Transcript Final Presentation - Dr. Mona Fouda - Home

PREGNANCY AND THE
DIABETIC PATIENT
PRECONCEPIONAL
COUNSELING
Dr Mona Fouda Neel
MBBS, FRCP, edin.
Consultant Endocrinologist
Associate Professor of Medicine
College of Medicine
King Saud University
Introduction
GESTATIONAL DIABETES MELLITUS
Gestational Diabetes Mellitus is carbohydrate intolerance
with onset or first recognition during pregnancy,
It has been recognized for decades but the potential
significance of the condition as well as criteria for screening
and diagnosis remain controversial.
It affects up to 14% of the pregnant population.
The main pathogenic factor is insulin resistance, which
occurs to some degree in all pregnancies, but those who are
unable to compensate develop GDM.
Women at greater risk of developing GDM are those
who are:
 Obese
 Older than 25 years
 Have a previous history of abnormal glucose
metabolism
 Have prior poor obstetric outcome
 Have first-degree relatives with diabetes
 Are members of ethnic groups with high
prevalence of DM
At the fourth International Workshop Conference on
Gestational Diabetes Mellitus sponsored by the ADA,
the glucose concentrations considered diagnostic of
GDM was lowered.
This was based on data suggesting that lower degrees of
glucose intolerance were associated with increased risk of
adverse perinatal outcome.
The recommendation to test all pregnant women was
changed and women who appear to be at a low risk of
GDM will no longer be screened with a glucose load test
Members of ethnic groups with a low prevalence of GDM
• No known DM in first-degree relatives
• Those younger than 25 years
• Not obese before pregnancy
• No history of abnormal glucose metabolism
• No history of poor obstetric outcome
*
In an identified low-risk group the risk of GDM is
less than 2%.
Women within the high-risk group should undergo
glucose testing as soon as feasible.
Women of average risk of found negative or initial
screening should undergo the testing at 24-28 weeks of
gestation.
A FBS > 7 mmo1 or causal plasma glucose > 11.1 meets
the threshold for diagnosis of DM and if confirmed on a
subsequent day there is no need to do any glucose
challenge.
ON-STEP APPROACH
An OGTT is performed without prior screening. It
is cost effective in high-risk patients or populations.
TWO-STEP APPROACH
An initial screening test using 50gm glucose load and
during 1hr blood sugar level and of higher than a
certain threshold do OGTT.
A glucose threshold value > 7.8 mmo1/L identifies
approximately 80% of women with GMD and the
yield is further increased to 90% if the threshold is
lowered to 7.2.
Table 1:
Criteria for the Diagnosis of Gestational Diabetes Mellitus
______________________________________________________________________________________________________________________________________________
WHO
National
Diabetes Data
Group
American
Diabetes
Association
Impaired
Glucose
Tolerance
Diabetes
______________________________________________________________________________________________________________________________________________
Glucose load for oral
Glucose tolerance
Glucose level fating
100
100 + 75
75
105
95
95
Time, h 1
190
180
180
NA
NA
2
165
155
155
140
200
3
145
140
NA
NA
NA
NA
75
140
_____________________________________________________________________________________________________________________________________________
The most important tool in reducing perinatal
morbidity and mortality owing to major
malformation attributed to uncontrolled diabetes
mellitus remains prevention. Glycaemic control in
the first trimester is not only relevant it is critical.
Since many women do not recognize their pregnancies
until they are will into the first trimester, and since it
usually takes several weeks of effort to attain good
glycaemic control, preconception control must be the
goal for women with diabetes. In their reproductive
years, they must be educated and impressed with the fact
that they must plan their pregnancies and make
concerted effort to maximize control before conception.
Diabetes mellitus should be monitored carefully in
pregnancy. If left untreated, whether it is pregnancy
associated (Gestational Diabetes Mellitus) or preexisting before pregnancy, increases the risk of material
and fetal/neonatal mortality and morbidity.
Before the era of insulin, maternal mortality was a high as
30% and perinatal mortality varied from 66-90%. Till the
mid 1970s physicians were still advising diabetic women to
avoid pregnancies.
Table I:
Maternal Complication In Diabetic Pregnancy
 Hyperglycaemic ketoacidosis
 Pregnancy induced hypertension
 Pyelonephritis and other infections
 Polyhydramnios
 Preterm labour
 Worsening of chronic complications, e.g., Retinopathy Nephropathy,
Neuropathy, Cardiac Diseases.
