Transcript Diabetes in Pregnancy: Insulin

Diabetes
&
Pregnanc
y

Women with diabetes in the first trimester would be
classified as having type 2 diabetes.

GDM is diabetes diagnosed in the second or third
trimester of pregnancy that is not clearly overt
diabetes.
Prevalence of GDM
Epidemiology of glucose intolerance and GDM in women of child bearing age, Diabetes Care, 21, 1998
Population
Preval
yea Diagnostic
ence of
r
method
GDM%
Chinese
Melborne-Australia(Indian-born)
0.6
15.0
IRAN
4.7-8.9
Larijani
Tehran
2003
50&100g GTT
4.7
Hadaegh
Bandar-abbas
2005
50&100g GTT
8.9
Keshavarz
Shahrood
2005
50&100g GTT
4.8
Maghbooli
Tehran
2007
50&100g GTT
7
Shirazian
Tehran
2008
75g GTT
6.1
Shirazian
Tehran
2009
75g GTT
7.4
Why Diagnose and Treat
GDM?
Dysglycemia in Pregnancy can Result
in Adverse Pregnancy Outcome
 Elevated glucose levels can have adverse effects on
the fetus
 1st trimester  ↑ fetal malformations
 2nd and 3rd trimester:
metabolic complications
↑ risk of macrosomia and
Risk of Fetal Anomaly Relative
to Peri-conceptional A1C
Glycemic control pre-conception = essential
Guerin A et al. Diabetes Care 2007;30:1-6.
Risks of Gestational Diabetes
Mother
Fetus
Newborn
Child/Adult
Birth trauma
Hyperinsulinemia
Hypoglycemia
Obesity
Respiratory
distress
syndrome
Type 2 diabetes
Hypocalcemia
Metabolic syndrome
Increased cesarean
Cardiomyopathy
delivery
Preeclampsia/
Gestational
hypertension
Fetal
organomegaly
Hydramnios
Stillbirth
Type 2 diabetes
LGA/
macrosomia
Metabolic
syndrome
Birth trauma
Hyperviscosity
impaired fine and
gross motor
Hypomagnesemia
functions
Cardiomyopathy
higher rates of
Hyperbilirubinemia inattention and/or
Perinatal mortality
hyperactivity
Polycythemia
GDM Pathogenesis
• Pregnancy is characterized by insulin resistance and hyperinsulinemia
due to:
– placental secretion of diabetogenic hormones including:
 GH
 CRH
 Human placental lactogen (hPL)
 Progesterone
– increased maternal adipose deposition
– decreased exercise
– increased caloric intake
• These and other endocrinologic and metabolic changes ensure that the
fetus has an ample supply of fuel and nutrients at all times.
• GDM occurs when pancreatic function is not sufficient to overcome the
insulin resistance created by changes in diabetogenic hormones during
pregnancy.
Risk Factors for Gestational Diabetes
Diabetes in Pregnancy:
2 Categories
Pregestational diabetes
Pregnancy in
pre-existing diabetes
• Type 1 diabetes
• Type 2 diabetes
Gestational diabetes
Diabetes diagnosed in
pregnancy
 Women with diabetes in the first trimester would be
classified as having type 2 diabetes.
 GDM is diabetes diagnosed in the second or third
trimester of pregnancy that is not clearly overt
diabetes.
Need a Preconception Checklist for
Women with Pre-existing Diabetes
 1. Attain a preconception A1C of ≤7.0% (if safe)
 2. Assess for and manage any complications
 3. Switch to insulin if on oral agents
 4. Folic Acid 5 mg/d: 3 months pre-conception to 12
weeks post-conception
 5. Discontinue potential embryopathic meds:
 Ace-inhibitors/ARB (prior to or upon detection of pregnancy)
 Statin therapy
PRECONCEPTION COUNSELING
 All women of childbearing age with diabetes should
be counseled about the importance of strict glycemic
control prior to conception.
