |
0/23 |
0% |
3/19 |
16% |
7/13 |
54% |
|
Price49 (1984) |
31 |
0/14 |
0% |
0/10 |
0% |
5/7 |
71% |
|
Ohrt56 (1984) |
100 |
4/50 |
8% |
15/48 |
31% |
1/2 |
50% |
|
Jovanovic45 (1984) |
21 |
0/0 |
0% |
0/11 |
0% |
4/10 |
40% |
|
Phelps58 (1986) |
38 |
3/13 |
23% |
13/20 |
65% |
5/5 |
100% |
|
Serup70 (1986) |
45 |
6/19 |
32% |
11/21 |
52% |
0/5 |
0% |
|
Rosenn37 (1992) |
154 |
18/78 |
23% |
28/68 |
41% |
5/8 |
63% |
|
Chew55 (1995) |
140 |
4/39 |
10% |
31/101 |
31% |
a |
|
|
Axer-Siegel53 (1996) |
65 |
10/38 |
26% |
17/22 |
77% |
2/5 |
40% |
|
Lovestam-Adrian38 (1997)‘ |
65 |
10/39 |
26% |
3/14 |
21% |
5/12 |
42% |
|
Lapolla71 (1998) |
16 |
0/9 |
0% |
1/7 |
14% |
0/0 |
0% |
|
Temple47 (2001) |
152 |
6/136 |
4% |
3/10 |
30% |
0/6 |
0% |
|
Vestgaard72 (2010) |
102 |
8/38 |
21% |
16/55 |
29% |
4/9 |
44% |
|
Rasmussen73 (2010) |
160 |
13/145 |
9% |
3/15 |
20% |
0/0 |
0% |
|
Total |
1357 |
103/779 |
13% |
170/486 |
35% |
40/92 |
43% |
aWomen with proliferative retinopathy were excluded from the study. ‘Includes women with severe nonproliferative retinopathy.
Hypertension During Pregnancy
In a cohort of 154 women, worsening of DR was more frequent in women with hypertension compared to normotensive subjects (55% vs. 25%). Both elevated systolic and diastolic BP have been independently linked to DR progression.38,50 Women with chronic hypertension had a 61% risk of DR progression, and those with preeclampsia a 50% risk.37,38 Considering the high incidence of hypertensive disorders in women with pregestational DM, increased emphasis should be placed on BP control to limit DR progression.
Long-term Outcomes
Several studies have focused on the long-term outcomes of pregnancy in women with pregestational diabetes. The EURODIAB PCS (Prospective Complications Study) followed 793 women for 7.3 years and compared the outcomes of 63 women who became pregnant to those who did not conceive.60 The presence and severity of retinopathy at the time of follow-up was predicted by duration of diabetes and HbA1c level, but not by history of pregnancy. A large retrospective study compared 776 nulliparous women to 582 parous women with type 1 diabetes.61 The prevalence of retinopathy was lower in women who had two or more pregnancies (35%), compared to those who had only one pregnancy (45%), and those who did not conceive (48%). Similarly, PDR rates were lower in parous women (8%) compared to nulliparous subjects (16%). These differences persisted in analyses adjusted for gly- cemic control, suggesting that pregnancy is not a risk factor for long-term DR and its progression. A nested case-control study performed within the Pittsburgh Epidemiology of Diabetes Complications study found no difference in the prevalence of proliferative retinopathy between 80 parous women and matched nulligravid controls (35% and 36%); by contrast, there was a trend toward increased incidence of proliferative retinopathy in the small subset of women who had a pregnancy within the two-year interval between study visits, underscoring differences between short- and long-term effects of pregnancy.62 Rosenn et al. followed 81 women with type 1 diabetes, who had no or mild retinopathy at the time of their first pregnancy for a mean of 5.5 (1-15) years.63 They estimated a 20% risk of incident or progressive DR within three years of pregnancy, similar to the expected rate in a general population of patients with diabetes. Proportional hazards models demonstrated that total parity was protective against DR progression (P = 0.04). The DCCT also demonstrated similar retinopathy rates between women who became pregnant and those who did not conceive, at an average follow-up of 6.5 years.60
SPECIAL CONSIDERATIONS DURING PREGNANCY
Gestational Diabetes
Women with only gestational diabetes are not at risk of DR during pregnancy because of the recent onset of their hypoglycemia. One report suggested that 50% of women with gestational diabetes exhibited retinal vessel tortuosity.64 Although this may be a marker for those women who will later develop overt diabetes, further research is needed to confirm this hypothesis. Since gestational diabetes mellitus (GDM) may be diagnosed in women who actually have previously unrecognized or new-onset type 2 DM, these women should be screened for DM postpartum, and then counseled to undergo retinal examination if DM is diagnosed.