Table II:
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Potential Perinatal Morbidity/Mortality in Infants of Diabetic Mothers
______________________________________________________________________________________________________________________________________
- Asphyxia
-
Increased blood volume
- Birth injury
-
Intra uterine growth retardation
- Cardiac hypertrophy
-
Macrosomia
- Congenital anomalies
-
Neurological instability: irritability
- Erythema and hyperviscosity
-
Organomegally
- Heart failure
-
Respiratory distress
- Hyperbilirubinaemia
-
Small lift colon syndrome
- Hhypocalcaemia
-
Still birth
- Hypoglycaemia
-
Transient haematuria
- Hypomagnesaemia
_____________________________________________________________________________________________________
In spite of all the advances achieved so far in the care of the
pregnant diabetic woman, many problems remain.
1. High incidence of congenital anomalies and spontaneous
abortion in infants of diabetic mothers (IDMs).
The true incidence of SAB in diabetic pregnancies is not
known, but has been reported to be as high as 30%, double
that of the general population.
The increased risk of congenital anomalies in IDMs ranges
from 6-12%, a two-five-fold increase over the general
population and accounts for around 40% of perinatal loss in
IDMs.
Table III:
Congenital Malformations in Infants of Diabetic Mothers (IDMs)
Anomaly
Caudal Regression
Ratio
252
Spina bifida, hydrocephalus and other CNS defects
2
Anencephalus
3
Heart Anomalies
4
Anal/Rectal Atresia
3
Renal anomalies
- Agenesis
- Cystic Kidney
- Ureter Duplex
5
6
4
23
Situs inversion
48
Ratio of incidence is in comparison to the general population.
The etiology of this increased incidence of congenital
anomalies in IDMs is not yet clearly defined. Some have
show that hyperglycaemia and other metabolic abnormalities
are teratogenic singly or in combination.
It is very important to understand that fetal organogenesis is
largely completed by eight weeks after the last menstrual
period (six weeks past conception) and therefore, poorly
controlled diabetes during the early week of pregnancy, in
many cases before the woman even know that she is
pregnant, significantly increases the rise of a first trimester
SAB or delivering an infant with a major anomaly.
The association between HbA1c, which expresses roughly
the control of blood glucose over the preceding 4-6 weeks
before its measurement, and increased risk of congenital
anomalies of SABs has made it a useful tool in assissing
the metabolic control in early pregnancy during the
critical period of organogenesis (< 13 weeks) and
therefore predicting such complications early on.
Therefore, normalizing blood glucose levels before and
during the early weeks of pregnancy can reduce
dramatically the risk of major anomalies as well and the
occurrence of SABs to almost near that of the nondiabetic population.
2.
Care of the difficult patient who often presents late for
antenatal care and/or is non compliant.
3.
Care of the woman with severe diabetic complications.
Therefore, pre-pregnancy counseling has emerged as a
vital component in the woman with diabetes. The major
component of a pre-pregnancy counseling include:
- Contraceptive advice.
- Risks of pregnancy, maternal and fetal/neonatal.
- Importance of maintaining normal blood glucose levels.
- Genetics counseling.
- Personal commitment by the woman.
A planned pregnancy is a major
objective of a
preconception counseling
Goals of Pregnancy Planning Program
Assessment of patient’s fitness for pregnancy
 Obstetric evaluation
 Intensive education of patient and partner
 Attainment of optimum Diabetic control
 Timing and planning of pregnancy
Blood glucose should be normalized as possible before
and throughout pregnancy to reduce the risk of
developing complications.
The woman should understand fully the increased risk
of complications both for her and for her diabetes is not
properly controlled before and during the early weeks of
pregnancy, but should also be reassured that with
continual optimal glucose control throughout
pregnancy, she can effectively reduce the reduce the risk
of complications.
She will also need to know that diabetic chronic
complications can worsen during pregnancy, e.g.
retinopathy and nephropathy, and preconception
evaluations of such complication must be emphasized.
Deep, personal commitment can never be overemphasized.
The woman has to understand that she will be seen
frequently by her physician and may need to be hospitalized
if problems arise. Personal involvement in maintaining
normal blood glucose throughout pregnancy is mandatory
and the pregnant woman has to understand the importance
of such deep personal commitment on the outcome of her
pregnancy.
