Gestational Diabetes Mellitus

Benha University Hospital, Egypt Email: [email protected]

Physiological changes

1· FBG: decrease G levels following a meal or glucose load: increase compared to the nonpregnant state. 2. GT: decreases progressively with increasing gestation {anti-insulin hormones secreted by the placenta; h pl lactogen, glucagon, cortisol}. 3. Doubling of insulin production from the end of 1st trimester to 3rd trimester: Increased insulin requirements in pre GD Development of GDM 4. The renal tubular threshold for glucose: falls: glycosuria Glycosuria is not a reliable diagnostic tool

COH intolerance with onset or first recognition during the present pregnancy (American Diabetes Association, 2002) The definition applies whether: insulin or only diet persists after pregnancy or not.

•Depend on: population studied diagnostic tests employed 4.0- 14.0%

Severe forms of GDM are linked to adverse outcome (Hyde et al, 2005).

Maternal problems •Pregnancy Anxiety Abnormal wt gain

PET Birth trauma (secondary to macrosomia)

Increased rate of CS •Later Increased rate of T2DM, hypertension, CVD

Problems in offspring •Fetal . ?Malformation IUFD Macrosomia Shoulder dystocia/hypoxiaacidosisl/Erb's palsy Iatrogenic prematurity •Neonatal Hypoglycaemia Polycythaemia Hyperbilirubinaemia Hypocalcaemia Cardiomyopathy •Adult Obesity Increased rate of T2DM, hypertension, CVD, ?Breast cancer

Abnormal fetal growth •Macrosomia: B. wt > 4000 g regardless of gest age or sex, or organ wt

•Etiology: -Maternal hyperglycaemia: fetal hyperinsulinaemia: stimulate fetal growth (Pederson hypothesis).

-Maternal obesity -Maternal hyper-triglyceridemia -Recent studies: The relation between maternal glycaemic control and fetal wt is very weak. Only a minority (25%) of infants of mothers with hyperglycaemia become macrosomic.

•The growth response of the fetus to hyperglycaemia is dependent upon whether the fetus has gene defect or not. Gene HNF4A, which is associated with diabetes Genetic test for HNF4A of the baby with low blood-sugar & family history of diabetes: Early diagnosis of maturity-onset diabetes of the young.

Fetal malformation •Pre-existing DM: Higher rate: cardiac, skeletal, NTD. Etiology: poor glycaemic control at the time of conception •GDM: Normal rate {euglycaemic at the time of conception}. Recent studies: Higher rate

Risk of major malformation (%) Normal population

2

Preexisting DM

10

Gestational DM

4

(Schaefer et al, 1997; Aberg et al, 2001; Sheffield et al, 2002)

Etiology: Unknown •FBS at time of diagnosis of GDM is high (Schaefer et al. 1997) •Some cases are (undiagnosed) pre-existing T2DM & occult hyperglycaemia at the time of organogenesis

Fetal death & occult GDM Perinatal mortality rate: 10-fold higher (Rudge et al, 2000)

Occult GDM (GDM pass undetected) contributes to a large proportion of unexplained late IUFD (Robson et aI, 2001)

Long-term health problems for offspring obesity, diabetes & CVD (Sattar & Greer, 2002) •Genetic predisposition: GDM is transmitted through the maternal line (Knowler et al, 1985)

Maternal long-term health problems •T2DM: General population: 8%. GDM: 30% (Kaufmann et al, 1995). GDM is a transient form of T2DM. •CVD & premature death.

Controversy: •Advantage of detecting GDM •What is the most effective test for screening •When? Timing •To whom it should be applied?.

• Advantage: • GDM is associated with adverse effects on pregnancy. • Identify future DM (de Soares et al, 1997). Medical or life-style intervention resulted in reduction of DM • In Finland (Tuomilehto et al, 2001) Individuals with impaired glucose tolerance: dietary modification: 50% reduction of risk DM (11% Vs 23%). • In Washington (The Diabetes Prevention Research Croup, 2002) individuals at high risk of T2DM: life-style modification reduced risk of DM by 58% Metformin reduced it by 31%.

What? Ideal screening test: Sensitive Specific Simple cheap convenient to perform.

Screening tests Random blood glucose (RBG): Within 2 h: 125 mg/dl 2-6 h: 100 mg/dl

Fasting blood glucose (FBG): 86 mg/dl

1-h 50 g glucose challenge test (GCT) 140 mg/dl

2-h 50 g glucose challenge test

.

