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 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.

3.4  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 à 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) à GDM       If results not diagnostic of overt diabetes as per table 5 and fasting plasma glucose <  5.1mmol/L (92mg/dl)       à 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) à Pre-existing diabetes               If one or more values equals or exceeds thresholds as per table 6 à GDM               If all values less than thresholds indicated as per table 6 à 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
	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

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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)