European Association of Perinatal Medicine

EAPM

Diabetes and Pregnancy

Update and Guidelines

Working Group on Diabetes and Pregnancy

Chairmen

Moshe Hod and Umberto Simeoni

Secretaries

Eran Hadar , ...... ( Simeoni group)

Consultant Diabetologists:

Yoel Toledano and Anunziata Lapolla

Perinatal Division ,Helen Schneider Hospital for Women, Rabin Medical Centre, Petah Tiqva, Sackler School of Medicine, Tel Aviv University, Israel

and

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Advisory Board

  • A. Lapolla, Padova, Italy
  • Z. Alfirevic, Liverpool, UK
  • A. Antsaklis, Athens, Greece
  • N. Asatiani, Tbilisi, Giorgia
  • Z. Abraham , Tel-Aviv, Israel
  • P. Banfield,UK
  • J. Bar, Petah Tiqva, Israel
  • A. Ben-Haroush, Petah Tiqva, Israel
  • M. Bonomo, Milano, Italy
  • G. Breborowitz, Poznan, Poland
  • K. J. Buehling, Berlin, Germany
  • L. Cabero, Barcelona, Spain
  • M. Campogrande, Torino, Italy
  • R. Chen, Petah Tiqva, Israel
  • R. Corcoy, Barcelona, Spain
  • M.Gy.Csakany, Budapest,Hungary
  • P. Damm, Copenhagen, Denmark
  • A. De Leiva, Barcelona, Spain
  • H. De Valk , Utrecht, Netherlands
  • G. Di Cianni, Livorno, Italy
  • G.C. Di Renzo, Perugia, Italy
  • J. Djelmis, Zagreb, Croatia
  • GP. Donzelli, Firenze, Italy
  • J. Dudenhausen, Berlin, Germany
  • F.Dunne, Birmingham,UK
  • S. Eik-Nes, Trudenheim, Norway
  • F. Fallucca, Rome , Italy
  • D. Fedele, Padova, Italy
  • J. Egyed, Budapest, Hungary
  • J. Gadzinowski, Poznan, Poland
  • P. Greco, Bari, Italy
  • S. Heller, Sheffield.UK
  • U.Hanson, Uppsala, Sweden
  • H. Ilkova, Istanbul,Turkey
  • M. Ivanisevic, Zagreb, Croatia
  • I. Kalu, Copenhagen, Denmark
  • R. Kaaja, Helsinki,Finland
  • A. Kapur, Copenhagen, Denmark
  • A. Kautzky-Willer, Viena, Austria
  • H. Kleinwechter, Kiel, Germany
  • A. Kurjak, Zagreb, Croatia
  • N. Lohse, Copenhagen, Denmark
  • A. Lapolla, Padova, Italy
  • R. Laurini, Porto, Portugal
/
  • J. Lepercq, Paris, France
  • G. Lingmam, Lund, Sweden
  • G.P. Mandruzzato, Trieste, Italy
  • K. Marsal, Lund, Sweden
  • M. Maresh, Manchester, UK
  • M. Massi-Benedetti, Perugia, Italy
  • E. Mathiesen, Copenhagen, Denmark
  • J. Mazela, Poznan, Poland
  • F. Mecacci, Firenze, Italy
  • G. Mello, Firenze, Italy
  • I. Meizner, Petah Tiqva, Israel
  • M. Merialdi, Geneva, Switzerland
  • L. Molsted-Pedersen, Copenhagen, Denmark
  • A. Napoli, Rome, Italy
  • U. Nicolini, Milano, Italy
  • L. Nugmanova , Uzbekistan
  • E. Ozegowska, Poznan, Poland
  • G. Pardi ,Milano,Italy
  • E. Parretti, Firenze, Italy
  • B. Persson, Stockholm, Sweden
  • Y. Peled, Petah Tiqva, Israel
  • D. Pfeifer, Zagreb, Croatia
  • M. Philip , Petah Tiqva, Israel
  • T. Pieber, Graz, Austria
  • T. Premru-Srsen, Ljubljana, Slovenia
  • A. Rabben, Copenhagen,Denmark
  • G. Roglic, Geneva, Switzerland
  • C. Savona-Ventura, Malta
  • C.Sen, Istanbul, Turkey
  • O.D.Saugstad,Oslo, Norway
  • U. Schaefer-Graf, Berlin, Germany
  • T. Somville, Berlin, Germany
  • C. Speer, Wuerzburg, Germany
  • K. Teramo, Helsinki, Finland
  • J. Timsit, Paris, France
  • E. Torlone, Perugia, Italy
  • M. Torok, Budapest , Hungary
  • G. Visser, Utrecht, The Netherlands
  • S. Walkinshaw, Liverpool, UK
  • J. Wilczynski, Lodz, Poland
  • Y. Yogev, Petah Tiqva, Israel
  • C. Zoupas, Athens, Greece