Fetal Growth Effects
Progression of DR during pregnancy has been associated with an increased risk for fetal growth restriction. In a study by McElvy et al., birth weight was reduced by a mean of 268 g, and the overall birth weight distribution shifted to the left in women with progressive DR, perhaps reflecting generalized microvascular disease.65
Considerations for Mode of Delivery
Another concern related to pregnancy is whether the abrupt changes in maternal BP during delivery may cause acute retinal hemorrhages in women with advanced DR. Some advocate cesarean delivery in these cases, albeit with little evidence. By contrast, a secondary analysis of 192 women with type 1 diabetes and close follow-up during pregnancy revealed no difference in DR progression from early or late pregnancy to postpartum comparing women who underwent elective cesarean delivery with those who had cesarean delivery before the second stage of labor and those who experienced a second stage of labor.66 Since retinal vascular changes are predominantly postarteriolar, they are unlikely to be affected by Valsalva maneuvers including expulsive efforts in the second stage of labor. Vaginal delivery, if not otherwise contraindicated, should be considered in women with stable retinal status throughout their pregnancies.
Treatment of Retinopathy During Pregnancy
With adequate metabolic control and treatment of preexisting retinopathy, progression to sight-threatening DR during pregnancy is unlikely. Although there are no randomized trials of pregnancy in women with retinopathy to assess the indications and efficacy of laser photocoagulation therapy, insights may be extrapolated from the nonpregnant population. Current guidelines for nonpregnant individuals recommend laser photocoagulation for significant neovascularization of the optic nerve head or any neovascularization in the presence of vitreous hemorrhage. Also, laser therapy should be considered in cases with retinal neovascularization, or with severe nonproliferative retinopathy. A proactive treatment approach is recommended during pregnancy due to the risk of rapid progression with advanced disease or with newly tightened glycemic control. Women with completely regressed PDR, either spontaneously or following laser therapy, are very unlikely to experience further proliferation during pregnancy.48,67 A monitoring strategy that includes close surveillance and early intervention is paramount to reduce sight-threatening DR progression in pregnancy.
Recommendation for Periconceptional Care
The most recent standards of medical care in diabetes suggest the following for care of pregnant women with diabetes68:
- If possible, HbA1c level should be as close to normal as possible (<7%) before conception is attempted.
- Women with diabetes, who are contemplating pregnancy should be evaluated and, if indicated, treated for DR, nephropathy, neuropathy, and cardiovascular disease.
- Reproductive age women with type 1 diabetes should have an initial dilated and comprehensive eye examination within five years of disease onset.
- Reproductive age women with type 2 diabetes should have an initial dilated and comprehensive eye examination soon after the diagnosis is made.
- Women with diabetes, who are contemplating pregnancy or those who have become pregnant should undergo a comprehensive eye examination and be counseled on the risks of incident or progressive DR during pregnancy.
- During pregnancy, eye examination should initially occur during the first trimester with close follow-up during pregnancy and for one year postpartum.
- If the initial retinal examination is normal, a repeat exam should be performed at approximately 28 weeks of gestation.
- If mild or moderate nonproliferative retinopathy is evident in early pregnancy, an additional examination should be performed at 16-20 weeks of gestation.
- Women with either macular edema or severe nonproliferative retinopathy should be referred to possible laser photocoagulation. More frequent monitoring, possibly with monthly examinations, may be required.
- To reduce the risk or slow the progression of retinopathy, the treatment strategy should focus on optimizing glycemic as well as BP control.
CONCLUSION
Progression of DR may occur transiently during pregnancy and the immediate puerperium. While the mechanisms for DR progression are not fully understood, risk factors include poor early pregnancy glycemic control, rapid correction, baseline retinal status, duration of diabetes, and hypertension. Preconceptional control of glucose levels and BP, and treatment of retinal disease, when needed, are paramount in reducing the risk of DR progression. In itself, pregnancy does not appear to alter the course of retinopathy in women with diabetes.
