EUROPEAN ASSOCIATION OF PERINATAL MEDICINE EAPM DIABETES AND PREGNANCY

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29 THE SCOPE FOR ACTION OF EUROPEAN PARLIAMENT
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Е ВРОПЕЙСКИЙ ПРОЕКТ НПМ COUNCIL OF EUROPE EUROPEAN
EUROPEAN COURT OF HUMAN RIGHTS JUDGMENTS ON THE
EUROPEAN CURRICULUM VITAE FORMAT PERSONAL INFORMATION IEVA GRUNDSTEINE

THE OFFSRING OF DIABETIC MOTHERS

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

......................................................................................................................

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. 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 increases in 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 supply the “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

2.1 Definition:

Diabetes mellitus is a group of metabolic disorders characterized by hyperglycaemia due to insufficient pancreatic insulin secretion, impaired tissue response to insulin or a combination of both, with the consequent disturbances in carbohydrate, fat and protein metabolism. The chronic and sustained hyperglycaemia ultimately leads to multi-organ dysfunction. 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 ADA classification differentiates four clinical groups of diabetes mellitus:

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.

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 American College 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.

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.

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:

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).
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

Polyhydramnios
Hypertensive diseases
Recurrent genital and urinary tract infections
Traumatic labour
Instrumental delivery or caesarean section
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 90^th 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.

IADPSG Recommendations

The overall strategy recommended by the IADPSG Consensus Panel for detection and diagnosis of hyperglycemic disorders in pregnancy is summarized in Table 4. Thresholds for diagnosis of overt diabetes during pregnancy are summerized in Table 5, and for GDM diagnosis in table 6. The novel approach in the IADPSG suggested criteria is that overt diabetes can also be diagnosed during pregnancy, and that the criteria are evidence based on the HAPO study results.

At the first prenatal visit, all or only high-risk women should undergo testing of fasting plasma glucose (FPG), hemoglobin A1C, or random plasma glucose (RPG), based on the background frequency of abnormal glucose metabolism in the population and on local circumstances. Criteria for low risk include: Absence of diabetes in first-degree relatives, Age <25 years, Normal pre-pregnancy weight, No history of poor carbohydrate metabolism, No history of adverse pregnancy outcome . Criteria for high risk women for diabetes include: Pre-pregnancy obesity, Family history of type 2 diabetes mellitus, GDM in a past pregnancy and Known carbohydrate intolerance or glycosuria. To diagnose GDM at 24 to 28 weeks of gestation, a 2-hour, 75-g OGTT should be performed after overnight fast on all women not previously found to have overt diabetes or GDM during testing earlier in this pregnancy. All women diagnosed with GDM or overt diabetes during pregnancy should undergo postpartum glucose testing.

Table 4: Strategy for the detection and diagnosis of hyperglycemia disorder in pregnancy

First Prenatal Visit

Measure Fasting Plasma Glucose, Hemoglobin A1C or Random Plasma Glucose, on all or only high risk women:

If results indicate overt diabetes as per table 5  Pre-existing diabetes

If results not diagnostic of overt diabetes as per table 5 and fasting plasma glucose ≥ 5.1mmol/L (92mg/dl)

but < 7.0 mmol/L (126mg/dl)  GDM

If results not diagnostic of overt diabetes as per table 5 and fasting plasma glucose < 5.1mmol/L (92mg/dl)

 test for GDM from 24-28 weeks with a 75g OGTT

24-28 weeks of gestation

Perform a 75g OGTT on all women not previously diagnosed with overt diabetes or GDM:

If fasting plasma glucose ≥ 7.0 mmol/L (126 mg/dl)  Pre-existing diabetes

If one or more values equals or exceeds thresholds as per table 6  GDM

If all values less than thresholds indicated as per table 6  Normal

Table 5: Threshold Values for diagnosis of Overt diabetes in pregnancy
Measure of Glycemia	Threshold		Remarks
Fasting Plasma Glucose	≥ 7.0 mmol/L	≥ 126 mg/dl
Hemoglobin A1C	≥ 6.5%		DCCT/UKPDS Standardized
Random Plasma Glucose	≥ 11.1 mmol/L	≥ 200 mg/dl	If a random plasma glucose is the initial measure of glycemia, the tentative diagnosis of overt diabetes in pregnancy should be confirmed by fasting plasma glucose or hemoglobin A1C

Table 6: Threshold Values for diagnosis of GDM
Glucose Measure	Glucose Threshold
Glucose Measure	Mmol/L	mg/dl
Fasting Plasma Glucose	5.1	92
1 Hour Post 75g OGTT	10.0	180
1 Hour Post 75g OGTT	8.5	153

3.5 Treatment:

Researchers agree that when GDM is diagnosed early and treated properly, the risk of intrauterine fetal death decreases to levels matching those of the general population. Fetal morbidity is lower in affected women maintained under optimal glucose control than in women who are not. The major cause of perinatal morbidity in GDM is large-for-gestational-age fetus, which leads to a high rate of caesarean section and injury to both mother and child during delivery.

Repeated ultrasonographic scans to assess fetal weight and detect asymmetric growth will improve the ability of the physician to identify pregnancies at risk of macrosomia in order to focus treatment.

The optimal time of delivery and need to induce labour are still controversial. Nevertheless, the presence of macrosomia is clearly harmful to both fetus and mother (i.e., increases rate of caesarean section). Other important considerations are hypoglycaemia, hyperbilirubinaemia, and hypocalcaemia. The severity of these findings depends on the gestational age at birth and other metabolic parameters.

