A comprehensive guide to the management of hyperglycaemia in pregnancy aimed at the primary care physician and based on latest evidenced based criteria. Includes information from latest studies such as HAPO study and ACHOIS, and involves guidelines from the IADPSG, ADA, WHO and Malaysia.
3. What is DM?
A metabolic condition
characterized by chronic
hyperglycemia as a result
of defective insulin
secretion, insulin action
or both
•
•
•
•
Type 1(IDDM)
Type 2(NIDDM)
Gestational diabetes
Others -genetic defects in insulin processing or action
-endocrinopathies
-drugs
-exocrine pancreatic defects
-genetic syndromes associated with DM
3
4. Pregnancy predisposes to
persistent hyperglycaemia
• Glucose is made available to
the fetus
– ↑ placental hormones
– ↑ plasma cortisol
– A state of insulin resistance
– Further aggravated by ↑
body weight and ↑ caloric
intake during pregnancy
• GDM develops when the
pancreas cannot overcome the
effect of these hormones
4
• Pregestational
diabetes becomes
worse during
pregnancy
5. Diabetes & Pregnancy
This
prevalence
is
increasing
nowadays, more and more women go into pregnancy with
increased body weight and caloric intake
the prevalence of women with preexisting T2DM getting
pregnant (diabetic pregnancies) seems to be rising
5
6. • Glucose intolerance
of variable severity
with onset or first
identification during
the pregnancy
–
–
• resolving after delivery
6
Generally occurs in the
latter half of pregnancy
Previously, found to
constitute 90% of diabetes
in pregnancy
7. Important facts
To understand the effects of hyperglycaemia on the
fetus, it should be remembered that glucose crosses the
placenta freely but maternal insulin does not
Thus, maternal hyperglycaemia leads to fetal
hyperglycaemia with a consequent rise in fetal insulin
secretion
Pregnancy is a state of insulin resistance, especially
towards term
7
9. Pathogenesis of tissue injury
Hyperglycaemia leads to
the production of reactive
oxygen species (ROS)!
ROS lead to tissue damage
through various
mechanisms!
This ultimately leads to
micro- and macrovascular
complications
Giacco F. Circulation
Research, 2010
9
12. Maternal Complications postpartum
Increased risk of developing DM later in life
Past history of GDM increases the risk of recurrence in
subsequent pregnancies
Retnakaran R. Diabetes Care, 31, 1275–1281
12
19. The significance of GDM
mothers are at
risk of
future development
of T2DM
adverse obstetrical
outcomes!
- esp. fetal overgrowth
19
20. The significance of pregestational
DM
Most of the risk
is to the fetus
similar to GDM
complications
during
organogenesis!
growth
restriction
20
21. Pregestational diabetic
pregnancies
• carry a graver consequence$
• should be managed immediately once identified$
• Ideally, evaluation for DM should occur before
pregnancy$
• to prevent complications during organogenesis (1st
trimester)
21
22. Hyperglycaemia in the
st trimester
1
confers a significantly increased
risk of major malformations
Type of
Diabetes
in
pregnancy
Risk of
Major
congenital
abnormality
(%)
T1DM$
T2DM$
GDM$
(n=221)
(n=317)
(n=1822)
5.9
4.4
1.4
Farrel T 2002
22
23. Fetal malformations &
Glycaemic control
• HAPO study $
• a continuum of increasing risk of perinatal outcomes as
glucose levels increase$
• even within levels that were previously defined as
normal
HAPO study. NEJM 2008
23
24. Hyperglycaemia later in
pregnancy
• High blood glucose increases fetal growth$
• Postprandial normoglycemia can reduce the rate of
macrosomia
FBG>5mmol/L, HbA1c>5.3%
MAC
ROS
OMI
A!