Pregnancy Assessment for Diabetic Women
________________________________________________________________________________________
- Gynaecological evaluation
- Laboratory evaluation
• HbA1c level
• Urinalysis and culture
• 24-h Urine for creatinine clearance and total protein
- Thyroid panel (Type I Diabetic Women)
- Special studies
ECG or treadmill
Neuropathy testing if indicated
_______________________________________________________________________________________
POTENTIAL CONTRAINDICATIONS TO
PREGNANCY
1. Ischaemic heart diseases
2. Active proliferative retinopathy, untreated
3. Renal insufficiency: Cr. C1 < 50 m1/min or serum
creatinine > 2mg/d1 or heavy protein > 2g/24hr or
hypertension (BP > 140/90 despite treatment)
4. Severe gastroneuropathy: nausea, vomiting, and diarrhea
PRE-PREGNACY MANAGEMENT
Once the woman has undergone the pre-pregnancy
counselingand found fit to get pregnant, then a plan should
be outlined for pre-pregnancy management, with the goal of
normalizing the blood glucose level before conception and
maintaining of euglycaemia throughout the pregnancy.
Ideally, the Diabetes care team should include:
-
The primary care physician or an endocrinologist
The obstetrician
A nurse educator (preferably a certified Diabetes educator)
A registered dietitian
A paediatrician or neonatologist
Then she can be placed on an intensive human insulin regimen
with adequate coverage of premeal insulin as well as basal
insulin need. She could be taught self-monitoring of blood
glucose and she should do it frequently before and after meals.
Preconception goals for premeal glucose levels should be 70100mg/d1 (3.8-5.5 mmo1/L) and the 1-2 house post meal
blood glucose levels should fall at or below 150mg/d1
(8.3 mmol/L).
Adjustment in insulin doses according to blood glucose levels
can then be done by the patient\s team, or of she is quite
motivated and apt, she can do it herself at home. She should
also be warned about the symptoms and signs of
hypoglycaemia and taught how to mange it. Her partner or a
relative should also be instructed in the use of glucagons.
Serial HbAlc can be drawn monthly to confirm normalization
of blood glucose level in the preconceptional period to affirm
the safety of pursuing pregnancy form the metabolic
standpoint.
When maternal glucose levels are used, insulin therapy is
recommended when MNT fails to maintain self-monitored
glucose at the following levels:
Fasting whole blood glucose
 95mg/d1 (5.3 mmo1)
Fasting plasma glucose
 105mg/d1 (5.8 mmo1/L/1)
or
1-h postprandial whole blood glucose
 140mg/d1 (7.8 mmo1/L1)
1-h postprandial plasma level
 155mg/d1 (7.2 mmo1/1)
2-h postprandial whole blood glucose
 120mg/d1 (6.7 nni1/1)
2-h postprandial plasma level
 130mg/d1 (7.2 mmo1/1
PREGNANCY AND THE DIABETIC PATIENT
MONITORING AND CLINIC VISITS
Introduction:
The cornerstone of management of Diabetes in pregnancy is
a team approach with frequent visits to the clinic by the
pregnant woman as well as the daily home blood glucose
monitoring.
SMBG reduces hospital admissions and hospital stay in days
if required and it has been the single most important advance
in the management of diabetes in pregnancy in the last
decade because of its ability to provide intensive
management of diabetes without the need for frequent
admissions.
Achieving euglycaemia in pregnancy can promise an outcome
that shows no deleterious effect of diabetes.
Pre-existing diabetes has its own complications, which should
be carefully monitored during pregnancy.
“Controlled Diabetes is essential to fetal welfare”.
This statement made by Dr. Priscilla White in 1928 is as
pertinent now as it was then.
The major diabetogenic hormones of placenta are human
placental lactogen hPL, estrogen and progesterone. Also
serum cortisol is increased during pregnancy and prolactin
being elevated during gestation has a diabetogenic effect as
well.
Degradation of insulin is increased during pregnancy
because of certain placental enzymes comparable to liver
insulinases, and the function of the placental membrane,
which has an insulin degrading activity.
The normal pancreas compensate by increasing insulin
secretion. If the pancreas doesn’t respond adequately to
these changes or of the clearance of glucose is defective then
gestational diabetes occurs.
