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Diabetic retinopathy in pregnancy

1. R M BEST, 2. U CHAKRAVARTHY

+ Author Affiliations 1. Department of Ophthalmology, Queens University of Belfast 2. Royal Victoria Hospital, Belfast BT12 6BA Diabetic retinopathy is one of the major causes of preventable blindness in the UK and USA in those aged between 24 and 64 years.1 For a proportion of diabetic women, the first half of this period coincides with peak fertility and childbearing years. Diabetic eye disease may develop for the first time during pregnancy, and visual loss at this stage has serious implications for both the patient and her family. In the past, the prognosis for pregnancy in diabetic women with microvascular disease was so poor that many physicians advised avoidance or termination of pregnancy.2With the recognition that the level of glycaemia during pregnancy is directly related to the incidence of congenital malformations, the emphasis on the management of diabetic pregnancy has been one of meticulous control of blood sugar and this has undoubtedly resulted in lower rates of fetal malformations. However, intensive control of glycaemia may carry risks to diabetic mothers particularly to those with established microvascular diseases such as retinopathy and nephropathy. Studies on the influence of pregnancy on the natural history of diabetic retinopathy have shown that deterioration is frequently observed.3 4 Until recently there has been controversy as to whether the progression of retinopathy which occurs in such women is due to the natural tendency of diabetic retinopathy to worsen or to unique factors operative during pregnancy. Several major studies have gone some way towards explaining the mechanisms underlying progression of retinopathy during pregnancy. Klein et al performed a prospective study on a large series of individuals, comprising 171 pregnant and 298 non-pregnant insulin dependent diabetic women.5 The level of diabetic retinopathy in the first trimester was assessed using standard retinal photographs and compared with postpartum photographs. After adjusting for duration of diabetes, glycaemic control, and blood pressure current pregnancy was [Full text of this article] http://bjo.bmj.com/content/81/3/249.extract
6. Dibble CM, Kochenour NK, Worley RJ, Tyler FH, Schwartz M. Effect of pregnancy on diabetic retinopathy. Obstet Gynaecol. 59: 699-704; 1982 7. Soubrane G, Canivet J, Coscas G. Influence of pregnancy on the evolution of background retinopathy. Int Ophthalmol Clin. 8: 249-255; 1985 8. The Diabetes Control and Complications Trial Research Group. Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial. Diabetes Care 23: 1084-1091; 2000 9. Axer-Siegel R, Hod M, Fink-Cohen S, Kramer M, Weinberger D, Schindel B, Yassur Y. Diabetic retinopathy during pregnancy.

Ophthalmology 103(11): 1815-1819; 1996 10. MMWR. Blindness caused by diabetes-Massachusetts, 19871994. MMWR-Morbidity & Mortality Weekly Report 45: 937941; 1996 11. Trautner C, Icks A, Haastert B et al. Incidence of blindness in relation to diabetes. A population-based study. Diabetes Care 20: 1147-1153; 1997 12. Dinn RB, Harris A, Marcus PS. Ocular changes in pregnancy. Obstet Gynecol Surv. Feb 58(2):137-44; 2003 13. Klein R, Klein BEK, Magli YL, Brothers RJ, Meuer SM, Moss SE, David MD. An alternative method of grading diabetic retinopathy. Ophthalmology 93: 1183-1187; 1986 14. Lapolla A, Cardone C, Negrin P, Midena E, Marini S, Gardellin C, Bruttomesso D, Fedele D. Pregnancy does not induce or worsen retinal and peripheral nerve dysfunction in insulindependent diabetic women. J Diabetes Complications 12: 74-80; 1998 15. Lovestam-Adrian M, Agardh CD, Aberg A, Agardh E. Preeclampsia is a potent risk factor for deterioration of retinopathy during pregnancy in type I diabetic patients. Diabet Med. 14: 1059-1065; 1997 16. Chen HC, Newsom RS, Patel V, Cassar J, Mather H, Kohner EM. Retinal blood flow changes during pregnancy in women with diabetes. Invest Ophthalmol Vis Sci. 35(8): 3199-3208; 1994 17. 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. 44(4):14861491; 2003 18. Schocket LS, Grunwald JE, Tsang AF, DuPont J. The effect of pregnancy on retinal hemodynamics in diabetic versus nondiabetic mothers. Am J Ophthalmol. 128(4): 477-484; 1999 19. Klein BE, Moss SE, Klein R. Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care 13(1): 34-40; 1990 20. Lauszus F, Klebe JG, Bek T. Diabetic retinopathy in pregnancy during tight metabolic control. Acta Obstet Gynecol Scand. 79(5): 367-370; 2000 21. Chew EY, Mills JL, Metzger BE, Remaley NA, JovanovicPeterson L, Knopp RH, Conley M, Rand L, Simpson JL, Holmes LB 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 18(5): 631-637; 1995 22. Shamoon H, Duffy H, Fleischer N, Engel S, et al. 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(14): 977; 1993 23. Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensive blood-glucose control on late complications of type I diabetes. Lancet 341(8856): 1306-1309; 1993 24. McCulloch DK. Pathogenesis and natural history of diabetic retinopathy. Up-To-Date Online V11.3. 2002

148 McGill Journal of Medicine 2005


25. Sharp PS, Fallon TJ, Brazier OJ, Sandler L, Joplin GF, Kohner EM. Long-term follow-up of patients who underwent yttrium-90 pituitary implantation for treatment of proliferative diabetic retinopathy. Diabetologia 30(4): 199-207; 1987 26. Rosenn B, Miodovnik M, Kranias G, Khoury J, Combs CA, Mimouni F, Siddiqi TA, Lipman MJ. Progression of diabetic retinopathy in pregnancy: association with hypertension in pregnancy. Am J Obstet Gynaecol. 166(4): 1214-1218; 1992 27. Sheth BP. Does pregnancy accelerate the rate of progression of diabetic retinopathy? Current Diabetes Reports 2(4): 327-330; 2002 28. Diabetic Retinopathy. Preferred Practice Patterns (pamphlet).

San Francisco, CA: The American Academy of Ophthalmology 13: 28; 1998 29. Aiello LP, Gardner TW, King GL, Blankenship G, Cavallerano JD, Ferris FL 3rd, Klein R. Diabetic retinopathy. American Diabetes Association: Position Statement. Diabetes Care 23: S73-S76; 2000 30. Anonymous. Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial. Diabetes Care 23: 1084-1091; 2000

Jeff Van Impe, MD, will be attending McMaster University for his first year of residency in Psychiatry. His research interests have shifted from Ophthalmology to substance abuse and addiction.

Effect of Pregnancy on Diabetic Nephropathy and Retinopathy


J Coll Physicians Surg Pak Feb 2004;14(2):75-8.
Bahawal Victoria Hospital, Bahawalpur

Objective: To determine whether pregnancy worsens renal function in women with diabetic nephropathy and the effect of pregnancy on diabetic retinopathy. Design: Cross-sectional analytical study. Place and Duration of Study: The study was conducted in OPD, Bahawal Victoria Hospital, Bahawalpur from September 1997 to June 2003. Subjects and Methods: Thirty-five patients (aged 20-36 years ) identified with diabetic nephropathy and moderate to severe renal dysfunction(creatinine {Cr} > 1.4 mg/dl) at pregnancy onset by retrospective chart review. Alterations in glomerular filtration rate (GFR) were estimated. An equal number of non-pregnant premenopausal type I diabetic women with similar degrees of renal dysfunction served as controls for non-pregnant rate of decline of renal function and potential contributing factors. Student`s t-test and repeated measures analysis of variance were analyzed. Results: Mean serum Cr rose from 1.8 mg/dl prepregnancy to 2.5 mg/dl in the third trimester. Renal function was stable in 27%, showed transient worsening in pregnancy in 27%, and demonstrated a permanent decline in 45%. Proteinuria increased in pregnancy in 79%.Exacerbation of hypertension or pre-eclampsia occurred in 73% and 71% of these showed acceleration of disease during the pregnancy. All the patients had diabetic retinopathy, though proliferative retinopathy was diagnosed and treated in only 54.5.% prepregnancy. The retinopathy progressed, requiring laser therapy, in 45.4%. Macular edema was noted in 6 of the patients. Other diabetic complications included peripheral and autonomic neuropathy in 8 patients. Conclusion: Pregnancy induced progression is seen in the decline of renal functions. Patients with diabetic nephropathy were found to have a > 40% chance of accelerated progression of their disease as a result of pregnancy. Forty-five percent of the patients had permanent decline in GFR in association with pregnancy. Category: Obstetrics and Gynecology Keywords: Diabetes Mellitus. Pregnancy. Diabetic Complications. Diabetic Nephropathy. Diabetic Retinopathy. Nephropathy. Retinopathy. Click here for Full Text Article

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DIABETIC RETINOPATHY
What is diabetic retinopathy? Diabetic retinopathy is a complication of diabetes and a leading cause of blindness. It occurs when diabetes damages the tiny blood vessels inside the retina, the light-sensitive tissue at the back of the eye. A healthy retina is necessary for good vision. If you have diabetic retinopathy, at first you may notice no changes to your vision. But over time, diabetic retinopathy can get worse and cause vision loss. Diabetic retinopathy usually affects both eyes.
What are the stages of diabetic retinopathy?

Diabetic retinopathy has four stages:


1. Mild Nonproliferative Retinopathy. At this earliest stage, microaneurysms occur. They are small areas of balloon-like swelling in the retina's tiny blood vessels.

2. Moderate Nonproliferative Retinopathy. As the disease progresses, some blood vessels that nourish the retina are blocked.

3. Severe Nonproliferative Retinopathy. Many more blood vessels are blocked, depriving several areas of the retina with their blood supply. These areas of the retina send signals to the body to grow new blood vessels for nourishment.

4. Proliferative Retinopathy. At this advanced stage, the signals sent by the retina for nourishment trigger the growth of new blood vessels. This condition is called proliferative retinopathy. These new blood vessels are abnormal and fragile. They grow along the retina and along the surface of the clear, vitreous gel that fills the inside of the eye.

By themselves, these blood vessels do not cause symptoms or vision loss. However, they have thin, fragile walls. If they leak blood, severe vision loss and even blindness can result.
Who is at risk for diabetic retinopathy?

All people with diabetes--both type 1 and type 2--are at risk. That's why everyone with diabetes should get a comprehensive dilated eye exam at least once a year. Between 40 to 45 percent of Americans diagnosed with diabetes have some stage of diabetic retinopathy. If you have diabetic retinopathy, your doctor can recommend treatment to help prevent its progression. During pregnancy, diabetic retinopathy may be a problem for women with diabetes. To protect vision, every pregnant woman with diabetes should have a comprehensive dilated eye exam as soon as possible. Your doctor may recommend additional exams during your pregnancy.
How does diabetic retinopathy cause vision loss?

Blood vessels damaged from diabetic retinopathy can cause vision loss in two ways:
1. Fragile, abnormal blood vessels can develop and leak blood into the center of the eye, blurring vision. This is proliferative retinopathy and is the fourth and most advanced stage of the disease.

2. Fluid can leak into the center of the macula, the part of the eye where sharp, straight-ahead vision occurs. The fluid makes the macula swell, blurring vision. This condition is called macular oedema. It can occur at any stage of diabetic retinopathy, although it is more likely to occur as the disease progresses. About half of the people with proliferative retinopathy also have macular oedema Does diabetic retinopathy have any symptoms?

Diabetic retinopathy often has no early warning signs. Don't wait for symptoms. Be sure to have a comprehensive dilated eye exam at least once a year.
What are the symptoms of proliferative retinopathy if bleeding occurs?

At first, you will see a few specks of blood, or spots, "floating" in your vision. If spots occur, see your eye care professional as soon as possible. You may need treatment before more serious bleeding occurs. Haemorrhages tend to happen more than once, often during sleep. Sometimes, without treatment, the spots clear, and you will see better. However, bleeding can reoccur and cause severely blurred vision. You need to be examined by your eye care professional at the first sign of blurred vision, before more bleeding occurs. If left untreated, proliferative retinopathy can cause severe vision loss and even blindness. Also, the earlier you receive treatment, the more likely treatment will be effective.
How are macular oedema and diabetic retinopathy detected?

Macular oedema and diabetic retinopathy are detected during a comprehensive eye exam that includes:

Visual acuity test. This eye chart test measures how well you see at various distances.

Dilated eye exam. Drops are placed in your eyes to widen, or dilate, the pupils. Your eye care professional uses a special magnifying lens to examine your retina and optic nerve for signs of damage and other eye problems. After the exam, your close-up vision may remain blurred for several hours.

Tonometry. An instrument measures the pressure inside the eye. Numbing drops may be applied to your eye for this test.

Your eye care professional checks your retina for early signs of the disease, including:

Leaking blood vessels.

Retinal swelling (macular oedema).

Pale, fatty deposits on the retina--signs of leaking blood vessels.

Damaged nerve tissue.

Any changes to the blood vessels.

If your eye care professional believes you need treatment for macular oedema, he or she may suggest a fluorescein angiogram. In this test, a special dye is injected into your arm. Pictures are taken as the dye passes through the blood vessels in your retina. The test allows your eye care professional to identify any leaking blood vessels and recommend treatment.
How is a macular oedema treated?

Macular oedema is treated with laser surgery. This procedure is called focal laser treatment. Your doctor places up to several hundred small laser burns in the areas of retinal leakage surrounding the

macula. These burns slow the leakage of fluid and reduce the amount of fluid in the retina. The surgery is usually completed in one session. Further treatment may be needed. A patient may need focal laser surgery more than once to control the leaking fluid. If you have macular oedema in both eyes and require laser surgery, generally only one eye will be treated at a time, usually several weeks apart. Focal laser treatment stabilizes vision. In fact, focal laser treatment reduces the risk of vision loss by 50 percent. In a small number of cases, if vision is lost, it can be improved. Contact your eye care professional if you have vision loss.
How is diabetic retinopathy treated?

During the first three stages of diabetic retinopathy, no treatment is needed, unless you have macular oedema. To prevent progression of diabetic retinopathy, people with diabetes should control their levels of blood sugar, blood pressure, and blood cholesterol. Proliferative retinopathy is treated with laser surgery. This procedure is called scatter laser treatment. Scatter laser treatment helps to shrink the abnormal blood vessels. Your doctor places 1,000 to 2,000 laser burns in the areas of the retina away from the macula, causing the abnormal blood vessels to shrink. Because a high number of laser burns are necessary, two or more sessions usually are required to complete treatment. Although you may notice some loss of your side vision, scatter laser treatment can save the rest of your sight. Scatter laser treatment may slightly reduce your colour vision and night vision. Scatter laser treatment works better before the fragile, new blood vessels have started to bleed. That is why it is important to have regular, comprehensive dilated eye exams. Even if bleeding has started, scatter laser treatment may still be possible, depending on the amount of bleeding. If the bleeding is severe, you may need a surgical procedure called a vitrectomy. During a vitrectomy, blood is removed from the center of your eye.
What happens during laser treatment?

Both focal and scatter laser treatment are performed in your doctor's office or eye clinic. Before the surgery, your doctor will dilate your pupil and apply drops to numb the eye. The area behind your eye also may be numbed to prevent discomfort. The lights in the office will be dim. As you sit facing the laser machine, your doctor will hold a special lens to your eye. During the procedure, you may see flashes of light. These flashes eventually may create a stinging sensation that can be uncomfortable. You will need someone to drive you home after surgery. Because your pupil will remain dilated for a few hours, you should bring a pair of sunglasses.

For the rest of the day, your vision will probably be a little blurry. If your eye hurts, your doctor can suggest treatment.
What is a vitrectomy?

If you have a lot of blood in the center of the eye (vitreous gel), you may need a vitrectomy to restore your sight. If you need vitrectomies in both eyes, they are usually done several weeks apart. A vitrectomy is performed under either local or general anaesthesia. Your doctor makes a tiny incision in your eye. Next, a small instrument is used to remove the vitreous gel that is clouded with blood. The vitreous gel is replaced with a salt solution. Because the vitreous gel is mostly water, you will notice no change between the salt solution and the original vitreous gel. You will probably be able to return home after the vitrectomy. Some people stay in the hospital overnight. Your eye will be red and sensitive. You will need to wear an eye patch for a few days or weeks to protect your eye. You also will need to use medicated eyedrops to protect against infection.
Are scatter laser treatment and vitrectomy effective in treating proliferative retinopathy?

Yes. Both treatments are very effective in reducing vision loss. People with proliferative retinopathy have less than a five percent chance of becoming blind within five years when they get timely and appropriate treatment. Although both treatments have high success rates, they do not cure diabetic retinopathy. Once you have proliferative retinopathy, you always will be at risk for new bleeding. You may need treatment more than once to protect your sight.
What can I do if I already have lost some vision from diabetic retinopathy?

If you have lost some sight from diabetic retinopathy, ask your eye care professional about low vision services and devices that may help you make the most of your remaining vision. Ask for a referral to a specialist in low vision. Many community organisations and agencies offer information about low vision counselling, training, and other special services for people with visual impairments. A nearby school of medicine or optometry may provide low vision services.
What can I do to protect my vision?

The NEI urges everyone with diabetes to have a comprehensive dilated eye exam at least once a year. If you have diabetic retinopathy, you may need an eye exam more often. People with proliferative retinopathy can reduce their risk of blindness by 95 percent with timely treatment and appropriate followup care. A major study has shown that better control of blood sugar levels slows the onset and progression of retinopathy. The people with diabetes who kept their blood sugar levels as close to normal as

possible also had much less kidney and nerve disease. Better control also reduces the need for sight-saving laser surgery. This level of blood sugar control may not be best for everyone, including some elderly patients, children under age 13, or people with heart disease. Be sure to ask your doctor if such a control programme is right for you. Other studies have shown that controlling elevated blood pressure and cholesterol can reduce the risk of vision loss. Controlling these will help your overall health as well as help protect your vision.
What should I ask my eye care professional?

You can protect yourself against vision loss by working in partnership with your eye care professional. Ask questions and get the information you need to take care of yourself and your family.

What are some questions to ask? About my eye disease or disorder...


What is my diagnosis? What caused my condition? Can my condition be treated? How will this condition affect my vision now and in the future? Should I watch for any particular symptoms and notify you if they occur? Should I make any lifestyle changes?

About my treatment...

What is the treatment for my condition? When will the treatment start and how long will it last? What are the benefits of this treatment and how successful is it? What are the risks and side effects associated with this treatment? Are there foods, drugs, or activities I should avoid while I'm on this treatment? If my treatment includes taking medicine, what should I do if I miss a dose? Are other treatments available?

About my tests...

What kinds of tests will I have? What can I expect to find out from these tests? When will I know the results? Do I have to do anything special to prepare for any of the tests? Do these tests have any side effects or risks? Will I need more tests later?

Other suggestions

If you don't understand your eye care professional's responses, ask questions until you do understand. Take notes or get a friend or family member to take notes for you. Or, bring a tape recorder to help you remember the discussion. Ask your eye care professional to write down his or her instructions to you. Ask your eye care professional for printed material about your condition. If you still have trouble understanding your eye care professional's answers, ask where you can go for more information. Other members of your health care team, such as nurses and pharmacists, can be good sources of information. Talk to them, too.

Today, patients take an active role in their health care. Be an active patient about your eye care.
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Diabetic retinopathy
From Wikipedia, the free encyclopedia Jump to: navigation, search Main article: Diabetes Mellitus
Diabetes mellitus
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Prediabetes: Impaired fasting glycaemia Impaired glucose tolerance Diabetes mellitus type 1 Diabetes mellitus type 2 Gestational diabetes

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Blood sugar Glycosylated hemoglobin Glucose tolerance test Fructosamine

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Diabetic diet Anti-diabetic drugs Insulin therapy Glossary of diabetes

Complications

Cardiovascular disease Diabetic comas: Diabetic hypoglycemia Diabetic ketoacidosis Nonketotic hyperosmolar Diabetic myonecrosis Diabetic nephropathy Diabetic neuropathy Diabetic retinopathy Diabetes and pregnancy

Diabetic retinopathy
Classification and external resources H36. (E10.3 E11.3 E12.3 E13.3 E14.3) 250.5

ICD-10

ICD-9

DiseasesDB 29372 MedlinePlu s eMedicine MeSH

000494 001212

oph/414 oph/415 D003930

Diabetic retinopathy is retinopathy (damage to the retina) caused by complications of diabetes mellitus, which can eventually lead to blindness. It is an ocular manifestation of systemic disease

which affects up to 80% of all patients who have had diabetes for 10 years or more[1]. Despite these intimidating statistics, research indicates that at least 90% of these new cases could be reduced if there was proper and vigilant treatment and monitoring of the eyes[2].

Normal vision. Courtesy NIH National Eye Institute

The same view with diabetic retinopathy.

Contents
[hide]

1 2 3 4 5

Signs and symptoms Pathogenesis Risk factors Diagnosis Management o 5.1 Laser photocoagulation o 5.2 Panretinal photocoagulation o 5.3 Intravitreal Triamcinolone acetonide o 5.4 Vitrectomy 6 Experimental treatments o 6.1 C-peptide o 6.2 Pine bark extract 7 References 8 See also 9 External links

[edit] Signs and symptoms


Diabetic retinopathy often has no early warning signs. Even macular edema, which may cause vision loss more rapidly, may not have any warning signs for some time. In general, however, a person with macular edema is likely to have blurred vision, making it hard to do things like read or drive. In some cases, the vision will get better or worse during the day. As new blood vessels form at the back of the eye as a part of proliferative diabetic retinopathy (PDR), they can bleed (hemorrhage) and blur vision. The first time this happens, it may not be very severe. In most cases, it will leave just a few specks of blood, or spots, floating in a person's visual field, though the spots often go away after a few hours. These spots are often followed within a few days or weeks by a much greater leakage of blood, which blurs vision. In extreme cases, a person will only be able to tell light from dark in that eye. It may take the blood anywhere from a few days to months or even years to clear from the inside of the eye, and in some cases the blood will not clear. These types of large hemorrhages tend to happen more than once, often during sleep. On funduscopic exam, a doctor will see cotton wool spots, flame hemorrhages (similar leisons are also caused by the alpha-toxin of Clostridium novyi), and dot-blot hemorrhages.

[edit] Pathogenesis
Diabetic retinopathy is the result of microvascular retinal changes. Hyperglycemia-induced intramural pericyte death and thickening of the basement membrane lead to incompetence of the

vascular walls. These damages change the formation of the blood-retinal barrier and also make the retinal blood vessels become more permeable.[3] The pericyte death is due to the "hyperglycemia persistently activates protein kinase C- (PKC-, encoded by Prkcd) and p38 mitogen-activated protein kinase (MAPK) to increase the expression of a previously unknown target of PKC- signaling, Src homology-2 domaincontaining phosphatase1 (SHP-1), a protein tyrosine phosphatase. This signaling cascade leads to PDGF receptordephosphorylation and a reduction in downstream signaling from this receptor, resulting in pericyte apoptosis..."[4] Small blood vessels such as those in the eye are especially vulnerable to poor blood sugar (blood glucose) control. An overaccumulation of glucose and/or fructose damages the tiny blood vessels in the retina. During the initial stage, called nonproliferative diabetic retinopathy (NPDR), most people do not notice any change in their vision. Some people develop a condition called macular edema. It occurs when the damaged blood vessels leak fluid and lipids onto the macula, the part of the retina that lets us see detail. The fluid makes the macula swell, which blurs vision. As the disease progresses, severe nonproliferative diabetic retinopathy enters an advanced, or proliferative, stage. The lack of oxygen in the retina causes fragile, new, blood vessels to grow along the retina and in the clear, gel-like vitreous humour that fills the inside of the eye. Without timely treatment, these new blood vessels can bleed, cloud vision, and destroy the retina. Fibrovascular proliferation can also cause tractional retinal detachment. The new blood vessels can also grow into the angle of the anterior chamber of the eye and cause neovascular glaucoma. Nonproliferative diabetic retinopathy shows up as cotton wool spots, or microvascular abnormalities or as superficial retinal hemorrhages. Even so, the advanced proliferative diabetic retinopathy (PDR) can remain asymptomatic for a very long time, and so should be monitored closely with regular checkups.

[edit] Risk factors


All people with diabetes mellitus are at risk those with Type I diabetes (juvenile onset) and those with Type II diabetes (adult onset). The longer a person has diabetes, the higher the risk of developing some ocular problem. Between 40 to 45 percent of Americans diagnosed with diabetes have some stage of diabetic retinopathy. [5] After 20 years of diabetes, nearly all patients with type 1 diabetes and >60% of patients with type 2 diabetes have some degree of retinopathy.[6] Prior studies had also assumed a clear glycemic threshold between people at high and low risk of diabetic retinopathy.[7][8] However, it has been shown that the widely accepted WHO and American Diabetes Association diagnostic cutoff for diabetes of a fasting plasma glucose 7.0 mmol/l (126 mg/dl) does not accurately identify diabetic retinopathy among patients.[9] The cohort study included a multi-ethnic, cross-sectional adult population sample in the US, as well as two crosssectional adult populations in Australia. For the US-based component of the study, the sensitivity was 34.7% and specificity was 86.6%. For patients at similar risk to those in this study (15.8% had

diabetic retinopathy), this leads to a positive predictive value of 32.7% and negative predictive value of 87.6%. Published rates vary between trials, the proposed explanation being differences in study methods and reporting of prevalence rather than incidence values.[10] During pregnancy, diabetic retinopathy may also be a problem for women with diabetes. It is recommended that all pregnant women with diabetes have dilated eye examinations each trimester to protect their vision.[citation needed] People with Down's syndrome, who have three copies of chromosome 21, almost never acquire diabetic retinopathy. This protection appears to be due to the elevated levels of endostatin[11], an anti-angiogenic protein, derived from collagen XVIII. The collagen XVIII gene is located on chromosome 21.

[edit] Diagnosis
Diabetic retinopathy is detected during an eye examination that includes:

Visual acuity test: This test uses an eye chart to measure how well a person sees at various distances (i.e., visual acuity). Pupil dilation: The eye care professional places drops into the eye to widen the pupil. This allows him or her to see more of the retina and look for signs of diabetic retinopathy. After the examination, close-up vision may remain blurred for several hours. Ophthalmoscopy: This is an examination of the retina in which the eye care professional: (1) looks through a device with a special magnifying lens that provides a narrow view of the retina, or (2) wearing a headset with a bright light, looks through a special magnifying glass and gains a wide view of the retina. Note that hand-held ophthalmoscopy is insufficient to rule out significant and treatable diabetic retinopathy. Optical coherence tomography (OCT): This is an optical imaging modality based upon interference, and analogous to ultrasound. It produces crosssectional images of the retina (B-scans) which can be used to measure the thickness of the retina and to resolve its major layers, allowing the observation of swelling and or leakage. Digital Retinal Screening Programs: Systematic programs for the early detection of eye disease including diabetic retinopathy are becoming more common, such as in the UK, where all people with diabetes mellitus are offered retinal screening at least annually. This involves digital image capture and transmission of the images to a digital reading center for evaluation and treatment referral. See Vanderbilt Ophthalmic Imaging Center [1] and the English National Screening Programme for Diabetic Retinopathy [2] Slit Lamp Biomicroscopy Retinal Screening Programs: Systematic programs for the early detection of diabetic retinopathy using slit-lamp biomicroscopy. These exist either as a standalone scheme or as part of the Digital program (above) where the digital photograph was considered to lack enough clarity for detection and/or diagnosis of any retinal abnormality.

