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1.  Introduction

1.1. Intention of the presented work

Gestational diabetes mellitus (GDM) is one of the most common complications in pregnancies. Presently, 3-5% up to 14% of the pregnant women are affected, dependent on the ethnical group investigated. Actual estimations suggest that the prevalence of GDM will significantly increase in the near future due to the rising rate of obesity and glucose intolerance in young women in industrialized countries. Optimal medical care has to be provided to avoid short and long term sequelae for the fetus and the mother. On the other side there is clearly a need for a concept of management of GDM which guarantees a reasonable balance of efficacy and costs. For more than two decades there is an ongoing discussion about the optimal management strategy in pregnancies with GDM.

In 2001 the guidelines for diagnosis and therapy of GDM in Germany had been modified based on the suggestions of an expert panel of the German Society of Obstetrics and Gynecology (DGGG) and the German Diabetes Association (DDG). The major goal of this attempt was an adaptation of the German guidelines to the international standard. Although a concept was developed that considers all available data well as clinical experience and best practicability, several questions remain. There is controversy about the best glycemic thresholds for the diagnosis of GDM as well as the optimal glucose targets during pregnancy. While intensive glucose control in women with GDM has been proven to reduce neonatal morbidity, the rates of accelerated growth (macrosomia) and it's associated complications are still elevated, as compared to the normal obstetrical population. Thus, do we have to modify our criteria for insulin therapy to reduce morbidity? In studies that target to reduce macrosomia, intensive insulin therapy was required in the majority of the women. This does not seem reasonable. How can we identify pregnancies with a high risk for neonatal morbidity? Are the maternal glucose values reliable predictors for morbidity or do we have to include other parameters to improve the outcome? Do we really have to monitor intensively the glucose metabolism in all woman with GDM?

This manuscript constitutes a part of the ongoing attempt to find for answers to these questions. It summarizes the quintessence of almost 10 years of clinical research in the field of gestational diabetes. Our research covers various aspects of pregnancies complicated by diabetes including congenital anomalies, maternal and fetal predictors for neonatal morbidity, predictors for postpartum diabetes after GDM and the influence of contraception on the [page 5↓]development of diabetes after pregnancies with GDM and. Based on the clinical experience in our Diabetic Prenatal Care Clinic we became more and more aware of an urgent need to modify the principles of the management of GDM. When looking at the outcome parameters it seemed that several of the women were under-treated, while others were over-treated when therapy was based solely on strict glycemic control.

In the first part, based on own data and several studies by others this thesis assesses the importance of maternal glucose values to predict adverse neonatal outcome. In the second part, the results of intervention trials done by our group will be presented that investigated a modified management combining maternal and fetal criteria to guide therapy. The advantage of this approach will be demonstrated that provides the opportunity to adjust the intensity of surveillance and therapy based on antenatal risk assessment.

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1.2.  Gestational diabetes

1.2.1. Epidemiology and pathophysiology

GDM is defined as glucose intolerance of varying degrees of severity with onset or first recognition during pregnancy 1. The prevalence of GDM is dependent on the prevalence of type 2 diabetes in the given population and varies from 1-14% with 2-5% being the most common figure 2-4. Risk factors for GDM are increasing age, positive family history of diabetes, increasing obesity and descent from selected ethnic groups with high prevalence of diabetes.

Pregnancy is associated with profound hormonal changes that have a direct effect on the carbohydrate tolerance. In the 1st trimester, progesterone and estrogen rise but counterbalance regarding their insulin action. Once the 2nd trimester is entered, human placental lactogen (HPL) , cortisol and prolactin increases, causing decreased phosphorylation of the insulin receptor substrate-1 5 and profound insulin resistance 6, 7. In most women, pancreatic insulin secretion adapts to this need, but in those with underlying beta-cell defects, hyperglycemia ensues. Women typically return to euglycemia postpartum but defects in insulin secretion and action are still evident. 8

1.2.2. Morbidity

Maternal morbidity

Maternal hyperglycemia in GDM is rarely severe enough to cause concern for the mother. Women with GDM are more likely to develop hypertensive disorders than women without GDM which might be partly related to the underlying risk factors for GDM (obesity, increasing age). There is a higher risk of vaginal and urinary infections causing preterm labor. At delivery, neonatal macrosomia results in a higher risk of C-section and birth traumata for mother and child. A pregnancy with GDM indicates a maternal long-term risk of diabetes in later life. Approximately 10-15% of the women remain diabetic postpartum 9, 10, the cumulative risk is approximately 50% for diabetes and 75 % for any other impairment of glucose intolerance within 10 years after the index pregnancy. 10-13