 Observational studies show an increased risk of
diabetic embryopathy, especially anencephaly,
microcephaly, and congenital heart disease, that
increases directly with elevations in A1C.
 Spontaneous abortion is also increased in the setting
of uncontrolled diabetes.
A1C<7% prior to conception to minimize risk.
 Diabetes specific management should include A1C,
thyroid-stimulating hormone, creatinine, and urine
albumin-to-creatinine ratio testing;
 Review of the medication list for potentially
teratogenic drugs (i.e., ACE inhibitors, statins); and
referral for an ophthalmologic exam.
Preconception Counseling for Pregestational Diabetes
 Advise reproductive age women with diabetes about
reliable birth control
 NOTE: Metformin in PCOS may improve fertility 
need to warn about possible pregnancy
 Metformin safe for ovulation induction in PCOS
 Achieving a healthy weight is essential – obesity
associated with adverse pregnancy outcomes
Screen for Complications:
Pre-pregnancy and Intrapartum
Screening for:
1.Retinopathy: Need ophthalmological evaluation
2.Nephropathy: Assess creatinine + urine microalbumin
/ creatinine ratio (ACR)

Women with microalbuminuria or overt nephropathy
are at ↑ risk for hypertension and preeclampsia
b) Strive to attain a preconception A1C of ≤7.0% (or A1C
as close to normal as can safely be achieved) to decrease
the risk of:
 Spontaneous abortion
 Congenital anomalies
 Pre-eclampsia
 Progression of retinopathy in pregnancy
c) Supplement their diet with multivitamins containing
5 mg of folic acid at least 3 months pre-conception
and continuing until at least 12 weeks postconception .
d) Discontinue medications that are potentially
embryopathic, including any from the following
classes:

ACE inhibitors and ARBs prior to conception or
upon detection of pregnancy

Statins
Women with type 2 diabetes who are planning a
pregnancy
should
switch
from
non-insulin
antihyperglycemic agents to insulin for glycemic control
.
Women with pregestational diabetes who also have
PCOS may continue metformin for ovulation
induction .
Women should undergo an ophthalmological evaluation
by an eye care specialist .
Women should be screened for chronic kidney disease
prior to pregnancy .Women with microalbuminuria or
overt nephropathy are at increased risk for the
development of HTN and preeclampsia and should be
followed closely for these conditions .
Diagnosis
 GDM carries risks for the mother and neonate.
 The Hyperglycemia and Adverse Pregnancy Outcome
(HAPO) study demonstrated that risk of adverse
maternal, fetal, and neonatal outcomes continuously
increased as a function of maternal glycemia at 24–28
weeks.
 GDM diagnosis can be accomplished with either of
two strategies:
 1. “One-step” 75-g OGTT
or
 2. “Two-step” approach with a 50-g (non-fasting)
screen followed by a 100-g OGTT for those who
screen positive.
 In the 2011 Standards of Care ,the ADA for the first
time recommended that all pregnant women not
known to have prior diabetes undergo a 75-gOGTT at
24–28 weeks of gestation , based on a
recommendation of the International Association of
the Diabetes and Pregnancy Study Groups (IADPSG).
 In 2013, the National Institutes of Health (NIH)
convened a consensus development conference on
diagnosing GDM.
 The panel recommended the two-step approach of
screening with a 1-h 50-g glucose load test (GLT)
followed by a 3-h 100-g OGTT for those who screen
positive.
 Screening with a 50-g GLT does not require
fasting and is therefore easier to accomplish for
many women.
Diagnosis of GDM with a 100-g oral glucose load
Fasting
1-h
2-h
3-h
mg/dl
95
180
155
140
2 or more must be met or exceeded for a positive diagnosis. Test should be done in
the morning after an overnight fast (8-14 h & after at least 3 days of unrestricted diet
( 150 g CHO per day) & unlimited physical activity. CHO loading is probably not
necessary .The subject should remain seated and should not smoke throughout the
test.