Achieving optimal control of diabetes requires balancing
the meal, insulin dosage, an activity level with strong
commitment form all those involved in the care of the
diabetic pregnant woman, with the pregnant woman
herself being the most important member of the team.
Working with the pregnant population is a rewarding
experience as they are strongly motivated in the care of
their disease. The best chance for success comes when the
pregnancy is planned, as good metabolic control is
desired before conception.
Risk factors for developing GDM e.g. family history,
obesity, and poor obstetric history identify only 50% of
women at risk.
Deleterious effect of sustained of
intermittent hyperglycaemia on the fetus:
1. During orgaqnogenesis (weeks 2-8), an increased risk
of malformation
2. Premature stimulation of fetal insulin secretion leads t
to;
macrosomia
inhibition of pulmonary surfactant
maturation leading to fetal respiratory
distress
neonatal hypoglycaemia leading to
permanent neurological damage
GOALS IN THE DIABETIC PREGNANCY
The target range for blood glucose during pregnancy is
patterned after maternal plasma glucose levels in normal
pregnancies.
Mean plasma glucose level is about 20% lower in
pregnancy then pre-pregnancy level and the HbA1c
follows suit.
Table IV:
Blood Glucose Goals In Diabetic Pregnancy
Fasting
5.0 mmol)
Pre-meal
105mg/dl (3.3 – 5.8 mmol)
- 1 hr post prandial
130mg/dl (6.1 – 7.3 mmol)
- 2 hr post prandial
6.7 mmol)
- 02.00 – 06.00 AM
– 6.7 mmol)
-
60 – 90mg/dl (3.3 –
60
–
110
–
90 – 120mg/dl (5.0 –
60 – 120mm/dl (3.3
To achieve this, frequent SMBG readings are necessary.
Ideally, eight tests should be done; one before each meal
and one 1-2 hours after each meal; one at bedtime and
one in the middle of the night.
Pre-meal tests assess presence of asymptomatic
hypoglycemic and establish the pre-meal short-acting
insulin doses.
Post-meal tests are used to evaluate the effect of the
particular meal and insulin doses on the blood glucose.
Bedtime testing is necessary to rule out any hypo or
hyperglycemia, which requires attention before retiring
to bed and also determines the quantity and quality of the
bedtime snack.
03:00 testing is important in detecting hypoglycaemia if
nocturnal hypoglycaemia is suspected.
These test provide feedback about the match between
food and insulin and the effect of dietary changes.
Although eight tests per day is ideal, this can be
impractical for many patients and some centers
recommend for test each day –fasting 1-2 hours after
each meal.
Patients on more than two injections per day or
receiving continuous subcutaneous insulin injection
therapy will need to perform at least seven tests a daybefore each meal, after each meal, and at bedtime.
Results should be recorded in an organized manner so
that the glycaemic pattern is recognized and steps made
appropriately, according to blood glucose levels.
SBMG
-is one of the most important tools for maintaining
euglycaemia during pregnancy. It provides day-today information on which treatment
recommendations can be based, but it has the
inherent potential for gross inaccuracies and
therefore education and periodic reevaluation and
reeducation are vitally important for its success.
HOME MONITORING
Blood glucose should be maintained in the normal range
throughout the day, throughout pregnancy. This can
only be achieved by self-monitoring of blood glucose be
the patient at home. It should be taught at the initial
visit to the clinic to allow for immediate monitoring on a
daily basis.
There are two methods currently available for
SWMBG:
i. visual comparison of reacted reagent strips
ii.The use of reflectance or enzyme electrode
blood glucose meters.
Both methods depend on a glucose oxidase reaction
The members of the health care team looking after the pregnant
diabetic mother should verify that the patient is monitoring her
blood glucose accurately by frequent check-ups in the clinics.
PROBLEMS WITH SMBG
I.Objectivity
Errors in judgment, especially when patients are highly
motivated to keep their blood glucose readings in the normal
range, is not uncommon, especially with the visually read strips.
The meters are less likely to invite errors in judgment.
II.Accuracy
Improper technique can lead to variability in results and
this can be minimized if patients are adequately trained
and carefully monitored. Some systems are more
dependent upon user skills than others.
Others factors affecting accuracy include defective strips,
instrument malfunction, severe hypo or hyperglycaemia,
and haematocrite value. With current systems, SMBG
measurements should be within 15% of the results of a
reference measurement using the same blood sample.