GDM with onset in late pregnancy does not carry an increased risk of congenital anomalies. However, GDM detected in the first trimester, like PreDM, may be associated with an increased incidence of fetal developmental abnormalities. Therefore, these patients should be managed like those with pre-existing diabetes mellitus as far as auxiliary tests (ultrasonography, fetal echography) are concerned.

3.5.1 Goals of treatment - The main goals of treatment of GDM are to prevent adverse effects to mother and infant. Normalization of glucose levels is a proven factor in the attainment of this goal. In addition, postprandial glucose levels are more closely associated with macrosomia than fasting levels. There are as yet no controlled studies establishing the optimal blood glucose level for prevention of increased fetal risk. Table 7 shows the values known to be related to a similar risk in the general population ^(22-25).

Table 7: Goals of treatment
Fasting	95 mg/dl	5.3 mmol/l
1 hr after meal	140 mg/dl	7.8 mmol/l
2 hr after meal	120 mg/dl	6.7 mmol/l

3.5.2 Diet - Women with GDM must follow an individually tailored diet prepared by a dietician ^(26-34)

Nutritional advise should account for personal habits and preferences, body weight, type and rate of physical activity, blood glucose level, ketone level, and should consider timings and type of insulin (if necessary). The diet must deliver the minimum daily nutritional requirements for all pregnant women.
The caloric intake must be compatible with the state of pregnancy and ensure the proper weight gain according to the patient’s ideal weight before and during pregnancy. Recommended daily caloric intake is presented in table 8.

The recommended weight gain during pregnancy is 7 kg for women who were overweight before pregnancy (BMI >29kg/m²) and up to 18 kg in women who were underweight before pregnancy (BMI<19.8kg/m²).
In women with known obesity before pregnancy (BMI>30kg/m²), the number of calories may be decreased to 30% of recommended values. This limitation must be done carefully by an experienced professional in the field, with close surveillance by urine testing for ketonuria. There is evidence indicating that this restriction can decrease blood glucose and triglyceride levels.

The distribution of caloric intake should be 35-40% carbohydrates (complex carbohydrates are recommended), 20-25% protein, and 35-40% fat (10% polyunsaturated). In general, blood glucose levels can be well controlled by setting the correct amount of carbohydrates for every meal. An example is presented in Table 9.

The effect of the diet should be followed by postprandial SMBG, and changes made accordingly.
Sometimes, carbohydrates need to be decreased at breakfast and decreased at dinner.
Special attention should be directed to women who decrease their carbohydrate intake because of poor information or misdirected fear.
Urine ketones should be monitored to prevent starvation ketosis.
Artificial sweeteners may be used in moderation.

Table 8: Recommended daily caloric intake
Body mass index (kg/m²)	Caloric intake/kg body weight
<19.8	35-40
19.8-29	30-32
>29	24-25

Table 9: Daily distribution of carbohydrates
Hour	Meal	% of total daily carbohydrates
8:00	Breakfast	10
10:30	Mid-morning	5
13:00	Lunch-time	30
15:00	Early Mid-afternoon	10
17:00	Late Mid-afternoon	5
20:00	Dinner	30
23:00	Night snack	10

3.5.3 Glyburide - Glyburide (Glybenclamide, Gluben) may be used as drug therpay in GDM. It should be considered in women who failed to achieve glycemic control following a two week trial of diet. Accumilated evidence suggest that glyburide is both safe and effective during pregnancy. The following criteia sugges a lower chance of achieving appripriate metabolic control with glyburide, thus, in these cases insulin should be considered as the first line medical therapy: Diagnosis of hyperglycemia in pregnancy prior to 25 weeks, Need for medical therapy beyond 30 weeks, Fasting glucose levels >110mg/dl, 1hr post prandial glucose >140mg/dl and pregnancy weight gain >12Kg. Glyburide should be started on a dosage of 2.5mg/d, with dosage elevated according to glycemic control every 4-5 days, to a maximal dose of 20mg/d.

3.5.4 Insulin - When the glucose level cannot be maintained within recommended limits by diet alone and/or glyburide treatment, insulin treatment is required. There is no evidence supporting the advantages of any one dosage over another. Insulin programs should be individualized on a case-by-case basis (35-40)

Human insulin is recommended; the dosage schedule is dictated by the circadian glycemic profile.
Rapid-acting insulin analogues can improve glycemic levels, Although available data does not clearly find insulin lispro or insulin aspart to be superior to regular insulin in pregnant women in terms of glycemic control and risk of hypoglycemia, it appears they are as safe and as efficacious as regular insulin for the management of GDM.
Recently, a large randomized controlled trial comparing insulin detemir with long-acting human insulin has been published, and was found to be safe and effective as long acting insulin during pregnancy. Paucity of data exists on insulin glargine during pregnancy, adn although it appears to be safe and well tolerated, data is of low quality and fear of terategonicity has not been clearly removed.
Hyperglycaemia and hypoglycaemia should be prevented during delivery. Insulin should be given only if glucose levels rise above the maximum range. Clinicians should ensure an appropriate and balanced glucose-insulin supply during delivery, whether spontaneous or by caesarean section.

3.6 Labour and Delivery:

Labour and delivery is aimed to occur at term, or otherwise if indicated by maternal or fetal compromise. Normal vaginal delivery is preferred, but a liberal approach to operative delivery (caesarean sections) is used when estimated fetal weight is above 4,000 g. Assessment of fetal lung maturity is performed only when delivery is induced before the 38th week. Fetal weight is estimated sonographically at 38 weeks and the decision regarding timing and mode of delivery is undertaken ^(41-44).