HAPO study. NEJM 2008
24
25. Issues of concern
1. The frequently undiagnosed nature of T2DM before
pregnancy
2. Lack of preconception care
3. The increase in complications of pregnancy due to
the coexistence of obesity and T2DM
25
26. Difference between
GDM & DM
• DM + Pregnancy$
• GDM$
–
–
–
–
–
–
early pregnancy BS normal
Usually no effect on
organogenesis
less likely to have congenital
defects
diabetes disappears after
delivery
macrosomia more likely
–
–
–
elevated BS since before
pregnancy
effect during organogenesis
more likely to have
congenital fetal defects (up to
8x more than normal
pregnancy)
fetes may be growth
restricted
overall though, perinatal outcomes are worse
whatever the cause of the hyperglycaemia
26
27. How do we detect those
asymptomatic mothers with
DM?
27
28. Pregnant women
with DM are
frequently
asymptomatic
They need to be
identified before harm
can come to the fetus
28
29. Screening
• during antenatal check-ups, mothers
with unknown elevations of blood
glucose need to be identified
eleva
tions
of
mate
rnal
bloo
d glu
cose
deem
are
ed ha
rmfu
to th
l
e fet
us
• this process of looking for asymptomatic diabetics is
termed screening
• The benefits and importance of screening for GDM
have been proven (ACHOIS & HAPO study)
Crowther NEJM 2005
29
30. In Malaysia
we base our screening strategy on
• screen selectively
those considered
high risk (1-step
testing)
30
32. Added criteria
• In recent time, this list has been expanded$
• Include factors such as $
• physical inactivity$
• certain dietary patterns$
• polycystic ovarian syndrome (PCOS)$
• biochemical markers such as adiponectin & C-reactive
protein
Retnakaran R. Clin Endocrinol 2007
Lo JC. Diabetes Care, 2006
32
33. PCOS
• Ex-GDM mothers investigated for PCOS$
• A majority of them displayed characteristic polycystic
ovarian morphology
Kousta E. Clin Endocrinol, 2000
33
34. What is done now
• At booking - assess risk$
• if risk present, do OGTT
Current'screening'protocol'
First Obstetric Visit
Risk Factors
- check risk status
'
Absent
Consider'normal'
Present
Risk Factors
OGTT performed
after 24 weeks
gestation
Consider'GDM'if'
diagnostic'criteria'met'
34
Note:
•Age >=40 yrs
•Unexplained SB
•P/H recurrent miscarriages
•P/H BW >=4.0 kg
•Weight >100 kg
•P/H oligomenorrhoea
•Strong maternal/sibling F/H
OGTT not
performed in:
Known preexisting DM cases
& Cases with P/H
of GDM
35. Schedule for screening
Between 24-28 weeks of gestation
or earlier if there are stronger
indications
If the original OGTT is
negative, recommend periodic
repeat testing (may be required
until 34 weeks of gestation)
If the glucose
tolerance remains
normal at 34 weeks,
stop testing
35
36. Recent Recommendations
• Based on HAPO study data - even the slightest
hypoglycaemia increases pregnancy adversity$
• IADPSG formulated recommendations
• In a bid to achieve international consensus$
• Try to catch as many patients with pregnancy
hyperglycaemia as possible
IADPSG. Diabetes Care 2010
36
41. OGTT
• The first-line diagnostic test$
• Initially developed to identify the diabetic
in the general population
because of the many controversies
surrounding this topic, numerous
iterations of the OGTT abound
with different criteria for diagnosis
O’Sullivan, Mahan.
Diabetes 1964.