HbA1c MEASUREMENT IN PREGNANCY
I.Pre-existing Diabetes
It is useful in evaluation of the degree of diabetic control over
the period of 4-6 weeks before its measured and it is
therefore very useful in the critical early weeks of pregnancy.
Its level has been directly correlated with the increased
incidence of congenital malformation in infants of diabetic
mothers.
The risks of congenital anomalies when the HbA1c is higher
than the man value of the non-diabetic women in the first 8
weeks of gestation reached 28%. Therefore, it is important to
measure the HbA1c level when the diabetic woman first
presents with plans for pregnancy. This should be advised to
be as early as possible and continue with serial measurements
every 4-6 weeks until the pre-pregnancy goal of near normal
HbA1c value is achieved.
Once pregnant, the HbA1c should be checked every 4-6
weeks to assess the degree of glycaemic control throughout
the pregnancy and should be maintained within or near the
non-diabetic range.
II.Gestational Diabetes Mellitus
An initial HbAlc measurement is helpful
I.
II.
III.
If it is in the non-diabetic range, which is usually the
case. It reassures the woman the GDM was
diagnosed at the appropriate time and was probably
not present earlier in gestation.
If is elevated: then it warns that glucose intolerance or
even overt DM may have been present earlier in the
pregnancy or even predated the pregnancy.
It serves as a baseline value in pregnancy
It should be measured every 4-6 weeks to monitor the
control and help in adjustment of the insulin doses.
URINARY KETONE TESTING
Ketonaemia during pregnancy has been associated with
changes in the developing nervous system of the fetus and
with decreased intelligence. It may also signal development
of maternal ketoacidosis, which is associated with 50-90%
mortality rate in the fetus.
Starvation ketosis commonly occurs after an overnight fast;
so it is best to test for urinary ketones in a first monitoring
urine sample.
If ketonuria occurs despite good glucose control and is
repeatedly seen at a particular tome of the day, then
the patient may need the addition of a snack before
that particular time. Urinary ketones need also to be
checked if a meal is delayed or missed, with any
illness, and with any blood glucose > 200mg/dl.
Persistent ketonuria not responding to dietary change
will require adjustment in the insulin doses.
In pregnant women with pre-existing diabetes,
certain tests may be required in addition:
- Thyroid function test (type IDDM).
- A clear catch dipstick urine analysis should be evaluated
for protein, ketones and WBC each visits to R/O occult
UTI or incipient toxamia.
- A finger stick blood glucose measurement should be done
each visit to verify self-testing results.
- Serial HbAlc levels every 4-6 weeks to assess overall
glycaemic control
Surveillance of diabetes related complications are
also vital:
- A 24-hour urinary sample for creatinine clearance and
protein should be collected each trimester with referral to
a nephrologist if nephropathy is present.
- A baseline retinal examination done by an opthalogist
with the necessary follow up examinations.
- Careful attention to cardiac status with referral to a
cardiologist
Table VII:
_______________________________________________________________________________
Frequency of Testing Maternal Status During Pregnancy for
Women with Pr-existing Diabetes
_______________________________________________________________________________
Test
HbAlc
Glucose
visits in the clinic
Fastin ketones
Urinalysis
clinic visits
Kidney function
Thyroid function
needed
Eye status
as necessary
Frequency
Every 4-6 weeks
During weekly of bi-weekly
SMBG 4-8 times daily
Daily
During weekly or bi-weekly
Each trimester
Baseline & repeated if
First trimester and repeated
________________________________________________________________________________
FOLLOW UP VISITS
The pregnant woman with diabetes should be seen
every 1-2 week with fasting and/or random blood
glucose collected at each visit to document control and
assess how this value compares with SMBG at home.
MSU analysis and HbAlc should be followed up as
stated in the above table.
Table VIII:
_________________________________________________________________________
Pregnancy Diet Calculation
_______________________________________________________________________________________________________________
_
Determination of desirable body weight:
100 lbs for first 5 ft of height + 5 lb/inch for each l inch over 5 ft ±
10% for large/small frame.
Determination of daily calorie requirement:
30 kcal/kg (2.2 lb) current body weight for active woman
25 kcal/kg (2.2 lb) current body weight for sedentary, obese women
to lose l lb/week, subtract 500 kcal from daily requirement or
increase exercise.