3.7 Long-Term Effects and Postnatal Care:

Women with GDM are at risk of developing type 2 diabetes mellitus, and sometimes type 1, after pregnancy, depending on their age at diagnosis of GDM, glucose level on the first postpartum assessment, beta cell function, weight, and another pregnancy. All In women in whom glucose intolerance was diagnosed during pregnancy, the glycaemic status should be re-evaluated at 6-12 weeks after delivery with a 75 g glucose load ^(45-46). Diagnosis is based on the currently recommended criteria, as presented in table 10. Women who do not have diabetes according to these definitions should undergo repeated OGTT once yearly. Women who had GDM should be advised to maintain a healthy life-style with regular exercise and normal body weight for their habits and to seek consultation before their next pregnancy.

Table 10. Reclassification of disease after diabetic pregnancy by 75 g OGTT
Diagnosis	Fasting blood glucose	2 hr blood glucose
Normal values	<110 mg/dl (<6.1 mmol/l)	<140 mg/dl (<7.8 mmol/l)
Interim state	110-125 mg/dl (6.1 - 7.0 mmol/l)	140-199 mg/dl (7.8 - 11.0 mmol/l)
Diabetes	>126 mg/dl on two tests (>7.0 mmol/l)	>200 mg/dl (> 11.1 mmol/l)

4. PRE-EXISTING DIABETES MELLITUS

Metabolic changes in the pregnant mother also affect her child – in utero and thereafter, in infancy, childhood and even adulthood. Many researchers are attempting to define and describe the known obstetric risks and complications associated with maternal diabetes, the underlying pathophysiology of the disease, and the manner in which hyperglycaemia affects these processes. Some of the recent improvement noted in the health of infants of diabetic women derives from the advances made in our understanding of the disease, in monitoring techniques, and in neonatal and paediatric medicine. However, for the most part it is due to prevention by means of good maternal metabolic regulation. Careful control of glucose levels for several months before conception can usually lower the risk of complications during pregnancy and delivery, in some cases to within the range of the normal population. Today, glucose analyzers are available for home use to enable self-regulation by women at risk. Clinicians can then combine these daily measures with monthly measurement of glycosylated haemoglobin (HbA1c) levels for precise and continuous surveillance. Together, the physician-patient team can achieve maximum balance and lower fetal and neonatal morbidity and mortality rates. It is essential to bring these issues to the awareness of all physicians so that diabetic women of reproductive age will be referred to the appropriate clinics before pregnancy. There, they will learn about the importance of glucose regulation already before conception, and during pregnancy and delivery.

4.1 Definition:

PreDM is a metabolic disturbance characterized by hyperglycaemia due to a disruption in the production or function of insulin, which is first detected before pregnancy. The diabetes may be type 1 or 2 or MODY or IGT.

4.2 Incidence:

About 10% of all diabetic women have PreDM, that is, about 0.3 to 0.5% of all pregnant women, or 15,000-25,000 women in Europe annually.

4.3 Preparation for Pregnancy:

Metabolic balance at the time of conception and even before is mandatory to prevent congenital anomalies. Therefore, careful, precise pre-pregnancy planning is necessary. Cumulative data indicate a target HbA1c level lower than 6SD of the laboratory mean at the medical centre.

Despite the advances in the clinical treatment of PreDM, the incidence of congenital malformations is still three times higher in women with diabetes than in healthy women (in whom the rate is 2-3% in the general population). Congenital malformations are currently the major cause of perinatal mortality in this population. Much of the clinical research of the last 20 years indicates that close clinical surveillance and proper treatment to maintain glucose within pre-pregnancy physiological levels (with family planning and metabolic preparation) can drastically decrease congenital anomalies, to rates almost equal to those in the general population, i.e., about 3%. According to prospective studies, the rate of anomalies in offspring of diabetic mothers who were properly treated before conception in specialised clinics is 2.2%, compared to 8.7% in offspring of mothers who started treatment after conception (in most cases, after organogenesis). Clinicians must counsel all women of reproductive age who have diabetes to use contraceptive means and not to get pregnant without proper planning ^(47-53).

Evaluation of diabetic risk and treatment - Preparation should begin 3-6 months before the desired time of pregnancy, as outlined below.