1

1. PREFACE

Remarkable advances have been made in recent years in clarifying the metabolic processes that occur during pregnancy and their effect on intrauterine fetal development. As a result, clinicians have become increasingly aware of the compelling need to properly identify and manage states associated with metabolic dysfunctions in pregnancy, the most important of which is diabetes mellitus.In Europe, the incidence of diabetes in pregnancy ranges from 8% to 10%. That means that of the 5,000,000 women who give birth each year, some 400,000 to 500,000 suffer from diabetes during the course of pregnancy.

Diabetes in pregnancy is divided into two types. It is very important to distinguish between them, as each has a different impact on the course of pregnancy and the development of the fetus. Gestational diabetes mellitus (GDM) usually appears in the second half of pregnancy and affects mainly fetal growth rate; it can cause obesity and slow systemic development, and probably has other long-term effects. Pre-gestational diabetes mellitus (PreGDM) - type 1, type 2 or Maturity Onset Diabetes of the Young (MODY) - is more serious because it is present before pregnancy, so that their effects begin already at fertilization and implantation, and continue throughout pregnancy and thereafter. In particular, organogenesis may be disrupted, leading to a high risk of early abortion, congenital anomalies and retarded growth. Maternal manifestations are also more serious, especially in the presence of vascular complications such as retinopathy or nephropathy.

1.1 Implications for Diabetes in Pregnancy:

With advancing pregnancy,considerable demands are placed upon insulin to meet increasing demands of maternal and fetal metabolism. If the threshold is surpassed maternal hyperglycaemia may occur.In their mildest form - that of women with gestational diabetes and normal fasting blood glucose - these changes arise predominantly in the “fed” state. During this phase, postprandial fluctuations of virtually every maternal fuel are exaggerated. As the insulin demands become progressively compromised, hyperglycaemia occurs in association with further increasesin postprandial fuel changes. At the extreme end of the spectrum of the insulin deficiency effect are women with insulin-dependent diabetes and no insulin secretion, who are totally dependent on exogenous insulin for metabolic control. Thus, the entire range of maternal diabetes is expressed by quantitative and/or qualitative changes in the maternal fuel mixer and reflecting upon the metabolic environment of the conceptus.

1.2 Implications for the Conceptus:

Growth and development of the human conceptus occur within the metabolic milieu provided by the mother and are ultimately dependent upon circulating maternal fuels and tissue building blocks. An increasing body of evidence supports the hypothesis that the abnormal gestational environment of the diabetic mother may imprint on certain fetal developing tissues and organs, eventually leading to permanent long-term implications for postnatal function. The fetal tissues most likely to be affected are neural cells, adipocytes, muscle cells and pancreatic  cells. Maternal fuels supplythe “building blocks” for fetal development. Freinkel introduced the concept of pregnancy as a “tissue culture experiment”, in which the placenta and the fetus develop in an “incubating medium” totally derived from maternal fuels. All these fuels, glucose, amino acids, lipids, etc., traverse the placenta in a concentration-dependent fashion and thus contribute to the fetal milieu. Since all these constituents are regulated by maternal insulin, disturbances in its supply or actions will influence the whole nutritional content to which the fetus is exposed and, eventually, lead to fetal hyperinsulinaemia. According to Freinkel’s hypothesis, the abnormal maternal mixture of metabolites gains access to the developing fetus in utero, modifying the phenotypic gene expression in newly-formed cells, which in turn may determine permanent, short- and long-term effects in the offspring. Depending upon the time of embryo-fetus exposure to the aberrant fuel mixture, different events may develop. Early in the first trimester, intrauterine growth retardation and organ malformation, described by Freinkel as “fuel-mediated teratogenesis” may happen. During the second trimester, at the time of brain development and differentiation, behavioural, intellectual or psychological damage may occur. During the third trimester, the abnormal proliferation of fetal adipocytes and muscle cells, together with pancreatic  cells and neuroendocrine cells hyperplasia may be responsible for the development of obesity, hypertension and non-insulin diabetes mellitus later in life.

