لاحق للسكري المرافق للحمل. unchanged during conditions of maternal hypoglycemia in the range of 45–55 mg/dL. It is clear, however, that maternal compromise may result, i.e., from coma, convulsions, trauma, etc. Thus maternal hypoglycemia should be avoided if possible. However, the relaxing of metabolic control to levels of hyperglycemia that are potentially dangerous to the fetus is not usually justified. Studies of glucose tolerance tests among nondiabetic pregnant women suggest that mild degrees of hyperglycemia and hypoglycemia42 may carry similar fetal risk, and that the safest levels of glucose are those that are within normal ranges for pregnancy. The work of Lev-Ran et al.43 suggests that brittleness, or the tendency toward wide swings in glucose levels even under the best of circumstances, tends to ameliorate in mid-pregnancy, and improved metabolic control may be more easily accomplished at this time than in the nonpregnant state. Medical problems of diabetes NEPHROPATHY Overt diabetic nephropathy, generally detected by the presence of albuminuria ≥300 mg/day, complicates both type 1 and type 2 diabetes. However, because type 2 diabetes tends to have a later age at onset than type 1 diabetes, and because the prevalence of nephropathy is associated with the duration of diabetes, pregnant women with type 1 diabetes are considerably more likely to have nephropathy than are those with type 2 diabetes. In one series from a tertiary care institution 23% of pregnant women with preexisting diabetes manifested nephropathy, defined as a urinary protein excretion ≥300 mg/day prior to the third trimester.44 Nephropathy develops in stages,45 with the first stage manifested by renal hypertrophy and hyperfunction, and then renal lesions without clinical signs. It is only in the next stage, occurring within 7–15 years in 25–40% of individuals with type 1 diabetes, that albuminuria is manifest, and at that point it is microalbuminuria, only 30–299 mg/day. Once this microalbuminuria is present, it is highly likely that a given individual will progress to clinically evident diabetic nephropathy and ultimately end stage renal disease, a progression which usually occurs at a rate of 10 mL/min decrease in glomerular filtration rate (GFR) per year. Hypertension and retinopathy are often present when nephropathy is detected. Probable risk factors predisposing toward the development of diabetic nephropathy include genetic factors, hyperglycemia in the first stages, hypertension in the later stages, and possibly the protein content of the diet which is believed to be associated with increased intracapillary pressure in the glomeruli. Restriction of dietary protein may slow the progression of renal damage in diabetic individuals with clinically manifest nephropathy,46 although the benefits appeared to be only modest in a randomized trial involving a population with chronic renal disease not due to type 1 diabetes.47 Such protein restriction is generally not advisable during pregnancy. The use of angiotensin converting enzyme (ACE) inhibition has been shown to significantly impede progression of nephropathy in a randomized trial involving nonpregnant, nonhypertensive individuals with type 1 diabetes.48 Unfortunately, ACE inhibitors are contraindicated during pregnancy because of potential adverse fetal effects. Most importantly, the Diabetes Control and Complications Trial (DCCT), published in 1993,49 demonstrated, in a randomized study of 1441 patients with type 1 diabetes, that intensive control of ambient glucose levels to an average of approximately 150 mg/dL, over a 6–7 year interval, significantly reduced the appearance and progression of nephropathy. The ADA and the National Kidney Foundation subsequently issued a consensus statement50 recommending that optimization of metabolic control is the cornerstone of prevention of progression of diabetic nephropathy. Protein restriction may be of value, and control of hypertension may also be advantageous, particularly with ACE inhibitors in the absence of pregnancy. During normal pregnancy renal plasma flow and GFR rate are markedly increased. In women with diabetic nephropathy the quantity of albuminuria tends to increase dramatically, such that many individuals with microalbuminuria in early pregnancy may excrete more than 5 g/day by the third trimester. This not only raises concerns about a possible adverse effect of pregnancy on nephropathy, but can make the diagnosis of hypertensive disorders of pregnancy quite difficult. Most of the evidence available to date suggests that pregnancy has no long-lasting effect on diabetic nephropathy, and that most women who develop marked proteinuria during pregnancy revert to their pre-pregnancy renal status after delivery.45 Approximately one third of women with nephropathy experience a fall in creatinine clearance during the course of pregnancy.45 Diabetic nephropathy clearly is associated with greater risk of adverse outcomes in pregnancy.44, 45 Perinatal morality is higher, and preterm delivery is necessary in over half the patients, one quarter prior to 34 weeks. Approximately 18% of infants are growth restricted, and nonreassuring fetal status is common. Almost half of such individuals develop preeclampsia. Severe anemia often accompanies pregnancy in women with nephropathy, because of the renal disease as well as the usual hemodilution of pregnancy. The management of nephropathy during pregnancy may be difficult since risks and benefits must be constantly balanced. For example it is usual to prescribe a relatively high protein diet to pregnant women in order to provide amino acids for fetal growth and development, and also to help maintain relative euglycemia in individuals with diabetes. However, high protein intake may have an adverse effect on the progression of nephropathy. A middle ground is probably most appropriate, and it may be reasonable to decrease the protein content of the diet but to no less than 60 