aGESTATIONAL DIABETES MELLITUS
Gestational diabetes mellitus (GDM) is one of the most common metabolic complications during pregnancy, and affects up to 14% of all pregnancies.1,2 The prevalence of GDM is difficult to estimate as it largely depends on the population studied and the diagnostic criteria applied.1,2 Nationwide data on the prevalence of GDM in the Netherlands are scarce, but the estimated prevalence varies between 2-5%.3 Worldwide, the prevalence of GDM is still rising due to an increasing number of women with overweight and obesity during reproductive age and also the (recent) introduction of more stringent diagnostic criteria.2,4-6 It is estimated that 14% to 20% of women of reproductive age are obese in developed countries.7
GDM is characterized as a medical condition in pregnancy in which women without previously diagnosed diabetes mellitus (DM) exhibit high blood glucose levels (hyperglycaemia) during pregnancy, classically developing during the second or third trimester. For women diagnosed with GDM in the first trimester of pregnancy, pre-existing DM or Maturity-Onset Diabetes of the Young (MODY) should be considered. In most of the women with GDM, blood glucose levels return to normal values after delivery.8
PHYSIOLOGY AND PATHOPHYSIOLOGY
In pregnancy maternal metabolic changes occur to ensure continuous supply of nutrients for foetal development and growth. Early pregnancy is characterized as an “anabolic state” and nutrients are stored in maternal tissue. In contrast, late pregnancy is more characterized as a “catabolic state”.9 During second and third trimester of pregnancy the neonate is growing more and to facilitate glucose across the placenta there is an increase in maternal insulin resistance (decreased insulin sensitivity) which results in an increase in maternal glucose concentrations.9 The physiological factors partially responsible for the increase in insulin resistance are the combination of increased maternal adiposity and in the insulin-desensitizing effects of placental hormones, including human placental lactogen, progesterone, corticotrophin-releasing hormone and estrogen.10,11 To maintain normal glucose control during pregnancy, the pancreatic β-cells of the mother have to increase insulin secretion to meet the increased insulin requirements.10,11
The development of GDM occurs when the woman’s pancreatic function fails to compensate for the increased resistance to insulin.10 Studies have suggested that a majority of the women with GDM already have pancreatic β-cell dysfunction and/or chronic insulin resistance before pregnancy. 10,11
PREGNANCY COMPLICATIONS
Comparable with pre-existent maternal DM in pregnancy, GDM is also associated with an increased risk of complications for both the mother and child. These complications are attributed to the effects of uncontrolled hyperglycaemia in the second and third trimester of pregnancy. It has been demonstrated that there is a graded linear association between maternal blood glucose concentrations and the risk of adverse pregnancy outcomes.12-14 Moreover, there is growing evidence of long-term health consequences for both the mother and child.15-19
Short-term complications
The presence of GDM can adversely affect neonatal and maternal outcomes during pregnancy and childbirth. When GDM pregnancy remains untreated, the neonate is exposed to elevated blood glucose levels. Maternal insulin cannot cross the placental barrier, as a result the neonate increases its own insulin production, resulting in foetal hyperinsulinaemia.20 The combination of hyperinsulinaemia and hyperglycaemia will lead to excessive foetal growth.20,21 Excessive foetal growth is also called “macrosomia”, and at delivery macrosomia is defined as a birth weight >4000 gram or “large for gestational age (LGA)”, defined as a birth weight >90th percentile. Excessive foetal growth is one of the most common complications of GDM and can lead to an increased risk of birth injury (shoulder dystocia) and maternal morbidity from instrumental vaginal delivery or caesarean section.20,21 Other neonatal complications associated with GDM include neonatal hypoglycaemia, neonatal hyperbilirubinaemia (jaundice), preterm delivery, and admission to the neonatology department.13,22-24 Additionally, GDM increases the maternal risk of hypertensive disorders during pregnancy including pregnancy-induced hypertension and preeclampsia.13,23
Long-term complications
Although in most of the women with GDM blood glucose levels return to normal values after delivery, GDM is a strong predictor to develop future impaired glucose tolerance and type 2 DM (T2DM). Epidemiological studies have demonstrated that the risk of developing T2DM may be as high as 50% in the first 5-10 years postpartum.15,16 In addition, recent studies have suggested that women with a history of GDM also carry an increased risk for cardiovascular diseases.25-27
Several studies have indicated that children born to mothers with GDM also have an increased risk to develop obesity, metabolic syndrome, and T2DM.17-19 However, this topic is still contradictory and awaiting confirmation.28,29
DETECTION AND TREATMENT