The eye care professional will look at the retina for early signs of the disease, such as: (1) leaking blood vessels, (2) retinal swelling, such as macular edema, (3) pale, fatty deposits on the retina (exudates) signs of leaking blood vessels, (4) damaged nerve tissue (neuropathy), and (5) any changes in the blood vessels. Should the doctor suspect macular edema, he or she may perform a test called fluorescein angiography. In this test, a special dye is injected into the arm. Pictures are then taken as the dye passes through the blood vessels in the retina. This test allows the doctor to find the leaking blood vessels.

[edit] Management
There are three major treatments for diabetic retinopathy, which are very effective[citation needed] in reducing vision loss from this disease. In fact, even people with advanced retinopathy have a 90 percent chance of keeping their vision when they get treatment before the retina is severely damaged. These three treatments are laser surgery, injection of triamcinolone into the eye and vitrectomy. It is important to note that although these treatments are very successful, they do not cure diabetic retinopathy. Caution should be exercised in treatment with laser surgery since it causes a loss of retinal tissue. It is often more prudent to inject triamcinolone. In some patients it results in a marked increase of vision, especially if there is an edema of the macula. Avoiding tobacco use and correction of associated hypertension are important therapeutic measures in the management of diabetic retinopathy. [12] The best way of addressing diabetic retinopathy is to monitor it vigilantly. By 2008 there were other drugs (eg kinase inhibitors and anti-VEGF) available.[13]
[edit] Laser photocoagulation

Laser photocoagulation can be used in two scenarios for the treatment of diabetic retinopathy. It is widely used for early stages of proliferative retinopathy.
[edit] Panretinal photocoagulation

Panretinal photocoagulation, or PRP (also called scatter laser treatment), is used to treat proliferative diabetic retinopathy (PDR). The goal is to create 1,000 - 2,000 burns in the retina with the hope of reducing the retina's oxygen demand, and hence the possibility of ischemia. In treating advanced diabetic retinopathy, the burns are used to destroy the abnormal blood vessels that form in the retina. This has been shown to reduce the risk of severe vision loss for eyes at risk by 50%.
[14]

Before the laser, the ophthalmologist dilates the pupil and applies anesthetic drops to numb the eye. In some cases, the doctor also may numb the area behind the eye to prevent any discomfort.

The patient sits facing the laser machine while the doctor holds a special lens to the eye. The physician can use a single spot laser or a pattern scan laser for two dimensional patterns such as squares, rings and arcs. During the procedure, the patient may see flashes of light. These flashes may eventually create an uncomfortable stinging sensation for the patient. After the laser treatment, patients should be advised not to drive for a few hours while the pupils are still dilated. Vision may remain a little blurry for the rest of the day, though there should not be much pain in the eye. Patients may lose some of their peripheral vision after this surgery, but the procedure saves the rest of the patient's sight. Laser surgery may also slightly reduce colour and night vision. A person with proliferative retinopathy will always be at risk for new bleeding, as well as glaucoma, a complication from the new blood vessels. This means that multiple treatments may be required to protect vision.
[edit] Intravitreal Triamcinolone acetonide

Triamcinolone is a long acting steroid preparation. When injected in the vitreous cavity, it decreases the macular edema (thickening of the retina at the macula) caused due to diabetic maculopathy, and results in an increase in visual acuity. The effect of triamcinolone is transient, lasting up to three months, which necessitates repeated injections for maintaining the beneficial effect. Complications of intravitreal injection of triamcinolone include cataract, steroid-induced glaucoma and endophthalmitis.
[edit] Vitrectomy

Instead of laser surgery, some people require a vitrectomy to restore vision. A vitrectomy is performed when there is a lot of blood in the vitreous. It involves removing the cloudy vitreous and replacing it with a saline solution. Studies show that people who have a vitrectomy soon after a large hemorrhage are more likely to protect their vision than someone who waits to have the operation. Early vitrectomy is especially effective in people with insulin-dependent diabetes, who may be at greater risk of blindness from a hemorrhage into the eye. Vitrectomy is often done under local anesthesia. The doctor makes a tiny incision in the sclera, or white of the eye. Next, a small instrument is placed into the eye to remove the vitreous and insert the saline solution into the eye. Patients may be able to return home soon after the vitrectomy, or may be asked to stay in the hospital overnight. After the operation, the eye will be red and sensitive, and patients usually need to wear an eyepatch for a few days or weeks to protect the eye. Medicated eye drops are also prescribed to protect against infection.

[edit] Experimental treatments


[edit] C-peptide

Though not yet commercially available, c-peptide has shown promising results in treatment of diabetic complications incidental to vascular degeneration. Once thought to be a useless byproduct of insulin production, it helps to ameliorate and reverse many symptoms of diabetes[15].
[edit] Pine bark extract

A pine bark extract of oligomeric proanthocyanidins has been shown to improve microcirculation, retinal edema and visual acuity in the early stages of diabetic retinopathy[16].

[edit] References
1. ^ PJ Kertes, TM Johnson Eds. Evidence Based Eye Care (c) 2007 2. ^ Tapp, R. et al (2003) The prevalence of and factors associated with diabetic retinopathy in the Australian population. Diabetes care. 26(6), pg. 1371. 3. ^ Understanding diabetic retinopathy by Pardianto G et al., in Mimbar Ilmiah Oftalmologi Indonesia.2005;2: 65-6. 4. ^ http://www.nature.com/nm/journal/v15/n11/full/nm.2052.html "Activation of PKC- and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy" 2009 5. ^ "NIHSeniorHealth: Diabetic Retinopathy - Causes and Risk Factors". Diabetic Retinopathy. NIHSenior Health. 2005. http://nihseniorhealth.gov/diabeticretinopathy/causesandriskfactors/02.html. 6. ^ "Screening for Diabetic Retinopathy". Diabetic Retinopathy. American Diabetes Association. 2002. http://care.diabetesjournals.org/cgi/content/full/25/suppl_1/s90. 7. ^ "Report of the expert committee on the diagnosis and classification of diabetes mellitus". Diabetes Care 26 Suppl 1: S520. 2003. PMID 12502614. http://care.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=12502614. 8. ^ "Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus". Diabetes Care 20 (7): 118397. 1997. PMID 9203460. 9. ^ Wong TY, Liew G, Tapp RJ, et al. (2008). "Relation between fasting glucose and retinopathy for diagnosis of diabetes: three population-based crosssectional studies". Lancet 371 (9614): 73643. doi:10.1016/S01406736(08)60343-8. PMID 18313502. http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(08)60343-8. 10.^ Williams R, Airey M, Baxter H, Forrester J, Kennedy-Martin T, Girach A (2004). "Epidemiology of diabetic retinopathy and macular oedema: a systematic review". Eye 18 (10): 96383. doi:10.1038/sj.eye.6701476. PMID 15232600. 11.^ http://journals.lww.com/jcraniofacialsurgery/Abstract/2009/03001/Role_of_Endo genous_Angiogenesis_Inhibitors_in_Down.9.aspx 12.^ "Diabetes Ocular complications". Chronic Complications of Diabetes. Armenian Medical Network. 2006. http://www.health.am/db/diabetes-ocularcomplications/.

13.^ http://www.ncbi.nlm.nih.gov/pubmed/18408491? ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pu bmed_SingleItemSupl.Pubmed_Discovery_RA&linkpos=5&log$=relatedreviews &logdbfrom=pubmed 14.^ PJ Kertes TM Johnson, Eds, Evidence-Based Eye Care (C)2007 15.^ Wahren, J., Ekberg, K., & Jrnval, H. 2007. C-peptide is a bioactive peptide. Diabetologia. Volume 50, Number 3 16.^ http://www.eurekalert.org/pub_releases/2009-12/mg-ssp113009.php "Study shows pine bark improves circulation, swelling and visual acuity in early diabetic retinopathy" Dec 2009

The original text of this document was taken from the public domain resource document "Facts About Diabetic Retinopathy", at http://www.nei.nih.gov/health/diabetic/retinopathy.asp See the copyright statement at http://www.nei.nih.gov/order/index.htm, which says "Our publications are not copyrighted and may be reproduced without permission. However, we do ask that credit be given to the National Eye Institute, National Institutes of Health."

[edit] See also

PERSPECTIVE

Diabetic retinopathy in pregnancy


R M Best, U Chakravarthy
Diabetic retinopathy is one of the major causes of preventable blindness in the UK and USA in those aged between 24 and 64 years.1 For a proportion of diabetic women, the first half of this period coincides with peak fertility and childbearing years. Diabetic eye disease may develop for the first time during pregnancy, and visual loss at this stage has serious implications for both the patient and her family. In the past, the prognosis for pregnancy in diabetic women with microvascular disease was so poor that many physicians advised avoidance or termination of pregnancy. 2 With the recognition that the level of glycaemia during pregnancy is directly related to the incidence of congenital malformations, the emphasis on the management of diabetic pregnancy has been one of meticulous control of blood sugar and this has undoubtedly resulted in lower rates of fetal malformations. However, intensive control of glycaemia may carry risks to diabetic mothers particularly to those with established microvascular diseases such as retinopathy and nephropathy. Studies on the influence of pregnancy on the natural history of diabetic retinopathy have shown that deterioration is frequently observed. 3 4 Until recently there has been controversy as to whether the progression of retinopathy which occurs in such women is due to the natural tendency of diabetic retinopathy to worsen or to unique factors operative during pregnancy. Several major studies have gone some way towards explaining the mechanisms underlying

progression of retinopathy during pregnancy. Klein et al performed a prospective study on a large series of individuals, comprising 171 pregnant and 298 non-pregnant insulin dependent diabetic women. 5 The level of diabetic retinopathy in the first trimester was assessed using standard retinal photographs and compared with postpartum photographs. After adjusting for duration of diabetes, glycaemic control, and blood pressure current pregnancy was found to be a major risk factor for the progression of retinopathy. 5 Similarly, Moloney and Drury, also using retinal photography as a means of assessing retinopathy, found that current pregnancy in 53 pregnant diabetic women was associated both with an increased prevalence (from 62% to 77%) and severity of retinopathy whereas in the control group of 39 non-pregnant diabetic women the prevalence of retinopathy remained unchanged at 46% throughout the study period.3 That retinopathy worsens during pregnancy is now undisputed, although the mechanism by which progression occurs is not entirely clear. Risk factors for the progression of retinopathy in pregnancy
METABOLIC CONTROL

An elegant study by Phelps et al 6 monitored changes in diabetic retinopathy status during pregnancy and correlated these findings with blood sugar measurements made at corresponding time points. These findings were further supported and extended by the Diabetes in Early Pregnancy Study (DIEP), 7 a prospective cohort study on 140 pregnant diabetic women who were followed from early pregnancy to delivery using retinal photography. It was clearly shown that those women with the greatest reduction in glycosylated haemoglobin (HbA1c) over the first 14 weeks of pregnancy were at an increased risk of progression of retinopathy. 7 Patients in whom retinopathy was most likely to progress had both the poorest control at baseline and the largest improvement during early pregnancy. However, it was impossible to separate these two risk factors as virtually all patients had improved metabolic control during early pregnancy.
DURATION OF DIABETES

Another risk factor which has been shown to adversely influence progression of retinopathy is the duration of diabetes before pregnancy. 8 Dibble et al followed 55 insulin dependent diabetic women through their pregnancies and found a positive correlation between duration of diabetes and progression of retinopathy. 8 However, the results of the more recent and larger DIEP study suggest that duration of diabetes is probably not as important a risk factor for any change in retinopathy as baseline severity of retinopathy. Retinopathy was noticed to progress by two or more steps in 55% of patients with less than 15 years of disease and 50% of those with more than 15 years of disease and these differences were not significant. 7 But, when the rate of development of retinopathy was compared in patients stratified by duration of diabetes, retinopathy progressed to proliferative levels in 39% of patients with more than 15 years of diabetes as opposed to 18% of patients with a disease duration of less than 15 years.7 These findings indicate that duration of diabetes, which is strongly correlated with level of baseline retinopathy, may be a significant factor in the development of more severe changethat is, proliferative

retinopathy in pregnancy.
BASELINE SEVERITY OF RETINOPATHY

It has been shown that risk of visual loss is low in those with no pre-existing retinopathy. Approximately 12% of women with no retinopathy at the start of pregnancy will develop minor background retinopathy consisting of a few microaneurysms but regression in the postpartum period is the norm.9 Using fluorescein angiography Soubrane et al showed that in women with mild background diabetic retinopathy the number of retinal microaneurysms increased progressively during pregnancy but underwent substantial regression postpartum though not quite returning to preconception levels.10 On the other hand when pre-existing retinopathy is more severe, proliferative changes can develop in a significant number of cases. Thus in the DIEP study, 29% of patients whose fundal appearance was classified as showing moderate retinopathy at baseline went on to develop proliferative changes during pregnancy. This was in contrast with those women who had minimal retinopathy at baseline where only 6.3% progressed to the proliferative category. 7 These findings
British Journal of Ophthalmology 1997;81:249251 249

indicate that severity of existing diabetic retinopathy profoundly influences the level of progression.
RETINAL BLOOD FLOW

Pregnancy is associated with major changes in the systemic vasculature. There is an augmentation in cardiac output and plasma volume and a decrease in peripheral resistance, all of which cause increased blood flow. Chen et al, using laser Doppler velocimetry to measure retinal blood flow, demonstrated the lack of change of retinal blood flow in normal pregnancy, thus confirming the efficacy of the autoregulatory processes in the retinal vasculature. 11 In diabetic patients who showed progression of retinopathy in pregnancy, an increase in blood flow was documented in the first trimester. By contrast, women with diabetes whose retinal blood flow remained unchanged developed no retinopathy. 11 They therefore suggested that the hyperdynamic circulatory state of early pregnancy is accompanied by compensatory mechanisms both in normal women and in those diabetes sufferers who retain autoregulatory control of retinal blood flow. In some diabetic women, however, these autoregulatory mechanisms are flawed resulting in an increase in blood flow. Such a hyperdynamic circulatory state could potentially inflict additional shear stress and cause endothelial damage particularly at the capillary level.12 However, local hypoxia associated with worsening retinopathy could account for the compensatory increase in blood flow which may merely represent an epiphenomenon rather than failure of autoregulation in pregnancy.
HYPERTENSION

Hypertension is a known risk factor for the progression of retinopathy and is additionally hazardous during pregnancy. 5 13 Rosenn et al followed 154 insulin dependent diabetic women throughout their pregnancies of whom approximately a third had either chronic hypertension or pregnancy induced hypertension or both. Fifty five per cent of those with a hypertensive disorder developed progression of retinopathy as opposed to 25% of those that did not.13 Pharmacological treatment of hypertension in pregnancy is most suitable for early onset, severe disease when an attempt to delay delivery is indicated and methyldopa,

blockers, and vasodilators have been used with some success.14 A recent report has indicated that treatment of women with diabetes with the angiotensin converting enzyme (ACE) inhibitor captopril for 6 months before the onset of pregnancy reduces proteinuria, improves renal function, and is associated with favourable maternal and fetal outcome. 15 In at least one major study all patients with severe proliferative retinopathy also had proteinuria indicating a generalised vasculopathy. 6 Thus, it is not inconceivable that functional improvement in one circulatory bed might be mirrored in others. However, the use of ACE inhibitors during pregnancy is not recommended as they are extremely fetotoxic resulting in hypotension, renal tubular dysplasia, anuriaoligohydramnios, growth restriction, and death of the fetus.16 Nevertheless, clinical studies of ACE inhibitors in diabetic retinopathy carried out before the onset of pregnancy might well be worthwhile. Fundus changes in diabetic retinopathy in pregnancy Cotton wool spots develop in a proportion of patients with background retinopathy as pregnancy advances and have been seen to be associated with low fasting blood sugar. 3 As hypoglycaemia often occurs in the wake of institution of rapid metabolic control,6 it has been suggested that low plasma glucose may be responsible for the retinal hypoxia and damage.3 These morphological alterations are not dissimilar to those observed in non-gravid diabetic individuals who may experience transient worsening of retinopathy when subjected to strict glycaemic control in whom the major changes are cotton wool spots and intraretinal microvascular abnormalities.17 However, Phelps et al 6 have reported that the components of retinopathy which increased most commonly in pregnancy were haemorrhages and microaneurysms, suggesting that there may be differences in pathophysiological aetiology between gravid and non-gravid subjects. Effect of diabetic retinopathy on pregnancy Increasing severity of diabetic retinopathy has been shown to adversely affect outcome in pregnancy. Price et al retrospectively reviewed 23 pregnancies in insulin dependent diabetics who had had serial retinal examinations during pregnancy. 18 They noted that 30% of patients who had no observable retinopathy and 70% of patients with background retinopathy at the inception of pregnancy developed obstetric complications. It was noteworthy that all of those with proliferative retinopathy at the start of pregnancy developed pregnancy induced hypertension or other obstetric complications.18 In another study the impact of diabetic retinopathy on pregnancy was examined in 179 women with diabetes.19 The pregnancies in 43% of the women with proliferative retinopathy had an unfavourable outcome compared with 13% of those with nonproliferative or no retinopathy and, overall, a fifth of the pregnancies resulted in fetuses with severe congenital malformations and/or fetal death. 19 Thus, severity of retinopathy at baseline was strongly predictive of an adverse outcome in these patients. Long term consequences of pregnancy on diabetic retinopathy In an attempt to determine whether pregnancy had an

unfavourable effect on retinopathy in the long term Klein and Klein investigated the severity of retinopathy in two groups of diabetic women, one of which had experienced pregnancy and the other had never been pregnant. 20 No difference was observed in severity of retinopathy between the groups suggesting the absence of any deleterious effects attributable to pregnancy. 20 These findings have been supported by other studies which have shown no long term detrimental effects due to pregnancy in other organs such as the kidney or peripheral nervous system. 21 22 Conversely, retinopathy of less overall severity in parous women has been reported,21 and the rigorous and intensive control of diabetes instituted during pregnancy in these women has been cited as having a possible protective effect in the long term. Management of diabetic retinopathy in pregnancy Before the advent of laser photocoagulation, proliferative retinopathy was a contraindication to pregnancy because of the substantial risk of severe visual loss, so that women with diabetes who became pregnant were advised to consider termination.2 With the use of laser photocoagulation and the establishment and recognition of high risk characteristics23 the likelihood of visual loss has been reduced. Progression of proliferative retinopathy may depend upon whether or not laser photocoagulation has been carried out before pregnancy. One study of patients with proliferative retinopathy detected in early pregnancy and subsequently treated by laser showed that 58% experienced significant progression and visual loss.9 On the other hand only 26% of patients in whom retinopathy was diagnosed and treated before onset of pregnancy showed progression of retinopathy during an ensuing gestation
250 Best, Chakravarthy

period.9 The indications for treatment and the response to laser photocoagulation are exactly the same as for other diabetes sufferers.24 Nevertheless, some studies have found that vascular proliferation is reversible and postpartum regression is common,25 and currently therefore most ophthalmologists would perform a restricted or limited photocoagulation procedure. However, there are a group of women in whom retinopathy is aggressive, responds poorly to photocoagulation, and continues to progress postpartum. 26 Thus, it is important that proliferative retinopathy is detected and treated preferably before the onset of pregnancy. Those who develop proliferative retinopathy during pregnancy should have prompt laser photocoagulation treatment sufficient to induce regression. Sinclair et al 27 have identified a group of insulin dependent diabetics who developed macular oedema in pregnancy and who also typically developed proteinuria and mild hypertension concomitantly. Laser photocoagulation may be required to treat macular changes but this in itself can exacerbate the oedema particularly in those with a compromised macular capillary circulation. Alternative therapies for this condition include salt restriction diets and diuretics which have been used with limited success. 28 When macular oedema occurs it is thought to be due to an ischaemic capillaropathy and may be accompanied by proliferative retinopathy. In some cases macular oedema regresses postpartum but in others it may persist and cause long term visual loss.27 Generally, the diagnosis of sight

threatening retinopathy is made on ophthalmoscopic appearances. However, fluorescein angiography is a more sensitive tool to assess the extent of capillary non-perfusion and early neovascularisation and may be of value in the management of pregnant diabetics particularly since there is no evidence that it has any detrimental effect on the developing fetus.29 Despite the tendency for retinopathy to worsen after the institution of strict glycaemic control, there is an overall strong beneficial effect of near normoglycaemia which includes a reduction of retinopathy by 50% at 2 years of follow up.30 31 It is also recognised that normalisation of blood sugar during pregnancy is the most important factor for the successful outcome of pregnancy in diabetes, 32 33 as a high rate of preterm deliveries (39%) and frequent occurrence of intrauterine growth retardation (9%) characterise the fetal outcome in women with uncontrolled diabetes.34 It is therefore recommended that diabetic women who are contemplating pregnancy and who are suboptimally controlled (glycosylated haemoglobin > 6 SD above the control mean) should be targeted for the institution of strict glycaemic control.7 Ideally, young women with diabetes should be seen for counselling and management before the onset of pregnancy. Although studies suggest that most patients recognise the value of good blood glucose control,35 a significant proportion may be unaware of the potential risks to vision. In summary, progression of retinopathy in pregnancy depends on a variety of factors including severity of retinopathy at conception, adequacy of treatment, duration of diabetes, metabolic control before pregnancy, and the presence of additional vascular damage such as preexisting or concomitant hypertensive disorder. The risks of visual loss in those with minimal retinopathy at the inception of pregnancy are minor, and for these mothers a fundus examination every 3 months should suffice. In those with moderate background retinopathy, funduscopy should be performed at each obstetric visit (which is usually every 4 to 6 weeks) and if progression is detected the patient should be examined at 2 week intervals to detect any high risk characteristics. If high risk characteristics develop photocoagulation should be carried out promptly and monitored by funduscopy. In those with severe sight threatening retinopathy, laser photocoagulation should be performed before pregnancy or promptly when high risk characteristics develop.
R M BEST U CHAKRAVARTHY Department of Ophthalmology, Queens University of Belfast, Royal Victoria Hospital, Belfast BT12 6BA
1 Kohner EM, Porta M. Protocols for screening and treatment of diabetic retinopathy in Europe. Eur J Ophthalmol 1991;1:4554. 2 White P. Diabetes mellitus in pregnancy. Clin Perinatol 1974;1:33147. 3 Moloney JB, Drury MI. The effect of pregnancy on the natural course of diabetic retinopathy. Am J Ophthalmol 1982;93:74556. 4 Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. 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;102:52732. 5 Klein BE, Moss SE, Klein R. Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care 1990;13:3440. 6 Phelps RL, Sakol P, Metzger BE, Jampol LM, Freinkel N. Changes in diabetic retinopathy during pregnancy. Correlations with regulation of hyperglycemia. Arch Ophthalmol 1986;104:180610. 7 Diabetes in Early Pregancy Study. Metabolic control and progression of retinopathy. Diabetes Care 1995;18:6317. 8 Dibble CM, Kochenour NK, Worley RJ, Tyler FH, Swartz M. Effect of

pregnancy on diabetic retinopathy. Obstet Gynecol 1982;59:699704. 9 Sunness JS. The pregnant womans eye. Surv Ophthalmol 1988;32:21938. 10 Soubrane G, Canivet J, Coscas G. Influence of pregnancy on the evolution of background retinopathy. Preliminary results of a prospective fluorescein angiography study. Inte Ophthalmol 1985;8:24955. 11 Chen HC, Newsom RS, Patel V, Cassar J, Mather H, Kohner EM. Retinal blood flow changes during pregnancy in women with diabetes. Invest Ophthalmol Vis Sci 1994;35:3199208. 12 Tooke JE. Microvascular function in human diabetes. A physiological perspective. Diabetes 1995;44:7216. 13 Rosenn B, Miodovnik M, Kranias G, Khoury J, Combs CA, Mimouni F, et al Progression of diabetic retinopathy in pregnancy: association with hypertension in pregnancy. Am J Obstet Gynecol 1992;166:12148. 14 Erman A, Boner G, Ovadia J. Diabetic nephropathy and pregnancy. The effect of ACE inhibitors prior to pregnancy on fetomaternal outcome. Nephrol Dial Transplant 1995;10:232833. 15 Pipkin FB, Rubin PC. Pre-eclampsiathe disease of theories. Br Med Bull 1994;50:38196. 16 Sedman AB, Kershaw DB, Bunchman TE. Recognition and management of angiotensin-converting enzyme-inhibitor. Pediatr Nephrol 1995;9:3825. 17 KROC collaborative study group. Blood glucose control and the evolution of diabetic retinopathy and albuminuria. N Engl J Med 1984;311:36572. 18 Price JH,Hadden DR, Archer DB, Harley JM.Diabetic retinopathy in pregnancy. Br J Obstet Gynaecol 1984;91:117. 19 Klein BE, Klein R, Meuer SM, Moss SE, Dalton DD. Does the severity of diabetic retinopathy predict pregnancy outcome? J Diabet Complications 1988;2:17984. 20 Klein BE, Klein R. Gravidity and diabetic retinopathy. Am J Epidemiol 1984;119:5649. 21 Chaturvedi N, Stephenson JM, Fuller JH. The relationship between pregnancy and long-term maternal complications in the EURODIAB IDDM Complications Study. Diabetic Med 1995;12:4949. 22 Hemachandra A, Ellis D, Lloyd CE, Orchard TJ. The influence of pregnancy on IDDM complications. Diabetes Care 1995;18:9504. 23 Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of diabetic retinopathy. XIV Ten-year incidence and progression of diabetic retinopathy [see comments]. Arch Ophthalmol 1994; 112:121728. 24 Hercules BL,Wozencroft M, Gayed II, Jeacock J. Peripheral retinal ablation in the treatment of proliferative diabetic retinopathy during pregnancy. Br J Ophthalmol 1980;64:8793. 25 Serup L. Influence of pregnancy on diabetic retinopathy. Acta Endocrinol 1994;27(Suppl 1986):1224. 26 Conway M, Baldwin J, Kohner EM, Schulenburg WE, Cassar J. Postpartum progression of diabetic retinopathy. Diabetes Care 1991;14:11101. 27 Sinclair SH, Nesler C, Foxman B, Nichols CW, Gabbe S. Macular edema and pregnancy in insulin-dependent diabetes. Am J Ophthalmol 1984;97: 15467. 28 Cassar J, Hamilton AM, Kohner EM. Diabetic retinopathy in pregnancy. Int Ophthalmol Clin 1978;18:17988. 29 Halperin LS, Olk RJ, Soubrane G, Coscas G. Safety of fluorescein angiography during pregnancy. Am J Ophthalmol 1990;109:5636. 30 Diabetes Control and Complications Trial Research 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 1993;329:97786. 31 Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes treatment on the progression of diabetic retinopathy in in insulin-dependent diabetes mellitus. Arch Ophthalmol 1995;113:3651. 32 Reid M, Hadden D, Harley JMG, Halliday HL, McClure BG. fetal malformations in diabetics with high haemoglobin A1c in early pregnancy. BMJ 1984;289:1001. 33 Jovanovic R, Jovanovic L. Obstetric management when normoglycemia is maintained in iabetic pregnant women with vascular compromise. Am J Obstet Gynecol 1984;149:61723. 34 Hopp H, Vollert W, Weitzel H, Glockner E, Jahrig D. Diabetic retinopathy and nephropathy. Complications during pregnancy and delivery. Geburtshilfe und Frauenheilkunde 1995;55:2759. 35 Gibb D, Hockey S, Brown LJ, Lunt H. Attitudes and knowledge regarding contraception and prepregnancy. NZ Med J 1994;107:4846.