g/day.45 Renal function should be evaluated early in the course of pregnancy in order to detect the presence of incipient nephropathy, lest its discovery later in pregnancy be confused with preeclampsia. This evaluation should include 24-hour urinary protein and creatinine measurements as well as serum creatinine. At least two studies have demonstrated an increased risk of preeclampsia in diabetic women who manifest mild to moderate microalbuminuria during the first half of pregnancy.51, 52 We have found it helpful to obtain a baseline serum uric acid measurement in order to compare values obtained later in pregnancy if preeclampsia is suspected. Follow-up renal function studies are obtained at least once per trimester if proteinuria was present early in pregnancy. Hypertension should be treated in order to maintain diastolic blood pressure below 100 torr, or even below 90 torr if chronic hypertension is not present. ACE inhibitors and angiotensin receptor blockers (ARBs) should be avoided during pregnancy because of potential adverse fetal effects. Methyldopa, beta blockers, and hydralazine all have been used in this situation. One group has reported the successful use of recombinant human erythropoietin to treat severe anemia during pregnancy in three patients with chronic renal disease, one of whom had diabetic nephropathy.53 Because of the propensity of patients with diabetic nephropathy for intrauterine growth restriction it is appropriate to evaluate fetal growth on a regular basis, using ultrasound. Antepartum fetal testing is instituted earlier in pregnancy in women with vascular disease than in those without. RETINOPATHY Diabetic retinopathy is a form of vascular disease, resulting from damage to retinal capillaries and arterioles; the exact mechanism is unclear at present. An association between elevated glycosylated hemoglobin and retinopathy has been demonstrated.54, 55 Intensive control of diabetes has been shown to slow the progression of retinopathy in both type 156 and type 257 diabetes. Background retinopathy, the earliest manifestation, includes microaneurysms, small vessel obstruction, cotton wool spots, intraretinal microvascular abnormalities (venous abnormalities and small retinal hemorrhages), and hard exudates.58 Vision is generally not threatened by background retinopathy unless macular edema or ischemia supervene. Background retinopathy is almost universally present in diabetic individuals 20 years after the diagnosis is made.58 Proliferative diabetic retinopathy is characterized by new vessel formation, or neovascularization. This growth may be a response to underlying retinal ischemia. The new vessels are poorly supported, and may leak and adhere to the vitreous. Resultant shrinkage and contraction of the vitreous may put pressure on the new vessels, causing retinal hemorrhages. These hemorrhages may lead to scarring and/or retinal detachment, and are the primary cause of visual loss in affected patients. One of the most important advances in management of diabetic retinopathy has been the discovery that laser photocoagulation therapy may prevent or forestall retinal hemorrhage and visual loss if applied at the appropriate time. Proliferative retinopathy is found in approximately 17% of individuals with type 1 diabetes 5 years after the diagnosis of diabetes, and afflicts most diabetic individuals after 15 years.58 The DCCT results56 demonstrated that improved metabolic control in individuals with type 1 diabetes is associated with a decreased rate of development of retinopathy, as well as nephropathy. Among individuals with preexisting nonproliferative retinopathy, intensive management was associated with a higher likelihood of progression of retinopathy during the first year. However, by 36 months of therapy retinopathy was less likely to advance in the intensive management group, and this benefit continued throughout the study period. Overall, subjects in the intensive management group manifested a 50% lower likelihood of significant progression compared to those in the conventional treatment group. This and other studies confirm that the institution of tight metabolic control may be associated with a transient worsening of diabetic retinopathy, but that long term good control has a salutary effect. It is currently uncertain whether pregnancy exerts any independent effect on accelerating the progression of retinopathy, although the most appropriately controlled prospective study suggests such an effect independent of glycemic control.59 Factors such as hyperglycemia and hypertension60 appear to accelerate the course of retinopathy in pregnancy. The sudden institution of intensive metabolic control that is generally carried out in early pregnancy may be expected to have a transient adverse effect on retinopathy. This phenomenon has been demonstrated in individuals with glycohemoglobin as low as 6 standard deviations above the control mean.61 The effect of diabetic retinopathy on pregnancy outcome has not been widely investigated. One small retrospective series of 20 subjects with advanced retinopathy, none of whom underwent pregnancy termination, reported a perinatal survival rate of 94%.62 NEUROPATHY Little information is available about the frequency with which diabetic neuropathy complicates pregnancy. However, since various forms of neuropathy are common among individuals with diabetes, and since pregnancy is not known to be protective against these problems, it is likely that they will be encountered among pregnant women.32 Autonomic neuropathy may cause symptoms referable to the bladder or gastrointestinal tract. Gastroparesis, with gastric atony and delayed emptying, may cause early satiety, fullness, nausea, vomiting, and pain.32 It has been described in pregnant women with diabetes, and in one case series of four affected individuals the gastric symptoms were associated with cardiovascular problems, particularly postural blood pressure changes.63 The