GLYCEMIC TARGETS IN PREGNANCY
Targets for maternal capillary glucose concentrations:
 Preprandial≤95 mg/dL
and either
 One-hour postmeal ≤140 mg/dL
or
 Two-hour postmeal ≤120 mg/dL
 Due to increases in red blood cell turnover associated with pregnancy,
A1C levels fall during pregnancy. Additionally, as A1C represents an
average, it may not fully capture physiologically relevant glycemic
parameters in pregnancy.
 A1C should be used as a secondary measure, next to self-monitoring of
blood glucose.
 The recommended A1C target in pregnancy is 6% if this can be
achieved without hypoglycemia.
 Given the alteration in red blood cell kinetics during pregnancy, A1C
levels may need to be monitored more frequently than usual(monthly).
 For women with preexisting type 1 diabetes or type 2
diabetes who become pregnant, the following are
recommended as optimal glycemic goals if they can
be achieved without excessive hypoglycemia :
 Pre-meal, bedtime, and overnight glucose: 60–99 mg/dL
 Peak postprandial glucose: 100–129mg/dL
 A1C < 6.0%
GDM: Glycemic Management During
Pregnancy
 Perform SMBG, both fasting and postprandially
 Glycemic Targets during pregnancy:
Target glucose values
Fasting PG <95
1h postprandial PG <140
2h postprandial PG <120
 Receive nutrition counseling
 Moderate carbohydrate restriction: 3 meals + 3 snacks
 Targets not met within 2 weeks start insulin
 Avoid hypocaloric diet  weight loss + ketosis
Glucose Monitoring
Should measure blood glucose at least;
4 times /day
(fasting & 1-hour or 2-hour after first bite of each meal)
ROLE OF EXERCISE
 The patient and provider should discuss the role of
exercise during pregnancy and consider potential
medical and obstetrical complications .
 Exercise may provide several maternal benefits,
including minimizing weight gain, improving glycemic
control, and preparing for the physical rigor of labor,
as well as fetal benefits, such as reducing fetal
adiposity.
 In the absence of these contraindications, 30 or more
minutes of moderate intensity, low fall-risk, physical
activity can be performed by women on most days of
the week .
 Hypoglycemia may be more severe and more frequent
in pregnancy compared with the non-pregnant state,
so a carbohydrate-based snack prior to exercise may be
needed .
MANAGEMENT OF GESTATIONAL
DIABETES MELLITUS
 GDM is characterized by increased risk of macrosomia
and birth complications.
 Treatment starts with medical nutrition therapy,
exercise, and glucose monitoring aiming for the targets
described previously.
 A total of 70 to85% of women diagnosed with GDM
can control GDM with lifestyle modification alone.
MEDICAL NUTRITION THERAPY
 Consensus recommendations for management of
diabetes in pregnancy advise individualized medical
nutrition therapy (MNT) supervised by a registered
dietician with expertise in MNT during pregnancy .
Goals of therapy
 The optimal diet to maintain glycemic control during
pregnancy takes into account caloric intake,
carbohydrate content, and distribution of meals
throughout the day. The goals of MNT are to:
● Provide adequate nutrient intake for a healthy pregnancy.
● Achieve normoglycemia
● Provide adequate weight gain
● Provide appropriate food, physical activity, and
behavior education
Calorie requirements
 Caloric requirements for a singleton pregnancy are
increased by an average of approximately 300 kcal/day
above basal daily needs in non-pregnant women .
 These recommendations are based on pre-pregnancy
BMI;
clinical
judgment
and
provider-patient
discussions regarding diet and physical activity will
influence the weight achieved within these ranges. In
addition, women with twin gestations will have higher
weight gain targets.
 Excessive weight gain should be avoided as it, like
hyperglycemia, contributes to development of large for
gestational age infants and thus can potentially negate
some of the benefits of good glycemic control .