Diabetic retinopathy in pregnancy 251

Diabetes Mellitus in Pregnancy (Gestational Diabetes)

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(See also Diabetes Mellitus and Disorders of Carbohydrate Metabolism) Pregnancy aggravates preexisting type 1 (insulin-dependent) and type 2 (non insulin-dependent) diabetes but does not appear to exacerbate diabetic retinopathy, nephropathy, or neuropathy. Gestational diabetes (diabetes that begins during pregnancy) can develop in overweight, hyperinsulinemic, insulin-resistant women or in thin, relatively insulin-deficient women. Gestational diabetes occurs in 1 to 3% of all pregnancies, but the rate may be much higher in certain groups (eg, Mexican Americans, American Indians, Asians, Indians, Pacific Islanders). Diabetes during pregnancy increases fetal and maternal morbidity and mortality. Neonates are at risk of respiratory distress, hypoglycemia, hypocalcemia, hyperbilirubinemia, polycythemia, and hyperviscosity. Poor control of preexisting or gestational diabetes during organogenesis (up to about 10 wk gestation) increases risk of major congenital malformations and spontaneous abortion. Poor control of diabetes later in pregnancy increases risk of fetal macrosomia (usually defined as fetal weight > 4000 or > 4500 g at birth), preeclampsia, and spontaneous abortion. However, gestational diabetes can result in fetal macrosomia even if plasma glucose is kept nearly normal. Treatment

Close monitoring Tight control of plasma glucose Management of complications

Preconception counseling and optimal control of diabetes before, during, and after pregnancy minimize maternal and fetal risks, including congenital malformations. Because malformations may develop before pregnancy is diagnosed, the need for constant, strict control of glucose levels is stressed to women who have diabetes

and who are considering pregnancy (or who are not using contraception). Most experts recommend that all pregnant women be screened for gestational diabetes. A glucose tolerance test is usually recommended, but the diagnosis can probably be made by a fasting plasma glucose of > 126 mg/dL or a random plasma glucose > 200 mg/dL (see Approach to the Pregnant Woman and Prenatal Care: Laboratory testing). To minimize risks, clinicians should do all of the following:

Involve a diabetes team (eg, physicians, nurses, nutritionists, social workers) and a pediatrician Promptly diagnose and treat complications of pregnancy, no matter how trivial Plan for delivery and have an experienced pediatrician present Ensure that neonatal intensive care is available

In regional perinatal centers, specialists in management of diabetic complications are available. During pregnancy: Treatment can vary, but some general management guidelines are useful (see Table 1: Pregnancy Complicated by Disease: Management of Type 1 Diabetes Mellitus* During Pregnancy , Table 2: Pregnancy Complicated by Disease: Management of Type 2 Diabetes Mellitus* During Pregnancy , and Table 3: Pregnancy Complicated by Disease: Management of Gestational Diabetes During Pregnancy ). Women with type 1 or 2 should monitor their plasma glucose levels at home. During pregnancy, normal fasting plasma glucose levels are about 76 mg/dL (4.2 mmol/L); treatment aims to keep fasting plasma glucose levels at < 95 mg/dL (5.3 mmol/L) and 2-h postprandial levels at 120 mg/dL ( 6.6 mmol/L). The goals are no wide plasma glucose fluctuations and glycosylated Hb (Hb A1c) levels kept at < 8%. Table 1 Management of Type 1 Diabetes Mellitus* During Pregnancy Time Frame Measures Before conception Diabetes is controlled. Risk is lowest if Hb A1c levels are 8% at conception. Evaluation includes

24-h urine collection (protein excretion and creatinine clearance) to check for renal complications Ophthalmologic examination to check for

retinal complications Prenatal ECG to check for cardiac complications Prenatal visits begin as soon as pregnancy is recognized. Frequency of visits is determined by degree of glycemic control.

Diet should be individualized according to ADA guidelines and coordinated with insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph administration. Three meals and 3 snacks/day are recommended, with emphasis on consistent timing. Women are instructed in and should do plasma glucose self-monitoring. Women should be cautioned about the dangers of hypoglycemia during exercise and at night. Women and their family members should be instructed in glucagon administration. Hb A1c level should be checked every trimester. Fetal monitoring with the following should be done weekly from 32 wk to delivery (or earlier if indicated):

Nonstress tests Biophysical profiles Kick counts

Amount and type of insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph should be individualized. In the am; 2/3 of total dose (60% NPH, 40% regular) is taken; in the pm; 1/3 (50% NPH, 50% regular) is taken. During labor and delivery Vaginal delivery at term is possible if women have documented dating criteria and good glycemic control.

Amniocentesis is not done unless indicated for another problem or requested by the couple. Cesarean delivery should be reserved for obstetrical indications or fetal macrosomia (>4500 g), which increases risk of shoulder dystocia. Delivery should occur by 38-40 wk. During delivery, a constant low-dose insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph infusion is usually preferred, and the usual sc administration of insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph is stopped. If induction is planned, the usual PM NPH insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph dose is given on the day before induction. Postpartum and continuing diabetes care should be arranged. Postpartum insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph requirements may decrease by up to 50%. * Guidelines are only suggested; marked individual variations require appropriate adjustments. Normal values may differ depending on laboratory methods used. Some hospital programs recommend up to 4 insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph injections daily. Continuous sc insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph

infusion, which is labor-intensive, can sometimes be given in specialized diabetic research settings. ADA = American Diabetes Association; Hb A1c = glycosylated Hb; NPH = neutral protamine Hagedorn. Table 2 Management of Type 2 Diabetes Mellitus* During Pregnancy Time Frame Measures Before conception Hyperglycemia is controlled. Risk is lowest if Hb A1c levels are 8% at conception. Weight loss is encouraged if BMI is >27 kg/m2. The diet should be low in fat, relatively high in complex carbohydrates, and high in fiber. Prenatal Exercise is encouraged. For overweight women, diet and caloric intake are individualized and monitored to avoid weight gain of >9 kg; daytime snacks are discouraged. Moderate walking after meals is recommended. Women are instructed in and should do plasma glucose self-monitoring. The 2-h postbreakfast plasma glucose level is checked weekly at clinic visits. Hb A1c level should be checked every trimester. Fetal monitoring with the following should be done weekly from 32 wk to delivery (or earlier if indicated):

Nonstress tests Biophysical profiles Kick counts

Amount and type of insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph is individualized. For obese women, regular insulin Some Trade Names HUMULIN NOVOLIN

Click for Drug Monograph is taken before each meal. For women who are not obese, 2 /3 of total dose (60% NPH, 40% regular) is taken in the am; 1/3 (50% NPH, 50% regular) is taken in the pm. During labor and Management is the same as for type 1 (see Table 1: delivery Pregnancy Complicated by Disease: Management of Type 1 Diabetes Mellitus* During Pregnancy ). * Guidelines are only suggested; marked individual variations require appropriate adjustments. Normal values may differ depending on laboratory methods used. BMI = body mass index; Hb A1c = glycosylated Hb; NPH = neutral protamine Hagedorn. Table 3 Management of Gestational Diabetes During Pregnancy Time Frame Measures Before conception Women who have had gestational diabetes in previous pregnancies should try to reach a normal weight and engage in modest exercise. The diet should be low in fat, relatively high in complex carbohydrates, and high in fiber. Fasting plasma glucose and Hb A1c levels should be checked. Diet and caloric intake are individualized and monitored to prevent weight gain of >9 kg. Obese women are discouraged from daytime snacks. Moderate exercise after meals is recommended. Fetal monitoring with the following should be done weekly from 32 wk to delivery (or earlier if indicated):

Prenatal

Nonstress tests Biophysical profiles Kick counts

Insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph therapy is reserved for persistent hyperglycemia (fasting plasma glucose >95 mg/dL or 2-h postprandial plasma glucose >120 mg/dL) despite a trial of dietary therapy

for 2 wk. The amount and type of insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph should be individualized. For obese women, regular insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph is taken before each meal. For women who are not obese, 2/3 of total dose (60% NPH, 40% regular) is taken in the am; 1/3 (50% NPH, 50% regular) is taken in the pm. During labor and delivery Vaginal delivery at term is possible if women have a well-documented delivery date and good diabetic control. Amniocentesis may not be required. Cesarean delivery should be reserved for obstetric indications or fetal macrosomia (>4500 g), which increases risk of shoulder dystocia. Delivery should occur by 38-40 wk. Hb A1c = glycosylated Hb; NPH = neutral protamine Hagedorn. Insulin is the traditional drug of choice because it cannot cross the placenta and provides more predictable glucose control; it is used for types 1 and 2 diabetes and for some women with gestational diabetes. Human insulin is used if possible because it minimizes antibody formation. Insulin antibodies cross the placenta, but their effect on the fetus is unknown. In some women with long-standing type 1 diabetes, hypoglycemia does not trigger the normal release of counterregulatory hormones (catecholamines, glucagon, cortisol, and growth hormone); thus, too much insulin can trigger hypoglycemic coma without premonitory symptoms. All pregnant women with type 1 should have glucagon kits and be instructed (as should family members) in giving glucagon if severe hypoglycemia (indicated by unconsciousness, confusion, or plasma glucose levels < 40 mg/dL [< 2.2 mmol/L]) occurs. Oral hypoglycemic drugs (eg, glyburide Some Trade Names DIABETA GLYNASE MICRONASE

Click for Drug Monograph ) are being increasingly used to manage diabetes in pregnant women because of the ease of administration (pills compared to injections), low cost, and single daily dosing. Several studies have demonstrated that glyburide Some Trade Names DIABETA GLYNASE MICRONASE Click for Drug Monograph is safe during pregnancy and that it provides control equivalent to that of insulin for women with gestational diabetes. For women with type II diabetes before pregnancy, data for oral drugs are scant; insulin is most often preferred. Oral hypoglycemics taken during pregnancy may be continued postpartum during breastfeeding, but the infant should be closely monitored for signs of hypoglycemia. Management of complications: Although diabetic retinopathy, nephropathy, and mild neuropathy do not contraindicate pregnancy, they require preconception counseling and close management before and during pregnancy. Retinopathy requires that an ophthalmologic examination be done every trimester. If proliferative retinopathy is noted at the first prenatal visit, photocoagulation should be used as soon as possible to prevent progressive deterioration. Nephropathy, particularly in women with renal transplants, predisposes to pregnancy-induced hypertension. Risk of preterm delivery is higher if maternal renal function is impaired or if transplantation was recent. Prognosis is best if delivery occurs 2 yr after transplantation. Congenital malformations of major organs are predicted by elevated Hb A1c levels at conception and during the first 8 wk of pregnancy. If the level is 8.5% during the 1st trimester, risk of congenital malformations is significantly increased, and targeted ultrasonography and fetal echocardiography are done during the 2nd trimester to check for malformations. If women with type 2 diabetes take oral hypoglycemic drugs during the 1st trimester, fetal risk of congenital malformations is unknown (see Table 2: High-Risk Pregnancy: Drugs With Adverse Effects During Pregnancy ). Labor and delivery: Certain precautions are required to ensure an optimal outcome. Timing of delivery depends on fetal well-being. Women are told to count fetal movements during a 60-min period daily (fetal kick count) and to report any sudden decreases to the obstetrician immediately. Nonstress testing (see Normal Pregnancy, Labor, and Delivery: Fetal Monitoring) is begun at 32 wk and, if

results are nonreassuring, is followed by a biophysical profile (measurement of amniotic fluid and fetal muscle tone, movement, and breathing pattern). These tests and similar noninvasive prenatal fetal monitoring tests (called antenatal testing) are initiated earlier if women have severe hypertension or a renal disorder or if fetal growth restriction is suspected. Amniocentesis to assess fetal lung maturity is often necessary in women with the following:

Obstetric complications in past pregnancies Elective delivery before 39 wk Inadequate prenatal care Uncertain delivery date Poor glucose control

Type of delivery is usually spontaneous vaginal delivery at term. If labor does not begin spontaneously by 38 to 40 wk, induction is necessary because of the increasing risk of stillbirth and shoulder dystocia. Dysfunctional labor, fetopelvic disproportion, or risk of shoulder dystocia may make cesarean delivery necessary. Plasma glucose levels are best controlled during labor and delivery by a continuous low-dose insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph infusion. If induction is planned, women eat their usual diet the day before and take their usual insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph dose. On the morning of labor induction, breakfast and insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph are withheld, baseline fasting plasma glucose is measured, and an IV infusion of 5% dextrose in 0.45% saline solution is started at 125 mL/h, using an infusion pump. Initial insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph infusion rate is determined by capillary glucose level. Insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph dose is determined as followed:

Initially: 0 units for a capillary level of < 80 mg/dL (< 4.4 mmol/L) or 0.5 units/h for a level of 80 to 100 mg/dL (4.4 to 5.5 mmol/L) Thereafter: Increased by 0.5 units/h for each 40-mg/dL (2.2-mmol/L) increase in glucose level over 100 mg/dL up to 2.5 units/h for levels > 220 mg/dL (> 12.2 mmol/L) Every hour during labor: Measurement of glucose level at bedside and adjustment of dose to keep the level at 70 to 120 mg/dL (3.8 to 6.6 mmol/L) If the glucose level is significantly elevated: Possibly additional bolus doses

For spontaneous labor, the procedure is the same, except that if intermediateacting insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph was taken in the previous 12 h, the insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph dose is decreased. For women who have fever, infection, or other complications and for obese women who have type 2 and have required > 100 units of insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph /day before pregnancy, the insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph dose is increased. Postpartum: After delivery, loss of the placenta, which synthesizes large amounts of insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph antagonist hormones throughout pregnancy, decreases the insulin requirement immediately. Thus, women with gestational diabetes and many of those with type 2 require no insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph postpartum. For women with type 1, insulin requirements decrease dramatically

but then gradually increase after about 72 h. During the first 6 wk postpartum, the goal is tight glucose control. Glucose levels are checked before meals and at bedtime. Breastfeeding is not contraindicated but may result in hypoglycemia if oral hypoglycemics are taken. Women who have had gestational diabetes should have a 2-h oral glucose tolerance test with 75 g of glucose at 6 to 12 wk postpartum to determine whether diabetes has resolved. Last full review/revision December 2008 by Sean C. Blackwell, MD Content last modified December 2008

Progression of retinopathy during pregnancy in type 1 diabetes mellitus.


Rahman W, Rahman FZ, Yassin S, Al-Suleiman SA, Rahman J. University Hospitals of Leicester, Leicester, UK. PURPOSE: The incidence and risk factors for progression of retinopathy during pregnancy in women with type 1 diabetes mellitus were retrospectively evaluated. METHODS: Fifty-four insulin-dependent diabetic patients at a teaching hospital in Saudi Arabia were followed throughout the pregnancy/puerperium with serial ophthalmic examination. Dilated fundus examination was performed in each trimester and puerperium. RESULTS: Progression of diabetic retinopathy in the study occurred in 13/54 (24%) patients--2/22 (9.1%) patients had no diabetic retinopathy initially, 4/20 (20%) had non-proliferative diabetic retinopathy (NPDR) and 7/12 (58.3%) had proliferative diabetic retinopathy (PDR). Of the eight patients with PDR who had no laser treatment before pregnancy, six (75%) showed progression but only one of the four patients who had PDR and laser treatment prior to pregnancy experienced progression of retinopathy. Eight patients in total received panretinal photocoagulation to arrest the progression of retinal disease during pregnancy and only one of them had laser treatment prior to pregnancy. CONCLUSION: Laser photocoagulation for severe NPDR or early PDR prior to pregnancy may protect against rapid progression of PDR. Visual impairment resulting from progression of PDR can be prevented by aggressive laser treatment during pregnancy. Duration of diabetes>15 years, poor glycaemic control and hypertension are high-risk factors in the progression of diabetic retinopathy in pregnancy. PMID: 17430509 [PubMed - indexed for MEDLINE]

MeSH Terms
http://www.pakmedinet.com/4704

Chapter 36

Pregnancy in Preexisting Diabetes


Thomas A. Buchanan, M.D.
SUMMARY

ata from birth certificates in the United

States indicate that maternal diabetes complicates 2%-3% of all pregnancies, but these data may underestimate the true prevalence of maternal diabetes in pregnancy. Two major forms of maternal diabetes may occur during pregnancy: preexisting or "pregestational" diabetes, and gestational-onset or gestational diabetes mellitus (GDM). Only the former is known prior to pregnancy, and this form constitutes ~10% of cases of maternal diabetes. Thus, prevalence rates for pregestational diabetes appear to be in the range of 0.1%-0.3% of all pregnancies. These pregnancies are at risk for both maternal and fetal complications. Fetal complications of maternal diabetes can be divided into two major categories. Complications that arise from the effects of maternal diabetes on early fetal development (i.e., in the first trimester) include spontaneous abortions and major congenital malformations. In the absence of special preconceptional diabetes management, spontaneous abortions occur in 7%-17% of diabetic pregnancies and major malformations occur in 7%-13%. Rates of both complications are highest in women with the most marked hyperglycemia during the first trimester, and the rates of malformations appear to be decreasing in countries and medical centers where standards of diabetes care result in improved maternal blood glucose control prior to and during early pregnancy. The most prominent

fetal complications that can arise during the second and third trimesters are stillbirth and macrosomia (an excessively large infant). Stillbirths are now uncommon in diabetic pregnancies; congenital malformations and complications of maternal hypertensive disorders account for most of the 1.5- to 2-fold increase in perinatal mortality compared with nondiabetic pregnancies. Macrosomia appears to be the most frequent fetal complication, affecting 10%33% of infants, depending on the definition used for macrosomia. Macrosomia increases the risk of birth trauma and has been associated with a long-term risk of obesity in offspring. Maternal risks in diabetic pregnancies are greatest in the presence of preexisting microvascular disease (retinopathy and nephropathy). Diabetic retinopathy is present in 15%-66% of women early in pregnancy, and the retinopathy frequently worsens during gestation, especially when severe background or proliferative changes are present early on. Laser photocoagulation therapy prior to pregnancy can reduce the risk that proliferative retinopathy will worsen during gestation. Overt diabetic nephropathy is present before pregnancy in 5%-10% of patients; of these, two-thirds manifest hypertensive disorders during gestation. The hypertensive disorders precede pregnancy in approximately half of the cases and develop during pregnancy in the other half. Overt diabetic nephropathy in mothers increases the prevalence of intrauterine growth retardation and prematurity in infants; fetal morbidity and mortality increase as well. The long-term impact of pregnancy on diabetic retinopathy and nephropathy in mothers is not known.

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There is no national surveillance program for diabetes during pregnancy in the United States. As a result, it is not possible to determine true national prevalence rates for diabetes during pregnancy or for the various maternal and fetal complications that can occur when diabetes and pregnancy coexist. Data to help estimate prevalence rates for diabetes and its complications during pregnancy come from several sources. Since 1989, birth certificates in most states and the District of Columbia have included information on a variety of maternal and infant risk factors, including diabetes1. The birth certificate data provide the first national estimates of the prevalence of diabetes during pregnancy. However, the certificates do not distinguish between the focus of this chapter, diabetes that existed prior to pregnancypregestational diabetes, including insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM)

and diabetes that is first detected during pregnancy (GDM, discussed in Chapter 35). Birth certificate data may also suffer from inaccurate reporting of maternal and fetal complications (e.g., only 65% of maternal diabetes was recorded on birth certificates surveyed in Tennessee in 1989)2. Other data sources include regional or statewide data derived from a combination of birth certificate and hospital record information and published reports from individual medical centers. The former source may be the most complete for a specific region, although the magnitude of inaccurate reporting on birth certificates and hospital discharge summaries is difficult to assess. The latter source may suffer from at least two forms of bias related to patterns of patient referral and care. First, the medical centers that have published their patient data were predominantly specialized referral centers. It is likely that these centers managed the most complicated cases of maternal diabetes, so that prevalence rates of various maternal complications may be overestimated compared with the entire population. Second, physicians in most of these centers have extensive experience in the management of diabetes during pregnancy, so that maternal and fetal outcomes might be better for a given severity of diabetes than would be true for less specialized medical centers. Because of the limitations imposed by the lack of national data for many aspects of pregestational diabetes in pregnancy in the United States, some information from other countries has been included in this chapter, particularly when the structure of the health care system in those countries has allowed the collection of reasonably good national data on pregnancies complicated by maternal diabetes. Data from the 1991-92 National Health Interview Survey (NHIS)3,4 on the prevalence of known diabetes in white and black women age 18-44 years are shown in Figure 36.1. These data are based on self-reporting of physician-diagnosed diabetes and they indicate that 1.2% of white women and 2.2% of black women in the age group (525,000 and 140,000 women, respectively) have been diagnosed by a physician as having diabetes. The responses did not distinguish between IDDM and NIDDM, which have different age distributions in the population (see Chapter 2). Data from the National Health and Nutrition Examination Surveys (NHANES), in which medical history and oral glucose tolerance testing were used to ascertain diabetes, indicate that an additional 0.7%-1.3% of women age 20-44 years have undiagnosed diabetes (Figure 36.2). Of the women without diabetes, many have impaired glucose tolerance (IGT) (Figure 36.2), a condition in which

blood glucose concentrations are above normal but not in the diabetic range (Chapter 2). When diabetes and IGT estimates are combined, 10%-18% of nonpregnant women age 20-44 years have some type of abnormal glucose tolerance that would be associated with fetal or maternal risks if those women became pregnant. INTRODUCTION
Percent Number 0 0.5 1 1.5 2 2.5 0 1 2 3 4 5 6600 400 300 200 100 0 500 White Black

Figure 36.1

Prevalence of Diagnosed Diabetes in Women Age 18-44 Years, U.S., 1991-92


Data are based on self-reported information on physician-diagnosed diabetes in the 1991-92 National Health Interview Surveys. Source: References 3 and 4

PREVALENCE OF DIABETES IN WOMEN OF CHILDBEARING AGE 720

Precise details on the age distribution of diabetes in women of childbearing age are not available. However, data have been collected on the maternal age distribution for all live births and on birth rates according to maternal age in the entire U.S. population5. In 1992, 39% of births occurred to women age <25 years and only 10% occurred to women age 35 years (Figure 36.3). The birth rate was highest for white women age 25-29 years, and for black women age 20-24 years and birth rates declined almost linearly at older ages (Figure 36.4). This decline contrasts with the rising prevalence rates of diabetes with increasing age among women who are pregnant, as presented below. Data from birth certificates indicate that 2%-3% of pregnancies in the United States are complicated by some form of maternal diabetes1,6-8. These data do not distinguish between pregestational diabetes and GDM. However, since prevalence rates for the latter condition are in the range of 2%-4% when routine blood glucose screening is employed during pregnancy 9,10 (see Chapter 35), it is likely that: 1) the birth certificate data underestimate the overall prevalence of maternal diabetes during pregnancy2; and 2) a minority

of diabetic pregnancies occur in women with pregestational diabetes. Age-specific prevalence rates for all types of diabetes in white and black pregnant women, based on U.S. birth certificate data, are shown in Figure 36.5. Combined prevalence rates rise from <1% for women age <20 years to >6% for women age >40 years. Prevalence rates are higher for white women at age <25 years, when IDDM predominates and NIDDM and GDM are relatively uncommon. Rates are higher for black
Non-Hispanic White Black Mexican American Puerto Rican (New York, NY) Cuban American 0 5 10 15 20 IGT Undiagnosed diabetes Diagnosed diabetes <15 15-19 20-24 25-29 30-34 35-39 40 Maternal Age (Years) 0 5 10 15 20 25 30 35 White Black $ 15-19 20-24 25-29 30-34 35-39 40-44 Maternal Age (Years) 0 2 4 6 8 10 12 14 16 18 White Black

Figure 36.2

Prevalence of NIDDM and IGT in Women Age 20-44 Years, U.S., 1976-82
Figure 36.4

Birth Rates by Maternal Age for All Black and White Women, U.S., 1992
Figure 36.3

Distribution of All Live Births by Maternal Age for Black and White Women, U.S., 1992
Diagnosed diabetes is based on self-reported information on physician-diagnosed diabetes; undiagnosed NIDDM and impaired glucose tolerance (IGT) were determined by a 75-g, 2-hour oral glucose tolerance test interpreted acccording to World Health Organization criteria. Source: 1976-80 Second National Health and Nutrition Examination Survey and 1982-84 Hispanic Health and Nutrition Examination Survey Rates were determined from data on all birth certificates filed in the U.S. in 1992. Source: Reference 5 Data are from all birth certificates filed in the U.S. in 1991. Rates are expressed as the percent of births at all ages that occurred to women in each age group. Source: Reference 5

PREVALENCE OF PREGESTATIONAL DIABETES IN PREGNANT WOMEN 721

women at age >30 years, when NIDDM and GDM are more common complications of pregnancy. This pattern is consistent with the relative prevalence rates of IDDM and NIDDM or GDM in the two ethnic groups: IDDM is more common in whites, while NIDDM and GDM are more common in blacks. Population-based data from hospital records in the state of Washington11 indicate a prevalence rate for pregestational diabetes (both IDDM and NIDDM) of 2.1 per 1,000 live births in 1979-80. This figure is close to the prevalence rate for IDDM of 1.8 per 1,000 live births reported for 1982-85 in Sweden, where national data for IDDM in pregnancy are available. A slightly lower rate of diabetes has been reported from a population-based study (birth certificate data followed up by telephone interviews) of congenital malformations in Georgia; 1 per 1,000 pregnancies were complicated by pregestational diabetes in that study, which included both live-born and stillborn infants rather than live births alone12. On the basis of these limited population data, it appears that preexisting diabetes complicates pregnancies at a rate of ~1-3 per 1,000 births. A slightly higher prevalence rate would be expected if all pregnancies complicated by preexisting diabetes were considered, since 10%-20% of such pregnancies end in spontaneous abortions (discussed below) and an unknown number end in elective terminations. Even if these two factors are taken into account, the prevalence rate for pregestational diabetes appears to be somewhat less than predicted by the background prevalence of diagnosed diabetes in women of reproductive age (14 per 1,000 women age 18-44 years in 1991-92)3,4. Whether the discrepancy represents an underestimation of the rates of pregestational diabetes in pregnancy or a true reduction in the fertility rates of diabetic women is not known. The relative proportion of IDDM compared with NIDDM in pregestational diabetes is likely to vary according to the ethnicity of the population and the background prevalence of IDDM and NIDDM. For example, only NIDDM complicates pregnancies in Pima Indians with pregestational diabetes13, since IDDM does not occur in that ethnic group. By contrast, ~25% of pregestational diabetic pregnancies were complicated by NIDDM in the Washington state11 and Georgia12 studies. A large majority (>80%) of women with pregestational diabetes at Californias Los Angeles County/USC Medical Center, which provides care for a predominantly Latino population,

have clinical characteristics consistent with NIDDM14. Maternal diabetes may be associated with abnormal fetal development and excess fetal morbidity and mortality compared with nondiabetic pregnancies (discussed below). The frequencies of fetal abnormalities vary according to the type and timing of medical care delivered to women with diabetes. As a result, frequencies of fetal morbidity and mortality in diabetic pregnancies have been changing over the past six decades15, and the frequencies vary according to the intensity of maternal medical care provided during specific developmental periods. Thus, it is difficult and perhaps inappropriate to derive a single prevalence rate for any fetal complication of maternal diabetes in the absence of some knowledge of maternal health care. In the discussion below, an attempt had been made to express fetal risks in relation to measures of maternal health care such as glycemic control or access to specialized prenatal centers.