Distribution of calories:
55-60% of carbohydrate (preferably unrefined carbohydrate with
fiber)
12-20% protein
< 30% fat (composed of up to 10% polyunsaturated fats, < 10%
saturated fats,
and remainder from monounsaturated fats).
_______________________________________________________________________________________________________________
___
Table IX:
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Sample Pregnancy Daily Insulin Therapy
_________________________________________________________________________________________________________________________________
Goals for therapy
Fasting, premeal blood glucose < 150mg/dl (< 8.3-5.5 mM)
1-2 h postmeal blood glucose < 150mg/dl (8.3 mM)
HbAlc should be < 6.1%
Human insulin regiments
Combination of short-acting insulin with intermediate-acting or
Long-acting insulin in 1 2 to 4-injection routine
0.5-1.0 Ukg –1 day –1 (0.2-0.4 Ulb–1 day) -⅔ total dose in A.N,
⅓ total dose in P.M
Examples
Short-and intermediate-acting insulin prebreakfast and predinner*
Short-acting insulin before each meal + intermediate or long-acting
insulin at bedtime
Short-intermediate-action insulin before lunch
___________________________________________________________________________________________________________________________________
*
Most intensive insulin regimes will consist of > 2 injections/day to
maintatin euglycemia
__________________________________________________________________________________________________________________________________
Table IX:
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Sample Algorithms for Pregnancy
Insulin Adjustment
___________________________________________________________________________________________________________________________________
Adjustments for unexplained hyperglycemia: check for deviations in diet and/or
illness, then:
1-2U.
If prebreakfast blood glucose BG > 100mg/dl (5.5 mM) for 2-3 day,
increase P.M intermediate-acting insulin by 2U or long-acting insulin by
If prelunch BG > 100mg/dl (5.5 mM) for 2-3 day,
increase prebreakfast short-acting insulin by 2U or prelunch short-
acting
insulin by 1-2U.
If predinner BG > 100mg/dl (5.5 mM) for 2-3 days,
shout- increase prebreakfast intermediate-acting insulin by 2U or prelunch
acting insulin by 1-2U
If bedtime BG > 120mg/dl (6.6 mM) for 2-3 days,
increase predinner shot-acting insulin by 1-2U.
_______________________________________________________________________________________________________________________________________
__
Adjustments for unexplained hyperglycemia: review meal plan,
then:
If breakfast BG > 70mg/dl (3.8mM) twice during a week of is
symptoms of low BG overnight.
decrease evening intermediate-acting insulin by 2U or long actinginsulin by 1-2U.
If predinner BG > 70mg/dl (3.8mM) or reaction occurs between
breakfast and lunch,
decrease prebreakfast shot-acting insulin by 1-2U
If predinner BG > 70mg/dl (3.8mM) or reaction occurs between lunch
and dinner,
decrease prebreakfast intermediate-acting insulin by 2U or prelunch
short-acting insulin by 1-2U.
If prebedtime BP< 70mg/dl (3.8mM) or reaction occurs between
dinner and bedtime,
Decrease predinner short-acting insulin by 1-2U.
___________________________________________________________________________
Labour and Delivery:
Patients with documented good blood glucose control
do not need early delivery but if a fetus with
documented poor pulmonary maturity as assessed by
aminiocentesis and poor results on fetal surveillance
protocols (heart rate, kicks count etc….) then
immediate delivery is advised.
Maternal insulin requirements usually drop quickly
postpartum and gestational diabetic mother will require
no further insulin. Pre-gestational diabetic mother will
require resumption of insulin treatment but the
requirement will be less for 48-96 hours post
operatively.
Almost 98% of gestational diabetic women revert
to nomoglycaemic postpartum. An OGTT test
should be performed 6 weeks postpartum Diabetes
Mellitus will recur in each subsequent pregnancy
in 90% of cases. If they remain overweight 60%
will have overt DM within 20 years.
REFERENCES:
 Medical Management of Pregnancy complicated by diabetes.
 American Diabetes Association Clinical Education
 Series, June
1993.
 Diabetes Complicating Pregnancy. The Joslin Clinic
Method,
 editor John W.
 Hare, MD. Allan T. Liss, Inc. New York, 1989.
 Endocrinology and Metabolism Clinics of North America
Diabetes Mellitus, Perspectives on Therapy, June 1992.
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