IOM Guidelines for Gestational
Weight Gain
Pre-Pregnancy BMI
Recommended range
of total weight gain
(Kg)
Recommended range
of total weight gain
(lb)
BMI <18.5
12.5 – 18.0
28 – 40
BMI 18.5 - 24.9
11.5 – 16.0
25 – 35
BMI 25.0 - 29.9
7.0 – 11.5
15 – 23
BMI > or = 30
5.0 – 9.0
11 – 20
Recommended rate of weight gain and total weight gain for singleton
Pregnancies according to pre-pregnancy BMI
Institute of Medicine. Weight gain during pregnancy: reexamining the guidelines. Consensus
Report. May 2009. The National Academies Press. Washington, DC.
 Maternal obesity can cause excessive fetal growth,
independent of diabetes, and often worsens impaired
glucose tolerance in both type 1 and type 2 diabetes.
 Despite these concerns, the safety of weight loss
during pregnancy has not been proven and is
controversial.
 Caloric composition — Nutritional intake is divided
among the macronutrient components to promote
optimal glycemic control and avoidance of
hypoglycemia and ketonemia. We suggest :
 ●Complex, high-fiber carbohydrates – 40 to 50 percent
of total calories
 ●Protein – 20 percent of total calories
 ●Fats – 30 to 40 percent of total calories, primarily
unsaturated
 Postprandial blood glucose concentrations are directly
dependent upon the carbohydrate content of a meal.
The postprandial glucose rise, therefore, can be
blunted if the diet is carbohydrate restricted.
 Complex carbohydrates, such as those in vegetables,
are more nutrient dense and raise postprandial blood
glucose concentrations less than simple sugars.
 Calorie distribution : Three meals per day and snacks “as




needed” .Caloric intake may be distributed as follows:
●Breakfast – 10 to 20 percent of total calories.
●Lunch – 20 to 30 percent of total calories
●Dinner – 30 to 40 percent of total calories
●Snacks – Up to 30 percent of total calories.
 Snacking
is based on caloric needs, support for
hypoglycemia, as well as consideration of pre-pregnancy
BMI, as overweight and obese women may not need to
snack. Bedtime snacks are often needed to minimize
nocturnal hypoglycemia.
PHARMACOTHERAPY
MANAGEMENT OF PREGESTATIONAL TYPE 1 DM AND
TYPE 2 DM IN PREGNANCY
 Insulin is the preferred agent for management of
diabetes in pregnancy because of the lack of long-term
safety data for noninsulin agents.
 Historically, insulin has been the recommended
treatment for GDM .
 Randomized controlled trials support the efficacy and
short-term safety of glyburide (pregnancy category B)
and metformin (pregnancy category B) for the
treatment of GDM.
 However, both agents cross the placenta, and long-
term safety data are not available .
 We do not start oral agents during pregnancy.
However, increasingly, patients with type 2 diabetes
and/or polycystic ovary syndrome and impaired
glucose tolerance are conceiving while on oral antihyperglycemic agents.
 We generally continue metformin in patients who are
on this drug, but discontinue other oral agents.
 We then initiate insulin therapy as needed to achieve
adequate metabolic control.
 Available data indicate that OHAs, such as glyburide
and metformin, may be both safe and effective
alternatives to insulin, but only in women with
gestational diabetes mellitus who cannot be
adequately treated with diet alone or simply refuse to
take insulin.
 OHAs are not as effective as insulin in all women with
gestational diabetes, such as those with more severe
degrees of hyperglycemia early in pregnancy ,and use
of these drugs in pregnancy has not been addressed by
the FDA.
 Several
observational series have also reported
generally good outcomes with use of metformin in
pregestational diabetes , and meta-analyses found no
evidence of an increased risk for major malformations
when metformin was taken during the first trimester.
 The British National Institute for Health and Clinical
Excellence (NICE) guideline states that metformin
may be used for women with pregestational diabetes as
an adjunct or alternative to insulin .