Fetal and neonatal morbidity

Fetal hyperinsulinism secondary to an excessive supply of substrate due to maternal hyperglycemia (Pederson hypothesis) 14 is the underlying cause for all short-and long term complications of GDM. The primary perinatal concern in GDM remains the excessive fetal [page 7↓]growth (fig 1). Macrosomia is significantly more common in pregnancies with GDM even when GDM is treated according to standard recommendations. Fat accumulation tends to be truncal with a larger shoulder circumference which leads to an increased risk for cephalopelvic disproportion and shoulder dystocia. 15 Other significant acute neonatal morbidities include hypoglycemia, hyperbilirubinemia, hypocalcemia and polycthemia.

Figure 1: Macrosomic newborn with diabetic fetopathy

The infant of women with GDM inherits an increased susceptibility for glucose intolerance not only due to genetic disposition but due to the exposure to hyperglycemia in utero. Studies in Pima Indians demonstrated that children from the same mother who were born after the mother developed diabetes were more obese and more likely to have insulin resistance 16. Numerous studies support an increased risk for obesity in the offspring. 17, 18

1.2.3. Diagnostic management

There is a lively ongoing discussion about the diagnostic procedure for detection of GDM. The major controversies exist regarding universal screening versus diagnostic limited to women with risk factors and the diagnostic criteria for GDM. It would exceed the capacity of this text to go into the details of this discussion. The following presentation will be limited to the major issues of the current recommendations valid for Germany 19 which represent a modified version of the Recommendations of the Fourth International Workshop Conference on GDM. 1

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Screening for GDM should be performed in every woman with 24-28 weeks of gestation. The diagnosis of GDM is based on the results of an oral glucose tolerance test (oGTT). The evaluation for GDM may be done in one or two steps. The one - step procedure requires a complete 75 g oGTT in all women. When two or more glucose values exceed the glycemic thresholds of fasting 90mg/dl, 180 mg/dl after 1 hour and 155 mg/dl after two hours, the criteria for GDM are met.20 The two-step procedure uses a 50 g glucose load (glucose challenge test) as selection criteria for the oGTT; it may be applied without regard to the time of day or last meal. The diagnostic oGTT is reserved for women with glucose values above 140 mg/dl in the screening test. When performed between 24-28 weeks of gestation, the screening test has a sensitivity of 80% at a 140 mg/dl cut point 1. Women with high-risk for GDM should be tested as soon as feasible and testing should be repeated at 24-28 weeks if GDM is not diagnosed. The cutoff values for the oGTT are derived from the original data from O’Sullivan from 1964 evaluating an increased risk for development of type 2 diabetes of the mother in later life. 21

Figure 2: Diagnostic procedure for GDM

In contrast to the recommendations of the German Diabetes Association, currently (up to spring 2003) the German health system covers only a diagnostic for GDM in women with risk factors for GDM following the one-step procedure. About 50% of the women with GDM are missed by this selective testing. 2 Thus in this text, all presented studies which had been [page 9↓]performed in Germany, are based on a population of women with GDM who were identified by selective testing. Additionally in the time period of the studies, the diagnosis of GDM was based on the O’Sullivan criteria (90/165/145 mg/dl) in most institutions in Germany.

1.2.4. Therapy

Antepartum treatment of women with GDM should be focused on the prevention of fetal complications. Dietary education is the first step in the treatment for GDM. The nutritional prescription should provide the caloric needs for pregnant women of 30 kcal per kilogram of actual body weight. The total intake should be reduced to 25 kcal for overweight women. Self monitoring of blood glucose is superior to less frequent measurements in the clinic. The recommended frequency of the glucose profiles consisting of 3 pre-and 3 postprandial measurements varies between twice per week or daily. Glycemic goals during pregnancy are fasting values < 90 mg/dl, 1 hour postprandial < 140 mg/dl and 2 hour values < 120 mg/dl. 19 In women who fail to achieve or maintain normoglycemia additional insulin therapy is recommended. Physical activity after meals increases glucose consumption and insulin sensitivity and it had been shown that in women with GDM insulin therapy could be avoided by a strict exercise protocol. 22

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