41
43. Procedure for
OGTT
75 grams of
oral glucose
given
is
3 readings fasting gluc
ose
level, 1 hr a
nd 2 hr post
glucose
IADPSG. Diabetes Care 2010
43
44. Table 1: Values for Diagnosis
Fasting
Random
Diagnostic Values
Venous Plasma Glucose
≥ 11.1 mmol/L
≥
Table 2: Diagnostic values for Type 2 Diabetes Mellitus/Glucose Intolerance – oral
glucose tolerance test (OGTT) [IDF 2005] 5 (Level III)
OGTT Plasma Glucose Values (mmol/L)
Category
0-hour
≥
DM
2-hour
≥ 11.1
2
Recommendations: Screening and Diagnosis
44
45. More recent diagnostic
criteria
Commonly referred to
diagnostic criteria for the
75 gram OGTT include
the WHO and the ADA
criteria
More recently, the
IADPSG have adopted
stringent criteria based
on the HAPO study
IADPSG. Diabetes Care 2010
45
46. Postpartum considerations
P/H GDM woman
Postpartum oGTT
Abnormal GT
IGT/DM
Normal GT
Diet & exercise
F/U Blood Glucose
Stable glucose
Raised glucose
Manage as
appropriate
75g oGTT
Diet & exercise
F/U Blood Glucose
12:20:10
Normal GT
46
Should be carried
out after 2 months
postpartum
47. Is there any other way to
diagnose DM in pregnancy?
47
48. Yes, but…
HbA1c limitations$
• costs!
• unavailability!
• inaccuracy in anaemia
• Only in early pregnancy$
• Glycated haemoglobin (HbA1c) and plasma glucose
(random or fasting)$
• HbA1c has been validated for the diagnosis of DM
outside of pregnancy (≥6.5%) with many authorities
favouring its use in pregnancy as well
In te r n a t i o n a l E x p e r t C o m m i t te e .
Diabetes Care 2009
48
49. Plasma glucose
• Fasting or random$
• FPG level of ≥7.0 mmol/L is diagnostic of overt diabetes$
• RPG of ≥11.1 mmol/L has to be confirmed with either an
FPG or A1c value ≥ the threshold
49
50. How do we manage
hyperglycaemia in
pregnancy?
50
51. Strategy
• Rapid normalisation of blood glucose$
• Limited weight gain$
• Monitoring for anomalies and complications$
• Avoiding macrosomia$
• Planned delivery
51
52. Optimization of metabolic
control
• BS control dependant upon diet modification, exercise
and hypoglycaemic medications
• Lifestyle modification (dietary advice & appropriate
exercise) should be the primary interventions considered
• Resort to medications only when these fail to achieve
the desired targets
52
53. What is the dietary advice
for diabetes in pregnancy?
53
54. Less weight gain
• In overweight or obese mothers$
• No specific guidelines for women with diabetes$
• Less weight gain is safe and has a beneficial effect on
perinatal outcomes in obese women$
• Access to dietitian
54
55. Individualised counselling
• From a registered dietician experienced with pregnancy
and diabetes$
• Basic plan - based on dietary recommendations for all
pregnant women, adjusted to the individual needs of the
patient
• Carbohydrate and caloric contents - modified based on
the woman’s height, weight, and degree of glucose
intolerance
55
56. Caloric restriction
• A 33% reduction of calories results in clinically relevant
improvement in glycemic parameters $
• 30-35 kcal/kg/day = 1200 Kcal/d is safe$
• 50% of these calories should be from complex carbs$
• Exact amount unknown - carbohydrates, like calories,
should be determined based on individual needs$
• mother’s weight, activity, home & personal circumstances$
• Base calculations on home blood glucose levels
56
57. Specific targets
• Avoid concentrated sweets and highly processed foods contribute to unwanted weight gain$
• soft drinks, ice cream, cakes and sweets$
• restrict CHO to those found in vegetables and dairy products like
cheese and cottage cheese
• Small frequent meals (4 hourly) instead of fewer
larger meals $
• reduces the amount of insulin needed at any one time,
resulting in lower glucose excursions$
• also reduce hunger and prevent overeating
Hone J. J Clin Endocrinol Metab 2010
57
58. Some more targets
• Breakfast should be especially small and low in carbs because
insulin resistance is highest in the morning$
• High-fiber and low-GI foods should be substituted wherever
possible for simple sugars $
• higher fiber/low GI may assist in delaying absorption of food, thus
allowing the insulin peak to “catch up”$
• Foods rich in antioxidants have a role in reducing the
incidence of fetal anomalies$
• fruits and vegetables are recommended
58
59. Folic acid
• Supplemental $
• Proven to reduce the risk of neural tube defects$
• The prescription should begin at least 3 months
preconceptionally and through the first trimester $
• Minimum dose of 4 mg daily
59
60. ical
Med nal
tritio Nu
apy
Ther T
MN
If MNT
doesn't work?