SPONTANEOUS ABORTIONS
Published data on overall rates of spontaneous abortion (SAB, generally defined as spontaneous loss prior to 20 weeks gestation) in pregestational diabetic pregnancies reveals no clear answer regarding whether the rates are increased compared with nondiabetic pregnancies. Some studies in the past16,17 reported rates
<20 20-24 25-29 30-34 35-39 40-49 All Ages Maternal Age (Years) 0 2 4 6 8 10 White Black

Figure 36.5

Percent of Birth Certificates Listing Diabetes in the Mother, U.S., 1991 FETAL COMPLICATIONS OF MATERNAL PREGESTATIONAL DIABETES
Rates were determined from birth certificates that contained a checkbox for the presence of maternal diabetes (most states and the District of Columbia). The checkboxes do not distinguish among IDDM, NIDDM, and gestational diabetes in the mother. Other limitations of birth certificate data that may have led to an underestimation of diabetes rates are discussed in the text. Source: Reference 1

722

that were twice as high as rates in nondiabetic women. More recent reports conclude that overall rates are no higher than observed18,19 or expected20,21 in the absence of maternal diabetes (Table 36.1). Some of the conflicting results may be attributed to methodological differences (e.g., ascertainment of SAB, recruitment of nondiabetic controls). However, in most studies there is a clear pattern of increased SAB rates when maternal metabolic control in early pregnancy is poor. For example, the Diabetes in Early Pregnancy Study reported SAB rates of 16.2% and

16.1% in prospectively recruited nondiabetic control subjects and patients with IDDM, respectively18. Among the diabetic women, the minority with evidence of poor metabolic control during the first trimester (as indicated by elevated blood glucose and glycosylated hemoglobin levels) had increased SAB rates (Table 36.2 and Figure 36.6). In a study of 303 women referred for management of pregestational diabetes, an overall SAB rate of 17% was found20. The SAB rate in nondiabetic control pregnancies was not determined, but diabetic women with poor glycemic control (elevated glycohemoglobin levels) in early pregnancy had much higher SAB rates than did women with good early-pregnancy control (Table 36.2). Population-based data from Sweden on SAB rates also indicate increased rates when maternal glycemic control is poor in early pregnancy. A study was made on 532 pregnancies complicated by pregestational IDDM, representing ~80% of all such pregnancies in Sweden during a 4-year period19. The SAB rate in these pregnancies was 7.7%, nearly the same as the 7.2% rate in
Table 36.2

Rates of Spontaneous Abortion in Pregnancies Complicated by Pregestational Diabetes, by Maternal GHb During the First Trimester
Reference 18 Reference 20 Reference 19 GHb Spontaneous GHb Spontaneous GHb Spontaneous SD>mean No. abortion (%) SD>mean No. abortion (%) SD>mean No. abortion (%)
<2 108 9.3 <6 113 12.4 <2 118 2.5 2-4 182 14.8 6-9 85 8.3 2-4 150 4.7 4-6 43 16.3 9-12 61 24.6 4-6 135 7.4 6-8 26 23.1 12-15 28 35.7 6-8 87 11.5 >8 16 37.5 >15 16 37.5 >8 42 26.2
GHb, glycohemoglobin; SD, standard deviation. GHb was determined during the first trimester or early second trimester and is expressed as SDs above the mean of nondiabetic individuals (References 18 and 19) or above the mean of the entire diabetic group (Reference 20). "No." denotes the number of diabetic women in each GHb category. Spontaneous abortion (%) denotes the percent of women in each GHb category who had a spontaneous abortion. Rates increased significantly with increasing GHb level in each study. Source: References are listed within the table <2 2-4 <6 4-6 6-8 >8 >12 GHb, Number of SDs Above the Mean 0 10 20 30 40 Reference 18 Reference 19 Reference 20

Figure 36.6

Rates of First Trimester Spontaneous Abortion in Pregnancies Complicated by Pregestational Diabetes, by Maternal GHb Levels
Table 36.1

Rates of Spontaneous Abortion in Recent Series of Pregnancies Complicated by Pregestational Diabetes and in Nondiabetic Pregnancies
Years Nondiabetic Diabetic Ref. of study No. % No. %
18 1980-85 70/432 16.2 62/386 16.1 19 1982-85 16/222 7.2 41/532 7.7

20 1983-87 52/303 17.2 21 1982-88 12/122 9.8


Nondiabetic control subjects were recruited prospectively in Reference 18 and were selected at random from one of the 36 hospitals at which diabetic women received care in Reference 19. Spontaneous abortion rates did not differ significantly between diabetic and nondiabetic groups in these two studies. No data from nondiabetic pregnancies were presented in References 20 or 21. Source: References are listed within the table GHb, glycohemoglobin; SD, standard deviation. Maternal GHb concentrations were measured during the first trimester or early second trimester of pregnancy. GHb is expressed as SDs above the mean of nondiabetic individuals (References 18 and 19) or as SDs above the mean of the entire diabetic group (Reference 20). See Table 36.2 for numbers of subjects in each study by GHb category. Source: References 18-20

723

a group of randomly selected, concurrent controls. However, the survey revealed that there was a progressive increase in the SAB rate among diabetic women as glycohemoglobin levels increased above normal (Table 36.2). Thus, it seems clear that the prevalence of SABs in women with pregestational diabetes is increased when blood glucose control is poor during the first trimester of pregnancy. Women with good control, whether recruited into a prospective program of preconceptional diabetes management or not, do not appear to have increased rates of SAB compared with nondiabetic women. Populations in which overall diabetes control is good (e.g., in Sweden19 ) can be expected to have no excess of SABs even in the absence of preconceptional diabetes management programs. By contrast, populations in which many diabetic women of reproductive age have poor metabolic control may be expected to have an increased rate of SABs unless specific programs of planned pregnancy and preconceptional diabetes management are implemented. It is important to note that, although the type of diabetes was not noted in all studies, most of the data cited above were derived from studies on patients with IDDM.

PERINATAL MORTALITY
Data from pregnancies complicated by maternal diabetes in 225 hospitals in North America and Europe reveal a large decline in the perinatal mortality rate, from 250-300 per 1,000 live births in 1940 to 30-50 per 1,000 live births in 198822 (Figure 36.7). Perinatal mortality also fell in nondiabetic pregnancies during the same period, but the magnitude of the fall was not as great. For example, in the United States, overall perinatal mortality declined from 60 per 1,000 in the 1940s to 15 per 1,000 in the 1980s. Specific disease processes that accounted for the higher perinatal mortality in diabetic pregnancies in past decades were not given. However, the number of perinatal deaths that were related to congenital malformations (discussed below) remained relatively constant over this period, so the reduction in overall mortality must have resulted from a progressive lowering of deaths not related

to congenital malformations. Prevention of stillbirths in non-malformed infants and improvement in maternal diabetes management and neonatal care likely accounted for much of the reduced mortality. As a result of the reduction in mortality not related to congenital malformations, the contribution of malformations to overall perinatal mortality in diabetic pregnancies has risen from 10%-15% in the 1940s to ~50% in the 1980s (Figure 36.8). The perinatal mortality rates shown in Figure 36.7 are hospital-based and may reflect the favorable impact of high-level medical, obstetrical, and neonatal care on infant mortality in diabetic pregnancies. Analyses of vital records and hospital discharge data from the states of South Carolina in 19786 and Washington in 1979-8011 revealed perinatal mortality rates of 182 per 1,000 and 108 per 1,000 births, respectively. The data from South Carolina included all insulin-treated patients, some of whom may have had gestational diabetes. The data from Washington state were limited to
1940 50 60 70 80 Decade 0 100 200 300 U.S. and Canada Europe <1960 60 70 80 Decade 0 10 20 30 40 50 Diabetic pregnancies All pregnancies

Figure 36.7

Perinatal Mortality Rates in Pregnancies Complicated by Insulin-Treated Diabetes, 1940-88


Figure 36.8

Contribution of Congenital Anomalies to Overall Perinatal Mortality in Diabetic and Nondiabetic Pregnancies, 1940-88
Data are from 12,893 pregnancies in insulin-treated diabetic women at hospitals in the United States and Canada; data for all pregnancies were derived from published hospital-based data for all women. Source: Reference 22 Data are from 225 hospitals in the United States and Canada (12,893 pregnancies) and Europe (17,538 pregnancies). Source: Reference 22

724

women with pregestational diabetes and indicated an increased perinatal mortality in both IDDM and NIDDM compared with the overall state perinatal mortality rate of 14 per 1,000. The apparently greater perinatal mortality in statewide data compared with data from specific medical centers (Figure 36.7) suggests that access to specialized medical centers may have an important beneficial impact on perinatal mortality in diabetic pregnancies. However, since no specific

information on management practices or metabolic regulation were available from any of the three studies, it is not possible to ascertain the impact of different medical practices on the reported perinatal mortality rates.

CONGENITAL MALFORMATIONS
Data collected during the past five decades from centers specializing in the care of pregnant women with diabetes indicate that major congenital malformations (generally defined as malformations that are fatal, require surgical correction, or lead to marked physical or psychological handicaps) occur in 7%-13% of pregestational diabetic pregnancies in the absence of special preconceptional diabetes care (Table 36.3)20,21,23-28. These data suffer from the potential bias created by patterns of referral to specialty centers. However, the fact that the prevalence rates are remarkably similar across centers and over time suggests that the bias may be relatively small. The precise types of anomalies that occur in excess in diabetic pregnancies remains controversial. In 1971, data on >7,000 pregnancies in diabetic women in Europe, North America, Australia, and South Africa were summarized29. Congenital malformations were reported in 4.8% of those pregnancies, compared with only 0.65% of nondiabetic pregnancies in different published series. Malformations of the spine, skeleton, kidneys/ureters, and heart, along with situs inversus, were significantly increased in the diabetic pregnancies. The study suffers from a lack of populationbased data and appropriate nondiabetic control pregnancies, as well as a lack of systematic methods for ascertainment of malformations. However, the study is frequently cited in reference to the types of anomalies in diabetic pregnancies because of the large number of pregnancies considered. Most subsequent reports on malformations in diabetic pregnancies have involved too few women to determine whether specific anomalies were increased. However, a population-based, case-control study in the metropolitan Atlanta, GA area found that the risks of anomalies of the central nervous system and the cardiovascular system were increased significantly (15- to 18-fold) in infants of women with pregestational diabetes compared with nondiabetic women12. Anomalies of these two systems were also among the most frequently reported in most of the series in Table 36.3, so it appears very likely that the cardiovascular and central nervous systems are specifically affected by maternal diabetes. The caudal regression syndrome has also been reported to be much more frequent in diabetic compared with nondiabetic pregnancies, so the risk of that rare abnormality is likely to be increased

by maternal pregestational diabetes as well. Whether major malformations of other organ systems are related specifically to maternal diabetes in the United States remains in question. Prevalence rates of minor congenital anomalies (those not requiring surgical or medical intervention and not causing significant morbidity) do not appear to be increased by the presence of maternal diabetes28,30,31. The above discussion considers pregnancies in which no special preconceptional diabetes management was provided. Data from at least five studies21,28,32-34, two of which were conducted in the United States, indicate that rates of major congenital malformations are lower in offspring of women who participate in special preconceptional diabetes management programs than in offspring of diabetic women who first seek medical attention while they are pregnant (Table 36.4). This suggests that careful metabolic regulation prior to and during early pregnancy can lower the incidence of malformations in diabetic pregnancies. However, it is also possible that women who participate in preconceptional care programs are more health conscious
Table 36.3

Rates of Major Congenital Malformations in Offspring of Women with Pregestational Diabetes


Years of % with anomalies in infants of: Ref. study Diabetic mothers Nondiabetic mothers
23 1946-78 8 3 24 1961-70 11 26 1971-75 7 27 1977-80 13 25 1977-81 8 2 28 1980-85 9 2 20 1983-87 8 21 1982-88 11
Definitions of a major malformation vary among studies but usually require significant impact on the well-being of the infant. A control group of nondiabetic women was recruited prospectively only in References 25 and 28; malformation rates were significantly higher in the diabetic groups in these studies. The nondiabetic malformation rate in Reference 23 is the rate in nondiabetic women at the same hospital. Source: References are listed within the table

725

and at lower risk for a malformed infant for reasons unrelated to improved metabolic control. Data from countries such as Sweden19, Denmark31, and parts of England35, where diabetes care has improved in the population as a whole, suggest that improved metabolic control does contribute to reduction in malformations associated with participation in preconception care programs. Congenital malformation rates in diabetic pregnancies have declined in these regions in the last decade, even among women who do not participate in preconceptional care programs35. Thus, it is likely that at least some of the differences in anomaly rates in Table 36.4 are related to an effect of improved metabolic control during early pregnancy. Efforts to improve general diabetes care in the United States36

are likely to result in an overall reduction in malformation rates in diabetic pregnancies similar to the reductions observed in Sweden, Denmark, and parts of England. A reduction in malformation rates would effect a significant reduction in the cost of diabetic pregnancies in the United States37.

MACROSOMIA AND HYPOGLYCEMIA


One of the major effects of maternal diabetes during the second and third trimesters is fetal overnutrition, which may result in excessive fetal growth (macrosomia) and fetal hyperinsulinemia with neonatal hypoglycemia. The reported prevalence of these two complications varies due to at least two factors: 1) lack of standard definitions for macrosomia and neonatal hypoglycemia, and 2) different approaches to clinical management of diabetic pregnancies. Prevalence rates reported from medical centers for infants that are large-for-gestational-age (LGA, >90th percentile weight for age) in pregestational diabetic pregnancies have been in the range of 29%-33% during the past decade38-40. These rates are significantly greater than the expected prevalence of 10% based on the definition of LGA as >90th percentile. Among all births in the United States in 1991, the proportion of infants weighing >4,000 grams at birth was 10.6% (Figure 36.9). Prevalence rates were highest in Native Americans (12.6%) and whites (11.9%) and lowest in blacks (5.2%) and Asian Americans (5.2%-8.9%)5. At least two significant morbidities may result from fetal macrosomia. Birth trauma may result from fetal size that is disproportionate to the birth canal. This complication was reported to be twice as common in infants of diabetic compared with nondiabetic mothers in a statewide survey based on birth certificate data from North Carolina in 1989-907. Reports from centers specializing in the care of diabetic pregnancies indicate lower rates of birth trauma41, although rates of cesarean delivery are often high in these centers (see below). The second major complication that may occur following fetal macrosomia is a long-term risk of obesity. When measured at age 7-8 years42 or age 15-19 years43, offspring of mothers with diabetes (including NIDDM, IDDM, and GDM) were overweight compared with offspring of nondiabetic mothers. The long-term impact of this phenomenon on the prevalence of obesity in offspring of diabetic mothers remains to be determined. Prevalence rates of neonatal hypoglycemia (i.e., serum or plasma glucose <30 mg/dl for term infants or <20 mg/dl for preterm infants) in infants of mothers
Table 36.4

Rates of Major Congenital Malformations in Infants of Women with Pregestational Diabetes,

by Participation in a Preconception Care Program


Malformation rate (%) in infants of women who: Ref. Did not participate Participated
32 7.5 0.8 33 9.6 0.0 34 10.4 1.4 21 10.9 1.2 28 9.0 4.9
Those who did not participate received no special preconceptional care; those who participated were enrolled in a diabetes care program prior to conception (up to the third week postconception in Reference 28). In References 21 and 32-34, attempts were made to maintain maternal glycemia as close to normal as possible prior to conception; no special preconception glycemic goals were used in Reference 28. The infants of women who participated in a preconceptional care program had significantly lower malformation rates in each study. Source: References are listed within the table 0 2 4 6 8 10 12 14

Figure 36.9

Percent of All U.S. Births with Birthweight 4,000 Grams, by Race of Mother, 1992
Data are from all birth certificates filed in the United States in 1992. Source: Reference 5

726

with pregestational diabetes have been reported to be in the range of 8%-37%6,40,44-47. The prevalence rates may vary according to degree of maternal metabolic regulation and intensity of neonatal glucose monitoring, since many infants show no physical signs of low blood glucose concentration. Hypoglycemia requiring glucose infusion was more common in diabetic than nondiabetic pregnancies in one study40. However, strict criteria for institution of glucose infusion were not provided in that study, so it is possible that knowledge of the maternal condition biased the treatment for hypoglycemia.

OTHER MORBIDITIES IN OFFSPRING


Offspring of women with pregestational diabetes have been reported to be at increased risk for several other perinatal complications based on studies at single or multiple medical centers. These complications include polyhydramnios48, polycythemia44,47, neonatal jaundice40,44,47, hypocalcemia44,49, and respiratory distress syndrome44,47. The last three of these complications may be made more frequent by premature delivery 44,50,51, which was a routine practice 10-15 years ago but has become less common with the advent of improved glycemic control and noninvasive techniques for fetal monitoring. Thus, the frequencies of most of these fetal complications have fallen in the past decade. Population-based data for these perinatal complications are not available from diabetic pregnancies in the United States. However, data from a populationbased study of IDDM in Sweden provides an estimate of the frequency of polycythemia, jaundice, hypoglycemia,

and respiratory distress syndrome in neonates when diabetic mothers have ready access to specialized diabetes care before and during pregnancy47. In this study, each of these four complications was more frequent in diabetic than nondiabetic pregnancies (Table 36.5). Gestational ages at delivery were slightly lower in diabetic compared with control pregnancies in the study, so prematurity may have contributed to the intergroup differences in fetal complications.

MORTALITY
Prior to the advent of exogenous insulin therapy, maternal survival during pregnancy was severely compromised by the presence of preexisting diabetes. For example, survival was <50% in one small series reported from the early 1900s52. Today, maternal mortality is a rare event in diabetic and normal pregnancies. Commonly cited figures for maternal mortality during pregnancy have been in the range of 3-7 per 100,000 for diabetic women and 7-9 per 100,000 for the general population53. A lack of good population-based data makes it impossible to determine whether mortality rates differ between these two groups in the United States. Women with maternal vascular disease, particularly coronary artery disease, do appear to be at increased risk for mortality during pregnancy. In a series of pregnancies managed at the Joslin Clinic in Boston, MA during 1963-75, only one of four diabetic women with symptomatic heart disease survived pregnancy and the perinatal period52. The only survivor had coronary bypass surgery prior to pregnancy. In a separate study, only three of 11 diabetic women with symptomatic heart disease survived pregnancy54. Data on survival of patients who have had successful coronary revascularization are largely anecdotal, so no firm conclusions can be drawn about maternal mortality in these women.

DIABETIC RETINOPATHY
Virtually all data on diabetic retinopathy in pregnancy are based on diabetic women whose pregnancies were managed at medical centers. Thus, it is impossible to determine the true population-based prevalence rate for diabetic retinopathy among pregnant women with pregestational diabetes. Published data indicate that 15%-66% of women with pregestational diabetes have retinopathy at the start of pregnancy26,47,48,55-57 . To the extent that patients with diabetic complications are preferentially referred to specialized centers, these figTable 36.5

Neonatal Morbidity in Pregnancies Complicated by Pregestational IDDM, Sweden, 1982-85


Infants with morbidity (%) Neonatal

morbidity Diabetic mothers (n=491 births) National data (n=279,000 births) p


Idiopathic respiratory distress syndrome 1.6 0.6 <0.01 Hypoglycemia 8.0 0.2 <0.001 Jaundice 16.3 3.9 <0.001 Polycythemia 2.2 0.1 <0.001
Data from diabetic mothers come from ~80% of all pregnancies with IDDM in Sweden during the study period. Hypoglycemia denotes blood glucose <30 mg/dl with signs of hypoglycemia. Jaundice denotes serum bilirubin >300 mol/L. Polycythemia denotes a central venous hematocrit >70%. Source: Reference 47

MATERNAL COMPLICATIONS OF PREGESTATIONAL DIABETES 727

ures may represent an overestimate of the prevalence of retinopathy among all women with pregestational diabetes. While data from specialized referral centers may not provide accurate estimates of the prevalence of diabetic retinopathy in pregnant women, these data are useful for assessing changes in retinopathy during pregnancy. Data from many published series indicate that retinopathy often worsens during pregnancy and the risk of worsening is greatest for women who enter pregnancy with existing retinopathy. Thus, incidence rates for development of background retinopathy in women with no retinopathy prior to pregnancy were reported to be 0%-33%55,56,58,59 . Progression from background to proliferative changes occurred in 10%-65% of patients and worsening of proliferative changes occurred in 14%-100% of patients55,56,58,59. Three additional facts are of note. First, many of the new background and mild proliferative changes regressed without laser therapy within 1 year after delivery, so the deterioration that occurred during pregnancy was not necessarily permanent. Second, it is likely that some of the deterioration was related to rapid improvements in glycemic control60 that are often initiated to protect the fetus. Thus, the incidence of new retinal changes may be altered by the degree of metabolic control at the start of pregnancy, with worse control predisposing to a higher risk of retinopathy55. Finally, incidence rates for retinal complications during pregnancy may be altered by prior treatment. For example, of six diabetic women who had laser therapy for proliferative changes prior to conception, worsening of proliferative changes during pregnancy occurred in only one (17%)59. This rate was much lower than the 86% rate in women with untreated proliferative changes at the beginning of pregnancy. The long-term status of vision in women who have had diabetic

retinopathy during pregnancy is not known.

DIABETIC NEPHROPATHY
As was true for retinopathy, most data on diabetic nephropathy during pregnancy in the United States come from specialized referral centers, so the data may overestimate the true prevalence of nephropathy in women with pregestational diabetes. The data suggest that 2%-22% of diabetic women have overt nephropathy (generally defined as proteinuria >300-500 mg/24 hours during the first half of gestation)21,26,47,6164. The study with a 2% prevalence of nephropathy involved Latino patients, most of whom had NIDDM26. The later age at onset of NIDDM compared with IDDM may explain the relatively low prevalence of overt nephropathy in this study. Population-based data from Sweden47 indicate that ~5% of women with IDDM have proteinuria consistent with overt nephropathy in early pregnancy. Statewide data from Washington11 indicate that ~10.5% of women with IDDM have diabetic nephropathy or retinopathy, but the exact prevalence of nephropathy is not clear from these data. On the basis of these two studies, it appears that 5%-10% is a reasonable estimate for the overall prevalence of overt nephropathy in women with IDDM who become pregnant. Similar data for women with NIDDM are not available. Several obstetrical and perinatal complications are common in women with overt nephropathy. These women have a high prevalence (13%-48%) of chronic hypertension antedating pregnancy26,62,64-66 . In addition, patients without preexisting hypertension frequently (21%-52% of cases) develop pregnancy-induced hypertension or preeclampsia (see below) 47,62,65,67 . Thus, a majority of patients with overt nephropathy have elevated blood pressure by the third trimester. Premature delivery is common. Delivery at <37 weeks gestation occurs in 23%-60% of women with nephropathy and 9%-31% are delivered at <34 weeks gestation65,68,69 . Hypertensive disorders account for 17%-63% of deliveries before 37 weeks62,65,66,69 . Prematurity is associated with a variety of neonatal complications, including respiratory distress syndrome, intracranial bleeding, jaundice, hypocalcemia, and hypoglycemia. Infants have been reported to be small-for-gestational-age at birth in 10%21% of pregnancies with overt nephropathy64,66,68. The growth retardation may be related to hypertensive disorders, placental vascular abnormalities, or undetermined factors. Maternal anemia has been reported in ~40% of women with overt diabetic nephropathy 62,64. The effect of pregnancy on renal function in women with overt diabetic nephropathy has been studied primarily

during and shortly after pregnancy. Many patients with overt nephropathy experience a rise in protein excretion during the last half of gestation 62,66,70. For example, in one study about two-thirds of patients manifested a >3g/24 hour increase in proteinuria between the first and third trimesters; most of the increase occurred during the third trimester62. Patients with marked proteinuria often develop significant fluid retention and edema. Protein excretion has been reported to return to prepregnancy or early pregnancy levels soon after delivery in 66%-100% of patients62,66,70. Creatine clearance often remains stable or declines slightly during gestation62, in contrast to the increase in creatinine clearance that normally occurs during pregnancy. 728 Whether pregnancy causes any long-term deterioration in renal function is largely unknown. Two uncontrolled studies measured renal function in a small number of women with overt nephropathy for several years after delivery62,64. In both, rates of decline in renal function were consistent with the natural course of diabetic nephropathy, suggesting that pregnancy per se did not accelerate the decline. Nonetheless, the natural history of diabetic nephropathy dictates that women who have overt nephropathy during pregnancy are likely to experience a worsening of renal function in the years following delivery. Actual rates of development of renal failure in these patients remain to be determined, particularly with the implementation of renal protective therapy such as blood pressure control71 or angiotensin converting enzyme inhibition72. Diabetic nephropathy may be detected prior to the development of overt proteinuria by measuring the urinary albumin excretion rate. Patients who do not have overt proteinuria detectable by indicator strips but who excrete albumin at greater-than-normal rates (i.e., microalbuminuria) are at risk for developing overt nephropathy and renal failure. The prevalence of microalbuminuria has not been reported in women with pregestational diabetes. However, in one report the prevalence rates for hypertensive disorders of pregnancy and for premature deliveries were increased in women whose albumin excretion rates were 190-299 mg/24 hours (i.e., in the range of microalbuminuria) in early pregnancy65. This finding may account for some of the increased prevalence of hypertensive disorders of pregnancy observed in diabetic women without overt nephropathy (see below).

