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Benha University Hospital, Egypt

Email: elnashar53@hotmail.com
Physiological changes
1· 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 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 Problems in offspring
•Pregnancy •Fetal
?Malformation
.
Anxiety
IUFD
Abnormal wt gain
Macrosomia
PET Shoulder dystocia/hypoxia-
Birth trauma (secondary to acidosisl/Erb's palsy
macrosomia) Iatrogenic prematurity
Increased rate of CS •Neonatal
•Later Hypoglycaemia
Increased rate of T2DM, Polycythaemia
hypertension, CVD 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 2
population
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 Mg/dl


Fasting 100
2-h 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
08/01/09

more clinical trails are available (Ahn & Hibbard,


Indications:
1.
whole blood Plasma glucose
glucose mg/dl mg/dl
Fasting 95 105
1h postprandial 140 155
2 h postprandial 120 135

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 Mg/dl(mmol/L)


Fasting <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 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
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.
Thank You
Prof. Aboubakr Elnashar

Email: elnashar53@hotmail.com