Dilated retinal examination. Patients should be seen by an ophthalmologist. All laser treatments should be completed before onset of pregnancy.
Kidney function tests. Measurement of electrolyte levels is required in addition to blood kidney function tests and 24-hour urine collection for creatinine clearance test (CCT) and microalbumin levels. When microalbumin measures more than 300 m/day, quantitative urine collection for protein should be performed. A recent study determined the influence of microalbuminuriaon pregnancy outcome in women with type 1 diabetes. They found that the prevalence of preterm delivery is considerablyincreased in women with microalbuminuria, mainly caused by preeclampsia.Accordingly they suggested that classification according to urinary albumin excretion and metaboliccontrol around the time of conception are superior to the Whiteclassification in predicting preterm delivery in women withtype 1 diabetes.
Thyroid function test- due to high rate of co-morbidity, screening for thyroid dysfunction is recommended.
Blood pressure. Blood pressure should be controlled with medications that are not indicated in pregnancy.
Cardiac evaluation. Women with adverse findings on anamnesis or physical examination should undergo electrocardiography and, according to these findings, echocardiography, an exercise test, and further work-up as needed with nuclear and angiographic imaging. Women over 40 years old or who have had diabetes for more than 10 years should undergo echocardiography regularly.
Neurologic evaluation/electromyography. These should be done in women with suspicious neuropathic findings.
All oral antidiabetic medications should be stopped and balance achieved with insulin.
Intensive treatment with insulin is necessary to balance glucose levels and achieve an optimal HbA1c. There is evidence that maintaining an HbA1c level at less than 6 SD of the average laboratory level will prevent an increased incidence of congenital anomalies.
Insulin analogues - Rapid-acting insulin analogues can improve glycemic levels, Although available data does not clearly find insulin lispro or insulin aspart to be superior to regular insulin in pregnant women in terms of glycemic control and risk of hypoglycemia, it appears they are as safe and as efficacious as regular insulin for the management of GDM. Recently, a large randomized controlled trial comparing insulin detemir with long-acting human insulin has been published, and was found to be safe and effective as long acting insulin during pregnancy. Paucity of data exists on insulin glargine during pregnancy, and although it appears to be safe and well tolerated, data is of low quality and fear of terategonicity has not been clearly removed.
Blood tests. Routine blood tests should be conducted before pregnancy, as for the general population of pregnant women. Thyroid function should also be assessed.
Hospitalization. In general, glucose regulation before pregnancy can probably be done in outpatient clinics. Sometimes patients need to be hospitalised to start intensive treatment because of technical limitations or complications of diabetes, such as ketoacidosis or severe hyperglycaemia.

Diet - Consultation with a dietitian with expertise in the field of diabetes is an integral part of the preparatory program. Patients are given personal diets formulated according to their BMI. Usually, blood glucose can be better controlled by establishing the correct amount of carbohydrates for every meal (see Table 8). The effects of the diet should be followed by postprandial self-monitoring, with changes made accordingly. Sometimes, the amount of carbohydrates needs to be increased at breakfast and reduced at dinner.

Treatment of hypoglycaemia - At every intensive intervention before and during pregnancy, an increased prevalence of hypoglycaemic events may be expected (especially in the first weeks of pregnancy as a result of oestrogen release). Clinicians should educate their patients to recognise the early signs of hypoglycaemia, which can be different from the pre-pregnancy period, and apply proper treatment, such as two teaspoons sugar, rapidly absorbed tablets (dextro-pur), appropriate liquids, and one portion of bread. Patients should be equipped with a glucagon injection for emergencies, and family members, too, should be taught to use it.

Treatment of high blood pressure - All ACE inhibitors should be stopped near to the expected onset of pregnancy, as early as possible. The accepted treatment for high blood pressure in pregnancy includes several class C drugs:

Beta blockers (propranolol) – Beta blockers have been linked to retarded growth in utero and to neonatal hypoglycaemia and bradycardia. However, in general, they are considered safe in pregnancy. As beta blockers may mask signs of hypoglycaemia, they should be used with care in patients with PreDM.
Calcium channel blockers (mainly nifedipine) – Calcium blockers do not affect glucose metabolism and are effective in lowering blood pressure. They are considered relatively safe for use in pregnancy.
Apresoline (hyralazine) – This drug, too, does not affect glucose metabolism and is relatively safe for use in pregnancy. It is very effective in lowering blood pressure and is the preferred drug in moderate and severe cases.
Aldomin (methyldopa) – Aldomin does not affect glucose metabolism and is relatively safe for use in pregnancy. As much experience with this drug has been gained over the years, it is preferred in cases of chronic high blood pressure.

Aspirin - Recent Cochrane analysis has shown that aspirin may be prescribed, in low doses (75-100 mg), in selected high risk groups - such as type 1 and 2 diabetes – for the prevention of preeclampsia

Vitamins - As in normal pregnancy, women with PreDM should be prescribed folic acid at a dose of 400 mcg/day. In women with a previous child with a central nervous system anomaly (neural tube defect), the dose should be raised to 5 mg/day. Folic acid should be added starting about three months before pregnancy.

Smoking - Patients should be counselled to stop smoking already at their first visit.

Physical activity - Moderate physical activity is recommended both before and during pregnancy. Adding carbohydrates before physical activity to prevent hypoglycaemia might be considered.

4.4 Treatment and Follow-Up in Pregnancy:

The ultimate goal for the management of pregnancies complicated by diabetes should be a normal outcome for both mother and baby. Since maternal survival has been nearly uniform for several decades, fetal and neonatal survival has, until recently, been the primary therapeutic goal. With the advent of reliable techniques for outpatient assessment of fetal well-being and for control of maternal diabetes, perinatal survival approaching that of the non-diabetic population may now be achieved in many cases with a minimum of in-hospital care. Fetal and maternal outcome is directly correlated with the degree of maternal metabolic derangement.

Frequency of visits - The physician should be seen at least once monthly and the dietician as necessary.
Weight, blood pressure, and urine protein. These should be measured every two weeks in the second and third trimesters, and once a week starting from the 36th week of pregnancy.
Kidney function. Twenty-four-hour urine collection for protein analysis and CCT is recommended once each trimester.
Ophthalmologic complications. Retinal examination should be performed every trimester and treatment initiated as necessary. Pregnancy is not a contraindication for laser treatment of diabetic retinopathy.

Glucose Monitoring - Blood glucose level can be measured in one of three ways - Glycosylated haemoglobin concentration (Hemoglobin A1C), Self Monitoring of Blood Glucose (SMBG) and continuous glucose monitoring (CGM).