1.3 Implications for the Mother:

Until the discovery of insulin by Banting and Best in 1921, very few women with diabetes became pregnant spontaneously, and even fewer achieved a successful pregnancy outcome. At that time, about 50% of women died during pregnancy from diabetes-related complications (mainly ketoacidosis) and about 50% of the fetuses failed to develop in utero. Later studies documented a much higher rate than expected of both maternal and fetal complications in diabetic pregnancy compared to normal pregnancy. Diabetic women have a markedly higher risk for a number of pregnancy adverse events, including spontaneous abortion, preterm labour, recurrent genital and urinary tract infections, pyelonephritis, polyhydramnios, hypertensive disorders, traumatic birth and hyper- and hypo-glycemic events. These complications, together with the increased rate of vascular alteration (retinopathy and nephropathy) along with a higher cesarean section rate, contribute to higher maternal morbidity and mortality among diabetic patients. However, once the major issue is addressed - namely, that the diagnosis of gestational diabetes mellitus is thought to be associated with a high risk of developing diabetes in later life - efforts should be made to prevent or ameliorate the emergence of this complication.Women with diabetic pregnancy today are enjoying the benefits of the extraordinary progress made in all areas of medicine in general and in obstetrics in particular. State-of the art tools have been developed for diagnosis, treatment and follow-up of both mother and fetus, such as fetal heart rate monitors, ultrasonography, and glucose self-monitors and insulin pumps. As a result, leading medical centres worldwide report a major reduction in maternal and fetal complications of diabetic pregnancy to levels similar to those in normal pregnancy. Clinicians today recognize unequivocally that early diagnosis, adequate treatment, and close follow-up are essential to eliminate most complications of diabetic pregnancy and achieve a successful outcome. However, even in developed countries the overall results are far from good.

2. DEFENITION AND CLASSIFICATION OF DIABETES

Eran Hadar & Moshe Hod

2.1Definition:

Diabetes mellitus is a group of metabolic disorders characterized by hyperglycaemia due to insufficientpancreatic insulin secretion, impaired tissue response to insulinor a combination of both, with the consequent disturbances in carbohydrate, fat and protein metabolism. The chronic and sustained hyperglycaemia ultimately leads to multi-organdysfunction. Damage, predominantly involving the small blood vessels, affects mainly the eyes, kidneys, and nervous system; damage to the large blood vessels affects the brain, heart, and legs.

2.2 Classification:

In 1997, the American Diabetes Association (ADA) published new criteria for the classification and diagnosis of diabetes mellitus to replace those in effect since 1979(1).The terms insulin-dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes (NIDDM) were eliminated because they often led to misclassifications on the basis of the treatment administered rather than the underlying cause.

The new ADAclassification differentiates four clinical groups of diabetes mellitus:

  1. Type 1 diabetes mellitus(2-4)- In type 1 diabetes, which accounts for about 10% of all cases of diabetes, beta cell destruction leads to insulin deficiency and the risk of ketoacidosis. There are three forms.
  • Immune-mediated type 1 diabetes - This is the most common form, and can be confirmed by the presence of antibodies against the islet cells (ICA) or their components, such as GAD, IAA, and ICA5/2.
  • Idiopathic type 1 diabetes - This type is less well-defined and includes cases in which signs of autoimmune processes are absent.
  • Latent autoimmune diabetes in adults (LADA) – this subtype is apparently more prevalent than previously thought, accounting for 5-10% of all cases of diabetes diagnosed in adults.
  1. Type 2 diabetes(3-6) - Type 2 diabetes includes most forms of diabetes that derive from combined insulin resistance and imbalance of insulin secretion. Approximately 90% all diabetics have this type. Over recent years, in developed countries, contrary to a decade or so ago, type 2 diabetes has accounted for up to 1/3 of all PreDM). The AmericanCollege of Obstetricians and Gynecologists (ACOG) has classified GDM and PreGDM into diagnostic subgroups, as shown in Tables 1. PreDM is grouped on the basis of age at onset, duration of disease, and presence of vascular complications – all direct prognostic factors for mother and fetus in the course of pregnancy.
  1. Other specific types(4)- About 3% of all cases of diabetes are of other specific types. The many states that fall into this category, albeit relatively rare, include proven genetic defects in beta cell function, genetic defects in insulin activity, exocrine pancreatic diseases, endocrinopathies, diabetes due to medications or chemicals, infections, and the rare autoimmune diabetes and genetic syndromes that involve diabetes. One of the genetic defects in beta cell function is maturity onset diabetes of the young (MODY), which was previously classified under type 2 diabetes mellitus.
  1. Gestational diabetes mellitus(4,9-10)- GDM is defined as carbohydrate intolerance of variable severity that is first diagnosed during pregnancy.GDM is grouped on the basis of the fasting blood glucose level, and the mode of treatment, either diet or medical therapy by insulin or oral hypoglycemic agents (Table 2). A fasting level below 95 mg/dl [5.3 mmol/l], requires only dietary management and is designated A1. A level above 95 mg/dl [5.3 mmol/l] is treated with diet and insulin and is designated A2.

2.3 The Intermediate states:

The Intermediate states(1,7-8), are characterized by glucose levels ranging between normal to the lower limit of diabetic values. The intermediate states are risk factors for both diabetes mellitus (1/3 of individuals with IGT will develop diabetes within 10 years) and macrovascular disease (the cardiovascular risk is two- to three times higher). They are usually not associated with the development of microvascular complications unless the blood glucose reaches levels diagnostic of full-blown diabetes (thereby changing the classification). It should be emphasised that although the prognostic significance of IFG is well established, data are still too sparse to determine if it constitutes a risk of macrovascular morbidity equal to that of IGT. The intermediate states are divided into two types:

  1. Impaired fasting glucose (IFG) - This is a relatively new concept that defines individuals with fasting glucose levels between 110 to 125 mg/dl (6.1 - 7.0 mmol/l).
  2. Impaired glucose tolerance (IGT) – This has long been recognized and defines individuals with glucose levels of 140 to 199 mg/dl (7.8 - 11.0 mmol/l) two hours after a 75 g oral glucose load.

Table 1: Classification of PreDM

Group

/ Age at onset(yr) / Duration of disease (yr) / Vascular complication /

Treatment

B / Over 20 / Less than 10 / None / Diet-insulin
C / Less than 10 and/or 10-19 / None / Diet-insulin
D / Less than 10 and/or over 20 / Retinopathy-Background type / Diet-insulin
F / All ages / Any duration / Nephropathy / Diet-insulin
R / All ages / Any duration / Retinopathy-Proliferative / Diet-insulin
H / All ages / Any duration / Cardiac disease / Diet-insulin
T / All ages / Any duration / After organ transplant / Diet-insulin
Table 2: Classification of GDM

Group

/

Fasting Glucose

/
2-hr Postprandial Glucose
/

Treatment

A1 / <95 mg/dl (<5.3 mmol/l) / <120 mg/dl (<6.7 mmol/l) / Diet only
A2 / >95 mg/dl and/or >120 mg/dl
>5.3 mmol/l and/or >6.7 mmol/l / Diet + Insulin / Oral Hypoglycemics

3. GESTATIONAL DIABETES MELLITUS

GDM is defined as carbohydrate intolerance of variable severity that is first diagnosed during pregnancy (4).

3.1 Epidemiology of GDM:

The occurrence of GDM parallels the prevalence of type 2 diabetes in a given population, both of which having been rising sharply during recent years. The prevalence of GDM, and the occurrence of related complications, depends upon the definition of normal glucose values during gestation (20). The estimated incidence of GDM in Europe ranges from 8% to 10%. That means that of the 5,000,000 women who give birth each year, some 400,000 to 500,000 suffer from diabetes during the course of pregnancy.