DIABETIC NEUROPATHY
No prevalence rates are available for any form of diabetic neuropathy during pregnancy. One cross-sectional

study in Finland suggests that pregnancy does not increase the prevalence of diabetic autonomic neuropathy73, although symptoms of autonomic neuropathy may worsen during pregnancy74, 75.

HYPERTENSIVE DISORDERS
Definitions of pregnancy-induced hypertension (PIH) vary among studies. The definitions apply to women who do not have hypertension at the beginning of pregnancy and usually are based on the development of a defined level of elevated blood pressure (e.g., systolic >140/90 mmHg or diastolic >105 mmHg) or an increase in blood pressure above a first trimester value (e.g., by 20 mmHg in mean arterial pressure). Preeclampsia is generally defined as PIH with overt proteinuria. Population-based data from Sweden47 indicate that PIH and preeclampsia occur three to four times more frequently in women with pregestational diabetes than in nondiabetic women. Undoubtedly, some of the increase is due to women with overt diabetic nephropathy, since approximately half of these women develop hypertensive disorders during pregnancy. However, even women without overt nephropathy are at increased risk for PIH and preelampsia. For example, in a Swedish study hypertensive disorders occurred in 18.7% of pregnant women with IDDM who did not have overt diabetic nephropathy in early pregnancy47. This prevalence was significantly higher than the 5% prevalence of hypertensive disorders in nondiabetic women in Sweden. At least two factors might explain the association between pregestational diabetes and hypertensive disorders in the absence of overt nephropathy: 1) the presence of incipient nephropathy with microalbuminuria in some patients, and 2) an association between diabetes (especially NIDDM) and hypertensive disorders in general76, 77. The relative contributions of these factors to hypertensive disorders of pregnancy in women with IDDM and NIDDM and in women from different ethnic groups remain to be determined.

PRETERM AND CESAREAN DELIVERY


The prevalence of cesarean deliveries has consistently been reported to be higher in pregestational diabetic pregnancies than in nondiabetic pregnancies in patients at specialized medical centers. Cesarean rates have been in the range of 24%-66% in diabetic patients 48, rates that were three to five times the rates in nondiabetic women26,45,47,78 . Cesarean rates are higher in women with retinopathy or nephropathy than in women without these complications48. Reasons for cesarean delivery are seldom specified in published reports, so it is difficult to determine factors that underlie the increased cesarean rates. Undoubtedly, the practice of early delivery to avoid fetal demise

contributed to the high rate of cesarean delivery in the past. However, recent information indicates that rates of cesarean delivery are still three to four times the rates in nondiabetic pregnancies44. The relative contributions of hypertensive disorders, fetal distress, and fetal macrosomia to the excess of cesarean deliveries remain to be established. Preterm deliveries have also been reported to be more frequent in diabetic compared with nondiabetic preg729 nancies. Recent population-based data from Sweden47 revealed a 25% rate of preterm delivery (<37 weeks gestation) in women with IDDM, compared with only 6% in the general population. At the University of Cincinnati69 in Ohio and McMaster University in Canada 40, preterm delivery rates in patients with pregestational diabetes were 24% and 30%, respectively. The diabetic rate was greater than the 12% rate of preterm delivery in nondiabetic women in the Cincinnati study. Hypertensive disorders accounted for 48% of preterm deliveries in the McMaster series but only 16% of preterm deliveries in Cincinnati. In the latter, 54% of the preterm deliveries resulted from spontaneous preterm labor. Other factors that may contribute to preterm deliveries in diabetic pregnancies include fetal distress (16% at the University of Cincinnati) and suspected fetal macrosomia.

MATERNAL HYPOGLYCEMIA
Strict glucose regulation in diabetic patients is known to increase the frequency of hypoglycemic episodes79. Relatively few recent data are available to define the prevalence of symptomatic hypoglycemia in pregestational diabetic women during pregnancy; none of the prevalence rates comes from population-based studies. Of 165 women with IDDM managed at the University of Cincinnati during 1978-86, 34% experienced symptomatic hypoglycemia80. A similar frequency of hypoglycemia (35% of patients) during the first trimester was reported for women with IDDM who received care during 1982-8821. Hypoglycemia that required assistance treatment from others was found in 72% of a small group of intensively treated patients with IDDM; 36% of these women had hypoglycemia requiring intravenous glucose81. No adverse effects of maternal hypoglycemia on fetal outcome were noted in these studies. Although a large amount of information has been published regarding pregnancy in women with diabetes, very few population-based data are available to reveal true prevalence rates for maternal pregestational diabetes or its complications during pregnancy. The information presented in this chapter, derived largely from specialized referral centers, provides

strong evidence that several fetal and maternal complications are increased in women with pregestational diabetes. Few of the studies made any distinction between IDDM and NIDDM; those that did presented data primarily on pregnancies complicated by IDDM. Very little of the information is reported on the basis of specific ethnic groups. Thus, although it seems clear that maternal diabetes is an important health risk during pregnancy, much additional information is needed to assess the true impact of pregestational IDDM and NIDDM on maternal and fetal well-being in different ethnic groups in the United States. Dr. Thomas A. Buchanan is Associate Professor of Medicine and Obstetrics and Gynecology, University of Southern California School of Medicine, and Staff Physician, Los Angeles County and University of Southern California Medical Center, Los Angeles, CA. CONCLUSION 730
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population-based case-control study. Pediatrics 85:1-9, 1990 13. Pettitt D: Personal communication 14. Buchanan TA: Unpublished data 15. Gabbe S: Medical complications of pregnancy. Management of diabetes in pregnancy: Six decades of experience. In Yearbook of Obstetrics and Gynecology. Part I: Obstetrics. Pitkin RK and Zlatnik FJ, eds. Chicago, IL, Yearbook Medical Publishers, 1980, p. 37-49 16. Sutherland HW, Pritchard CW: Increased incidence of spontaneous abortion in pregnancies complicated by maternal diabetes. Am J Obstet Gynecol 155:135-38, 1986 17. Miodovnik M, Lavin JP, Knowles HC, Holroyde J, Stys SJ: Spontaneous abortion among insulin-dependent diabetic women. Am J Obstet Gynecol 150:372-76, 1984 18. Mills JL, Simpson JL, Driscoll SG, Jovanovic-Peterson L, Van Allen M, Aarons JH, Metzger BE, Beiber FR, Knopp RH, Holmes LB, Peterson CM, Withiam-Wilson M, Brown Z, Ober C, Harley E, Macpherson TA, Duckles A, MuellerHeubach E, and the NICHD Diabetes in Early Pregnancy Study: Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception. N Engl J Med 319:1617-23, 1988 19. Hanson U, Persson B, Thunell S: Relationship between hemoglobin A1c in early type I (insulin-dependent) diabetic pregnancy and the occurrence of spontaneous abortion and fetal malformation in Sweden. Diabetologia 33:100-04, 1990 20. Greene MF, Hare JW, Cloherty JP, Benacerraf BR, Soeldner JS: First-trimester hemoglobin A1 and risk for major malformation and spontaneous abortion in diabetic pregnancy. Teratology 39:225-31, 1989 21. Kitzmiller JL, Gavin LA, Gin GD, Jovanovic-Peterson L, Main EK, Zigrang WD: Preconception care of diabetes. Glycemic control prevents congenital malformations. JAMA 265:731-36, 1991 22. Centers for Disease Control: Perinatal mortality and congenital malformations in infants born to women with insulindependent diabetes mellitus: United States, Canada and Europe, 1940-1988. Morbidity and Mortality Weekly Report 39:363-65, 1990 23. Pedersen J: The Pregnant Diabetic and Her Newborn: Problems and Management, 2nd Edition. Baltimore, MD, Williams and Wilkins, 1977, p. 191-97 24. Karlsson K, Kjellmer I: The outcome of diabetic pregnancies in relation to the mothers blood sugar level. Am J Obstet Gynecol 112:213-20, 1972 25. Simpson JL, Elias S, Martin AO, Palmer MS, Ogata ES, Radvany RA: Prospective study of anomalies in offspring of mothers with diabetes mellitus. Am J Obstet Gynecol 146:263-70, 1983 26. Gabbe SG, Mestman JH, Freeman RK, Goebelsman UT, Lowensohn RI, Nochimson D, Cetrulo C, Quilligan EJ: Management and outcome of pregnancy in diabetes mellitus, classes B to R. Am J Obstet Gynecol 129:723-32, 1977 27. Miller E, Hare JS, Cloherty JP, Dunn PJ, Gleason RE, Soeldner S, Kitzmiller JL: Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers. N Engl J Med 304:1331-34, 1981 28. Mills JL, Knopp RH, Simpson JL, Jovanovic-Peterson L, Metzger BE, Holmes LB, Aarons JH, Brown Z, Reed GF, Beiber FR, Van Allen M, Holzman I, Ober C, Peterson CM, Withiam MJ, Duckles A, Mueller-Heubach E, Polk BF, and

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1980 46. Anderson O, Hertel J, Schmolker L, Kuhl C: Influence of maternal plasma glucose concentration at delivery on the risk of hypoglycemia in infants of IDDM mothers. Acta Paediatr Scand 74:268-73, 1985 47. Hanson U, Persson B: Outcome of pregnancies complicated by type I insulin dependent diabetes in Sweden: Acute pregnancy complications, neonatal mortality and morbidity. Am J Perinatol 10:330-33, 1993 48. Cousins L: Pregnancy complications among diabetic women: Review 1965-1985. Obstet Gynecol Surv 42:140-49, 1987 49. Demarini S, Mimouni F, Tsang R, Khoury J, Hertzberg V: Impact of metabolic control of diabetes during pregnancy on neonatal hypocalcemia: A randomized study. Obstet Gynecol 83:918-22, 1994 50. Soler NG, Soler SM, Malins JM: Neonatal morbidity among infants of diabetic mothers. Diabetes Care 1:340-50, 1978 51. Mimouni F, Miodovnik M, Whitsett JA: Respiratory distress syndrome in infants of diabetic mothers in the 1980s: No direct effect of maternal diabetes with modern management. Obstet Gynecol 69:191-95, 1987 52. Hare JW, White P: Pregnancy in diabetes complicated by vascular disease. Diabetes 26:953-55, 1977 53. National Center for Health Statistics: Advance report of final mortality statistics, 1991. Monthly Vital Statistics Report, Vol. 42, no. 2, Suppl., August 31, 1993 54. Silfen SL, Wapner RJ, Gabbe SG: Maternal outcome in class H diabetes mellitus. Obstet Gynecol 55:749-51, 1980 55. Phelps RL, Sakol P, Metzger BE, Jampol LM, Freinkel N: Changes in diabetic retinopathy during pregnancy. Arch Ophthalmol 104:1806-10, 1986 56. Rosenn B, Miodovnik M, Kranias G, Khoury J, Combs CA, Mimouni F, Siddiqi TA, Lipman MJ: Progression of diabetic retinopathy in pregnancy: Association with hypertension. Am J Obstet Gynecol 166:1214-18, 1992 57. Maloney JBM, Drury MI: The effect of pregnancy on the natural course of diabetic retinopathy. Am J Ophthal 93:74556, 1982 58. Serup L: Influence of pregnancy on diabetic retinopathy. Acta Endocrinol 277 (Suppl.):122-24, 1986. 59. Dibble CM, Kochenour NK, Worley RJ, Tyler FH, Swartz M: Effect of pregnancy on diabetic retinopathy. Obstet Gynecol 59:699-704, 1982 60. The Kroc Collaborative Study Group: Blood glucose control and the evolution of diabetic retinopathy and albuminuria: A preliminary multicenter trial. N Engl J Med 311:365-72, 1984 61. Jovanovic-Peterson L, Peterson C, Reed GF, Metzger BE, Mills JL, Knopp RH, Aarons JH, and the NICHD Diabetes in Early Pregnancy Study: Maternal postprandial glucose levels and infant birth weight: The diabetes in early pregnancy study. Am Obstet Gynecol 164:103-11, 1991 62. Kitzmiller JL, Brown ER, Phillippe M, Stark AR, Acker D, Kaldany A, Singh S, Hare JW: Diabetic nephropathy and perinatal outcome. Am J Obstet Gynecol 141:741-51, 1981 63. Berk MA, Miodovnik M, Mimouni F: Impact of pregnancy on complications of IDDM. Am J Perinatol 5:359-67, 1988 64. Reece EA, Coustan DR, Hayslett JP, Holford T, Coulehan J, OConnor TZ, Hobbins JC: Diabetic nephropathy: Pregnancy performance and fetomaternal outcome. Am J Obstet Gynecol 159:56-66, 1988

65. Combs EA, Rosenn B, Kitzmiller JL, Khoury JC, Wheeler BC, Miodovnik M: Early-pregnancy proteinuria in diabetes related to preeclampsia. Obstet Gynecol 82:802-07, 1993 66. Grenfell A, Brudenell JM, Doddridge MC, Watkins PJ: Pregnancy in diabetic women who have proteinuria. Quart J Med 59:379-86, 1986 67. Garner PR, DAlton ME, Dudley DK, Huard P, Hardie M: Preeclampsia in diabetic pregnancies. Am J Obstet Gynecol 163:505-08, 1990 68. Kitzmiller JL, Combs EA: Maternal and perinatal implications of diabetic nephropathy. Clin Perinatol 20:561-70, 1993 69. Rosenn B, Miodovnik M, Combs CA, Khoury J, Siddiqi TA: Poor glycemic control and antepartum obstetric complications in women with insulin-dependent diabetes. Int J Gynecol Obstet 43:21-28, 1993 70. Jovanovic R, Jovanovic L: Obstetric management when normoglycemia is maintained in diabetic pregnant women with

732
vascular compromise. Am J Obstet Gynecol 149:617-23, 1984 71. Mogensen CE: Long-term antihypertensive treatment inhibiting progression of diabetic nephropathy. Brit Med J 285:685-88, 1982 72. Lewis EJ, Hunsicker LG, Bain RP, Rhode RD: The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med 329:1456-62, 1993 73. Airaksinen KEJ, Salmela PI: Pregnancy is not a risk factor for a deterioration of autonomic nervous function in diabetic women. Diabetic Medicine 10:540-42, 1993 74. Steel JM: Autonomic neuropathy in pregnancy. Diabetes Care 12:170-71, 1989 75. MacLeod AF, Smith SA, Sonksen PA, Lowy C: The problem of autonomic neuropathy in diabetic pregnancy. Diabetic Med 7:80-82, 1990 76. Reaven GM: Banting Lecture, 1988: Role of insulin resistance in human disease. Diabetes 37:1595-1607, 1988 77. DeFronzo RA, Ferrannini E: Insulin resistance: A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14:173-94, 1991 78. Lavin JP, Lovelace DR, Miodovnik M, Knowles HC, Barden TP: Clinical experience with one hundred seven diabetic pregnancies. Am J Obstet Gynecol 147:742-52, 1983 79. The Diabetes Control and Complications Trial Research 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 329:97786, 1993 80. Miodovnik M, Mimouni F, St. John Dignan P, Berk MA, Ballard JL, Siddiqi TA, Khoury J, Tsang RC: Major malformations in infants of IDDM women. Vasculopathy and early first-trimester poor glycemic control. Diabetes Care 11:71318, 1988 81. Coustan DR, Reece EA, Sherwin RS, Rudolf MCJ, Bates SE, Sockin SM, Holford T, Tamborlane WV: A randomized clinical trial of the insulin pump vs intensive conventional therapy in diabetic pregnancies. JAMA 255:631-36, 1986

733 734

Long-Term Effects of Pregnancy on Diabetic Retinopathy


Diabetes Mellitus Aug 28, 2008 As mentioned previously, diabetic retinopathy has a high regression rate in the end of pregnancy or in the postpartum period. The DCCTs ancillary study was able to assess for any long-term effects of pregnancy on diabetic retinopathy [9]. In this study, the progression of diabetic retinopathy in pregnant women often continued into the first year postpartum. However, the end-of-study analysis demonstrated that this worsening of retinopathy during pregnancy had no long-term consequences. Women who did or did not have pregnancies during the DCCT had similar retinopathy levels at the studys end (average of 6.5 years of followup). Pathophysiology of Progression The pathogenesis for the progression of diabetic retinopathy during pregnancy is unclear. Several researchers have studied retinal circulatory changes in diabetic and control subjects during pregnancy. Schocket et al. [21] demonstrated a decrease in retinal venous diameter and volumetric blood flow in diabetic patients during pregnancy. They hypothesized that the decrease in retinal blood flow may exacerbate retinal ischemia and hypoxia, leading to progression of diabetic retinopathy [22]. Larsen et al. [22] noted a decrease in the retinal arteriolar diameter from the first to the third trimester of pregnancy in diabetic women. However, the change in arteriolar diameter did not correlate with the increase in diabetic retinopathy levels noted from the first to the third trimester. In contrast, several studies have reported an increase in retinal blood flow during pregnancy in diabetic patients. Chen et al. [23] observed an increase in the retinal blood flow during pregnancy. They suggested that this hyperperfusion of the retina causes an added stress to an already compromised retinal circulation, leading to retinopathy progression. In addition, Loukovaara et al. [24] demonstrated that the retinal capillary blood flow was higher in diabetic women during pregnancy compared with nondiabetic pregnant women. Management Diabetic women in their childbearing years should be counseled on the risk of development and progression of diabetic retinopathy, as well as the importance of ocular examination before and during pregnancy. Because patients with severe NPDR or proliferative retinopathy are at greatest risk of progression during pregnancy, postponement of conception should be considered until their ocular disease is treated and stabilized. Also, because the risk of retinopathy progression during pregnancy is higher in patients with inadequate glycemic control, tight glycemic control should be attained before conception [16]. In addition, diabetic patients in their childbearing years should consider planning

their pregnancies early (because the risk of progression of diabetic retinopathy is greater in women who have had diabetes for a longer time) [14,15,20]. Treating proliferative diabetic retinopathy during pregnancy is based on the same criteriaas defined by the Diabetic Retinopathy Study and many subsequent rigorous clinical studiesas in nonpregnant patients [25]. The effect of panretinal photocoagulation for proliferative disease appears to be the same in pregnant women as it is in nonpregnant women; however, one should monitor retinopathy levels closely and initiate treatment early once indicated because retinopathy can progress rapidly during pregnancy. Diabetic macular edema that is not threatening the center of vision is often observed without treatment because of its high rate of spontaneous regression in the postpartum period [11]. The American Academy of Ophthalmology offers guidelines for monitoring pregnant diabetic patients in the Preferred Practice Patterns for diabetic retinopathy [26]. Ideally, pregnant women should receive an ophthalmologic examination before conception and then again in the first trimester. Subsequent examinations should be based on the retinopathy level found. Women with gestational diabetes are not at an increased risk of diabetic retinopathy and thus do not need to be examined under these guidelines. Conclusions Diabetic retinopathy can be adversely affected by pregnancy. Diabetic women in their childbearing years should be counseled regarding the risk of development and progression of diabetic retinopathy during pregnancy. Also, the importance of glycemic control and ophthalmic evaluations before conception and during pregnancy should be emphasized. Ophthalmic evaluation should ideally occur before conception and then again in the first trimester of pregnancy. Careful follow-up thereafter will be based on retinal findings. The practitioner can better manage these patients by understanding the various factors that influence the progression of diabetic retinopathy in pregnancy. Disclosure This work is supported in part by an unrestricted grant from the Research to Prevent Blindness, New York, NY. References
1. 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, 12:7480. Lovestam-Adrian M, Agardh CD, Aberg A, Agardh E: Pre-eclampsia is a potent risk factor for deterioration of retinopathy during pregnancy in type 1 diabetic patients. Diabet Med 1997, 14:10591065. Horvat M, Maclean H, Goldberg L, Crock GW: Diabetic retinopathy in pregnancy: a 12-year prospective survey. Br J Ophthalmol 1980, 64:398403. Sunness JS: The pregnant womens eye. Surv Ophthalmol 1998, 32:219238. Axer-Siegel R, Hod M, Fink-Goldman S: Diabetic retinopathy during pregnancy. Ophthalmology 1996, 103:18151819. Phelps RL, Sakol P, Metzger BE, et al.: Changes in diabetic retinopathy during pregnancy. Arch Ophthalmol 1986, 104:18061810. Best RM, Chakravarthy U: Diabetic retinopathy in pregnancy. Br J Ophthalmol 1997, 81:249251.

2. 3. 4. 5. 6. 7.

8. Moloney JB, Drury M: The effect of pregnancy on the natural course of diabetic retinopathy. Am J
Ophthalmol 1982, 93:745756.

9. The Diabetes Control and Complications Trial Research Group: Effect of pregnancy on microvascular
complications in the Diabetes Control and Complications Trial. Diabetes Care 2000, 23:10841091.

10. Sinclair SH, Nesler C, Foxman B, et al.: Macular edema and pregnancy in insulin-dependent diabetes. Am
J Ophthalmol 1984, 97:154167.

11. Stoessel KM, Liao PM, Thompson JT, et al.: Diabetic retinopathy and macular edema in pregnancy.
Ophthalmology 1991, 98(Suppl):146.

12. Klein BE, Moss SE, Klein R: Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care
1990, 13:3440. 13. Lauszus F, Klebe JG, Bek T: Diabetic retinopathy in pregnancy during tight metabolic control. Acta Obstet Gynecol Scand 2000, 79:367370. 14. Klein BE, Davis MD, Segal P, et al.: Diabetic retinopathy assessment of severity and progression. Ophthalmology 1984, 91:1017. 15. Sinclair SH, Nesler CL, Schwartz S: Retinopathy in the pregnant diabetic. Clin Obstet Gynecol 1985, 28:536552. 16. Chew EY, Mills JL, Metzger BE, et al.: Metabolic control and progression of retinopathy. Diabetes Care 1995, 18:631637. 17. Kitzmiller JL, Main E, Ward B, et al.: Insulin lispro and the development of proliferative diabetic retinopathy during pregnancy. Diabetes Care 1999, 22:874876. 18. Buchbinder A, Miodivnik M, McElvy S, et al.: Is insulin lispro associated with the development or progression of diabetic retinopathy during pregnancy? Am J Obstet Gynecol 2000, 183:11621165. 19. Loukovaara S, Immonen I, Teramo KA, Kaaja RR: Progression of retinopathy during pregnancy in type 1 diabetic women treated with insulin lispro. Diabetes Care 2003, 26:11931198. 20. Rosenn B, Miodovnik M, Kranias G, et al.: Progression of diabetic retinopathy in pregnancy associated with hypertension in pregnancy. Am J Obstet Gynecol 1992, 166:12141218. 21. Schocket LS, Grunwald JE, Tsang AF, et al.: The effects of pregnancy on retinal hemodynamics in diabetic versus non-diabetic mothers. Am J Ophthalmol 1999, 128:477484. 22. Larsen M, Colmorn L, Bonnelycke M, et al.: Retinal artery and vein diameters during pregnancy in diabetic women. Invest Ophthalmol Vis Sci 2005, 46:709713. 23. Chen HC, Newsom RS, Patel V, et al.: Retinal blood flow changes during pregnancy in women with diabetes. Invest Ophthalmol Vis Sci 1994, 35:31993208. 24. 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, 44:14861491. 25. Four risk factors for severe visual loss in diabetic retinopathy. The Diabetic Retinopathy Study Research Group [no authors listed]. Arch Ophthalmol 1979, 97:654655. 26. Diabetic Retinopathy. Preferred Practice Patterns [pamphlet]. San Francisco, CA: The American Academy of Ophthalmology; 2003.

Does Pregnancy Accelerate the Rate of Progression of Diabetic Retinopathy?


Diabetes Mellitus Aug 28, 2008

Diabetes Mellitus Diabetes mellitus Essentials of diagnosis Epidemiologic Considerations Classification & Pathogenesis

Pregnancy may be associated with several ocular changes, including the development of new ocular conditions or modifications of existing conditions. The most common ocular condition modified by pregnancy is diabetic retinopathy. Pregnancy is associated with an increased risk of development and progression of diabetic retinopathy. The factors associated with its progression include the pregnant state itself, duration of diabetes, amount of retinopathy at conception, blood glucose control, and the presence of coexisting hypertension. Although the rate of regression of diabetic retinopathy at the end of pregnancy or the postpartum period is high, careful monitoring of these patients is necessary to optimize the vision and pregnancy outcomes. Introduction Diabetic retinopathy is a common ocular condition that is modified by pregnancy. The factors that influence the development and progression of diabetic retinopathy during pregnancy are outlined in this article. These include the pregnant state itself, duration of diabetes, degree of retinopathy at conception, metabolic control, and the presence of coexisting hypertension. In addition, guidelines for monitoring the ocular status of pregnant diabetic patients are described in this article. Progression of Diabetic Retinopathy Several studies have examined whether pregnancy alters the initial development or subsequent progression of diabetic retinopathy. Although some studies have suggested that pregnancy does not affect the course of retinopathy [13], most studies do report that pregnancy adversely affects diabetic retinopathy [4 8]. An ancillary study of the DCCT (Diabetes Control and Complications Trial) evaluated pregnancys effects on diabetic retinopathy and nephropathy [9]. The DCCT was a multicenter controlled clinical trial that compared the effects of intensive treatment with conventional diabetes therapy. A longitudinal analysis was conducted in 180 women who had 270 pregnancies and 500 women who did not become pregnant during an average of 6.5 years of follow-up. In this study, pregnant women had a higher risk of an increase in the level of retinopathy during pregnancy compared with nonpregnant women. In the conventional treatment group, the pregnant women had a 2.48-fold greater risk of worsening of retinopathy from before to during pregnancy compared with the non-pregnant women. In the intensive treatment group, the pregnant women had a 1.63-fold greater risk of worsening of retinopathy in the course of pregnancy compared with the nonpregnant women.