Continuous glucose monitoring (CGM) during pregnancy is recomeded for women with pre-gestational diabetes, and data suggest an improved glycemic control with reduced dosage of insulin.
Self-monitoring of blood glucose (SMBG) - Glucometer readings should be taken before meals, 2 hours after meals, and at bedtime. In the middle of the night, measurements should be made as necessary.

HbA1c - HbA1c levels should be measured every 4-6 weeks during pregnancy.

Nutritional treatment - In women with PreDM, the guiding principle is 1g protein/1 kg ideal body weight. In women with early signs of nephropathy, the clinician may consider lowering the protein dose to 0.6-0.8 g/kg ideal body weight. As before pregnancy, artificial sweeteners are allowed, but only in moderation.

Recommended weight gain - The recommended weight gain in pregnancy is 11-13 kg. Sometimes women who were overweight before pregnancy do not gain weight, and they need to be carefully followed for urine ketone levels and fetal development.

Diabetologic follow-up - The patient with PreDM should be seen by a diabetologist and nurse once every week to three weeks, as necessary, and a dietician as necessary. At each visit, the number of hypoglycaemic events should be documented and the patient’s glucose-measuring technique, physical activity (including time, duration, level), and understanding of the insulin treatment regimen should be checked.

Obstetric follow-up - Very close and careful obstetric follow-up is required after conception in a woman with PreDM. Examinations should be performed in a multidisciplinary clinic with professional expertise in high-risk pregnancy. Considered use should be made of the following tools:

Ultrasonography - early estimation of gestational age, detection of congenital anomalies, follow-up of fetal growth; and evaluation of biophysical profile and umbilical cord blood flow see above in detail.
Biochemical - Triple test adapted for diabetes (MSAFP, HCG, E2).
Fetal heart monitoring.
Follow-up of fetal movements.
Hospitalization - In most cases, hospitalization is required only for emergencies or extreme events that require follow-up and treatment every 24 hours (toxaemia, premature labour etc.).

4.5 Contraindications For Pregnancy

Severe nephropathy manifested as CCT<40 or creatinine above 2.5
Uncontrolled hypertension
Unmanageable proliferative retinopathy
Active coronary disease warranting in-depth evaluation

Table 11: Diabetes in Pregnancy Center
Staff	Equipment
1. Perinatologist (maternal-fetal medicine specialist)	1. Central Laboratory
2. Diabetologist-endocrinologist	2. Fetal heart rate monitors
3. Diabetes nurse/educator	3. Ultrasonography
4. Clinical dietitian	4. Echocardiography
5. Social worker/psychologist	5. Glucometers , Insulin Infusion Pumps (CSII) and Continuous glucose monitors (CGMS)
6. Secretary	6. Supply of insulin pens
7. Consultants: ophthalmologist, nephrologist

Table 12: Therapeutic approach to pregnant diabetic women with vascular complications
Stage of diabetes	Therapeutic measures
	Before conception	During pregnancy
Normoalbuminuria	Optimal metabolic control
Microalbuminuria	Optimal metabolic control
Microalbuminuria	ACE inhibitor treatment	–
Overt proteinuria	Optimal metabolic control
Overt proteinuria	Antihypertensive treatment as required
No diabetic retinopathy		Follow-up only
Mild NPDR	Inform patient about risk of aggravation	Follow-up each trimester
Moderate to severe non-proliferative diabetic retinopathy	Inform patient about high risk of aggravation	Monthly follow-up laser treatment as required
proliferative diabetic retinopathy	PRP before conception postpone conception until regression is observed	Panretinal photocoagulation consider cesarean section

5. CONTRACEPTIVE METHODS FOR DIABETIC WOMEN

Studies conducted in the last decade have shown that the rise in the incidence of congenital anomalies in children of diabetic women is due to the lack of metabolic control at the time of conception. With stringent metabolic control, the rate of congenital anomalies decreases to levels close to those in the general population. To properly plan her pregnancy, the diabetic woman must have access to effective contraceptive methods. Thanks to advances in contraceptive technology, clinicians can now offer their patients a relatively large range of options that meet medical criteria such as effectiveness and efficiency and satisfy individual preferences.

5.1. Women with GDM:

Women who had GDM and have normal findings on 75 g glucose loading after pregnancy can use any kind of contraceptive method, with the same considerations as healthy women. Regular metabolic follow-up is required with oral contraceptive use, even though oral contraceptives with low oestrogenic and low androgenic characteristics are generally considered not to adversely affect metabolic balance.

5.2 Women with PreDM and Normal Target Organs:

Women with diabetes before pregnancy are at the highest risk of congenital anomalies if glucose is not controlled at the time of conception. In the past, these patients were not considered candidates for oral contraceptives because of their side effects. This approach changed, however, with the development of oral contraceptives with a low oestrogen component (<30 mcg ethanyl estradiol) and progesterone with weak androgenic characteristics. Studies have shown that these new pills do not adversely affect the metabolic balance and often even improve it because of better patient compliance with treatment and follow-up. They also do not affect the blood lipid profile, and unlike the older type, do not lead to blood coagulation. Thus, the new oral contraceptives offer a good and safe solution for diabetic women who are under regular doctor’s care.

Another possibility that suits this patient group is the intrauterine device (IUD). Because it is not hormonal, the IUD does not have a metabolic effect. Research has proven it safe and effective in preventing pregnancy. The rate of side effects associated with the IUD in diabetic women does not exceed the rate and the rate in the general population.

5.3 Women with PreDM and Affected Target Organs:

Diabetic women in whom a microvascular disorder (nephropathy, retinopathy) has already developed are at higher risk of visual loss and renal dysfunction because of the diabetes. The safety of oral contraceptives, even the newer ones with lower hormone levels, has not been definitively proven in this patient group.