75 g glucose tolerance test (GTI) Glycated haemoglobin or Fructosamine: no role in diagnosis of GDM, useful in monitoring of effective glycemic control

•GCT: High sensitivity (69%), Specificity (91%),with a cut off of 140 mg/dl (7.8 mmol/l). poorly tolerated (induce nausea). Time consuming Expensive.

•FBG: High sensitivity (81%) relatively good specificity (76%) with a cut off of 86 mg/dl (4.8 mmol/l) (Perucchini et al, 1999) Easier, Cheaper More acceptable . Can be applied to all pregnant women more than once during pregnancy. Suitable for screening KJO Hospital

To whom it should be applied?. •Universal screening: screening all pregnant The only approach that will detect virtually all cases (Griffin et al,2000 ). •Selective screening: screening high-risk women For reasons of cost and convenience, Disadvantage: missing up to 50% of cases.

•Risk factors for selective screening Maternal age >30 Family history of T2DM Non-white ethnic origin Obesity Smoking Increased wt gain in early childhood PCOS Previous large infant (> 97th centile) Previous unexplained still-birth

The variation in recommendations •Diabetes UK: Routine screening Urine testing at every ANC visit RBG at booking, at 2l W and if glycosuria. 75 g GTT if FBG > (110mg/dl)6.1 mmol/L or RBG> (125mg/dl) 7.0 mmol/L within 2 h of food

•Scottish Guidance Network: Routine screening Urine and RBG at every ANC visit

•American Diabetic Association: Selective screening Age> 25' years' Overweight before pregnancy Ethnic group with high prevalence GDM Diabetes in first-degree relative History of abnormal glucose tolerance' History of poor obstetric outcome' .

With 50 g GCT. confirm with 100 g GTT •National institute for Clinical Excellence: No routine screening

•Society of Obstetricians and Gynecologists of Canada: Routine screening at 24-28 w with 50 g GCT with cut off 7.8 mmol/l . No screening as no definitive evidence to support Selective screening: as early as possible with repeat at 24-28 w

•The 75 g OGTT using recent WHO criteria is now used almost universally throughout the world as the gold standard test for diagnosing GDM (Piercy, 2006) . Fasting venous & capillary blood glucose are similar. After a meal or a glucose challenge, capillary are higher than venous levels.

Plasma glucose Fasting 2-h

Mg/dl 100 145

It is not necessary for both values to be abnormal

•No need for GTT FBS 125mg/dl (7.0 mmol/l) or Random venous plasma glucose 200 mg/dl (11.1 mmol/l) if confirmed on a subsequent day,

I. Diet II.Exercise III.Insulin IV.Hypoglycemic drugs

I. Diet

•The first line therapy for 1-2 w •3 meals & 4 snacks with the last snack at bed time { minimize the overnight hypoglycemia & starvation ketosis (during pregnancy, there is accelerated starvation)} (Maternal Nutrition of the National Research Council, 1995)

•Caloric needs acc to BMI

(The American Diabetes

Association, 2003) :

Normal wt: 30 Kcal/kg Obese (BMI>30 kg/m2): 25 Kcal/kg •Carbohydrates 40%

•Concentrated sweets and added sugars should be eliminated. •Complex CHO with high fiber contents are preferable {slower glucose rise after ingestion} (American Diabetes Association, 2003).

II. Exercise

•Regular daily exercise can reduce insulin requirement by as much as 50%. The effect appears after 4 w. •1h after mealtimes. •For 20-30 min •Exercise that uses either upper extremity ms or lower extremity ms while recumbent do not increase uterine contractions (Durak et al, 1990 ;de Veciana and Mason, 2000).

Gentle aerobic exercise Walking (Homko et al, 1998).

III. Insulin

insulin aspart

*Superior than regular human insulin in controlling postprandial hyperglycemia without increasing the risk of preprandial hypoglycemia before the next meal (Heinemann et al, 1998)

*Given immediately before eating Rapid onset of action: improves compliance & patient satisfaction *Category C medication *May accelerate maternal retinopathy Limited use in pregnancy, until data from more clinical trails are available (Ahn & Hibbard, 08/01/09

Indications: 1.