Clinical Findings Differential Diagnosis Clinical Trials in Diabetes Treatment Regimens Pre-Diabetes Steps of Management Patient Education Diabetes Mellitus Treatment Complications Diabetes Prognosis Diabetes and Infections Diabetes Chronic Complications Ocular complications Diabetic Nephropathy Diabetic Neuropathy Cardiovascular complications Skin and Mucous membrane complications Diabetic Coma Diabetic Ketoacidosis Hyperglycemic Hyperosmolar state

Other studies have supported this observation of worsening of diabetic retinopathy during pregnancy. The rates of development and progression of diabetic retinopathy during pregnancy range from 16% to 85% [49]. Axer-Siegel et al. [5] examined 65 patients with insulin-dependent diabetes who became pregnant. In this study, 26% of patients with no retinopathy at conception had developed mild nonproliferative diabetic retinopathy (NPDR) during the pregnancys course. In those patients with NPDR at the start of pregnancy, 55% had progression of their NPDR and 22.5% developed proliferative retinopathy requiring panretinal photocoagulation. Diabetic retinopathy that develops during the pregnancys course may demonstrate a high rate of spontaneous regression after delivery. In the AxerSiegel et al. [5] study of patients with no retinopathy at onset who then developed mild NPDR during pregnancy, 50% had complete regression and 30% had partial regression of their disease after delivery. Regression rates were not as high for patients with mild NPDR at onset that progressed to severe NPDR during pregnancy. In this group, only 17% had total regression and 58% had partial regression of their disease after delivery. Diabetic macular edema may also occur during pregnancy [10,11]. Similar to retinopathy, a high rate of spontaneous regression exists postpartum. Disclosure This work is supported in part by an unrestricted grant from the Research to Prevent Blindness, New York, NY. References
1. 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, 12:7480. Lovestam-Adrian M, Agardh CD, Aberg A, Agardh E: Pre-eclampsia is a potent risk factor for deterioration of retinopathy during pregnancy in type 1 diabetic patients. Diabet Med 1997, 14:10591065. Horvat M, Maclean H, Goldberg L, Crock GW: Diabetic retinopathy in pregnancy: a 12-year prospective survey. Br J Ophthalmol 1980, 64:398403. Sunness JS: The pregnant womens eye. Surv Ophthalmol 1998, 32:219238. Axer-Siegel R, Hod M, Fink-Goldman S: Diabetic retinopathy during pregnancy. Ophthalmology 1996, 103:18151819. Phelps RL, Sakol P, Metzger BE, et al.: Changes in diabetic retinopathy during pregnancy. Arch Ophthalmol 1986, 104:18061810. Best RM, Chakravarthy U: Diabetic retinopathy in pregnancy. Br J Ophthalmol 1997, 81:249251. Moloney JB, Drury M: The effect of pregnancy on the natural course of diabetic retinopathy. Am J Ophthalmol 1982, 93:745756. The Diabetes Control and Complications Trial Research Group: Effect of pregnancy

Lactic Acidosis Hypoglycemia Introduction Clinical Manifestations Causes Diagnosis Treatment Hypoglycemia of Infancy and Childhood Glucose Requirements of Infants and Children Hypoglycemia due to Pancreatic B cell tumors Persistent Islet Hyperplasia Hypoglycemia due to Extrapancreatic Tumors Postprandial Hypoglycemia AlcoholRelated Hypoglycemia Factitious Hypoglycemia Immunopatholo gic Hypoglycemia Drug-Induced Hypoglycemia Diabetes & Oral Health Introduction Epidemiology

2. 3. 4. 5. 6. 7. 8. 9.

on microvascular complications in the Diabetes Control and Complications Trial. Diabetes Care 2000, 23:10841091. 10. Sinclair SH, Nesler C, Foxman B, et al.: Macular edema and pregnancy in insulindependent diabetes. Am J Ophthalmol 1984, 97:154167. 11. Stoessel KM, Liao PM, Thompson JT, et al.: Diabetic retinopathy and macular edema in pregnancy. Ophthalmology 1991, 98(Suppl):146. 12. Klein BE, Moss SE, Klein R: Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care 1990, 13:3440. 13. Lauszus F, Klebe JG, Bek T: Diabetic retinopathy in pregnancy during tight metabolic control. Acta Obstet Gynecol Scand 2000, 79:367370. 14. Klein BE, Davis MD, Segal P, et al.: Diabetic retinopathy assessment of severity and progression. Ophthalmology 1984, 91:1017. 15. Sinclair SH, Nesler CL, Schwartz S: Retinopathy in the pregnant diabetic. Clin Obstet Gynecol 1985, 28:536552. 16. Chew EY, Mills JL, Metzger BE, et al.: Metabolic control and progression of retinopathy. Diabetes Care 1995, 18:631637. 17. Kitzmiller JL, Main E, Ward B, et al.: Insulin lispro and the development of proliferative diabetic retinopathy during pregnancy. Diabetes Care 1999, 22:874 876. 18. Buchbinder A, Miodivnik M, McElvy S, et al.: Is insulin lispro associated with the development or progression of diabetic retinopathy during pregnancy? Am J Obstet Gynecol 2000, 183:11621165. 19. Loukovaara S, Immonen I, Teramo KA, Kaaja RR: Progression of retinopathy during pregnancy in type 1 diabetic women treated with insulin lispro. Diabetes Care 2003, 26:11931198. 20. Rosenn B, Miodovnik M, Kranias G, et al.: Progression of diabetic retinopathy in pregnancy associated with hypertension in pregnancy. Am J Obstet Gynecol 1992, 166:12141218. 21. Schocket LS, Grunwald JE, Tsang AF, et al.: The effects of pregnancy on retinal hemodynamics in diabetic versus non-diabetic mothers. Am J Ophthalmol 1999, 128:477484. 22. Larsen M, Colmorn L, Bonnelycke M, et al.: Retinal artery and vein diameters during pregnancy in diabetic women. Invest Ophthalmol Vis Sci 2005, 46:709713. 23. Chen HC, Newsom RS, Patel V, et al.: Retinal blood flow changes during pregnancy in women with diabetes. Invest Ophthalmol Vis Sci 1994, 35:31993208. 24. 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, 44:14861491. 25. Four risk factors for severe visual loss in diabetic retinopathy. The Diabetic Retinopathy Study Research Group [no authors listed]. Arch Ophthalmol 1979, 97:654 655. 26. Diabetic Retinopathy. Preferred Practice Patterns [pamphlet]. San Francisco, CA: The American Academy of Ophthalmology; 2003.

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Provides American Academy of Opthalmology guidelines for monitoring acute changes in pregnant diabetic patients. Corresponding author Bhavna P. Sheth, MD Eye Institute, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

E-mail: bsheth@mcw.edu Current Diabetes Reports 2008, 8:270273 Current Medicine Group LLC ISSN 1534-4827 Bhavna P. Sheth, MD Provided by ArmMed Media

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Diabetic Retinopathy
DONALD S. FONG, MD, MPH LLOYD AIELLO, MD, PHD THOMAS W. GARDNER, MD GEORGE L. KING, MD GEORGE BLANKENSHIP, MD JERRY D. CAVALLERANO, OD, PHD FREDRICK L. FERRIS, III, MD RONALD KLEIN, MD, MPH FOR THE AMERICAN DIABETES ASSOCIATION

iabetic retinopathy is the most frequent

cause of new cases of blindness among adults aged 20 74 years. During the first two decades of disease, nearly all patients with type 1 diabetes and _60% of patients with type 2 diabetes have retinopathy. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), 3.6% of youngeronset patients (type 1 diabetes) and 1.6% of older-onset patients (type 2 diabetes) were legally blind. In the younger-onset group, 86% of blindness was attributable to diabetic retinopathy. In the olderonset group, in which other eye diseases were common, one-third of the cases of legal blindness were due to diabetic retinopathy. NATURAL HISTORY OF DIABETIC RETINOPATHY Diabetic retinopathy progresses from mild nonproliferative abnormalities, characterized by increased vascular permeability, to moderate and severe nonproliferative diabetic retinopathy (NPDR), characterized by vascular closure, to proliferative diabetic retinopathy (PDR), characterized by the growth of new blood vessels on the retina and posterior surface of the vitreous. Macular edema, characterized by retinal thickening from leaky blood vessels, can develop at all stages of retinopathy. Pregnancy, puberty, blood glucose control, hypertension, and cataract surgery can accelerate these changes. Vision-threatening retinopathy is rare in type 1 diabetic patients in the first 35 years of diabetes or before puberty. During the next two decades, nearly all type 1 diabetic patients develop retinopathy. Up to 21% of patients with type 2 diabetes

have retinopathy at the time of first diagnosis of diabetes, and most develop some degree of retinopathy over time. Vision loss due to diabetic retinopathy results from several mechanisms. Central vision may be impaired by macular edema or capillary nonperfusion. New blood vessels of PDR and contraction of the accompanying fibrous tissue can distort the retina and lead to tractional retinal detachment, producing severe and often irreversible vision loss. In addition, the new blood vessels may bleed, adding the further complication of preretinal or vitreous hemorrhage. Finally, neovascular glaucoma associated with PDR can be a cause of visual loss. RISK FACTORS AND TREATMENTS Duration of disease The duration of diabetes is probably the strongest predictor for development and progression of retinopathy. Among younger-onset patients with diabetes in the WESDR, the prevalence of any retinopathy was 8% at 3 years, 25% at 5 years, 60% at 10 years, and 80% at 15 years. The prevalence of PDR was 0% at 3 years and increased to 25% at 15 years (1). The incidence of retinopathy also increased with increasing duration. The 4-year incidence of developing proliferative retinopathy in the WESDR youngeronset group increased from 0% during the first 5 years to 27.9% during years 1314 of diabetes. After 15 years, the incidence of developing PDR remained stable. GLYCEMIC CONTROL The Diabetes Control and Complications Trial (DCCT) investigated the effect of hyperglycemia in type 1 diabetic patients, as well as the incidence of diabetic retinopathy, nephropathy, and neuropathy. A total of 1,441 patients who had either no retinopathy at baseline (primary prevention cohort) or minimal-to-moderate NPDR (secondary progression cohort) were treated by either conventional treatment (one or two daily injections of insulin) or intensive diabetes management with three or more daily insulin injections or a continuous subcutaneous insulin infusion. In the primary prevention cohort, the cumulative incidence of progression

in retinopathy over the first 36 months was quite similar between the two groups. After that time, there was a persistent decrease in the intensive group. Intensive therapy reduced the mean risk of retinopathy by 76% (95% CI 6285). In the secondary intervention cohort, the intensive group had a higher cumulative incidence of sustained progression during the first year. However, by 36 months, the intensive group had lower risks of progression. Intensive therapy reduced the risk of progression by 54% (95% CI 3966). The protective effect of glycemic control has also been for confirmed patients with type 2 diabetes. The U.K. Prospective Diabetes Study (UKPDS) demonstrated that improved blood glucose control reduced the risk of developing retinopathy and nephropathy and possibly reduces neuropathy. The overall rate of microvascular complications was decreased by 25% in patients receiving intensive therapy versus conventional therapy. Epidemiological analysis of the UKPDS data showed a continuous relationship between the risk of microvascular complications and glycemia, such that for every percentage point decrease in HbA1c (e.g., from 8 to 7%), there was a 35% reduction in the risk of microvascular complications. BLOOD PRESSURE CONTROL The UKPDS also investigated the influence of tight blood pressure control (2). A total of 1,148 hypertensive patients with type 2 diabetes were randomized to less

The recommendations in this paper are based on the evidence reviewed in the following publication: Diabetic retinopathy (Technical Review). Diabetes Care 21:143156, 1998. Abbreviations: DCCT, Diabetes Control and Complications Trial; ETDRS, Early Treatment Diabetic Retinopathy Study; HRC, high-risk characteristic; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; UKPDS, U.K. Prospective Diabetes Study; WESDR, Wisconsin Epidemiologic Study of Diabetic Retinopathy.
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tight (_180/105 mmHg) and tight blood pressure control (_150/85 mmHg) with the use of an ACE inhibitor or a _-blocker. With a median follow-up of 8.4 years, patients assigned to tight control had a 34% reduction in progression of retinopathy and a 47% reduced risk of deterioration in visual acuity of three lines in association with a 10/5 mmHg reduction in blood pressure. In addition, there

were reductions in deaths related to diabetes and strokes. To determine whether intensive blood pressure control offers additional benefit over moderate control, the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial (3) randomized patients to either intensive or moderate blood pressure control. Hypertensive subjects, defined as having a baseline diastolic blood pressure of _90 mmHg, were randomized to intensive blood pressure control (diastolic blood pressure goal of 75 mmHg) versus moderate blood pressure control (diastolic blood pressure goal of 8089 mmHg). A total of 470 patients were randomized to either nisoldipine or enalapril and followed for a mean of 5.3 years. The mean blood pressure achieved was 132/78 mmHg in the intensive group and 138/86 mmHg in the moderate control group. Although intensive therapy demonstrated a lower incidence of deaths (5.5 vs. 10.7%, P _ 0.037), there was no difference between the intensive and moderate groups with regard to the progression of diabetic retinopathy and neuropathy. To determine whether inhibitors of ACE can slow progression of nephropathy in patients without hypertension, the EURODIAB Controlled Trial of Lisinopril in Insulin Dependent Diabetes (EUCLID) study group investigated the effect of lisinopril on retinopathy in type 1 diabetes. Eligible patients were not hypertensive, and were normoalbuminuric (85%) or microalbuminuric. The proportion of patients with retinopathy at baseline was similar, but patients assigned to lisinopril had significantly lower HbA1c at baseline. Treatment reduced the development of retinopathy, but the effect may have been due to its pressure-lowering effect in patients who had undetected hypertension. Until these issues are addressed, these findings need to be confirmed before changes to clinical practice can be advocated. ASPIRIN TREATMENT The Early Treatment Diabetic Retinopathy Study (ETDRS) investigated whether aspirin (650 mg/day) could retard the progression of retinopathy. After examining progression of retinopathy, development

of vitreous hemorrhage, or duration of vitreous hemorrhage, aspirin was shown to have no effect on retinopathy. With these findings, there are no ocular contraindications to the use of aspirin when required for cardiovascular disease or other medical indications. LASER PHOTOCOAGULATION The Diabetic Retinopathy Study (DRS) investigated whether scatter (panretinal) photocoagulation, compared with indefinite deferral, could reduce the risk of vision loss from PDR. After only 2 years, photocoagulation was shown to significantly reduce severe visual loss (i.e., best acuity of 5/200 or worse). The benefit persisted through the entire duration of followup and was greatest among patients whose eyes had high-risk characteristics (HRCs; disc neovascularization or vitreous hemorrhage with any retinal neovasculariztion). The treatment effect was much smaller for eyes that did not have HRCs. To determine the timing of photocoagulation, the ETDRS examined the effect of treating eyes with mild NPDR to early PDR. The rates of visual loss were low with either treatment applied early or delayed until development of HRCs. Because of this low rate and the risk of complications, the report suggested that scatter photocoagulation be deferred in eyes with mild-to-moderate NPDR. The ETDRS also demonstrated the effectiveness of focal photocoagulation in eyes with macular edema. In patients with clinically significant macular edema, 24% of untreated eyes, compared with 12% of treated eyes, developed doubling of the visual angle. EVALUATION OF DIABETIC RETINOPATHY An important cause of blindness, diabetic retinopathy has few visual or ophthalmic symptoms until visual loss develops. At present, laser photocoagulation for diabetic retinopathy is effective at slowing the progression of retinopathy and reducing visual loss, but the treatment usually does not restore lost vision. Because these treatments are aimed at preventing vision loss and retinopathy can be asymptomatic, it is important to identify and treat

patients early in the disease. To achieve this goal, patients with diabetes should be routinely evaluated to detect treatable disease. Dilated indirect ophthalmoscopy coupled with biomicroscopy and seven standard field stereoscopic 30 fundus photography are both accepted methods for examining diabetic retinopathy. Stereo fundus photography is more sensitive at detecting retinopathy than clinical examination, but clinical examination is superior for detecting retinal thickening from macular edema and for early neovascularization. Fundus photography also requires both a trained photographer and a trained reader. The use of film and digital nonmydriatic images to examine for diabetic retinopathy has been described. Although they permit undilated photographic retinopathy screening, these techniques have not been fully evaluated. The use of the nonmydriatic camera for follow-up of patients with diabetes in the physicians office might be considered in situations where dilated eye examination cannot be obtained. Guidelines for the frequency of dilated eye examinations have been largely based on the severity of the retinopathy (1,4). For patients with moderate-tosevere NPDR, frequent eye examinations are necessary to determine when to initiate treatment. However, for patients without retinopathy or with only few microaneurysms, the need for annual dilated eye examinations is not as well defined. For these patients, the annual incidence of progression to either proliferative retinopathy or macular edema is low; therefore, some have suggested a longer interval between examinations (5). Recently, analyses suggested that annual examination for some patients with type 2 diabetes may not be cost-effective and that consideration should be given to increasing the screening interval (6). However, these analyses may not have completely considered all the factors: 1) The analyses assumed that legal blindness was the only level of visual loss with economic consequences, but other visual function outcomes, such as visual acuity worse than 20/40, are clinically important,

occur much more frequently, and have economic consequences. 2) The Position Statement
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analyses used NPDR progression figures from newly diagnosed patients with diabetes (7). Although rates of progression are stratified by HbA1c levels, newly diagnosed patients are different from those with the same level of retinopathy and have a longer diabetes duration. While rates of progression correlate with HbA1c levels, newly diagnosed patients with the same level of retinopathy progress differently than those with longer duration of disease. A person with a longer duration of diabetes is more likely to progress during the next year of observation (8). 3) The rates of progression were derived from diabetic individuals of northern European extraction and are not applicable to other ethnic and racial groups who have higher rates of retinopathy progression, such as African- and HispanicAmericans (9,10). In determining the examination interval for an individual patient, the eye care provider should also consider the implications of less frequent eye examinations. Older people are at higher risk for cataract, glaucoma, age-related macular degeneration, and other potentially blinding disorders. Detection of these problems adds value to the examination but is rarely considered in analyses of screening interval. Patient education also occurs during examinations. Patients know the importance of controlling their blood glucose, blood pressure, and serum lipids, and this importance can be reinforced at a time when patients are particularly aware of the implications of vision loss. In addition, long intervals between follow-up visits may lead to difficulties in maintaining contact with patients. Patients may be unlikely to remember that they need an eye examination after several years have passed. After considering these issues, and in the absence of empirical data showing otherwise, persons with diabetes should have an annual eye examination. SUMMARY AND RECOMMENDATIONS Treatment modalities exist that can prevent

or delay the onset of diabetic retinopathy, as well as prevent loss of vision, in a large proportion of patients with diabetes. The DCCT and the UKPDS established that glycemic and blood pressure control can prevent and delay the progression of diabetic retinopathy in patients with diabetes. Timely laser photocoagulation therapy can also prevent loss of vision in a large proportion of patients with severe NPDR and PDR and/or macular edema. Because a significant number of patients with vision-threatening disease may not have symptoms, ongoing evaluation for retinopathy is a valuable and required strategy. The recommendations for initial and subsequent ophthalmologic evaluation of patients with diabetes are stated below and summarized in Table 1. GUIDELINES Patients with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 35 years after the onset of diabetes. In general, evaluation for diabetic eye disease is not necessary before 10 years of age. However, some evidence suggests that the prepubertal duration of diabetes may be important in the development of microvascular complications; therefore, clinical judgment should be used when applying these recommendations to individual patients. (B) Patients with type 2 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist shortly after diabetes diagnosis. (B) Subsequent examinations for both type 1 and type 2 diabetic patients should be repeated annually by an ophthalmologist or optometrist who is knowledgeable and experienced in diagnosing the presence of diabetic retinopathy and is aware of its management. Examinations will be required more frequently if retinopathy is progressing. This followup interval is recommended recognizing that there are limited data addressing this issue. (B) When planning pregnancy, women with preexisting diabetes should have a comprehensive eye examination and

should be counseled on the risk of development and/or progression of diabetic retinopathy. Women with diabetes who become pregnant should have a comprehensive eye examination in the first trimester and close followup throughout pregnancy (Table 1). This guideline does not apply to women who develop gestational diabetes, because such individuals are not at increased risk for diabetic retinopathy. (B) Patients with any level of macular edema, severe NPDR, or any PDR require the prompt care of an ophthalmologist who is knowledgeable and experienced in the management and treatment of diabetic retinopathy. Referral to an ophthalmologist should not be delayed until PDR has developed in patients who are known to have severe nonproliferative or more advanced retinopathy. Early referral to an ophthalmologist is particularly important for patients with type 2 diabetes and severe NPDR, since laser treatment at this stage is associated with a 50% reduction in the risk of severe visual loss and vitrectomy. (E) Patients who experience vision loss from diabetes should be encouraged to pursue visual rehabilitation with an ophthalmologist or optometrist who is trained or experienced in low-vision care. (E)

Table 1Ophthalmologic examination schedule Patient group Recommended first examination Minimum routine follow-up* Type 1 diabetes Within 35 years after diagnosis of diabetes once patient is age 10 years or older Yearly Type 2 diabetes At time of diagnosis of diabetes Yearly Pregnancy in preexisting diabetes Prior to conception and during first trimester Physician discretion pending results of first trimester exam
*Abnormal findings necessitate more frequent follow-up. Some evidence suggests that the prepubertal duration of diabetes may be important in the development of microvascular complications; therefore, clinical judgment should be used when applying these recommendations to individual patients.

Diabetic Retinopathy
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AcknowledgmentsThis manuscript was developed in cooperation with the American Optometric Association (Michael Duneas, OD), and the American Academy of Ophthalmology (Donald S. Fong, MD, MPH). We gratefully acknowledge the invaluable assistance of these associations and their designated representatives.

References 1. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL: 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 102:520526, 1984 2. UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 317:708713, 1998 3. Estacio RO, Jeffers BW, Gifford N, Schrier RW: Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 23 (Suppl. 2):B54 B64, 2000 4. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL: 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 102:527532, 1984 5. Batchelder T, Barricks M: The Wisconsin Epidemiologic Study of Diabetic Retinopathy (Letter) Arch Ophthalmol 113:702 703, 1995 6. Vijan S, Hofer TP, Hayward RA: Cost-utility analysis of screening intervals for diabetic retinopathy in patients with type 2 diabetes mellitus. JAMA 283:889896, 2000 7. UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 12:352:854865, 1998 8. Klein R, Klein BE, Moss SE, Cruickshanks KJ: The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XIV. Ten-year incidence and progression of diabetic retinopathy. Arch Ophthalmol 112:1217 1228, 1994 9. Harris MI, Klein R, Cowie CC, Rowland M, Byrd-Holt DD: Is the risk of diabetic retinopathy greater in non-Hispanic blacks and Mexican Americans than in non-Hispanic whites with type 2 diabetes? A U.S. population study. Diabetes Care 21:12301235, 1998 10. Haffner SM, Fong D, Stern MP, Pugh JA, Hazuda HP, Patterson JK, van Heuven WA, Klein R: Diabetic retinopathy in Mexican Americans and non-Hispanic whites. Diabetes 37:878884, 1988

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Original Article 678

Retinal Outcomes in Proliferative Diabetic Retinopathy Presenting during and after Pregnancy
Yung-Jen Chen, MD; Hsi-Kung Kuo, MD; Hsuan-We Huang1, MD
Background: The aim of this study was to determine retinal outcomes in patients with proliferative diabetic retinopathy (PDR) presenting during pregnancy or within the first year postpartum. Methods: All patients with diabetes mellitus during pregnancy from 1992 through 2002 were included. Medical records were reviewed and data including obstetric history, pregnancy outcome, other medical complications, and course and management of retinal disease were analyzed. Results: The study group comprised 6 women with a total of 7 pregnancies complicated by PDR during pregnancy or during the first year postpartum. Two of these pregnancies were in patients who had long-standing PDR and had received panretinal photocoagulation prior to pregnancy. Both of them had stable retinas during pregnancy and during the postpartum period. Three patients (4 eyes) who presented with high risk PDR during pregnancy required either repeated laser therapy (3 eyes) or vitrectomy (one eye) during the first year postpartum. Two patients (3 eyes) who did not have PDR at delivery developed PDR during the first year postpartum. After the second year postpartum, nine eyes which had developed PDR during or post pregnancy had stable retinas, two had developed phthisis, and one manifested end stage PDR. Conclusions: Because of the persistent adverse effects of pregnancy on the retinas of women with diabetes mellitus, meticulous retinal surveillance and appropriate therapy are important not only during pregnancy but also during the postnatal period. (Chang Gung Med J 2004;27:678-84) Key words: pregnancy, diabetic retinopathy, proliferative retinopathy, proliferative diabetic retinopathy.
From the Department of Ophthalmology, 1Department of Obstetric and Gynecology, Chang Gung Memorial Hospital, Kaohsiung. Received: Jan. 7, 2004; Accepted: Jun. 15, 2004 Address for reprints: Dr. Yung-Jen Chen, Department of Ophthalmology, Chang Gung Memorial Hospital. 123, Dabi Road, Niausung Hsiang, Kaohsiung Hsien, Taiwan 833. Tel.: 886-7-7317123 ext. 2801; Fax: 886-7-7318762; E-mail: d2767@adm.cgmh.org.tw

etinopathy affects 20 to 27% of women with

diabetes mellitus in the reproductive-age group.(1,2) Pregnancy is a prominent risk factor for the development and progression of retinopathy in women with insulin-dependent diabetes mellitus (IDDM).(2-5) Reported rates of progression of retinopathy ranged from 17% to 70%.(4,6-10) The mechanisms by which pregnancy might alter the course of retinopathy are not entirely clear. The adverse effects of pregnancy on retinal status persist into the first

year postpartum.(3-5) The baseline level of retinopathy at conception is a major risk factor for progression of
Chang Gung Med J Vol. 27 No. 9 September 2004 Yung-Jen Chen, et al Diabetic retinopathy and pregnancy 679

retinopathy.(11-13) Proliferative diabetic retinopathy (PDR) manifests with ischemia and neovascularization, which can cause vitreous hemorrhage and retinal detachment resulting in rapid visual deterioration. In the past, PDR was even considered a relative contraindication to pregnancy. Termination of pregnancy to avoid permanent visual loss in patients with proliferative retinopathy had been advocated.(14,15) In this report, we describe the retinal outcomes of women with PDR presenting either during pregnancy or during the first year postpartum.

METHODS
From 1992 through 2002, all patients at our hospital with the diagnosis of diabetes mellitus during pregnancy were included in the study. Medical records were reviewed and data including obstetric history, pregnancy outcome, other medical complications, and course and management of retinal disease were collected. Ophthalmic management included dilated fundus examination, fundus photography, fluorescein angiography (either before or after pregnancy), panretinal photocoagulation (PRP) for patients with high risk PDR, and vitreoretinal surgery. Retinopathy grade was classified according to the criteria of the Wisconsin Epidemiological Study on Diabetic Retinopathy as follows: (1) No retinopathy. (2) a. Less than 20 hemorrhages and /or microaneurysms, or b. Cotton wool spots alone. (3) a. More than or = 20 hemorrhages and /or microaneurysms, or b. Hard exudates combined with any number of hemorrhages and /or microaneurysms, or c. Less than 5 cotton wool spots combined with hemorrhages and /or microaneurysms or hard exudates. (4) More than or = 5 cotton wool spots or intraretinal microvascular abnormalities (IRMA) of vessels combined with hemorrhages and /or microaneurysms with or without hard exudates. (5) Venous bleeding combined with hemorrhages and /or microaneurysms with or without hard exudates, IRMA vessels or cotton wool spots. (6) Proliferative retinopathy, or scars of photocoagulation known to have been directed at new vessels.(
16)

RESULTS
A total of 73 women diagnosed with of insulindependent diabetes mellitus (IDDM) during pregnancy during the ten-year study period were included.