REFERENCES
1. Prevention CfDCa. 2011 National Diabetes Fact Sheet. Atlanta, GA: Centers for Disease Control and Prevention. http://www.cdc. gov/diabetes/pubs/estimates11.htm. Accessed October 7, 2013.
2. Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556-564.
3. Frank RN. Diabetic retinopathy. N Engl J Med. 2004;350(1):48-58.
4. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329(14):977-986.
5. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-853.
6. Clustering of long-term complications in families with diabetes in the diabetes control and complications trial. The Diabetes Control and Complications Trial Research Group. Diabetes. 1997;46(11):1829-1839.
7. Grading diabetic retinopathy from stereoscopic color fundus photographs-an extension of the modified Airlie House classification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991 ;98 (5 suppl):786-806.
8. Kohner EM. Diabetic retinopathy. Br Med Bull. 1989;45(1):148-173.
9. Archer DB. Bowman Lecture 1998. Diabetic retinopathy: some cellular, molecular and therapeutic considerations. Eye. 1999;13 (Pt 4):497-523.
10. Engerman RL. Pathogenesis of diabetic retinopathy. Diabetes. 1989;38(10):1203-1206.
11. Forrester JV. Mechanisms of new vessel formation in the retina. Diabet Med. 1987;4(5):423-430.
12. Merimee TJ, Zapf J, Froesch ER. Insulin-like growth factors. Studies in diabetics with and without retinopathy. N Engl J Med. 1983;309(9):527-530.
13. Brownlee M. Lilly Lecture 1993. Glycation and diabetic complications. Diabetes. 1994;43(6):836-841.
14. Yeh PT, Yang CM, Huang JS, et al. Vitreous levels of reactive oxygen species in proliferative diabetic retinopathy. Ophthalmology. 2008;115(4):734-737.
15. Boulton M, Foreman D, Williams G, McLeod D. VEGF localisation in diabetic retinopathy. Br J Ophthalmol. 1998;82(5):561-568.
16. Smith LE, Shen W, Perruzzi C, et al. Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat Med. 1999;5(12):1390-1395.
17. Kohner EM, Patel V, Rassam SM. Role of blood flow and impaired autoregulation in the pathogenesis of diabetic retinopathy. Diabetes. 1995;44(6):603-607.
18. Wilkinson-Berka JL, Kelly DJ, Gilbert RE. The interaction between the renin-angiotensin system and vascular endothelial growth factor in the pathogenesis of retinal neovascularization in diabetes. J Vasc Res. 2001;38(6):527-535.
19. Harris EL, Sherman SH, Georgopoulos A. Black-white differences in risk of developing retinopathy among individuals with type 2 diabetes. Diabetes Care. 1999;22(5):779-783.
20. Matsubara Y, Murata M, Maruyama T, et al. Association between diabetic retinopathy and genetic variations in alpha2beta1 integrin, a platelet receptor for collagen. Blood. 2000;95(5):1560-1564.
21. Klein R, Klein BE, Moss SE, et al. The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol. 1984;102(4):527-532.
22. Klein R, Klein BE, Moss SE, et al. The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol. 1984;102(4):520-526.
23. Lecaire T, Palta M, Zhang H, et al. Lower-than-expected prevalence and severity of retinopathy in an incident cohort followed during the first 4-14 years of type 1 diabetes: the Wisconsin Diabetes Registry Study. Am J Epidemiol. 2006;164(2):143-150.
24. LeCaire TJ, Palta M, Klein R, et al. Assessing progress in retinopathy outcomes in type 1 diabetes: comparing findings from the Wisconsin Diabetes Registry Study and the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Diabetes Care. 2013;36(3):631-637.
25. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol. 1998;116(7):874-886.
26. Li W, Liu X, Yanoff M, et al. Cultured retinal capillary pericytes die by apoptosis after an abrupt fluctuation from high to low glucose levels: a comparative study with retinal capillary endothelial cells. Diabetologia. 1996;39(5):537-547.
27. Mizutani M, Kern TS, Lorenzi M. Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J Clin Invest. 1996;97(12):2883-2890.