Fasting 1h postprandial 2 h postprandial

whole blood glucose mg/dl

Plasma glucose mg/dl

95 140 120

105 155 135

2. Failed dietary treatment 3. AC >95th centile between 29 & 33 W Despite good glycemic control Reduce macrosomia from 45% to 14% (Buchanan et al, 2004)

IV. Oral hypoglycaemics •Not recommended for use in pregnancy. 1. Early agents crossed the placenta & stimulated fetal insulin secretion: fetal macrosomia & hyperinsulinaemic hypoglycaemia in neonates. 2. Major congenital malformations in animals (Greene, 2000)

•Advantage 1. Ease of administration 2. Ease of storage, 3. Convenience: No injections. No infection Continued 4. Cost. Recent studies evaluating its use in pregnancy

Glyburide: Micronase, 5 mg Upjon 2nd generation sulfonyl urea

in vitro studies: minimal maternal-fetal transfer (Garcia et al, 2003)

Glyburide Vs Insulin (Langer et al, 2000). 404 women with GDM that required treatment, were randomly assigned between 11& 33 w to receive 5-20 mg/d glyburide or insulin

•No significant differences between the glyburide & insulin groups Macrosomia N. Hypoglycemia Admission to the ICU Fetal anomalies •Glyburide was not detected in the cord serum effective & safe alternative to insulin

Metformin the only available biguanide. In contrast to glyburide, metformin does cross the placenta. Mechanism: Mainly by decreasing gluconeogenesis and by increasing peripheral utilization of glucose. At therapeutic doses, hypo glycaemia does not occur when used in isolation but it may exert a hypoglycaemic action when given in overdose. Side effects: 1. There is a lower incidence of weight gain and weight loss may occur. 2. Gastrointestinal side-effects are common initially but these usually settle within a few days. 3. Vitamin B12 deficiency

3 studies The accumulated experience is smaller with less than 200 women treated. Some disappointing outcome data. •Favorable PNMR but the comparison was with untreated patients for whom the PNMR was 146/1000.

Increase in neonatal jaundice (Coetzee & Jackson, 1979) •Met, tolbutamide, insulin: Glycaemic control was comparable to insulin-treated patients in both groups but Met was associated with a 3-fold increase in the incidence of PET and' an increased PNMR compared with those on tolbutamide and insulin (Hellmuth et al, 2001) •Met Vs insulin: both similar ability to control hyperglycaemia but Met was associated with a higher CS and more neonatal hypoglycaemia (Hauge et al, 2003) These outcomes may well reflect small study sizes but the safety of Met is not established and it is advocated that it should not be used for this purpose outside of well designed research studies (Dornan & Hollis, 2001; Glueck et al, 2002)

Antenatal

Intrapartum

Postpartum

1. Glycemic control

• Glycemic control

2. Fetal wellbeing

• Assessment

3. F. wt:

• Breast feeding 4. Contraception

4. Delivery:

5. Prevention

A. Antenatal Goals: Maintain Euglycemia Prevent macrosomia Glycemic control <32 w: Significant reduction >32W: No reduction (Sameshima et al, 2000).

I. Glycemic control. a. Blood glucose: • Objective: Capillary blood glucose Fasting

Mg/dl(mmol/L) <100(5.5)

1 Hour

<140 (7.8)

2 Hours

<125 (7.0)

• Preprandial OR postprandial?: In non-pregnant: Preprandial is preferred In pregnancy: Post prandial is preferred (Konje, 2004) 1. The fetus is more sensitive to hyperglycemia than to nadirs of glucose values 2. F & preprandial BG values are often normal even before treatment 3. Postprandial monitoring: improved glycaemic control decreased rate of macrosomia, CS, and neonatal hypoglycaemia (de Veciana et al, 1995).

• 1h or 2h post prandial?: No agreement (Ahn & Hibbard, 2005), but most authorities advocate 2h postprandial

• Frequency: Varied from weekly up to 7 times daily Mild: Twice daily Severe: 4 readings (Fasting, 2 h after breakfast, lunch & dinner) • Self-tested blood glucose, using hand-held digital readout devices

b. Glycosylated hemoglobin A1C: -Retrospective assessment of glycemic control. Evaluates blood glucose over the life span of the RBC i.e. 120 days. -Due to enhanced erythropoiesis during pregnancy, it is done every 6 w Excellent control: <7% Fructosamine: Not useful {low sensitivity}

II. Fetal wellbeing: Indications: Insulin is required Poorly controlled diabetics Hypertension History of IUFD Tests: no reliable test. A combination of tests must be employed. Kick chart, NST, CST, FBP, Doppler

Regimen Twice weekly NST with once weekly AFI or FBP Kick chart: At least 10 kicks/2h

III.