Six women (8.2%) had a total of seven pregnancies complicated by PDR during pregnancy or during the first year postpartum. Case summaries for these six patients are shown in Table 1. The mean maternal age was 30 years and mean duration of diabetes was 9 years. Two women had diabetes for more than 10 years at the time of pregnancy. Two women had history of abortion. Of the 2 women with the pregnancy complicated by preeclampsia, one decided to terminate the pregnancy at gestation week 16 and the other delivered a premature infant at week 29. Six continuing pregnancies resulted in live births at a mean gestational age at delivery of 35 weeks with a
Table 1. Clinical Summary of 6 Patients with Pregnancy Patient Age Duration of Obstetric Mode of Delivery Pregnancy Gestation age Birth body No. diabetes history insulin use mode complication of delivery weight (year) (weeks) (gm) 1 28 13 G1P0 C C/S None 38 3500 32 17 G2P1 C C/S None 34 3110 2 28 5 G1P0 C Termination Preeclampsia, abortion in in early nephropathy gestation pregnancy week 16 3 37 7 G4P0A3 C C/S Preeclampsia 29 884 4 32 12 G1P0 C C/S None 34 2200 5 25 0 G1P0 C C/S None 40 3101 6 31 8 G3P0A2 C C/S None 35 3660 Abbreviations: P: pregnancy; GxPyAz: times of gestation, partum, and abortion; C: conventional; C/S: cesarean section. Chang Gung Med J Vol. 27 No. 9 September 2004 Yung-Jen Chen, et al Diabetic retinopathy and pregnancy 680

mean birth weight of 2743 gm. Gestational age was over 36 weeks at the time of 2 of the 6 deliveries. Two of 6 live births had birth body weights below 2500 gm, respectively. Among the 5 deliveries by cesarean section in 5 women; one was a repeat cesarean section and 4 were primary. The ophthalmic data (6 patients; 12 eyes) before, during, and after pregnancy is shown in Table 2. Two patients (4 eyes) with a total of 3 pregnancies had long-standing PDR and underwent PRP prior to pregnancy. Both of these patients had stable retinas and none required laser therapy either during gestation or during the postpartum period. Three patients (4 eyes) presented with high risk PDR during pregnancy and received PRP during gestation. Among the four affected eyes in these patients, one eye had stable retinal appearance and the other three required repeated laser therapy (3 eyes) or vitrectomy (one eye) during the first year postpartum. One patient presented with PDR and total retinal detachment of her left eye at the beginning of pregnancy. This patient asked to continue the pregnancy and did not receive any ophthalmic treatment to her left eye. She also had the complications of preeclampsia and nephropathy during pregnancy and terminated the

pregnancy at gestation week 16. In the second year postpartum, the left eye of this patient showed phthisis and the fellow eye was in the end stage PDR. Two patients (3 eyes; patient No. 4 and 6) who had non-PDR after delivery developed high risk PDR during the first year postpartum (Table 2). After PRP, two of the affected eyes in these patients became stable and the other eye required vitrectomy because of vitreous hemorrhage. After multiple surgeries, this eye developed phthisis.
Table 2. Ophthalmic Data before, during, and after Pregnancy Patient Eye Prepregnancy Pregnancy 1st year 2nd year Final retinal No. Postpartum Postpartum status* DTDTDTDT 1 R PDR PRP RPDR M RPDR M RPDR M Stable (1st P) L PDR PRP RPDR M RPDR M RPDR M Stable R RPDR M RPDR M RPDR M RPDR M Stable (2nd P) L RPDR M RPDR M RPDR M RPDR M Stable 2 R Unknown None PDR PRP Progressive PRP End stage M End stage PDR PDR PDR L Unknown None PDR with None PDR with None Phthisis None Phthisis total TRD total TRD 3 R PDR PRP RPDR M RPDR M RPDR M Stable L PDR PRP RPDR M RPDR M RPDR M Stable 4 R Normal M Unknown None Progressive PRP RPDR M Stable NPDR L Normal M Unknown None Progressive PRP and PDR with VT and SB Phthisis NPDR VT RD 5 R Unknown None PDR PRP RPDR M RPDR M Stable L Unknown None PDR PRP Progressive PRP RPDR M Stable PDR 6 R Unknown None NPDRII M Progressive PRP RPDR M Stable NPDR L Unknown None PDR PRP Progressive PRP and RPDR M Stable PDR VT Abbreviations: D: diagnosis; T: therapy; P: pregnancy; PDR: proliferative diabetic retinopathy; PRP: panretinal photocoagulation; RPDR: regressed proliferative diabetic retinopathy; M: monitoring; TRD: tractional retinal detachment; NPDR: nonproliferative diabetic retinopathy; VT: citrectomy; SB: scleral buckling. * Final retinal status over 2 years postpartum Retinal status 2 years before pregnancy Progression of retinopathy from grade 5 to 6 II Diabetic retinopathy grade 5 Chang Gung Med J Vol. 27 No. 9 September 2004 Yung-Jen Chen, et al Diabetic retinopathy and pregnancy 681

DISCUSSION
The baseline level of retinopathy at conception is the major risk factor for progression of diabetic retinopathy.(11-13) The results of the Diabetes in Early Pregnancy Study (DIEP) demonstrated that women with mild or more severe retinopathy at the time of conception were at high risk for progression of retinopathy during pregnancy. The progression rates from nonproliferative retinopathy to proliferative retinopathy in the DIEP study were 6.76% and 30% in patients whose baseline retinopathies were mild and moderate, respectively.(11) PDR represents an advanced state of microvascular disease found in

long-standing diabetes patients, which can cause vitreous hemorrhage and retinal detachment resulting in rapid deterioration of the vision. Development or deterioration of PDR during pregnancy is uncommon and has been reported to occur in 2% to 11% of pregnancies in diabetics.(4,11,17) However, few researchers have assessed the outcomes in pregnant or postpartum patients with this severe retinal disease.(17-20) It remains unclear whether the counseling patients often received, which discourages conception or the continuation of pregnancy in the presence of PDR, is justifiable. In fact, it is unethical and impossible to answer this question with a randomized, prospective study. Hence, studies of related questions will have to be used in a retrospective design. The patient with the most severe complications in this study (patient 2) developed PDR and total retinal detachment in her left eye at the beginning of pregnancy. Whether to terminate the pregnancy immediately in order to slow the progression and allow for further ocular surgery or to continue the pregnancy in accordance with the strong desires of the mother was a complex problem. After considering the options, the patient asked to continue the pregnancy and did not receive any treatment to her left eye. Unfortunately, phthisis developed in the left eye and the fellow eye had endstage PDR during the second year postpartum. Several important risk factors can contribute to the aggravation of diabetic retinopathy, including the pregnancy itself,(4,8) duration of the diabetes,(17,21,22) elevated glycohemoglobin level,(8,17,22) rapid normalization of blood glucose level,(5,23,24) hypertension,(25) renal disease,(4,6,9,20,26) and the degree of retinopathy at the beginning of pregnancy.(6,8-10) The adverse effects of pregnancy on retinal status can persist into the first year postpartum.(3-5) In one report about retinal outcomes in the presence of PDR, laser therapy was required during 60 % of pregnancies, and in 65 % of pregnancies, treatment was also needed during the postpartum period.(18) In our study, three patients (4 eyes) presented with high risk PDR during pregnancy and all received PRP during gestation. Three of these eyes required repeated laser therapy or vitrectomy (one eye) during the first year postpartum. Progression of PDR may depend on whether laser photocoagulation has been performed before pregnancy. Treatment of PDR with laser before pregnancy may lessen the progression during pregnancy.( 17,18,27) In one review of 81 patients who had not been treated before pregnancy, 47 (58%) progressed. In contrast, of 35 patients who had received any laser photocoagulation before pregnancy, only 9 (26%) progressed.(27) In our study, two patients (4 eyes) with

a total of three pregnancies had undergone PRP prior to pregnancy. None of them required laser therapy either during pregnancy or during the postpartum period. Therefore, it is important that proliferative retinopathy is detected and treated, preferably before the onset of pregnancy. Three patients in our study did not have any clinical records of retinal status before pregnancy. This finding suggests that women with diabetes mellitus in the reproductive-age group need better patient education about the how to establish good glucose control and the need to thoroughly monitor retinal status. Data on the long-term effects of pregnancy on diabetic retinopathy are controversial. Some researchers reported that retinal status in diabetics with multiple pregnancies was better in comparison with women matched for age and duration of diabetes.( 28,29) Complete or partial regression of retinopathy after delivery has been reported.(6,22,29) The effects of pregnancy on retinal status are considered to be relatively transient; most changes revert to pre-pregnancy levels within a year or more after the end of pregnancy.(4) However, the adverse effects of pregnancy on retinal status persists into the first year postpartum.(3-5) Pregnancy motivates diabetic women to achieve better metabolic control but it is not known if this motivation persists postpartum or if motherhood worsens the situation due to nursing the newborn child and lack of time for self care. In our study, 2 patients (3 eyes) presented with non-PDR after delivery but developed high risk PDR during
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the first year postpartum. After management, two eyes became stable but the other one developed phthisis. Thus, increased retinal surveillance by a retinal specialist should continue during the first year postpartum. In conclusion, women with diabetes mellitus who are in the reproductive-age group are especially in need of education about adequate glucose control and ophthalmic surveillance. In addition, patient education should explain the need for laser photocoagulation to be performed before pregnancy in women who have PDR and plan to become pregnant, in order to avoid progression of retinopathy during pregnancy. Because of the persistent adverse effects of pregnancy on the retina, meticulous retinal surveillance and appropriate therapy are important not only during pregnancy but also during the postnatal period.

REFERENCES
1. Johnston GP. Pregnancy and diabetic retinopathy. Am J Ophthalmol 1980;90:519-24. 2. Hovat M, MacLean H, Goldberg L, Crock GW. Diabetic retinopathy in pregnancy. A 12-year prospective survey. Br J Ophthalmol 1980;64:398-403. 3. Conway M, Baldwin J, Kohner EM, Schulenburg WE, Cassar J. Postpartum progression of diabetic retinopathy. Diabetes Care 1991;14:1110-1. 4. The Diabetes Control and Complications Trial Research Group. Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial. Diabetes Care 2000;23:1084-91. 5. Lauszus F, Klebe JG, Bek T. Diabetic retinopathy in pregnancy during tight metabolic control. Acta Obstet Gynecol Scand 2000;79:367-70. 6. Moloney JB, Drury MI. The effect of pregnancy on the natural course of diabetic retinopathy. Am J Ophthalmol 1982;93:745-56. 7. Price JH, Hadden DR, Archer DB, Harley JM. Diabetic retinopathy in pregnancy. Br J Obstet Gynaecol 1984;91: 11-7. 8. Klein BEK, Moss SE, Klein R. Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care 1990; 13:34-40. 9. Dibble CM, Kochenour NK, Worley RJ, Tyler FH, Swartz M. Effect of pregnancy on diabetic retinopathy. Obstet Gynecol 1982;59:699-704. 10. Soubrane G, Canivet J, Coscas G. Influence of pregnancy on the evolution of background retinopathy. Int Ophthalmol Clin 1985;8:249-55. 11. Chew EY, Mills JL, Metzger BE, Remaley NA, Jovanovic-Peterson L, Knopp RH, Conley M, Rand L, Simpson JL, Holmes LB. Diabetes in Early Pregnancy Study. Metabolic control and progression of retinopathy. Diabetes Care 1995;18:631-7. 12. Rosenn BM, Miodovnik M. Medical complications of diabetes mellitus in pregnancy. Clin Obstet Gynecol 2000; 43:17-31. 13. Star J, Carpenter MW. The effect of pregnancy on the natural history of diabetic retinopathy and nephropathy. Clin Perinatol 1998;25:887-916. 14. White P. Pregnancy in diabetes. In: Marble A, White P, Bradley RF, eds. Joslin's Diabetes Mellitus. Philadelphia: Lea & Febiger, 1971, pp870-2. 15. Best RM, Chakravarthy U. Diabetic retinopathy in pregnancy. Br J Ophthalmol 1997;81:249-51. 16. Poulsen PL, Bek T, Ebbehj, Hansen KW, Mogensen CE. 24-h ambulatory blood pressure and retinopathy in normoalbiminuric IDDM patients. Diabetologia 1998;41: 105-10. 17. Temple RC, Aldridge VA, Sampson MJ, Greenwood RH, Heyburn PJ, Glenn A. Impact of pregnancy on the progression of diabetic retinopathy in Type 1 diabetes. Diabet Med 2001;18:573-7. 18. Reece EA, Lockwood CJ, Tuck S, Coulehan J, Homko C, Wiznitzer A, Puklin J. Retinal and pregnancy outcomes in the presence of diabetic proliferative retinopathy. J Reprod Med 1994;39:799-804. 19. Agardh E. A case of progression of diabetic retinopathy during pregnancy. Acta Ophthalmol Scand 2002;80:52430.

20. Joseph SE, McHugh D, Blott M, Amiel SA, Watkins PJ. Acceleration of diabetic retinopathy in pregnancy: a case report. Diabet Med 2001;18:675-8. 21. Klein BE, Davis MD, Segal P, Long JA, Harris WA, Haug GA, Magli YL, Syrjala S. Diabetic retinopathy: assessment of severity and progression. Ophthalmology 1984; 91:10-7. 22. Axer-Siegel R, Hod M, Fink-Cohen S, Kramer M, Weinberger D, Schindel B, Yassur Y. Diabetic retinopathy during pregnancy. Ophthalmology 1996;103:1815-9. 23. Phelps RL, Sakol P, Metzger BE, Jampol LM, Freinkel N. Changes in diabetic retinopathy during pregnancy. Arch Ophthalmol 1986;104:1806-10. 24. Elman KD, Welch RA, Frank RN, Goyert GL, Sokol RJ. Diabetic retinopathy in pregnancy: a review. Obstet Gynecol 1990;75:119-27. 25. Rosenn B, Moidovnik M, Kranias G, Khoury J, Combs CA, Mimouni F, Siddiqi TA, Lipman MJ. Progression of diabetic retinopathy in pregnancy: association with hypertension in pregnancy. Am J Obstet Gynecol 1992;166: 1214-8. 26. Chang S, Fuhrmann M, Jovanovic L. The Diabetes in Early Pregnancy Study Group (DIEP): pregnancy, retinopathy, normoglycemia: a preliminary analysis Diabetes 1985;35(Suppl):3A. 27. Sunness JS. The pregnant woman's eye. Surv Ophthalmol 1988;33:219-38.
Chang Gung Med J Vol. 27 No. 9 September 2004 Yung-Jen Chen, et al Diabetic retinopathy and pregnancy 683

28. Chaturvedi N, Stephenson JM, Fuller JH. The relationship between pregnancy and long-term maternal complications in the EURO-DIAB IDDM complications study. Diabet Med 1995;12:494-9. 29. Kaaja R, Sjberg L, Hellsted T, Immonen I, Sane T, Teramo K. Long-term effects of pregnancy on diabetic complications. Diabet Med 1996;13:165-9.
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1 9317 93615 833 123 Tel.: (07)73171232801; Fax: (07)7318762; E-mail: d2767@adm.cgmh.org.tw


1
1 1992 2002 6 (8.2%) 7 1 2 3 2 3 ( 4 ) 3 1 ( 3) (1)2 1 2 9 2 1

( 2004;27:678-84)

CME With the growing prevalence of type 2 and gestational diabetes, all physicians who treat pregnant women will be managing more patients in the diabetic setting. With appropriate measures starting before conception, these mothers can be helped to achieve the best possible maternal and fetal outcome.

iabetes mellitus (DM) affects between 17

and 23 million people living in the United States. Many of these individuals are undiagnosed. The number of cases of type 1 DM is relatively constant, and the increase in prevalence of DM in the United States is attributed to a rise in type 2 DM cases. In reproductive-aged women, obesity, inappropriate diet, and sedentary lifestyle are risk factors for developing type 2 DM. Black, Hispanic, Asian, and Pacific Islander women are more prone to type 2 DM, and have rates of gestational diabetes mellitus (GDM) of up to 14%; GDM rates of up to 30% have been documented among American Pima Indians.1 Diabetes mellitus complicates 2.5% to 7% of all pregnancies, with GDM representing most of the cases of DM in pregnancy.2 A recent rise in the incidence of type 2 DM among obese children will increase the prevalence of DM in pregnancy even further. In the near future, it is possible that type 2 DM will become CONTINUING MEDICAL EDUCATION
Goal To provide guidelines based on the latest data for the management of pregnancy complicated by preexisting diabetes mellitus (DM) and gestational diabetes mellitus (GDM) in women. Objectives 1. To describe optimal preconception care for women with DM in terms of glycemic control and risks including nephropathy, cardiopathy, retinopathy, and neuropathy in women. 2. To discuss prenatal care with regard to insulin management, maternal/fetal risks, and appropriate monitoring in women. 3. To address intrapartum and postpartum management with attention to the special concerns of DM/GDM, including

cesarean delivery and insulin therapy during and after the birth in women. Accreditation This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Albert Einstein College of Medicine and Quadrant HealthCom Inc. Albert Einstein College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. This activity has been peer reviewed and approved by Brian Cohen, MD, professor of clinical OB/GYN, Albert Einstein College of Medicine. Review date: March 2005. It is designed for OB/GYNs. Albert Einstein College of Medicine designates this educational activity for a maximum of 1 category 1 credit toward the AMA Physicians Recognition Award. Each physician should claim only that credit that he/she spent in the educational activity. Participants who answer 70% or more of the questions correctly will obtain credit. To earn credit, see the instructions on page 71 and mail your answers according to the instructions on page 72. Disclosure The Faculty Disclosure Policy of the College of Medicine requires that faculty participating in a CME activity disclose to the audience any relationship with a pharmaceutical or equipment company that might pose a potential, apparent, or real conflict of interest with regard to their contribution to the activity. This disclosure also applies to any discussion of unlabeled or investigational use of any commercial product or device not yet approved in the United States. Drs Russell and Coustan both report no conflict of interest. Dr Brian Cohen reports no conflict of interest. 40 TheFEMALE PATIENT VOL. 30 APRIL 2005

Diabetes in Pregnancy*
Michelle A. Russell, MD; Donald R. Coustan, MD
Michelle A. Russell, MD, is fellow, maternal-fetal medicine; and Donald R. Coustan, MD, is Chace/Joukowsky professor and chair, and obstetrician and gynecologist chief. Both are at the Department of Obstetrics and Gynecology, Brown Medical School and Women and Infants Hospital of Rhode Island, Providence.

the predominant form of DM associated with pregnancy. Thus, obstetricians will be diagnosing DM and managing pregnancies complicated by DM with increasing frequency. PATHOPHYSIOLOGY Diabetes mellitus is the result of a derangement of insulin production or action that leads to hyperglycemia and its consequences. The underlying pathogenesis is a deficiency of insulin or resistance to insulin action. The etiologies are numerous and heterogeneous, including autoimmune pancreatic _-cell depletion; tissue resistance; defects in insulin receptors, insulin proteins, or enzymes; pancreatic injury; endocrinopathies; drug toxicity; viral infections; and various genetic syndromes. Diabetes mellitus is classified by the underlying pathogenesis or relationship to pregnancy as type 1, type 2, or gestational (Table 1).

DIAGNOSIS The criteria used for the diagnosis of DM outside of pregnancy have evolved, and lower thresholds of hyperglycemia were recently introduced. The American Diabetes Association (ADA) currently recommends three diagnostic strategies (Table 2).3 Two categories of prediabetes are now recognized as well: impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) (Table 3). Individuals with IFG and IGT are at high risk for developing overt DM.3 When the diagnosis of DM is made during pregnancy, it is referred to as GDM. Using the ADA criteria, individuals with new-onset type 1 DM or previously undiagnosed type 2 DM are occasionally diagnosed with GDM, and postpartum testing is required to confirm the persistence of a metabolic disorder in these individuals. It is recommended that all pregnancies be screened for GDM by some method. The ADA advises that laboratory screening for GDM be omitted only in women whose history meets all of the low-risk criteria (Table 4). Screening involves a two-step approach, with a glucose challenge test (GCT) followed by a diagnostic OGTT when indicated (see Testing Protocol).2,4 (ScreenTheFEMALE PATIENT VOL. 30 APRIL 2005 41 Russell and Coustan

TABLE 1. Classification of Diabetes Mellitus


Type 1
Autoimmune pancreatic _-islet cell destruction Human leukocyte antigen-associated (possible viral trigger) Often childhood-onset Insufficient insulin production (insulinopenia) At risk for diabetic ketoacidosis Complications include nephropathy, retinopathy, vasculopathy, and neuropathy

Type 2
Insulin deficiency or tissue resistance Strong genetic component Associated with obesity and sedentary lifestyle Usually adult-onset Increasing incidence in children/adolescents Rarely associated with diabetic ketoacidosis

TABLE 2. American Diabetes Association Criteria for Diagnosis of Diabetes Mellitus3


Symptoms of DM (polyuria, polydipsia, weight loss) and a random plasma glucose 200 mg/dL OR Fasting plasma glucose 126 mg/dL confirmed

on repeat test on a different day OR 2-h glucose 200 mg/dL with a 75-g OGTT confirmed on repeat test on a different day (not recommended for routine clinical care)
DM = diabetes mellitus; OGTT = oral glucose tolerance test.

TABLE 3. American Diabetes Association Diagnostic Criteria for Prediabetes3


Intermediate Group Test Results (plasma glucose)
IFG Fasting glucose 100-125 mg/dL IGT 75-g 2-h OGTT 140-199 mg/dL
IFG = impaired fasting glucose; IGT = impaired glucose tolerance; OGTT = oral glucose tolerance test.

ing thresholds are outlined in Tables 5 and 6).2,4 The ADA recommends the use of the Carpenter/Coustan modified criteria for the OGTT, whereas the American College of Obstetricians and Gynecologists (ACOG) states that either the Carpenter/Coustan or the National Diabetes Data Group (NDDG) criteria are appropriate for the diagnosis of GDM.2,5-7 PRECONCEPTION CARE To optimize maternal, obstetric, and neonatal outcomes, the management of pregnancies complicated by preexisting DM should begin prior to conception. Pregnancy should be planned only when glycemic control is excellent. Poor glycemic control during embryogenesis has been linked to congenital malformations and spontaneous abortion (SAB). Major congenital malformations of the cardiovascular, central nervous, skeletal, and genitourinary systems are the leading cause of neonatal morbidity and mortality, occurring in 7% to 18% of pregnancies in diabetic women.8-10 The degree of risk for congenital malformation and SAB is related to the degree of elevation in hemoglobin A1C above normal at the time of conception and during embryogenesis (Table 7).11 Preconception glycemic control has been shown to reduce the risk of both SAB and congenital malformations. Genetic counseling and patient education regarding risk reduction with excellent glycemic control can be beneficial. Use of a reliable form of contraception should be encouraged in diabetic women who do not intend to conceive or who have suboptimal glucose control. Risk Assessment In patients with preexisting DM, the preconception period is an opportune time to evaluate for evidence of complications, including retinopathy, nephropathy, neuropathy, and cardiovascular disease (CVD). The results of the baseline evaluation can be used to direct counseling. Retinopathy in individuals with DM is a result of poor glycemic control and genetic factors. Permanent

visual impairment can be a complication of proliferative retinopathy. Pregnancy may or may not have long-term detrimental effects on retinopathy. The rapid glycemic control recommended for optimal pregnancy outcome plus normal gestational hormone alterations are often associated with a transient progression of retinopathy.12 There are no well controlled trials evaluating the long-term effects of pregnancy on diabetic retinopathy. A preconception evaluation for retinopathy with retinal 42 TheFEMALE PATIENT VOL. 30 APRIL 2005 Diabetes in Pregnancy

TABLE 4. Criteria for Low Risk of Gestational Diabetes Mellitus2,5


Age < 25 y Normal body weight No first-degree relative with DM Not a member of an ethnic group with a high prevalence of type 2 DM No history of abnormal glucose metabolism No history of poor obstetric outcome associated with DM
DM = diabetes mellitus.

Testing Protocol for Gestational Diabetes Mellitus


Glucose Challenge Test
Administer 50 g oral glucose solution at 24-28 wk* Nonfasting, randomly timed Patient to avoid oral intake during test Assess venous plasma glucose level at 1 h Venous plasma glucose levels > 200 mg/dL do not require OGTT, as gestational DM is probable

Oral Glucose Tolerance Test


Recommend 3 days of unrestricted diet, including at least 150 g of carbohydrates daily Advise usual physical activity Testing should be performed after an overnight fast (8 14 h) Administer 100 g oral glucose solution Patient should remain seated and abstain from smoking
*Earlier testing may be indicated in patients with history of GDM, obesity, prior obstetric complications, or a strong family history of DM. Two values meeting criteria are required for the diagnosis of gestational diabetes mellitus. OGTT = oral glucose tolerance test; DM = diabetes mellitus; GDM = gestational diabetes mellitus.

dilation should be performed by an ophthalmologist and repeated in early pregnancy. Subsequent retinal examinations can be scheduled during pregnancy and postpartum based on the presence or degree of retinopathy. Ideally, laser therapy should be completed prior to conception, but it can be performed safely during pregnancy if required. Nephropathy affects 5% to 10% of pregnancies in

women with DM.13 Poor glycemic control, hypertension, and genetic factors contribute to the development of DM-related renal disease. Maternal and perinatal complications are significantly increased when nephropathy is present. These complications include chronic hypertension, preeclampsia, preterm birth, and intrauterine growth restriction (IUGR). Preconception and early-pregnancy assessments of renal function should be performed in women with known microalbuminuria or longstanding DM. This is accomplished by testing blood urea nitrogen and serum creatinine, plus a 24-hour urine collection measuring excretion of protein and creatinine clearance. Microalbuminuria is early evidence of renal dysfunction and is defined by albumin excretion of 30 to 300 mg in 24 hours. Preexisting or early pregnancy urinary protein excretion exceeding 190 mg in 24 hours confers a 3fold increased risk of hypertensive disease and a higher risk of IUGR.14 Overt nephropathy is defined as proteinuria of more than 300 to 500 mg in 24 hours. Preeclampsia complicates 50% of pregnancies with diabetic nephropathy; women with reduced creatinine clearance, proteinuria, and hypertension carry the highest risk of poor perinatal outcome, and should be counseled accordingly. Hypertension should be managed aggressively in this group of women, with target blood pressures of less than 130/80 mm Hg. Angiotensin converting enzyme (ACE) inhibitors are frequently used for their beneficial effects on renal function, but pregnancy is a contraindication to ACE inhibitor use, so an alternative antihypertensive agent must be used once pregnancy is confirmed. Controversy surrounds the effects of pregnancy on progression of diabetic nephropathy. Proteinuria often increases during pregnancy, but long-term detrimental effects on renal function are rare.15 However, in women with hypertension, chronic renal failure, and serum creatinine levels of more than 1.5 to 3 mg/dL or creatinine clearance of less than 50 to 75 mL/min, progression of renal disease during pregnancy may lead to an irreversible decline in renal function or endstage renal disease necessitating dialysis.11,12,16 Coronary artery disease (CAD) is rare in pregnant women but can occur in the setting of long-standing DM, nephropathy, and hypertension. Preconception electrocardiography should be performed in all women with DM, but particularly in those who are older than age 35 years or who have hypertension, nephropathy, vascular disease, obesity, hyperlipiTheFEMALE PATIENT VOL. 30 APRIL 2005 43 Russell and Coustan

TABLE 5. Glucose Challenge Test Threshold Values at One Hour2,4


Venous plasma Patients glucose Sensitivity requiring (mg/dL) (%) OGTT (%)
> 130 90-100 25 > 135 98 20 > 140 80-90 15
OGTT = oral glucose tolerance test.