Medication is implemented if 2 or more
glucose values are elevated after 1 wk of
lifestyle management
60
61. What to do if dietary
intervention does not work?
61
62. Oral medication?
• Previously, next step would be insulin therapy $
• because oral medications were thought unsafe, ineffective &
teratogenic$
• enough data to show the utility and safety of oral
hypoglycaemic agents (OHAs) in pregnancy
62
63. When to start OHAs?
• When fasting or premeal BS values constantly exceed 5.5
mmol/L$
• OHAs should be started without hesitation whilst
encouraging dietary and exercise efforts
63
64. Glibenclamide
• The first OHA to have proven efficacy and safety in
pregnancy $
• At a dose of 2.5 mg daily to a maximum of 20 mg per day$
• Similar birth outcomes can be achieved when comparing
glibenclamide use to insulin initiation in pregnancy
Langer et al. N Eng J Med 2000
64
65. Metformin
• The starting dose is 500 mg once daily & increasing to
500 mg tds$
• Similar outcomes between metformin and insulin
initialisation$
• Although 46% of mothers on metformin required additional
insulin supplementation for blood sugar optimisation$
• An early indicator that metformin therapy alone might be
inadequate to achieve target values is a higher fasting glucose
Rowan et al. N Eng J Med 2008
65
66. General considerations
• OHA dosage should be increased every 4-5 days to
achieve the desired blood sugar target values
• Although both metformin and glibenclamide cross the
placenta, there have been no reports of fetal adversity
so far
• The long term effects of these OHAs are still under
study but there is optimism that their safety will be
proven$
• decreased overall weight gain has been noted in pregnant
mothers on metformin
Rowan et al. N Eng J Med 2008
66
68. When MNT & OHA fails to
achieve glycemic goals after 1 wk
68
69. be encouraged to walk for about 30 minutes per day.
An example of a therapy
guide
agents need to be introduced when lifestyle and dietary measures fail to control the glycaem
ropriate to consider starting oral hypoglycaemic agents in the first instance whenever the fastin
levels consistently exceed 5.5 mmol/l, definitely if the value exceeds 7.0 mmol/l. Recent research
clinical efficacy of glibenclamide [gliburide] during pregnancy. Glibenclamide should be started a
ncreased every 4-5 days to a maximum of 20 mg/day. If control is not achieved, then the sulpho
insulin. An alternative oral hypoglycaemic agent if metformin, though the use of this is still unde
started as a 500 mg daily dose, increasing the dose to 500 mg t.d.s. depending on gastrointestina
Class
A1
A2
Fasting/preprandial
Blood glucose
Always <5.1 mmol/l
5.1-7.0 mmol/l
B1
>7.0 mmol/l
2-hour postpradial
Blood glucose
Always <6.7 mmol/l
6.7-7.0 mmol/l
>7.0 mmol/l
Management options
Management
option
Diet alone
Diet +/pharmacological Rx
Diet + Insulin
Savonna-Ventura. UMMS Malta 2011
69
71. Insulins
A basic understanding of the dynamics and actions
• Each type of insulin has an onset time, a peak and
duration of action$
• The onset time is delineates how soon the blood glucose
lowering action comes into effect and is commonly used
to classify this class of medications$
• either rapid-, short-, intermediate- or long-acting
71
72. Development of Insulins
• Originally, from animals$
• Biosynthetic preparations in the 1970s - more effective and cheaper
preparations$
• The first such insulins - regular insulin (or “human” insulins)$
• classed as short-acting, $
• mainstay of diabetes treatment in pregnancy in the 1980s $
• not fully satisfactory due to a late peak (2-3 h after injection) - not very
effective for postprandial control$
• too long duration of action - tending to cause hypoglycaemia
72
73. Insulin analogues
• They provide more optimal glucose control during pregnancy$
• technically not insulin, but something similar that retains the hormone’s
glucose lowering function$
• They are considered safe for pregnancy use - no teratogenic or
embryotoxic effects have ever been demonstrated$
!
