GESTATIONAL DIABETES

• Gestational diabetes mellitus (GDM) is defined as any abnormal carbohydrate intolerance that begins or first recognized during pregnancy.

• Gestational diabetes mellitus complicates 2% to 5% of all pregnancies. The incidence of GDM is rising, paralleling to the rise in type 2 diabetes and obesity prevalence.

Pathophysiology• Relative pancreatic β-cell dysfunction.• post-receptor defects • Immunological: antigenic load of the

fetus. It has been postulated that the development of DM in patients who have undergone organ transplantation is analogous to GDM development. (Oztekin , 2007)

Screening & Diagnosis

• High risk ( one of the following)– Marked obesity.– First-degree relative with diabetes.– Previous gestational diabetes, large-for-

gestational age baby, or unexplained stillbirth.– Polycystic ovarian syndrome.

Screening & Diagnosis

• Low risk ( all of the following)1. Age < 25 y.2. Normal weight.3. Have no family history of diabetes mellitus.

• Intermediate risk. includes women who does not fall either into low

or high-risk group.

• According to American Diabetes Association [ADA], women belonging to high risk should undergo glucose testing as soon as possible. If they have a negative result, they should be rechecked between 24 and 28 weeks of gestation.

• Those with intermediate risk require screening at 24—28 weeks.

• Screening for women falling into low risk category not recommended.

How?

(1) One-step approach–—suitable for high-risk patients/population. A diagnostic oral glucose tolerance test without prior screening is acceptable.

(2) Two-step approach–—in this 1st perform initial screening test by measuring plasma glucose 1 h after 50 g oral glucose load (glucose challenge test). A 1 h value > 140 mg/dl identifies 80% of women with GDM.

• Lowering down the threshold to 130 mg/dl increases the sensitivity to 90% but increase the cost.

• Diagnostic criteria of GDM following OGTT ( 100 g glucose load ) ( Carpenter & Coustan, 1982 )

Plasma glucose level mg/dl

fasting 95

1 H 180

2 H 155

3 H 140

• World health organization (WHO) have proposed different diagnostic criteria for the diagnosis of GDM.

• It is based on 75 g OGTT with diagnosis being confirmed if either the fasting plasma glucose > 126 mg/dl or 2 h plasma glucose > 140 mg/dl.

• The Hyperglycemia and adverse pregnancy outcomes (HAPO) study was designed to determine the actual levels of blood glucose during a 75-g OGTT performed between 24 and 32 weeks of pregnancy, lower than that of overt diabetes, that predicted adverse perinatal outcomes.

• The study showed a continuous relationship between maternal hyperglycaemia and the adverse pregnancy outcomes of LGA babies, primary caesarean section, clinically defined hypoglycaemia and cord C-peptide >90th percentile, (Metzger et al, 2008).

• Based on HAPO study the international association of diabetes and pregnancy study groups (IADPSG) consensus recommended.– Cut-off level for fasting 92 md/dl & 2 hrs 153

mg/dl.– Selective screening based on risk factors for

GDM has not been recommended.

– A screening test to be performed at the first prenatal visit to avoid late diagnosis of pre-existing overt diabetes by HbA1c test for this screen, but the use of fasting plasma glucose or random blood glucose was suggested as alternative options if HbA1c testing is not feasible.

(International Association of Diabetes in Pregnancy Groups Consensus Panel, 2010)

Prevention

• Prevention of obesity.• Weight loss of 4.5 kg between pregnancies has

been shown to reduce the risk of developing GDM in a subsequent pregnancy by 40% (Callaway et al, 2006).

• Life style modification & Exercise.

TREATMENT

The goals of treatment

– Mean blood glucose: 90 to 105 mg/dl– Fasting blood glucose: 60 to 90 mg/dl.– Pre-prandial blood glucose: 80 to 95 mg/dl.– Postprandial blood glucose: less than 120

mg/dl.– Hemoglobin A1c levels of less than 6.0%.