Intervention studies have clearly shown that GDM is a treatable condition and that adequate glucose control during pregnancy can effectively decrease pregnancy complications like excessive foetal growth, shoulder dystocia, caesarean delivery, and hypertensive disorders.30,31 National and international guidelines recommend to screen for GDM. However, there is no worldwide uniformly accepted and implemented guideline for screening and diagnosis of GDM.32 In the Netherlands, the Dutch Society of Obstetrics and Gynaecology developed a guideline “Diabetes and Pregnancy” for the screening, diagnosis and treatment of GDM, which was implemented in 2010.33 This guideline focuses on active screening and treatment policy provided by “usual care”, where its diagnostic cut-off values are primarily based on the World Health Organization (WHO) criteria originating from 1999.34 The latter largely differ from recent updates in diagnostic criteria by the International Association of Diabetes in Pregnancy Study Group (IADPSG) and WHO 2013 thresholds for diagnosis of GDM.35,36
Screening and diagnosis
GDM is seldomly recognized because of hyperglycaemic symptoms and is mostly diagnosed by a screening oral glucose tolerance test (OGTT). According to the Dutch national guideline33, screening for GDM is recommended in women with one or more risk factors for GDM or signs suggestive of GDM (like foetal macrosomia and/or polyhydramnion). Risk factors related to GDM are: a history of GDM, pre-gestational body mass index ≥30 kg/m2, previous infant with a birth weight ≥4500 gram (birth weight >95th percentile), a first degree relative with DM, certain ethnic groups were DM is more common (South-Asian, Hindu, Afro-Caribbean, Middle-Eastern, Morocco, and Egypt), history of an (unexplained) intrauterine foetal death or history of polycystic ovary syndrome. Pregnant women carrying at least one GDM risk factor should therefore be routinely screened with an OGTT between 24 to 28 weeks of pregnancy. Women with a history of GDM are screened at 16 to 18 weeks of gestation and between 24 to 28 weeks of gestation. The Dutch national guideline recommends the one-step screening strategy for GDM. The one-step screening strategy means the single use of a 75-gram OGTT, whereby GDM is diagnosed on the basis of one abnormal value for either the fasting or the 2-h glucose levels. GDM is diagnosed when the fasting plasma glucose exceeds 7.0 mmol/l and/or 2-h value ≥7.8 mmol/l after the 75-gram glucose load.33 The values of the diagnostic criteria are based on the old WHO 1999 consensus and have until now not been updated to the newest IADPSG/WHO 2013 criteria (fasting plasma glucose ≥5.1 mmol/l, 1-h value ≥10.0 mmol/l, 2-h value ≥8.5 mmol/l).34-36
Treatment
The main goal of treatment of GDM is to maintain adequate glucose levels during pregnancy. Lifestyle changes (healthy eating and physical activity) are often sufficient to achieve adequate glucose control. The first step of GDM treatment is nutritional advice by a dietician, which includes advice about carbohydrate distribution and carbohydrate intake. Moreover women receive advice regarding self-monitoring of the blood glucose values by a diabetes nurse. Treatment targets for GDM are a fasting plasma glucose level <5.3 mmol/l and/or 1-h postprandial plasma glucose level <7.8 mmol/l.33 When dietary advice fails to maintain glycaemic control, insulin therapy is the second step in GDM treatment. To date, the use of insulin therapy is the medication of choice in GDM as recommended in most international guidelines, although there is debate whether oral blood glucose-lowering agents may have a place in the treatment. In the United Kingdom, metformin has already been incorporated into the National Institute for Health and Care Excellence (NICE) guideline.37
Glucose testing after pregnancy is very important to reduce the rising T2DM pandemic. In the Netherlands, women are advised to visit the general practitioner (GP) at six weeks after delivery and subsequently once a year for the next five years for follow-up glucose testing.33,38 Moreover, the GP can motivate women to adopt and maintain a healthy lifestyle to prevent T2DM.
International guidelines
Although screening, diagnosis and treatment of GDM importantly reduce the risk connected to GDM, international guidelines on diagnostic cut-off values and treatment vary and are predominantly the result of consensus instead of well-defined controlled outcome studies.
Chapter 2 provides a more extensive overview of the different diagnostic criteria and treatment modalities worldwide and the reasons for the discrepancies. In chapter 2 we describe both the current knowledge regarding GDM and the unmet needs of this condition. We review the diagnostic criteria, different treatment regimens available (including diet, insulin therapy, and the use of oral blood glucose-lowering agents), and the long-term consequences of GDM.
AIM OF THE THESIS
The Dutch Society of Obstetrics and Gynaecology guideline “Diabetes and Pregnancy” for the screening and treatment of GDM, was implemented in 2010 and largely follows the older WHO 1999 diagnostic criteria. However, new insights regarding hyperglycaemia during pregnancy have been reported and this has led to a national and international debate regarding the diagnoses and treatment of GDM encouraged by the newer more stringent diagnostic criteria proposed by the IADPSG/WHO 2013. There is much uncertainty regarding the optimal glucose thresholds to define GDM.
Therefore, the aim of this thesis is to evaluate the current Dutch national guidelines for diagnosis and treatment of GDM, what is the outcome of GDM pregnancies using this guideline. And, to study what the consequences would be when the current diagnostic criteria of GDM were to be reconsidered.