• They act rapidly, peak in about 1 hour with a duration of action
between 2-4 hours. $
• The first such insulin developed was insulin lispro followed soon
after by insulin aspart
73
74. NPH insulin
• An intermediate acting insulin originally developed in the 1930’s $
• now synthetically produced to give better absorption rates when injected
subcutaneously$
• May be mixed with shorter acting ones in the same syringe to
complement its longer duration of action and to allow for better
dosing and blood sugar control$
• NPH remains in the market today specifically for the reason
that it can be marketed in premixed formulations for ease of use
74
75. More recent insulin
analogues
• Insulin glargine and detemir$
• Absorbed more steadily after injection, providing a “peakless” mode of
action, followed by a rapid decline and all the while producing a more
constant glucose lowering effect$
• Duration of action is approximately 24 hours, thus needing only once-daily
administration - long-acting insulins$
• also induce less hypoglycaemia and weight gain compared to conventional
insulins$
• Despite these attractive features, they are currently unlicensed for
pregnancy use due to lack of systematic data although several reports
have not demonstrated any adverse effects or teratogenicity.
75
77. Modes of administration
• The most frequent mode of parenteral administration is
via subcutaneous injection $
•
using repeat-use insulin pens with fine needles$
• Intravenous administration - in intensive care settings$
• Insulin pumps provide fine-tuned insulin delivery &
consequent better blood glucose control$
• financial & technical considerations
77
78. How do we calculate the
amount of insulin to use?
78
79. Philosophy behind insulin
• Mimic physiologic secretion of insulin as close as
possible$
• In pregnancy, this entails multiple injections of various
combinations of rapid, short and intermediate-acting
insulin
A tried and tested insulin combination is a rapidacting and NPH one
79
80. Starting values
• Slightly higher starting doses may be used for obese
patients$
• These values are a safe guide to insulin initiation $
• Must be optimised rapidly to achieve the target blood
glucose values by using (home blood glucose monitoring)
HBGM
80
81. Starting dose calculation
Time of pregnancy
Dose
Prepregnancy
0.6 U/kg/day
First trimester
0.7 U/kg/day
Second trimester
0.8 U/kg/day
Third trimester$(29-34 wks)
0.9 U/kg/day
Term (35-39 wks)
1.0 U/kg/day
Jovanovic. Diab Care 1982$
Lapolla et al. Diab Med 2009
81
82. Starting doses
• The regimens are based on predicted total daily insulin
requirements - based on current weight and stage of pregnancy $
• 50% of the total dose is given as a basal dose using NPH
insulin (intermediate-acting)$
• at bedtime or bedtime+breakfast time$
• the other 50% of the total dose - given as boluses before
meals using insulin analogues (rapid-acting)$
• before meals (within 15 minutes) in divided doses (1/6 of the total dose
per meal)
82
83. Adjustments
• These doses are starting doses only$
• Necessary to rapidly adjust dose to achieve glucose goals
using HBGM data & A1C testing$
• Serial blood sugars - carried out between 3-7 days after
starting & the dosage of insulin adjusted
commensurately
83
84. How do we know if the
diabetes is under control?
84
85. Pillar of assessment
• Glycaemic adequacy is assessed through regular blood
glucose estimations$
• Tight glucose control achieved through dietary, physical
and pharmaceutical interventions
Adequate BS control is proven beneficial to the
pregnancy. Despite this, no clearly established
glucose targets exist.