28. Klein R, Klein BE, Moss SE, et al. Retinopathy in young-onset diabetic patients. Diabetes Care. 1985;8(4):311-315.
29. Groop LC, Teir H, Koskimies S, et al. Risk factors and markers associated with proliferative retinopathy in patients with insulin-dependent diabetes. Diabetes. 1986;35(12):1397-1403.
30. Chase HP, Garg SK, Jackson WE, et al. Blood pressure and retinopathy in type I diabetes. Ophthalmology. 1990;97(2):155-159.
31. Norgaard K, Feldt-Rasmussen B, Deckert T. Is hypertension a major independent risk factor for retinopathy in type 1 diabetes? Diabet Med. 1991;8(4):334-337.
32. Jackson WE, Holmes DL, Garg SK, et al. Angiotensin-converting enzyme inhibitor therapy and diabetic retinopathy. Ann Ophthalmol. 1992;24(3):99-103.
33. Duvekot JJ, Peeters LL. Maternal cardiovascular hemodynamic adaptation to pregnancy. Obstet Gynecol Surv. 1994;49(12 suppl):S1-S14.
34. Hellstedt T, Kaaja R, Teramo K, Immonen I. The effect of pregnancy on mild diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 1997;235(7):437-441.
35. Loukovaara S, Harju M, Kaaja R, Immonen I. Retinal capillary blood flow in diabetic and nondiabetic women during pregnancy and postpartum period. Invest Ophthalmol Vis Sci. 2003;44(4):1486-1491.
36. Chen HC, Newsom RS, Patel V, et al. Retinal blood flow changes during pregnancy in women with diabetes. Invest Ophthalmol Vis Sci. 1994;35(8):3199-3208.
37. Rosenn B, Miodovnik M, Kranias G, et al. Progression of diabetic retinopathy in pregnancy: association with hypertension in pregnancy. Am J Obstet Gynecol. 1992;166(4):1214-1218.
38. Lovestam-Adrian M, Agardh CD, Aberg A, Agardh E. Preeclampsia is a potent risk factor for deterioration of retinopathy during pregnancy in Type 1 diabetic patients. Diabet Med. 1997;14(12):1059-1065.
39. Chantelau E. Evidence that upregulation of serum IGF-1 concentration can trigger acceleration of diabetic retinopathy. Br J Ophthalmol. 1998;82(7):725-730.
40. Larinkari J, Laatikainen L, Ranta T, et al. Metabolic control and serum hormone levels in relation to retinopathy in diabetic pregnancy. Diabetologia. 1982;22(5):327-332.
41. Lauszus FF, Klebe JG, Bek T, Flyvbjerg A. Increased serum IGF-I during pregnancy is associated with progression of diabetic retinopathy. Diabetes. 2003;52(3):852-856.
42. Kuhl C. Etiology and pathogenesis of gestational diabetes. Diabetes Care. 1998;21(suppl 2):B19-B26.
43. Butte NF. Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J Clin Nutr. 2000;71(5 suppl):1256S-1261S.
44. Catalano PM, Tyzbir ED, Roman NM, et al. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol. 1991;165(6 Pt 1):1667-1672.
45. Jovanovic L, Peterson CM. Optimal insulin delivery for the pregnant diabetic patient. Diabetes Care. 1982;5(suppl 1):24-37.
46. Burt RL, Leake NH, Rhyne AL. Glucose tolerance during pregnancy and the puerperium. A modification with observations on serum immunoreactive insulin. Obstet Gynecol. 1969;33(5):634-641.
47. Temple RC, Aldridge VA, Sampson MJ, et al. Impact of pregnancy on the progression of diabetic retinopathy in Type 1 diabetes. Diabet Med. 2001;18(7):573-577.
48. Moloney JB, Drury MI. The effect of pregnancy on the natural course of diabetic retinopathy. Am J Ophthalmol. 1982;93(6):745-756.
49. Price JH, Hadden DR, Archer DB, Harley JM. Diabetic retinopathy in pregnancy. Br J Obstet Gynaecol. 1984;91(1):11-17.
50. Klein BE, Moss SE, Klein R. Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care. 1990;13(1):34-40.
51. Dibble CM, Kochenour NK, Worley RJ, et al. Effect of pregnancy on diabetic retinopathy. Obstet Gynecol. 1982;59(6):699-704.