(kitzmiller , 2008)

Continuous glucose monitoring system (CGMS)

• Recently, several companies have attempted to develop a new technology that measures continuous glucose. The MiniMed CGM System (Sylmar, CA, USA).

• The system measures glucose levels every 10s, based on the electrochemical detection of glucose by its reaction with glucose oxidase.

• It stores an average value every 5 min for a total of 288 measurements per day.

Medical nutrition therapy (MNT) and exercise

• The calculated daily calorie intake is based on prepregnant body weight. For body mass index 20-25, 25-34 and >34 kg/m2, the respective calories intake are 30, 25 and 20 kcal/kg (American diabetic association, 2004).

• American Diabetes Association advice a 55% carbohydrate component at the diet.

• the euglycemic diet decreases carbohydrate content to 40% and incorporates more fat

• The diet also recommends the following overall caloric distribution: 12.5% at breakfast, 28% at both lunch and dinner, and the remainder divided among 3 snacks.

• There is also a limitation of carbohydrates to 33% at breakfast, as insulin resistance appears to be greatest in the morning.

(Jovanovic L, 2004)

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الممنوعات:.... 1 . المولد- حلوى و المكسرات و الشامية الحلويات2 . الطحينة- , , و الطحينية الحالوة الشوكوالتة االسود العسل3 . المربى- و الجاتوهات و التورتات4 . الكحولية- المواد الروحيةو المشروبات

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االنفعال- 4 عدم .

• Exercise can also play an important role in lifestyle interventions employed to minimize the complications of diabetes in pregnancy.

• It is recommended that all pregnant women “capable of exercising” …….at least 30 minutes of planned physical activity each day.

Insulin therapy

• The discovery of insulin in 1922 by Banting is one of the greatest discoveries in the history of medicine.

• The 1923 Nobel Prize in Physiology and Medicine was awarded for this landmark discovery.

• Insulin therapy is the most validated treatment option when MNT fails to achieve the target glycemic control.

• Lacking a general consensus for the initiation of insulin.– Fasting > 95 mg/dl.– Postprandial >140 mg/dl.

(Reece et al, 2002).

• Basal insulin– NPH– Long Acting insulin analogues

• Bolus insulin ( mealtime)– Regular insulin– Rapid Acting insulin analogues

Rapid acting insulin

• With respect to GDM, there have been several small randomized studies comparing the use of rapid acting insulin analogues with regular insulin.

• They have all demonstrated that the rapid acting analogues are as effective as regular insulin in the treatment of GDM.

(Pettitt et al, 2007).

• To mediate the postprandial peak, a rapid-acting insulin should be used immediately before each meal.

• There are 2 main types of rapid-acting insulin analogues that have been investigated and proven safe in pregnancy: insulin lispro and insulin aspart.

• Compared to regular human insulin, insulin lispro therapy lowers A1C in women with GDM and has also been shown to improve the postprandial glucose peak in comparison with regular insulin.

(Meccaci F et al, 2003)

Basal insulin• The second component of insulin therapy is an

insulin that acts throughout the day as the basal insulin release.

• The only effective choice is neutral protamine Hagedorn (NPH) insulin, which has a peak effect 5 to 7 hours after administration.

• Because of the timing of its peak effect, it is necessary for a pregnant woman to take 3 injections of NPH (1 every 8 hours) in order to maintain her glucose control with basal insulin.

long-acting insulin analogues

• Data regarding the long-acting insulin analogues are less clear than for rapid-acting analogues.

• There are a number of case reports and small case series of glargine being utilized without the development of pregnancy complications.

(Price et al, 2007)

Continuous Subcutaneous InsulinInfusion (CSII)

Continuous Subcutaneous InsulinInfusion (CSII)

Absolute Contradictions• Severe psychiatric disorders• Progressive ischaemic or proliferative

retinopathy• Non-educated patient.• Living with extreme circumstances of either heat

or cold for professional or personal reasons.• Underwater diving.• Exposure to high electromagnetic fields.