3.2 Fetal and Maternal Implications:

GDM is associated with a higher incidence of maternal morbidity - cesarean deliveries, post partum type 2 diabetes; and perinatal/neonatal morbidity - macrosomia, birth injury, shoulder dystocia, hypoglycemia, polycythemia and bilirubinemia. Long term sequela of in utero exposure to hyperglycemia may include a higher risk for obesity and diabetes later in life. Table 3 lists the implications of GDM for mother and fetus/baby (11-19).

Table 3: Risk to mother
  1. Polyhydramnios
  2. Hypertensive diseases
  3. Recurrent genital and urinary tract infections
  4. Traumatic labour
  5. Instrumental delivery or caesarean section
  6. Full blown diabetes in the future

3.3 Diagnosis:

The diagnostic criteria for GDM were first published more than 40 years ago, in pivotal research conducted by O’sullivan and Mahan (56). These criteria were established using non-pregnancy values, and were designed to predict the future occurrence of maternal type 2 diabetes. The classification, diagnosis, and treatment of GDM have been based on the recommendations of the International Workshop-Conference on Gestational Diabetes Mellitus (21). As of 2007, five such international meetings had been held and their recommendations were adopted by major medical institutions in Europe and America (American College of Obstetrics and Gynaecology, American Diabetes Association, European Association for the Study of Diabetes, World Health Organization). These still widely used criteria, are controversial mainly because they lack correlation to outcome, be it maternal or perinatal. The other widely used criteria are those of the World Health Organization. These criteria are those used to classify impaired glucose tolerance, again established for a non-pregnant population (57). To answer some of the above mentioned controversies, the hyperglycemia and adverse pregnancy outcome study (HAPO) was planned and executed(23-25). It was meant to set the evidence based criteria for diagnosis and classification of GDM, to be based upon the correlation between glycemic levels and perinatal outcome. The participating teams in the study included 15 medical centers, in 9 different countries. Pregnant women at a gestational age closely as possible to 28 weeks (range was 24-32 weeks) were tested for fasting plasma glucose, followed by a 75 gram oral glucose tolerance test (OGTT). Additional blood samples were collected 1 and 2 hours post glucose intake. Also, a sample for random plasma glucose was collected at 34-37 weeks of gestation, to identify late onset diabetes. The caregivers and the participating women were blinded to the results unless: fasting plasma glucose exceeded 105 mg/dL (5.8 mmol/L), 2-hour OGTT plasma glucose exceeded 200mg/dl (11.1 mmol/L), random plasma glucose was equal or greater than 160mg/dl (8.9 mmol/L) or if any glucose value was below 45mg/dl (2.5 mmol/L). Cord blood was collected at delivery for measurement of glucose and C-peptide (as a surrogate marker for plasma insulin levels). Prenatal care, timing and mode of delivery and post natal follow up were practiced according to standard care guidelines, for each of participating center.A total of 23,316 women completed the course of the study, not being lost to follow up, and remaining with their data blinded. The results of the HAPO study demonstrate an association between increasing levels of fasting, 1-hour and 2-hour plasma glucose post a 75g OGTT, to the 4 primary endpoints of the study: birth weight above the 90th percentile, cord blood serum C-peptide level above the 90th percentile, primary cesarean delivery and clinical neonatal hypoglycemia.Positive correlations were also found between increasing plasma glucose levels to the five secondary outcomes: premature delivery, shoulder dystocia or birth injury, intensive neonatal care admission, hyperbilirubinemia and pre-eclampsia. The HAPO study therefore demonstrates that fasting glucose levels and post 75g OGTT are correlated to maternal, perinatal and neonatal outcomes and this is essentially in a linear manner.There seems to be no apparent threshold, but rather a continuum of glucose levels. These results provided the evidence base for developing perinatal outcome based standards to diagnose and classify GDM. The International Association of Diabetes and Pregnancy Study Groups (IADPSG) has published new recommendations for the diagnosis of GDM.