F. wt: Screening for macrosomia

•Both clinical and US are inaccurate (±10-20%). •Clinical is more accurate than US (Sherman et al, 1998)

•US: huge variation in sensitivity 2488% & specificity 60-98% (Reece et al, 1995).

•Novel methods (cheek-to-cheek diameter, fetal thigh SC tissue at the level of the femoral diaphysis, thigh soft tissue/FL ratio, upper arm soft tissue thickness, EFW derived from a formula incorporating AC, FL & upper arm soft tissue thickness): Not superior to clinical & routine

IV. Delivery: • Time: In a well controlled GDM, delivery should be considered at 38-40w

There is very little evidence to support either induction of labor at 38w or expectant management (Cochrane Syst Rev 2000) Induction at 38w in insulin requiring GDM showed lower rate of: macrosomia (10% Vs 23%), CS (25% Vs 30%) and Shoulder dystocia (0% Vs 3%) (Kjos et al, 1993). Delivery before 38W: Poor glucose control Poor compliance Co morbidities e.g. hypertension Corticosteroids:

•Mode: Elective CS: Estimated F wt>4500 g (ACOG,2003 ) 4000 & 4500g (Inzucchi, 1999).

B. Intrapartum •The target glucose level: 75-145 mg/dl (4-8 mmol/l) •On diet: Bl glucose/h On insulin: <20 U/d: No need for insulin (Piercy, 2006) >20 U/d: IV dextrose & insulin Sliding scale

C. Postpartum 2.Glycemic control Stop Insulin: Most patient will have normal glucose level. Insulin be reinstituted as needed .

2. Postpartum Assessment •Unrecognized pre GDM is suspected when: 1-Initial fasting >125 mg/dl, 2-GDM during first trimester •75 g OGTT 6 w following delivery (ACOG, 2003)

•FBG: if abnormal: OGTT

3. Breast feeding: should be encouraged

(Gange et al,

1992).

. Reduces the insulin requirement by 25% . Breast- feed babies have a much lower risk of developing DM (Jovanovic,1998)

4. Contraception •Copper IUCD, Mirena: not associated with PID (Kimmerle et al, 1993 ; Kjos et al,1994)

•DMPA: Deterioration of CHO tolerance increase risk of diabetes

•NORPLANT: No deterioration (Fahmy et al, 1991 ; Konje et al,1992; Singh et al,1992)

GDM: Low-dose COCs

•didn't influence development of Diabetes (Kjos et al,1998) •Non smoker, <35 years, healthy: no hypertension, nephropathy, retinopathy, or other vascular disease.

Progestin-only Pill with breast feeding: 3 fold risk of diabetes (Kjos et al,1998)

Should be prescribed with caution, if at all.

5. Prevention of GDM • Preconceptual counseling. The risk of future DM Life style advice regarding diet & excerise Avoid obesity Obese to lose weight It may also prevent miscarriage, fetal malformation

2. Metformin before & during pregnancy in women with PCOS {high rate of GDM}. l0-fold reduction (Glueck et al.,2002) Significant reduction in first trimester miscarriage (Glueck et al, 2002; Jakubowicz et al, 2002)

Increased live birth rate with no increase in fetal abnormalities or teratogenicity

The differences between the results for the prevention and treatment of GDM are of interest. May reflect different responses because of different pathophysiologies of prediabetes and GDM. It seems that prevention may be better than control.

•GDM may be associated with a higher rate of fetal malformation, macrosomia; birth trauma & neonatal hypoglycaemia. •Longer term health risks to the mother have been confirmed. •GDM is not itself without risk; the incidence of CS is increased. •Early screening should be done in women with identified risk factors. •Fasting blood glucose is both highly sensitive & simple to implement.

•The goal of therapy is maintaining euglycemia & preventing macrosomia. •Glycemic control: FBS < 100 mg/dl, 2 h postprandial < 125 mg/dl & HbA1c <7%. •Management with diet in first instance, followed by insulin in resistant cases. •Induction of labour should be considered by 38w in insulin requiring GDM. • 75 g OGTT 6 w after delivery is recommended.

Prof. Aboubakr Elnashar

Thank You

Email: [email protected]