Crowther et al. N Eng J Med 2005
85
86. Techniques of assessment
• 2 techniques of assessment - HBGM & HbA1c $
• Most data regarding target values in pregnancy - derived
from pregnant T1DM & T2DM patients
Kitzmiller et al. Diab Care 2008
86
87. Target Values - FPG
• FPG of ≤5.0 mmol/L $
• Associated with a reduction in the risk of macrosomia,
neonatal hypoglycemia, and maternal preeclampsia in
GDM during the third trimester
Prutsky et al. JCEM 2013
87
88. Target Values - FPG &
postprandial
• FPG of ≤4.9 mmol/L & and 2-hour postprandial glucose
between 5.9–6.4 mmol/L$
• risk of birthweight greater than 4 kg, prematurity,
neonatal hypoglycaemia & preeclampsia are all lowered
Rowan et al. Diab Care 2010
88
89. Target Values - HbA1C
Amongst pregnant Type 1 diabetic mothers, maintaining
HbA1c levels to less than 6% before and during pregnancy
predicated outcomes similar to non-diabetic pregnant
mothers
Wyatt et al. Diab Med 2005
89
91. Monitoring
• Regular blood glucose monitoring - mainstay of objective
optimization of metabolic control$
• between 3-4 times a day$
• a prebreakfast and postprandial (2 hours post-lunch and dinner) and/or night
test$
• Initially, clinic attendance - primarily for patient education purposes$
• Subsequently, self-monitoring of blood glucose is the optimum$
• Assessment of long-term control and further optimization - 4-6
weekly by measuring HbA1c levels$
91
92. Postprandial blood
glucose monitoring
Do
This
• Glycaemic control has been shown to be improved by
limiting postprandial glucose excursions$
• Postprandial glucose correlates well with HbA1C$
• By measuring and controlling the postprandial and fasting
sugars, the occurrence of neonatal hypoglycaemia and
macrosomia may be reduced
de Veciana M. NEJM 2013
92
93. Assessment of the
pregnancy
The pregnancy must be treated as a whole$
Take precise history - maternal well-being, FM$
Examine for complications - remember; maternal, fetal
& placental$
Investigations - in order of priority$
ultrasound scan, urine, blood tests, CTG
93
95. Are you able to manage a
patient with diabetes in
pregnancy?
95
96. You can if..
• You routinely manage antenatal patients$
• You know how to screen for & diagnose this condition$
• You know how to implement & monitor treatment$
• You know how to monitor for complications
Do not hesitate to seek help!
96
98. Case 1
• A 34-year-old Malay woman, known DM, who is in her second pregnancy
and has had one live birth is seen for prenatal care at 8 weeks gestation
• Her weight is 96 kg, and her blood pressure is 130/80 mmHg. Uterine
size is appropriate for gestational age. Her family history reveals that her
mother has type 2 diabetes mellitus. A urine dipstick shows 3+ glycosuria
and negative ketones$
Q. . What tests should be done to evaluate the patient's glucose tolerance?
Q. How is the diagnosis of GDM established?
Q. What would be the best treatment and follow-up strategy?
98
99. Case 2
• 25 year old G1P0 at 10 weeks gestation. No significant
past medical, surgical or reproductive history. No family
history of DM. A regular patient of the GP, antenatal
booking bloods includes a diabetic screen utilizing
HbA1c. HbA1c was 6.2%. $
Q. Is this patient GDM?$
Q. Does she need to be started on insulin
99
100. Case 3
• 35 year old G2P1 at 8 weeks gestation. Her first pregnancy –
delivered LSCS for obstructed labour 4 years prior – 3.6 kg
baby girl. No contraception prior to this pregnancy. $
• Routine ANC by GP – incorporate HbA1c – 8%. Diagnosed
as DM with pregnancy. Based on local knowledge and
guidelines, this patient requires insulin but patient refuses.
Q. What should the GP do next?
Q. Should this patient be started on oral medication
immediately?
100
101. Case 4
• 38 year old G4P3 at 35 weeks, known DM diagnosed
since last pregnancy, on metformin 850 mg bd. Since the
patient is already on treatment, the GP has continued
the oral medication. Regular serial sugar estimations are
carried out – pre-breakfast, post-lunch and dinner –
6.2/7.7/7.8$
• Maternal and fetal well-being established$
!
Q. Should she be started on insulin now?
101