There are a few studies with some promising results regarding side effects, but further research is needed to evaluate long-term use. When no other means of contraception are available, clinicians may opt for oral contraceptives with low hormone doses in combination with meticulous follow-up in a multidisciplinary setting that includes experts in nephrology and ophthalmology, so that any worsening of the underlying disease is immediately detected and treated. As in women with PreDM and no vascular complications, the IUD is a feasible and safe solution.

In conclusion, clinicians have no problem today in suiting a contraceptive method to women with GDM. However, women with PreDM require close surveillance by a team with expertise in all the metabolic aspects of this disorder.

6. UNPLANNED PREGNANCY

As soon as pregnancy is detected, the mother should be treated as detailed above, and she should be informed of the risks of pregnancy in the presence of diabetes that is not carefully controlled (increased risk of congenital anomalies).
Oral medications should be replaced by insulin.
Blood glucose levels should be regulated immediately, and the patient should be warned about a possible worsening of retinopathy as a result of the rapid change in glucose balance. If the pregnancy is older than eight weeks and there are already signs of retinopathy, the risk to the mother from rapid glucose regulation outweighs the advantages to the fetus. Therefore, in these cases, the time to attainment of the target glucose level is extended to one month.
Patients should be given blood pressure lowering drugs that are not contraindicated in pregnancy.

7. SONOGRAPHIC ASSESSMENT IN DIABETIC PREGNANCY

Meizner I; Greco P

Antenatal ultrasound plays an important role in monitoring diabetic pregnancies. The ultrasound evaluation should take into consideration the differences between GDM (Gestational Diabetes Mellitus) and PreGDM and therefore, the sonographic approach must be tailored accordingly. The main issues associated with Sonographic assessment of these pregnancies include the following:

Assessment of gestational age
Detection of congenital anomalies
Surveillance of growth
Dynamic assessment of fetal status (BPS, Doppler)

7.1 Gestational Age Determination:

Evaluation of gestational age is extremely important for accurate monitoring of the advancing pregnancy. Estimation of gestational age should be performed in the first trimester of pregnancy, preferably, using TVS (trans-vaginal sonography). CRL is the best parameter for this purpose.

7.2 Congenital Anomalies:

With current care, perinatal mortality of the IDDM has been drastically reduced. The main contributor to perinatal mortality and morbidity in these patients is congenital malformations of the fetus. Abnormalities commonly affecting PreGDM include CNS, Heart, Skeletal, Genitourinary and GIT malformations. The lesion most associated with diabetic embryopathy, the caudal regression syndrome, is actually less common, with an incidence of 1.3 per 1000 diabetic pregnancies. Detection of congenital anomalies should be started in the first trimester of pregnancy and repeated in the second trimester. If possible, early anomaly scan using TVS (transvaginal sonography) may be helpful (14-16 weeks). A basic examination is mandatory in the second trimester of pregnancy and the following organs should be observed: cranium and brain, spine, stomach, bladder, kidneys and insertion of the umbilical cord. The four chamber view of the heart must be obtained; however, a detailed fetal echocardiography performed by a skilled paediatric cardiologist is preferred.

7.3 Fetal Growth Monitoring:

Monitoring fetal growth continues to be a challenging and highly inexact process. Although today’s tools, which involve serial plotting of fetal growth parameters, are superior to earlier clinical estimations, accuracy is still +/- 15%, using the most sophisticated ultrasound equipment. The most important task is to detect fetal macrosomia and IUGR. Since fetal macrosomia is the most frequent fetal complication of pregnant diabetic patients, a particular effort should be directed toward its diagnosis and management. Thus, unless the patient is not obese and periodic fundal measurements are normal, all pregnant diabetic patients should undergo ultrasound growth assessments of the fetus every several weeks, starting at around 20 weeks of pregnancy for preGDM’s and time of diagnosis for GDM’s. The macrosomic fetus, at some time will be above the 95^th percentile for one or more parameters, most frequently, the abdominal circumference. The positive predictive value for the diagnosis of macrosomia exceeds 90% when the abdominal circumference or the estimated fetal weight is above the 95^th percentile. In IDDM’s, macrosomia is more apparent in some fetal structures: liver, subcutaneous fat, soft tissues of arm, thigh and cheeks. These variables (selective organomegaly) are measurable and may aid in predicting early development of macrosomia. IUGR is associated with conditions that predispose to uteroplacental insufficiency, and therefore is most likely to appear in DM complicated by severe vasculopathy. In most centres the decision making process regarding time and mode of delivery takes place at around 37-38 weeks of gestation, therefore EFW should be performed at that time.

7.4 Assessment of Fetal Well-Being:

Dynamic assessment of diabetic pregnancies implies two types of investigations: BPS (Biophysical Score) and Doppler studies. The fetal BPS is often applied to evaluate the significance of a nonreactive NST. It may serve as an important tool for fetal surveillance, especially in order to prevent unnecessary early interventions, thereby allowing prolongation of pregnancy beyond 37 weeks. In diabetic gravidas, uteroplacental insufficiency may be difficult to detect by ultrasound assessment of fetal growth, since fetal weight gain can be excessive due to fuel metabolism even when uteroplacental circulation is compromised. Doppler umbilical artery velocimetry has been proposed as a clinical tool for ante-partum fetal surveillance in pregnancies at risk for placental vascular disease. The data is conflicting, and several large studies have now confirmed that ranges for umbilical artery waveforms indices are not different in a diabetic population without pregnancy complications than in the normal controls.