Pulmonary Inhalation of Insulin

• The exubera insulin is a fine powder insulin in doses of 1 or 3 mg, corresponding to approximately 3 and 9 units of human insulin.

• Duration of action between that of rapid-acting analogues and short acting human insulin.

• Patients were three times more likely to choose insulin when inhaled insulin was available compared with conventional insulin treatment

(Freemantle et al, 2005).

The future: a closed-loop system (an artificial pancreas)

one system which monitors glucose levels and accordingly supplies insulin.– Safe-delivery device that stores and releases insulin

accurately.– Accurate, biocompatible glucose-sensing unit.– Control system that modulates delivery of insulin,

glucose, and may be also glucagon according to blood glucose levels.

– This process must operate correctly all the time, to avoid errors leading to severe hypo- or hyperglycemia.

Metformin

• The use of metformin in pregnancy has been quite controversial with early reports of adverse effects in those exposed to this drug. ( Hellmuth E et al, 2000).

• However, metformin used in the treatment of women with polycystic ovary syndrome (PCOS), it is postulated to alleviate key pathogenetic mechanisms such as hyperinsulinaemic insulin resistance, would reduce the rate of early pregnancy loss (Jakubowicz et al, 2002).

• In a case control study, there was significant reduction of early pregnancy loss by continuation of metformin during pregnancy in 197 cases with polycystic ovarian disease 8.8% compared to 29.4% in control group.

( Nawaz & Rizvi, 2010).

• Metformin in gestational diabetes study (MiG Study) 751 women with GDM randomized to treatment with insulin or metformin.

• The authors have suggested that metformin is a safe and effective treatment for GDM (Rowan et al, 2008).

Glibenclamide (Glyburide)• In 1991 Elliott et al. demonstrated

experimentally that minimal glyburide was detectable crossing the placenta in an in vitro placental perfusion model.

• Lack of its significant appearance in the fetal circulation could also result from a very high protein binding of the drug.

• glyburide has a protein binding of 99.8%, compared to 96% percent for tolbutamide. This means that only 0.2% of circulating glyburide is free to cross the placenta, compared to 4% of circulating tolbutamide.

• In 2000 Langer et al published the results of their controlled randomized clinical trial where glyburide was compared with insulin in treatment of GDM.

• Ramos et al., 2007 retrospectively compared the effectiveness of glyburide and insulin for the treatment of GDM. There were no significant differences in birth weight, macrosomia, preeclampsia or cesarean delivery.

acarbose• The use of acarbose in pregnancy seems to be

a good option because it primarily acts in the gut by delaying carbohydrate absorption and is not absorbed, thereby having no systemic effects. However, this drug has not yet been studied well in pregnancy.

• In a small study by Zarate et al, 6 pregnant women with moderately elevated levels of fasting and postprandial blood glucose were treated with acarbose, after which, the fasting and postprandial glucose levels normalised.

Timing and mode of delivery

• Pregnancy should continue till 40 weeks as in nondiabetic pregnant women in setting of adequate glycemic control and no other known complications.

• Contrary to the general thinking, GDM by itself is not an indication for cesarean section.

• Even then increased incidence of cesarean section in pregnancy complicated by GDM is observed compared to women without diabetes. This is solely due to overestimation of obstetric complications.

Postpartum follow-up• Recurrence in subsequent pregnancy. An

estimate of 30—84% recurrence rate has been reported in a systemic review (Kim et al, 2007).

• development of type 2 DM.(37% versus 2%).• ADA recommendations for postpartum follow-up

of patients with GDM are:(1) Measurement of fasting plasma glucose annually.(2) OGTT with 75 g glucose at 6 week postpartum.(3) Adequate contraception to avoid pregnancy during

hyperglycemia.

Breast feeding

• The use of second-generation sulfonylureas, glyburide as well as glipizide, was examined in lactation. Both drugs appeared to be compatible with breast-feeding.

• Blood glucose levels were normal in all infants who were wholly breast-fed (Feig et al., 2005).

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