52. Soubrane G, Canivet J, Coscas G. Influence of pregnancy on the evolution of background retinopathy. Preliminary results of a prospective fluorescein angiography study. Int Ophthalmol. 1985;8(4):249-255.
53. Axer-Siegel R, Hod M, Fink-Cohen S, et al. Diabetic retinopathy during pregnancy. Ophthalmology. 1996;103(11):1815-1819.
54. Diabetes C, Complications Trial Research Group. Effect of pregnancy on microvascular complications in the diabetes control and complications trial. The Diabetes Control and Complications Trial Research Group. Diabetes Care. 2000;23(8):1084-1091.
55. Chew EY, Mills JL, Metzger BE, et al. Metabolic control and progression of retinopathy. The Diabetes in Early Pregnancy Study. National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study. Diabetes Care. 1995;18(5):631-637.
56. Ohrt V. The influence of pregnancy on diabetic retinopathy with special regard to the reversible changes shown in 100 pregnancies. Acta Ophthalmol. 1984;62(4):603-616.
57. Hellstedt T, Kaaja R, Teramo K, Immonen I. Macular blood flow during pregnancy in patients with early diabetic retinopathy measured by blue-field entoptic simulation. Graefes Arch Clin Exp Ophthalmol. 1996;234(11):659-663.
58. Phelps RL, Sakol P, Metzger BE, et al. Changes in diabetic retinopathy during pregnancy. Correlations with regulation of hyperglycemia. Arch Ophthalmol. 1986;104(12):1806-1810.
59. Lauszus F, Klebe JG, Bek T. Diabetic retinopathy in pregnancy during tight metabolic control. Acta Obstet Gynecol Scand. 2000;79(5):367-370.
60. Verier-Mine O, Chaturvedi N, Webb D, Fuller JH. Is pregnancy a risk factor for microvascular complications? The EURODIAB Prospective Complications Study. Diabet Med. 2005;22(11):1503-1509.
61. Chaturvedi N, Stephenson JM, Fuller JH. The relationship between pregnancy and long-term maternal complications in the EURODIAB IDDM Complications Study. Diabet Med. 1995;12(6):494-499.
62. Hemachandra A, Ellis D, Lloyd CE, Orchard TJ. The influence of pregnancy on IDDM complications. Diabetes Care. 1995;18(7):950-954.
63. Rosenn B, Miodovnik M, Kranias G, et al. Does pregnancy increase the risk for development and progression of benign diabetic retinopathy? Am J Obstet Gynecol. 1997;176:180.
64. Boone MI, Farber ME, Jovanovic-Peterson L, Peterson CM. Increased retinal vascular tortuosity in gestational diabetes melli- tus. Ophthalmology. 1989;96(2):251-254.
65. McElvy SS, Demarini S, Miodovnik M, et al. Fetal weight and progression of diabetic retinopathy. Obstet Gynecol. 2001;97(4):587-592.
66. Feghali M, Khoury JC, Shveiky D, Miodovnik M. Association of vaginal delivery efforts with retinal disease in women with type I diabetes. J Matern Fetal Neonatal Med. 2012;25(1):27-31.
67. Cassar J, Kohner EM, Hamilton AM, et al. Diabetic retinopathy and pregnancy. Diabetologia. 1978;15(2):105-111.
68. Executive summary: standards of medical care in diabetes-2013. Diabetes Care. 2013;36(suppl 1):S4-S10.
69. Horvat M, Maclean H, Goldberg L, Crock GW. Diabetic retinopathy in pregnancy: a 12-year prospective survey. Br J Ophthalmol. 1980;64(6):398-403.
70. Serup L. Influence of pregnancy on diabetic retinopathy. Acta Endocrinol Suppl. 1986;277:122-124.
71. Lapolla A, Cardone C, Negrin P, et al. Pregnancy does not induce or worsen retinal and peripheral nerve dysfunction in insulin-dependent diabetic women. J Diabetes Complications. 1998;12(2):74-80.
72. Vestgaard M, Ringholm L, Laugesen CS, et al. Pregnancy-induced sight-threatening diabetic retinopathy in women with Type 1 diabetes. Diabet Med. 2010;27(4):431-435.
73. Rasmussen KL, Laugesen CS, Ringholm L, et al. Progression of diabetic retinopathy during pregnancy in women with type 2 diabetes. Diabetologia. 2010;53(6):1076-1083.