7.5 Proposed Ultrasound Work-Up in DM Complicating Pregnancy

GDM patients - Ultrasound evaluation should start immediately following diagnosis.

Fetal growth and weight estimations starting at diagnosis and continuing at 3-4 weeks intervals.
Fetal weight estimation at 37-38 weeks.
BPS at weekly intervals starting at 34 weeks only for insulin treated and/ or patients with poor compliance and control.

PreGDM patients - Ultrasound evaluation should start immediately following diagnosis of pregnancy

8-10 weeks – TVS dating of pregnancy (CRL).
12 weeks – Nuchal translucency (optional).
15 weeks – Transvaginal first detailed anatomical survey of the fetus (optional). Level II evaluation of fetal congenital anomalies is performed at 14–15 weeks and repeated at 20–22 weeks of gestation.
22 weeks – Second detailed anatomical survey of the fetus (abdominal).
20-24 weeks – Fetal echocardiography
Fetal growth and weight estimations starting at 20 weeks, at 3-4 weeks intervals. In all examinations a thorough assessment of all fetal growth parameters is mandatory (BPD, OFD, HC, AC, FL).
Fetal weight estimation at 37-38 weeks
BPS at weekly intervals starting at 32-34 weeks.

REFERENCES

Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97.
Atkinson MA, Maclaren NK: The pathogenesis of insulin dependent diabetes. N Engl J Med 331:1428–1436, 1994
Watanabe RM, Black MH, et al. Genetics of gestational diabetes mellitus and type 2 diabetes. Diabetes Care 2007;30(2) s134-40.
National Diabetes Data Group. Diabetes in America. 2d ed. Bethesda, Md.: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 1995; NIH publication no. 95-1468.
Reaven GM, Bernstein R, Davis B, Olefsky JM: Nonketotic diabetes mellitus: insulin deficiency or insulin resistance? Am J Med 60:80–88, 1976
Olefsky JM, Kolterman OG, Scarlett, JA: Insulin action and resistance in obesity and noninsulin-dependent type II diabetes mellitus. Am J Physiol 243:E15–E30, 1982
Charles MA, Fontboune A, Thibult N, Warnet JM, Rosselin GE, Eschwege E: Risk factors for NIDDM in white population: Paris Prospective Study. Diabetes 40:796–799, 1991
Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H: Coronary-heart disease risk and impaired glucose tolerance: the Whitehall Study. Lancet i:1373–1376, 1980
White P: Pregnancy complicating diabetes. Am J Med 1949; 7:609.
Hare JW, White P, Gestational Diabetes and the white classification. Diabetes Care 1980; 3:294-6.
Rudge MV, Calderon IM, Ramos MD et al. Hypertension disorders in pregnant women with diabetes mellitus. Gynecol Obstet Invest 1997;44:11–5.
Yogev Y, Xenakis EM, Langer O. The association between preeclampsia and the severity of gestational diabetes: the impact of glycemic control. Am J Obstet Gynecol 2004;191:1655–60.
Ehrenberg HM, Durnwald CP, Catalano P et al. The influence of obesity and diabetes on the risk of cesarean delivery. Am J Obstet Gynecol 2004;191:969–74.
Peters RK, Kjos SL, Xiang A et al. Long-term diabetogenic effect of single pregnancy in women with previous gestational diabetes mellitus. Lancet 1996;347:227–30.
Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes. Diabetes Care 2002;25:1862–8.
ACOG. Practice Bulletin Clinical Management Guidelines: fetal macrosomia. 2000;number 22.
Langer O, Rodriguez D, Xenakis EM et al. Intensified versus conventional management of gestational diabetes. Am J Obstet Gynecol 1994;170:1036–47.
McFarland MB, Trylovich CG, Langer O. Anthropometric differences in macrosomic infants of diabetic and nondiabetic mothers. J Matern Fetal Med 1998;7:292–5.
Modanlou HD, Komatsu G, Dorchester W et al. Large-for-gestational- age neonates: anthropometric reasons for shoulder dystocia. Obstet Gynecol 1982;60:417–23.
Jovanovic L. American Diabetes Association's Fourth International Workshop-Conference on Gestational Diabetes Mellitus: summary and discussion. Therapeutic interventions. 1: Diabetes Care. 1998 Aug;21 Suppl 2:B131-7.
Metzger BE, Buchanan TA, Coustan DR, de Leiva A, Dunger DB, Hadden DR, Hod M, Kitzmiller JL, Kjos SL, Oats JN, Pettitt DJ, Sacks DA, Zoupas C. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007 Jul;30 Suppl 2:S251-60.
HAPO Study Cooperative Research Group. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Intl J Gyn Obstet 2002;78:69-77.
HAPO Study Cooperative Research Group. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Intl J Gyn Obstet 2002;78:69-77.
HAPO Study Cooperative Research Group. Metzger BE, Lowe LP, Dyer AR, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358:1991-2002.
The HAPO Study Cooperative Research Group. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study: associations with neonatal anthropometrics. Diabetes 2009; 58: 453–459.
Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS; Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Trial Group. N Engl J Med. 2005 Jun 16;352(24):2477-86. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes.
American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2004;27(Suppl 1):S88-90.
Jovanovic-Peterson L, Durak EP, Peterson CM. Randomized trial of diet versus diet plus cardiovascular conditioning on glucose levels in gestational diabetes. Am J Obstet Gynecol 1989;161:415–9.
Artal R, Wiswell R, Romem Y. Hormonal responses to exercise in diabetic and nondiabetic pregnant patients. Diabetes 1985;34:78–80.
Franz MJ, Horton ES, Bantle JP et al. Nutrition principles for the management of diabetes and related complications. Diabetes Care 1994;17:490–518.
American Diabetes Association. Nutrition principles and recommendations in diabetes. Diabetes Care 2004;27:S36–46.
American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2007;30:S4–41.
American Diabetes Association. Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 2003;26(Suppl 1):S51–61.
Metzger BE, Buchanan TA, Coustan DR et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007 Jul;30 Suppl 2:S251-60.
Management of Diabetes Mellitus Complicating Pregnancy, Gabbe
American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2003;26(Suppl 1):S103–5.
Buchanan TA, Kjos Sl, Schafer U et al. Utility of foetal measurements in the management of gestational diabetes mellitus. Diabetes Care 1998;21:B99–106.
Langer O, Anyaebunam A, Brustman L. Pregestational diabetes: Insulin requirements throughout pregnancy.
American Diabetes Association. Preconception care of women with diabetes. Diabetes Care 2002;25:S82–4.
Di Cianni G, Torlone E, Lencioni C et al.; Italian Diabetes and Pregnancy Study Group. Perinatal outcomes associated with the use of glargine during pregnancy. Diabet Med 2008;25:993–6.
Nachum Z, Ben-Shlomo I, Weiner E et al. Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy: randomised controlled trial. BMJ 1999;319:1223–7.
Chen R, Ben-Haroush A, Weismann-Brenner A et al. Level of glycemic control and pregnancy outcome in type 1 diabetes: a comparison between multiple daily insulin injections and continuous subcutaneous insulin infusions. Am J Obstet Gynecol 2007;197:e1–5.
Rouse DJ, Owen J, Goldenberg RL et al. The effectiveness and costs of elective cesarean delivery for fetal macrosomia diagnosed by ultrasound. J Am Med Assoc 1996;276:1480–6.
Kjos SL, Henry OA, Montoro M et al. Insulin-requiring diabetes in pregnancy: a randomized trial of active induction of labor and expectant management. Am J Obstet Gynecol 1993;169:611–5.
Yogev Y, Ben-Haroush A, Chen R et al. Active induction management of labor for diabetic pregnancies at term; mode of delivery and fetal outcome – a single center experience. Eur J Obstet Gynecol Reprod Biol 2004;114:166–70.
Pettitt DJ, Knowler WC, Baird HR et al. Gestational diabetes: infant and maternal complications of pregnancy in relation to third-trimester glucose tolerance in the Pima Indians. Diabetes Care. 1980 May-Jun;3(3):458-64.
American Diabetes Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003;26:S5–20.
American Diabetes Association. Preconception care of women with diabetes. Diabetes Care 2002;25:S82–4.
Holing EV, Shaw Beyer C, Brown ZA, Connell FA. Why don’t women with diabetes plan their pregnancies? Diabetes Care 1998;21 (6):889-95.
American Diabetes Association. Preconception care of women with diabetes. Diabetes Care 2002; 25 (Suppl 1): S82-4.
Dunne F, Brydon P, Smith K, Gee H. Pregnancy in women with Type 2 diabetes: 12 years outcome data 1990-2002. Diabet Med. 2003 Sep;20(9):734-8.
Sacks DA. Preconception care for diabetic women: background, barriers, and strategies for effective implementation. Curr Diabetes Rev. 2006 May;2(2):147-61.
White P. Classification of obstetric diabetes. Am J Obstet Gynecol 1978;130:228-30.
Diamond MP, Salyer SL, Vaughn WK, Cotton R, Boehm FH. Reassessment of White’s classification and Pedersen’s prognostically bad signs of diabetic pregnancies in insulin-dependent diabetic pregnancies. Am J Obstet Gynecol 1987;156(3):599-604.
American Diabetes Association. Preconception care of women with diabetes. Diabetes Care 2003;26(Suppl 1):S91–3.
O'sullivan JB, Mahan CM: Criteria for the oral glucose tolerance test in pregnancy. Diabetes. 1964;13:278-85.
Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation. 2006