vomiting can be intractable and interfere with nutrition, and thus fetal growth. Symptoms may be confused with hyperemesis, but their persistence and severity in a woman with diabetes should alert the clinician. Various treatments, including metoclopromide and intravenous erythromycin,64 have been utilized in nonpregnant individuals. Based on available case reports pregnancy outcome is often suboptimal in cases of gastroparesis.65 Autonomic dysfunction may also cause defective glucose counterregulation, and its presence may be suggested by the absence of normal respiratory variation in heart rate as well as the presence of postural hypotension. In one controlled study autonomic dysfunction was associated with a higher frequency of pregnancy complications, but not with any specific complication.66 Peripheral neuropathies are the most commonly encountered nerve disorder in individuals with diabetes.32 These neuropathies are usually sensory in nature with paresthesias and later anesthesia. They most often occur in the lower extremities, and may lead to skin ulceration, deep seated infection, and in extreme cases amputation. HYPERTENSION Hypertension is commonly present in diabetic gravidas with nephropathy. However, even in the absence of nephropathy women with diabetes are more likely than nondiabetic individuals to have hypertensive complications during pregnancy. Hinton and Sabai67 found that 50% of diabetic gravidas with nephropathy develop preeclampsia, and that 10–20% of gravidas with type 1 diabetes but without nephropathy do so. Cousins, in an earlier thorough literature review,68 found that chronic hypertension was present in 8% of pregnant women with preexisting diabetes, without known vascular disease, and in 2.5% of patients with gestational diabetes. Preeclampsia or hypertensive disorders of pregnancy were reported in 14% of the class B and C diabetic women and those with gestational diabetes, but in nearly 30% of those with known vascular disease. URINARY TRACT INFECTIONS Urinary tract infections appear to be generally more common among individuals with diabetes than nondiabetic patients. In Cousins literature review68 pyelonephritis complicated approximately 3% of pregnancies in women with preexisting diabetes. Urinary tract infections are of particular significance in women with diabetes because metabolic control may be adversely impacted by such problems. Diabetic ketoacidosis as well as more subtle derangements of control are commonly brought about by infections. HYDRAMNIOS Hydramnios, or excessive amniotic fluid, was found to complicate approximately 18% of overt diabetic pregnancies in Cousins literature review,68 but only 2% of gestational diabetic pregnancies. However, varying definitions of this complication, along with our inability to accurately measure amniotic fluid volume noninvasively, make its diagnosis problematic. Although it is tempting to speculate that maternal hyperglycemia with fetal osmotic diuresis is responsible for hydramnios, supportive data have not been convincing, and the cause of this complication in diabetic pregnancies must be considered unknown at the present time. One study reported significantly higher mean blood glucose values among 13 gestational diabetic subjects when hydramnios was present compared to the same patients at times when amniotic fluid volumes were more normal.69 In the general population, the presence of hydramnios is associated with an increased risk for congenital malformations. While this is no doubt also true in diabetic pregnancies, in which the a priori risk for malformations is increased, most diabetic pregnancies with hydramnios are productive of structurally normal offspring. Hydramnios is also considered to be a potential inducer of preterm labor, and can cause maternal respiratory embarrassment. Nevertheless, it is distinctly unusual for diabetes‑associated hydramnios to require therapeutic amniocentesis. FETAL/NEONATAL PROBLEMS Perinatal mortality Although the perinatal mortality rates associated with diabetes in pregnancy have declined considerably during the past eight decades and are now near those in the general population, it is only through continuing vigilance that such advances can be maintained. Both fetal and neonatal deaths occurred with increased frequency in diabetic pregnancies before the advent of modern management methods, and fetal deaths nationwide continue to be significantly higher among diabetic than non-diabetic pregnancies.70 The cause of fetal death remains incompletely understood. Maternal ketoacidosis, which was at one time associated with a 90% fetal mortality rate,35 is currently rare among appropriately treated diabetic women but still carries a fetal mortality rate of 10–30%.70 Even in the absence of DKA there appears to be a clear association between suboptimal metabolic control and perinatal death71 but appropriately controlled studies have not been carried out. However, animal studies72 suggest that fetal hyperinsulinemia which may be brought about by maternal hyperglycemia may cause fetal hypoxemia and lactic acidosis, with fetal death in extreme cases. Similarly, the infusion of large amounts of glucose containing solutions to pregnant women prior to delivery has been associated with fetal acidosis.73, 74 It thus seems likely that maternal hyperglycemia is at least partially the cause of the increased fetal death rate among diabetic pregnancies. These observations are consistent with the Pedersen hypothesis,75 which states that maternal hyperglycemia is translated into fetal hyperglycemia, which in turn causes fetal hyperinsulinemia, which is the cause of most abnormal outcomes in the fetus of the diabetic mother. Perinatal mortality rates are higher in poorly controlled diabetic pregnancies, as evidenced by the study of Karlsson and Kjellmer,76 in which perinatal deaths ranged from 4% when mean third trimester blood glucose was
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