Evaluation Before Conception

An outline of preconception management of women with established diabetes is included in table 1.

Table 1. Management of DN before and during pregnancy At all times

Prevent hyperglycaemia without untoward hypoglycemia

Control hypertension; angiotensin inhibition prior to pregnancy; other agents during pregnancy

Controlled carbohydrate, fat, and protein diet

Adequate rest

Prior to pregnancy

Measure renal function

Ophthalmologic exam

Cardiovascular evaluation

(history, exam, EKG, echocardiogram) Thyroid evaluation Hepatitis B surface antigen Serologic testing for syphilis Counseling and education First prenatal visit Measure renal function Ophthalmologic exam Sonogram for dating Second trimester

Measure renal function (12, 24 weeks)

Maternal serum alphafetoprotein (15-18 weeks)

Detailed sonogram with fetal echocardiogram (18-20 weeks)

Third trimester

Monthly sonogram

Weekly nonstress test (26 weeks)

Ophthalmologic exam

Measure renal function (36 weeks); Delivery planning

Evaluation for diabetic microvascular disease and hypertension are critical. Creatinine clearance (CrCl) as an estimate of glomerular filtration rate (GFR), and the degree of microalbuminuria (incipient DN, urinary albumin excretion {UAE} 30-299 mg/24 hrs, >20 ^.g/min) or urinary total protein excretion {TPE} (overt DN, >500 mg/24 hrs total protein or >300 mg/24 hrs albumin, >200 ^g/min albumin,) [12] should be quantified, preferably with a 24-hour specimen [13-20]. If overt DN is diagnosed, the patient should be thoroughly counseled regarding measures used to improve outcomes of pregnancy and the possible vascular complications and life expectancy. Hopefully then the decision on whether to attempt pregnancy will be more informed.

Current research is evaluating the use of plasma or serum cystatin C as an alternate indicator of GFR, since this positively charged cysteine protease inhibitor is produced at a constant rate in nucleated cells, freely filtered in the glomerulus and completely degraded in the tubules [21-26]. In a study of patients with type 1 diabetes and albuminuria, filtration of cystatin C was reduced along with mean podocyte filtration slit size, although GFR by iothalamate clearance was normal [27].

Renoprotective or antihypertensive therapy is indicated for patients with microalbuminuria or overt nephropathy [28] and agents used should be effective and safe in early pregnancy [29-31]. Although probably not teratogenic [32-33], angiotensin converting-enzyme (ACE) inhibitors or Ang-II receptor blockers are contraindicated during pregnancy because they are associated with neonatal renal failure [31,34]. This is unfortunate because there are extensive data, reviewed elsewhere in this volume, indicating that these drugs retard the development and progression of nephropathy, perhaps via direct effects on intrarenal cellular actions of angiotensin (AngII). On the other hand, control of blood pressure and renal hemodynamics with other antihypertensive agents is also effective [35]. The hypothesis that use of ACE-inhibitors in the preconception period will also decrease complications during pregnancy [36,37] should be tested in controlled trials in women with excellent glycemic control. In a study of 8 women with presumed DN, Jovanovic found that normoglycemia achieved by early pregnancy also resulted in stable renal function and low complication rates [38]. Diltiazem and other calcium-entry blockers are possibly best avoided during the first trimester since some data indicate an association with fetal limb defects (possibly related to reduced uteroplacental blood flow [39]), but not confirmed as teratogenic in a larger survey [40]. Diltiazem may have benefits for glomerular function not possessed by dihydropyridine calcium channel blockers [35,41-46]. Agents believed to be relatively safe for early pregnancy include alpha-methyldopa, clonidine, and beta-adrenergic antagonists with low lipid solubility [29-31].

Ophthalmologic examination is especially important for women with nephropathy because most also have diabetic retinopathy. Hyperglycemia induces retinal ischemia, and relatively rapid insulinization and normalization of blood glucose may elevate growth factor levels (IGF-1, VEGF, FGF) associated with worsening of retinopathy [47-53]. In the presence of background (BDR) or proliferative retinopathy (PDR) allow a few months to normalize blood glucose in the preconception period. PDR should be in remission or laser treated before pregnancy is attempted. In women with BDR at the beginning of pregnancy, the risk of development of neovascularization during gestation is 7-10% in hyperglycemic [54-56] or hypertensive women [57].

The association of DN with cardiovascular disease [58-64] gives concern in evaluating patients for pregnancy, since formerly there was a high mortality in pregnant diabetic women with coronary artery disease [65,66]. There are no cross-sectional or prospective studies of the coronary vessels in diabetic women preparing for pregnancy. However, Manske et al found little coronary disease by angiography in non-smoking diabetic patients <45 years old with end-stage renal disease if diabetes duration was less than 25 years, and there were no ST-T wave changes on ECG [67]. Therefore, pregnancy should be safe if these conditions are met. Otherwise, coronary angiography should be considered, since maternal-fetal outcome after the few reported coronary artery bypass grafts has been good [68-72]. Data are inadequate on pregnancy after percutaneous coronary revascularization procedures in diabetic women [7376]. Stress echocardiography is also important in pre-conception screening [77], and a restricted left ventricular diastolic filling pattern during pregnancy may be associated with ventricular arrhythmias or dysfunction during delivery in type 1 diabetic women [Schannwell03*]. This impairment of early diastolic filling velocity can be "an early sign of cardiac dysfunction even before there is a systolic disturbance along with a loss of contractility" [78], and may reflect diabetic cardiomyopathy [79-82].

Regarding treatment of diabetes prior to pregnancy, glycemic control is achieved with a meal plan, monitoring the food intake and blood glucose levels, and intensive insulin therapy. The diet prescription for pregnancy is 25-35

kcal/kg ideal body weight. With nephropathy, protein intake should be controlled, but 60 g/day is probably required for fetal development. The preferred insulin regimen includes a mix of short and intermediate-acting human insulins or continuous subcutaneous insulin infusion therapy. The optimal doses and timing are determined by self-monitored capillary blood glucose determinations before and after each meal. The targets for capillary blood glucose control before and during pregnancy are premeal values of 3.95.6 mM (70-100 mg/dL) and peak postprandial values of 5.6-7.2 mM (100-129 mg/dL) [1,3].

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