Benha University Hospital, EgyptEmail: elnashar53@hotmail.com

Physiological changes1· FBG: decrease G levels following a meal or glucose load: increase

compared to the non-pregnant 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 GDM4. The renal tubular threshold for glucose: falls: glycosuria Glycosuria is not a reliable diagnostic tool 5. Starvation: early breakdown of triglyceride: liberation of fatty acids

& ketone bodies.

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%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/hypoxia-acidosisl/Erb's palsy Iatrogenic prematurity •Neonatal HypoglycaemiaPolycythaemiaHyperbilirubinaemia HypocalcaemiaCardiomyopathy •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 withlow 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 Risk of major malformation (%)malformation (%)

Normal Normal populationpopulation

22

Preexisting DMPreexisting DM 1010

Gestational DMGestational DM 44

(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:

1.GDM is associated with adverse effects on pregnancy.

2. 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 screeningAge> 25' years' Overweight before pregnancyEthnic group with high prevalence GDMDiabetes in first-degree relativeHistory 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.Fasting venous & capillary blood glucose are similar.After a meal or a glucose challenge, capillary are higher than venous levels. After a meal or a glucose challenge, capillary are higher than venous levels.

It is not necessary for both values to be abnormal

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

Plasma glucosePlasma glucose Mg/dlMg/dl

FastingFasting 100100

2-h2-h 145145

I. Diet

II.Exercise

III.Insulin

IV.Hypoglycemic drugs

I. Diet 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% Protein 30%, Fat 30% (Garner, 1995).

•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. EII. Exercisexercise

•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 exerciseWalking (Homko et al, 1998).

III. InsulinIII. Insulin

04/08/2304/08/23

•Insulin Analog Lispro & 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 eatingRapid onset of action: improves compliance & patient satisfaction*Category C medication*May accelerate maternal retinopathyLimited use in pregnancy, until data from more clinical trails are available (Ahn & Hibbard, 2005)

Indications:

1.

2. Failed dietary treatment

3. AC >95th centile between 29 & 33 WDespite good glycemic controlDespite good glycemic controlReduce macrosomia from 45% to 14% Reduce macrosomia from 45% to 14% (Buchanan et al, 2004)(Buchanan et al, 2004)

whole blood whole blood glucose mg/dlglucose mg/dl

Plasma glucose Plasma glucose mg/dlmg/dl

Fasting 9595 105105

1h postprandial 140140 155155

2 h postprandial 120120 135135

IV. Oral hypoglycaemics 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

4. Lactic acidosis, extremely rare and probably only occurs in those with vascular disease and in renal patients, pre eclampsia.

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

1. Glycemic control

2. Fetal wellbeing

3. F. wt:

4. Delivery:

Intrapartum Postpartum

1. Glycemic control

2. Assessment

3. Breast feeding4. Contraception

5. Prevention

A. AntenatalA. AntenatalGoals:

Maintain EuglycemiaPrevent macrosomiaGlycemic control <32 w: Significant

reduction >32W: No reduction

(Sameshima et al, 2000).

I. Glycemic control.

a. Blood glucose:• Objective:

Capillary blood glucoseCapillary blood glucose Mg/dl(mmol/L)Mg/dl(mmol/L)

FastingFasting <100(5.5)<100(5.5)

1 Hour1 Hour <140 (7.8)<140 (7.8)

2 Hours2 Hours <125 (7.0)<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 dailyMild: Twice dailySevere: 4 readings (Fasting, 2 h after breakfast, lunch & dinner)

• Self-tested blood glucose, using hand-held digital read-out 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 24-88% & 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 US (Chauhan et al, 2000)• The best single measurement: Serial measurements of AC

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 controlPoor complianceCo morbidities e.g. hypertensionCorticosteroids:<36 w

•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. Postpartum1.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 Pillwith breast feeding: 3 fold risk of diabetes (Kjos et al,1998)Should be prescribed with caution, if at all.

5. Prevention of GDM

1.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.

Thank YouThank YouThank YouThank YouProf. Aboubakr Elnashar

Email: elnashar53@hotmail.com