TABLE 6. Diagnostic Values on Oral Glucose Tolerance Test6,7*


Time Venous plasma glucose (mg/dL)6
Fasting 95 105 1 h 180 190 2 h 155 165 3 h 140 145
*A single abnormal value is nondiagnostic of GDM, but is associated with an increased risk of obstetric complications similar to GDM. One approach to management is to prescribe nutrition counseling and repeat the OGTT in 1 month. GDM = gestational diabetes mellitus; OGTT = oral glucose tolerance test.

TABLE 7. Hemoglobin A1C and Risk of Congenital Malformations11


Infants With Congenital Hemoglobin A1C (%) Malformations (%)
< 7 None 7.2-9.1 14 9.2-11.1 23 > 11.2 25

demia, or DM of longer than 10 years duration. Echocardiography can also be considered in women with long-standing DM or hypertension. Suspected CAD should prompt a thorough cardiac evaluation, with cardiac stress testing prior to conception. In women with CAD, pregnancy-related hemodynamic changes and hypoglycemic episodes can lead to acute coronary syndrome (ACS) during gestation. Older reports of DM-related ACS during pregnancy indicated that maternal mortality of up to 73% could be expected.17 Given the many advances in coronary care, the current risk of maternal mortality due to DM-related ACS is unknown, but appears to be lower than previous estimates. Successful pregnancies have been reported in women with CAD who have preserved myocardial function via percutaneous transluminal coronary angioplasty with or without stent placement or via coronary artery bypass grafting. 14 Pregnancy should be undertaken cautiously in women with a history of treatment for CAD, and should be discouraged in those with untreated CAD or severe myocardial dysfunction. Neuropathy is yet another potential complication of DM. Autonomic neuropathy may manifest as gastroparesis, presenting clinically as protracted, severe, and refractory nausea and emesis of pregnancy.

Electrolyte disturbances, dehydration, malnutrition, aspiration syndromes, and complications of parenteral nutrition have been reported in women with gastroparesis during pregnancy.17 A history of digestive disorders prior to pregnancy may indicate gastroparesis. Orthostatic hypotension due to autonomic dysfunction may lead to falls, resulting in maternal or fetal injury. Peripheral neuropathy can predispose to maternal infectious complications. Preconception evaluation of orthostatic blood pressure, peripheral sensation, and integument integrity are recommended. Glycemic Control A history of diabetic ketoacidosis (DKA) and hypoglycemic episodes should be elicited. Attempts at strict glycemic control, coupled with the effects of fetal utilization of glucose, can predispose to maternal hypoglycemia. Hypoglycemic episodes occur in 73% of diabetic pregnancies, with nearly 50% of these episodes being severe.18 The patient and her family require education on recognition, testing, and treatment of hypoglycemia to avoid permanent neurologic sequela. Prescription of a glucagon pen is advised, especially for women with type 1 DM or those who have had prior episodes of severe hypoglycemia. Diabetic ketoacidosis is a life-threatening derangement of glucose metabolism resulting from inadequate insulin action that leads to hepatic gluconeogenesis, lipolysis of adipose tissue, and ketonebody formation. Pregnant women with type 1 DM are prone to DKA, which occurs in up to 3% of their pregnancies and carries an 11% or greater fetal loss rate.19 By contrast, DKA is rare in women with type 2 DM or GDM. Early recognition of DKA, treatment of the associated hypovolemia, hypoglycemia, hypokalemia, hyponatremia, and hypophosphatemia, and return to normal acid-base status are of great importance to the health of mother and fetus. Maternal and fetal mortality are associated with delay in treatment, but immediate and aggressive therapy generally yields a good outcome.17 Preconception glycemic control is best accomplished by self-monitoring of blood glucose (SMBG), dietary modifications, exercise, frequent assessment by a care provider, and ongoing patient education. The preconception capillary plasma glucose levels recommended by the ADA are 70 to 110 mg/dL preprandial and 155 mg/dL 2 hours postprandial.2 The goal A1C level should be 6.5% to 7% (ie, less than 1% above the upper limit of normal), which confers the lowest risk of fetal congenital malformations. Intensive preconception diabetic care reduces perinatal mortality and congenital anomaly rates in

individuals with type 1 DM.20 After conception, maternal glucose control is likewise important for the duration of the pregnancy. Individualization of the frequency and timing of SMBG is acceptable, but postprandial values should be included in the management of the pregnant diabetic patient. Postprandial glucose levels correlate best with maternal A1C levels and neonatal outcome.21 Self-monitoring at least 4 to 8 times dailyincluding measurements at fasting and 1- or 2-hour postprandialis advised to guide adjustments in the insulin regimen and improve outcome. Recently, the ADA changed its recommendation for antepartum target capillary plasma glucose levels to less than 105 mg/dL fasting, less than 155 mg/dL 1 hour postprandial, and less than 130 mg/dL 2 hours postprandial. These levels are higher than the physiologic levels of glucose in normal pregnant women, which rarely exceed 110 mg/dL. Accordingly, lower glycemic goals with capillary plasma glucose levels of less than 95 mg/dL 44 TheFEMALE PATIENT VOL. 30 APRIL 2005 Diabetes in Pregnancy fasting, 130 to 140 mg/dL 1 hour postprandial, and less than 120 mg/dL 2 hours postprandial are recommended by many authorities. The same thresholds are used to determine the need for insulin therapy in women with diet-treated GDM to reduce the risk of macrosomia and other perinatal complications. The major risks of strict glucose control are iatrogenic hypoglycemia and IUGR. Maternal mean blood glucose levels of less than 87 mg/dL are associated with IUGR.22 Nutrition counseling is a key component in the management of women with preexisting DM presenting for preconception care. Likewise, ongoing nutrition therapy is important in all pregnancies complicated by preexisting DM or GDM. Many women with GDM can be managed with medical nutrition therapy alone. Typically, an increase of 300 kcal per fetus per day above prepregnancy weight-based caloric intake is prescribed. The recommended weight gain for pregnant women with DM is the same as for nondiabetic women, and is based on prepregnancy weight (Table 8).23 PRENATAL CARE During pregnancy, insulin therapy is the mainstay of managing type 1 DM, type 2 DM, and GDM refractory to nutrition therapy. Insulin requirements are lowest early in pregnancy, and increase thereafter to peak at 28 to 32 weeks gestation. Traditionally, combinations of short-acting and intermediate-acting insulin are administered intermittently by the subcutaneous route (Table 9; also

see Typical Three-Injection Intermittent Regimen). Several types of insulin are available, but the most experience during pregnancy has been reported with short-acting human insulin injection and intermediate-acting isophane/protamine zinc insulin suspension (Table 10). Increasingly, though, the newer insulins and insulin analogs (eg, shortacting lispro, aspart) are being used during pregnancy and appear to be both effective and safe.24,25 There are minimal data on the use and safety of the newest long-acting insulin analogs detemir and glargine. Until more data are available regarding safety and efficacy in pregnancy, the use of these agents should be restricted to pregnant women who have demonstrated a history of inadequate glucose control on standard regimens. Use of long-acting insulins such as extended insulin zinc suspension TheFEMALE PATIENT VOL. 30 APRIL 2005 45 Russell and Coustan

TABLE 8. Weight Gain Recommendations for Pregnancy Complicated by Diabetes Mellitus/Gestational Diabetes Mellitus22*
Underweight (< 19.8) 28-40 lb Average weight (19.8-25) 25-35 lb Overweight (26-29) 15-25 lb Obese (> 29) 15-25 lb
*Total weight gain by body habitus/body mass index.

TABLE 9. Insulin Therapy for Diabetes Mellitus in Pregnancy*


Trimester Insulin (U/kg/d)
First 0.6-0.8 Second 0.7-1.0 Third 0.8-1.2
*Estimated insulin requirement by trimester.

Typical Three-Injection Intermittent Regimen*


AM 2/3 total insulin dose Breakfast/lunch 2/3 of AM dose as intermediate acting isophane/protamine zinc insulin suspension and 1/3 of am dose as regular or short acting insulin injection, combined PM 1/3 total insulin dose Dinner 1/2 of PM dose as regular or short acting insulin injection* Bedtime 1/2 PM of dose as intermediate acting isophane/protamine zinc insulin suspension
*A two-injection regimen administering mixed intermediate acting isophane/protamine zinc insulin suspension and regular or short acting insulin injection doses prior to dinner can be used in patients with type 2 diabetes mellitus or gestational diabetes mellitus, but higher fasting glucose levels and nocturnal hypoglycemia may occur.

during pregnancy has been limited by the unpredictable pattern of action. An alternative method of insulin administration, the open-loop continuous subcutaneous insulin infusion (CSII) pump, has been shown to be safe and beneficial in the management of DM during pregnancy. While CSII is more convenient and provides glycemic and perinatal outcomes comparable to intermittent dosing, it is more expensive and reserved for women who are

highly motivated and compliant.26,27 Outside of pregnancy, glucose control in women with type 2 DM is often achieved with oral glucoselowering agents. In general, the sulfonylureas, secretagogues, meglitinides, biguanides, _-glucosidase inhibitors, and thiazolidinediones are not recommended in pregnancy because of the potential for teratogenicity, placental transfer, and neonatal hypoglycemia. A notable exception is the sulfonylurea glyburide, which (unlike its first-generation predecessors) does not cross the placenta and is the only agent with data regarding treatment of pregnancyrelated DM. A randomized clinical trial comparing glyburide to insulin therapy in third-trimester patients with GDM who have failed with diet control showed no difference in maternal glucose control or perinatal outcome.28 A small cohort study looking at oral glucose-lowering agents used through the first trimester of pregnancy suggested a higher risk of congenital malformations.29 The biguanide metformin has been used to treat infertility due to polycystic ovary syndrome, and case series have shown a reduced incidence of GDM and SAB in these patients compared with historic controls, with no increased risk of congenital malformations or maternal hypoglycemia.30 On the other hand, metformin use in pregnancy has been associated with an increased risk of preeclampsia and a 10-fold increase in perinatal mortality.31 Cord-blood and 46 TheFEMALE PATIENT VOL. 30 APRIL 2005 Diabetes in Pregnancy

TABLE 10. Human Insulin and Insulin Analog Action Profiles


Type Onset (h) Peak (h) Duration (h) Pregnancy testing/safety data
Insulin injection (Humulin R, 0.5-1 1-5 5-12 Yes Velosulin-H, Novolin R) (REGULAR) Short-acting Insulin zinc suspension, 1-1.5 5-10 12-16 Yes prompt (SEMILENTE) Insulin lispro (HUMALOG) 0.25 0.5-1.5 6-8 Yes Insulin aspart (NOVOLOG) 0.25 1-3 3-5 Yes Intermediate-acting Humulin insulin isophane/ 1-1.5 6-12 24 Yes protamine zinc suspension (NPH) Humulin insulin zinc 1-2.5 6-12 24 Yes suspension (LENTE) Novolin L ~ 2.5 7-15 22 Yes Novolin N ~ 1.5 4-12 24 Yes Long-acting Glargine (LANTUS) 1 5 24 No Protamine zinc insulin 4-8 14-24 36 Yes Insulin zinc suspension, 4-8 10-30 36+ Yes extended (ULTRALENTE)

Insulin detemir (DETEMIR) 1-2 5 24 No

maternal measurements have demonstrated significant transplacental passage of metformin at term, and the mechanism of action through peripheral tissue uptake of glucose could theoretically increase the risk of macrosomia.32 Due to limited data in pregnancy, biguanides should not be prescribed routinely. In general, insulin therapy is recommended for the management of type 1, type 2, and GDM TheFEMALE PATIENT VOL. 30 APRIL 2005 47 Russell and Coustan

TABLE 11. Protocol for Management of Preexisting Diabetes Mellitus in Pregnancy


Preconception
Contraception until pregnancy desired Genetic counseling when planning pregnancy DM education and medical Self-blood glucose monitoring 4-8 x/d including fasting, 1-2 h nutrition therapy postprandial, and 3:00 AM if at risk for nocturnal hypoglycemia Target capillary plasma glucose levels are 70-110 mg/dL preprandial and < 155 mg/dL 2 h postprandial Educate patient and other reliable support persons regarding management of hypoglycemic episodes Optimize glucose control Consider changing type 2 diabetic patients on oral agents to an insulin regimen Follow hemoglobin A1C every 1-3 mo and adjust regimen to reach target level < 1% above normal 3 mo prior to planned conception Baseline assessment for Blood pressure assessment complications of DM Physical examination Electrocardiography 24-h urine collection for protein and creatinine clearance or spot protein/creatinine ratio Ophthalmology examination Thyroid function testing in type 1 diabetic patients

Pregnancy
Early management Early assessment for gestational dating and viability Genetic counseling if not performed in preconception period Nutrition counseling Diabetic education and reinforcement Optimize glucose control on insulin regimen Target capillary plasma glucose levels to 60-95 mg/dL fasting, < 140 mg/dL 1 h postprandial, and < 120 mg/dL 2 h postprandial Assess hemoglobin A1C Baseline assessment for DM complications if not completed in preconception period Ongoing management Repeat ophthalmology examination as indicated by degree of retinopathy Repeat 24-h urine collection for protein and creatinine clearance each trimester if baseline evaluation abnormal Offer maternal serum _-fetoprotein screening at 15-22 wk Detailed fetal anatomic survey at 18-22 wk Fetal echocardiogram at 20-22 wk Serial ultrasonography to assess fetal growth at 28-32 wk and at term Fetal movement counts starting at 28 wk Nonstress testing 2 x/wk and amniotic fluid index weekly starting at 32 wk, biophysical profile as indicated by nonstress testing Deliver at 39-40 wk if testing reassuring and glucose well controlled
DM = diabetes mellitus.

refractory to diet therapy during pregnancy.

In addition to glycemic control, medical nutrition therapy, and patient education, modifications in prenatal care must also be considered in diabetic pregnancies. Tables 11 and 12 outline the authors approach to prenatal care in the context of preexisting DM and GDM. The diabetic pregnancy requires surveillance to detect congenital malformations and prevent late intrauterine fetal demise (IUFD). Fetal echocardiography is important to exclude major congenital cardiac malformations in women with high A1C levels in the preconception or early prenatal period. Fetal well-being assessment is recommended due to an increased risk of IUFD in pregnancies complicated by preexisting DM and poorly controlled GDM.33 The timing of initiation of biophysical testing may be individualized, but assessment is generally commenced at 32 to 34 weeks in pregnancies complicated by preexisting DM and GDM requiring insulin. Biophysical testing may be started at 36 to 40 weeks in pregnancies complicated by diet-controlled GDM.34 Earlier biophysical testing may be indicated if glycemic control is poor, there are other maternal medical complications, or there is evidence of a fetal growth disorder. No biophysical testing regimen has been proved superior, but once-weekly nonstress testing is insufficient to monitor the diabetic pregnancy.35 Due to the higher incidence of fetal growth disorders in diabetic pregnancies (IUGR and macrosomia) ultrasonography is often performed for fetal growth assessment. Ultrasonographic assessment has been used successfully to determine the need for initiating insulin therapy in pregnancies complicated by diet-treated GDM.36 However, it is difficult to predict macrosomia accurately by either clinical estimates or ultrasonography.37 Furthermore, the ability to predict which fetuses will sustain birth trauma such as shoulder dystocia is limited. Late third-trimester ultrasonography can be associated with low sensitivity and a high false-positive rate in the prediction of fetal weight greater than 4,000 g,38,39 leading to a near doubling of the risk of cesarean delivery for macrosomia.40 Despite this inaccuracy, many authorities (including ACOG) recommend considering cesarean delivery in diabetic pregnancies with fetuses whose estimated weight exceeds 4,500 g to avoid birth trauma. Others recommend consideration of cesarean delivery if the estimated fetal weight exceeds 4,000 or 4,250 g. A cost-analysis study reveals that 443 to 489 cesarean deliveries costing $880,000 to $930,000 are required to prevent one case of permanent brachial plexus injury when the estimated fetal

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TABLE 12. Protocol for Management of Gestational Diabetes Mellitus


General Medical nutrition therapy Diabetic education Self-blood glucose monitoring 4-8 x/d, fasting, and 1- or 2-h postprandial until adequate glucose control achieved; then testing frequency can be reduced if insulin therapy not required Target plasma blood glucose levels are 60-95 mg/dL fasting; < 140 mg/dL 1 h postprandial; and < 120 mg/dL 2 h postprandial insulin therapy should be considered if capillary plasma glucose levels remain > 95-105 mg/dL fasting, > 130-155 mg/dL 1 h postprandial, or >120 mg/dL 2 h postprandial after dietary manipulation Diet-controlled Fetal movement counts starting at 28 wk Consider ultrasonography at term Nonstress testing 2 x/wk starting at 40 wk Biophysical profile as indicated by nonstress test results Deliver for usual obstetric indications if glucose well controlled Insulin-controlled Fetal movement counts starting at 28 wk Ultrasonography at 32 wk and at term Nonstress testing 2 x/wk and weekly amniotic fluid assessment starting at 32 wk Biophysical profile as indicated by nonstress test results Deliver for usual obstetric indications if glucose well controlled

weight is 4,000 to 4,500 g in the presence of DM.41 Each pregnancy must be assessed individually based on obstetric history, best estimate of fetal weight, and maternal pelvimetry. INTRAPARTUM CARE Delivery should be timed to optimize neonatal outcome. If maternal glucose control is excellent and fetal biophysical testing is reassuring, expectant management can permit the onset of spontaneous labor. Delivery is advised by 40 to 41 weeks in the pregnancy complicated by preexisting DM and GDM requiring insulin. In pregnancies with dietcontrolled GDM and an absence of fetal macrosomia, delivery can be accomplished using the same guidelines as for nondiabetic pregnancies. Induction of labor at 38 to 39 weeks has been reported to decrease neonatal macrosomia and shoulder dystocia without increasing the rate of cesarean delivery in pregnancies with GDM.42,43 When delivery is to be performed prior to 39 weeks for reasons other than maternal, fetal, or obstetric indications or the gestational dating is unreliable, amniocentesis should be considered to assess fetal lung maturity. Fetal lung maturation may be delayed in diabetic pregnancies with poor glycemic control, and respiratory distress syndrome may complicate the neonatal course. However, caution should be exercised when interpreting these tests; a phosphatidyglycerol level exceeding 3% is the best predictor of lung maturity. The protocol for insulin therapy on presentation for labor and delivery is described in the Intrapartum

Insulin Protocol box. Strict intrapartum glucose control is important to avoid fetal hypoxemia, neonatal depression and hypoglycemia, and maternal complications such as DKA (Table 13). Selected patients using CSII can self-manage intrapartum glucose control with the assistance of the medical team. Patients with diet-controlled GDM can be managed with less intensive monitoring, provided that excessive calories are not supplied orally or parenterally. POSTPARTUM CARE Insulin requirements decrease postpartum. Care of the patient with type 1 or type 2 DM requires reduction of the insulin dosage. Effective regimens are approximately 33% to 50% of the late-pregnancy dosage, or 50% of the prepregnancy dosage. Glycemic control can be relaxed to avoid hypoglycemic episodes, but glucose levels should be maintained below 200 mg/dL. Goals for continued postpartum diabetic care should be consistent with the guidelines for management of DM in nonpregnant patients. Ideally, plasma glucose levels should be maintained at 90 to 130 mg/dL preprandial and less than 180 mg/dL postprandial. Women with type 2 DM may resume oral glucose-lowering agents unless contraindicated in breast-feeding. Insulin therapy may be discontinued after delivery in women with GDM. In these women, fasting and postprandial glucose levels on the morning of postpartum day 1 or 2 can help to exclude an ongoing metabolic disorder; the criteria for diagnosing overt DM can be applied in this setting. Women who have had GDM should undergo testing for DM, IGT, and IFG with a 75-g 2-hour OGTT 6 weeks postpartum. Because many of these patients will develop type 2 DM, they should be advised to undergo periodic screening.44 Breast-feeding should be encouraged in women with DM, but therapy should take into account that insulin requirements are lower during lactation.18 Women with DM are at increased risk of cesarean wound complications and require close monitoring.45 A reliable method of contraception should be offered to all women with DM. Uncomplicated DM does not pose a contraindication to any specific form of birth control, and the method should be selected based on patient preference, reliability, TheFEMALE PATIENT VOL. 30 APRIL 2005 49 Russell and Coustan

Intrapartum Insulin Protocol


Glucose assessment on arrival for labor and delivery, then reassessment every 1-2 h with bedside glucose monitor Record amount and type of last insulin dose

IV infusion initiated with lactated Ringer solution or 0.9% normal saline solution containing 5% dextrose at 100-125 mL/h unless hyperglycemic at presentation IV short-acting insulin-injection infusion is started if glucose levels exceed 110-120 mg/dL Mix 15 regular insulin injection in 150 mL normal saline solution and start infusion at 1 U/h
IV = intravenous.

and safety profile with comorbidities such as hypertension and CVD. Infants of diabetic mothers are at increased risk of morbidity in the newborn period. Preterm birth occurs in 36% of diabetic pregnancies, with 14% occurring prior to 34 weeks. In one case series, these infants had a macrosomia risk of approximately 14%, yielding a 7% risk of birth trauma and a 30% risk of respiratory distress syndrome.9 Other possible complications include hypoglycemia, polycythemia, hypocalcemia, and hyperbilirubinemia. These complications are related to in-utero exposure to high glucose levels and resultant fetal hyperinsulinemia, and the risk of neonatal hypoglycemia correlates with the degree of maternal glucose control in the period preceding delivery. Infants of mothers with poor glycemic control should be delivered in a facility equipped to manage the potential complications. Long-term, these children are at increased risk of overweight and obesity, hypertension, IGT, and early development of type 2 DMagain probably attributable to in-utero fetal programming. CONCLUSION With intensive preconception and prenatal care, women with uncomplicated preexisting DM and GDM can anticipate a good obstetric outcome. Nonetheless, the offspring of diabetic pregnancies are at increased risk of complications that extend well beyond the perinatal period. To improve maternal and neonatal outcomes, physicians must make appropriate modifications in every phase of prenatal care provided for women with DM. REFERENCES
1. King H. Epidemiology of glucose intolerance and gestational diabetes in women of childbearing age. Diabetes Care. 1998; 21(Suppl 2):B9-B13. 2. American Diabetes Association. Gestational diabetes mellitus. Diabetes Care. 2004;27(Suppl 1):S88-S90. 3. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2004;27(Suppl 1):S5-S10. 4. Coustan D, Nelson C, Carpenter M. Maternal age and screening for gestational diabetes: a population-based study. Obstet Gynecol. 1989;73(4):557-561. 5. American College of Obstetricians and Gynecologists Committee on Practice BulletinsObstetrics. ACOG Practice Bulletin. Clinical management guidelines for obstetriciangynecologists.

Number 30, September 2001 (replaces Technical Bulletin Number 200, December 1994). Gestational diabetes. Obstet Gynecol. 2001;98(3):525-538. 6. Carpenter MW, Coustan DR. Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol. 1982;144(7):768773. 7. Classification of diabetes mellitus and other categories of glucose intolerance. National Diabetes Data Group. Diabetes. 1979;28(12):1039-1057. 8. Gabbe SG, Graves CR. Management of diabetes mellitus complicating pregnancy. Obstet Gynecol. 2003;102(4):857868. 9. Becerra JE, Khoury MJ, Cordero JF, Erickson JD. Diabetes mellitus during pregnancy and the risks for specific birth 50 TheFEMALE PATIENT VOL. 30 APRIL 2005

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TABLE 13. Intrapartum Insulin Management


Capillary Plasma Glucose (mg/dL) IV Insulin (U/h)
< 60 Briefly discontinue IV insulin and increase IV infusion rate of fluids containing 5% dextrose* 60-80 Decrease current rate by 0.5 U/h and increase IV infusion rate of fluids containing 5% dextrose 81-120 No change 121-140 Increase current rate by 0.5 U/h 141-160 Increase current rate by 1.0 U/h 161-180 Increase current rate by 1.5 U/h 181-200 Increase current rate by 2.0 U/h > 200 Bolus 2-5 U, then increase current rate by 2.5 U/h; physician should reassess
*IV insulin infusion may be discontinued in type 2 DM and GDM, but dextrose infusion should be increased in type 1 DM to avoid ketoacidosis. When converting from IV to subcutaneous, IV insulin infusion should not be discontinued until intermittent subcutaneous doses of short-acting insulin are effectively resumed in type 1 DM. Dextrose-containing solutions can be omitted in patients with type 2 DM and GDM unless hypoglycemic at presentation. IV = intravenous; DM = diabetes mellitus; GDM = gestational diabetes mellitus.

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36. Schaefer-Graf UM, Kjos SL, Fauzan OH, et al. A randomized trial evaluating a predominantly fetal growth-based strategy to guide management of gestational diabetes in Caucasian women. Diabetes Care. 2004;27(2):297-302. 37. Sandmire HF. Whither ultrasonic prediction of fetal macrosomia? Obstet Gynecol. 1993;82(5):860-862. 38. Combs CA, Rosenn B, Miodovnik M, Siddiqi TA. Sonographic EFW and macrosomia: is there an optimum formula to predict diabetic fetal macrosomia? J Matern Fetal Med. 2000;9(1):55-61. 39. Landon MB. Prenatal diagnosis of macrosomia in pregnancy complicated by diabetes mellitus. J Matern Fetal Med. 2000;9(1):52-54. 40. Parry S, Severs CP, Sehdev HM, Macones GA, White LM, Morgan MA. Ultrasonographic prediction of fetal macrosomia. Association with cesarean delivery. J Reprod Med. 2000;45(1):17-22. 41. Rouse DJ, Owen J, Goldenberg RL, Cliver SP. The effectiveness and costs of elective cesarean delivery for fetal macrosomia diagnosed by ultrasound. JAMA. 1996;276(18): 1480-1486. 42. Lurie S, Insler V, Hagay ZJ. Induction of labor at 38 to 39 weeks of gestation reduces the incidence of shoulder dystocia in gestational diabetic patients class A2. Am J Perinatol. 1996;13(5):293-296. 43. Kjos S, Henry O, Montoro M, Buchanan T, Mestman J. Insulin-requiring diabetes in pregnancy: a randomized trial of active induction of labor and expectant management. Am J Obstet Gynecol. 1993;169(3):611-615. 44. OSullivan JB. Diabetes mellitus after GDM. Diabetes. 1991;40(Suppl 2):131-135. 45. Takoudes T, Weitzen S, Slocum J, Malee M. Risk of cesarean wound complications in diabetic gestations. Am J Obstet Gynecol. 2004;191(3):958-963. TheFEMALE PATIENT VOL. 30 APRIL 2005 51

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