(OPIS W JĘZYKU ZAJĘĆ) MODULE NAME EUROPEAN UNION INTELLECTUAL
0150781 TOYOTA MOTOR EUROPEAN (TME) SUSTAINABLE LOGISTICS AN EXAMPLE
1 GRUPO «EUROPEAN 112 DAY 2016» ACTIVIDAD 112 EXTREMADURAUNIVERSIDAD

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EUROPEAN ASSOCIATION OF PERINATAL MEDICINE EAPM DIABETES AND PREGNANCY

THE OFFSRING OF DIABETIC MOTHERS

Diabetes and Pregnancy

1.1 Implications for Diabetes in Pregnancy:

1.2 Implications for the Conceptus:

1.3 Implications for the Mother:

Eran Hadar & Moshe Hod

2.1 Definition:

2.2 Classification:

Table 1: Classification of PreDM

Group

Treatment

Group

Fasting Glucose

2-hr Postprandial Glucose

Treatment

Table 7: Goals of treatment

Table 9: Daily distribution of carbohydrates

Hour

Meal

% of total daily carbohydrates

3.6 Labour and Delivery:

Diagnosis

Stage of diabetes

7. SONOGRAPHIC ASSESSMENT IN DIABETIC PREGNANCY

Meizner I; Greco P

7.5 Proposed Ultrasound Work-Up in DM Complicating Pregnancy

GDM patients - Ultrasound evaluation should start immediately following diagnosis.