 There are limited data on the use of other OHAs in
pregnancy.
Type of insulin
 Use of insulin preparations of low antigenicity will
minimize the transplacental transport of insulin
antibodies: human insulin is the least immunogenic of
the commercially available preparations.
AACE 2013
Diabetes in Pregnancy: Insulin
Insulin Options Shown to Be Safe During Pregnancy1
Peak
Onset
Effect
Durati
on
Recommend
ed Dosing
Interval
Name
Type
Aspart
Rapid-acting
(bolus)
15 min
60 min
2 hrs
Start of each
meal
Lispro
Rapid-acting
(bolus)
15 min
60 min
2 hrs
Start of each
meal
Regular
insulin
short-acting
60 min
2-4 hrs
6 hrs
60-90 minutes
before meal
NPH
Intermediateacting (basal)
2 hrs
4-6 hrs
8 hrs
Every 8 hours
Detemir
Long-acting
(basal)
2 hrs
n/a
12 hrs
Every 12 hours
 All insulins are pregnancy category B except for
glargine and glulisine, which are labeled C.
 The three rapid acting insulin analogs (lispro, aspart,
glulisine) are comparable in immunogenicity to
human regular insulin, but only lispro and aspart have
been investigated in pregnancy and shown to have
acceptable safety profiles, minimal transfer across the
placenta, and no evidence of teratogenesis .
 These two insulin analogs have also been shown to
reduce the risk of postprandial glycemic excursion and
delayed postprandial hypoglycemia compared with
regular human insulin .
Regular Insulin vs. Rapid Analogue
FDA labelling use for
®
NovoRapid
Date
Perinatal mortality
25
Perinatal mortality
(per 1000 births)
20
15
10
5
0
NovoRapid®
Hod M et al. Am J Obs Gyn,2007
Human insulin
Pre-term delivery – lower frequency
NovoRapid®
HI
% of deliveries
(live or still births ≥22 weeks)
90
n=110
80
n=93
70
60
50
40
*p = 0.053
n=41
30
20
n=28
10
0
Pre-term
(< week 37)
Presentation title
Hod M et al. Am J Obs Gyn,2007
At term
(> week 37–42)
Slide no 67
Date
Neonatal hypoglycaemia
50
Plasma glucose
< 50 mg/dl
n=52
40
NovoRapid®
% of live births
n=46
HI
30
20
n=12
10
n=8
0
Treatment
given
Presentation title
Hod M et al, Am J Obs Gyn,2007
No
treatment
given
Slide no 68
Date
 Longer-acting insulin analogs (insulin glargine, insulin
detemir) have not been studied extensively in
randomized trials of pregnant women.
 A meta-analysis of observational data from 331
pregnancies with glargine exposure during the first,
second, and/or third trimester showed no statistical
increase in any maternal or neonatal adverse outcome
compared with use of NPH .
 However, the number of women who have been
treated with this drug in the first trimester is too
small.
 The incidence of macrosomia was high in both
glargine treated women (23.6 percent) and women
treated with NPH (19.7 percent), and several-fold
higher than the <5 percent incidence of macrosomia
reported in nondiabetic pregnancies .
 A disadvantage of glargine is that its activity remains
constant over 24 hours, and this level of activity may
not be optimal for both daytime and nighttime basal
needs.
 The slow kinetics of glargine insulin may also be
problematic during the third trimester when frequent,
relatively large changes in insulin dose may be
required.
 Insulin detemir is another long-acting insulin.
 In 2012, insulin detemir : FDA approval for pregnancy
category B .
 Detemir was non-inferior to NPH with respect to
hypoglycemia rates and A1C achieved. The
pharmaceutical package insert notes that no
differences in pregnancy outcomes or the health of the
fetuses and newborns were seen with insulin detemir
compared to NPH.
AACE 2013
Diabetes in Pregnancy: Insulin Dosing
Insulin Dosing Guidelines During Pregnancy and Postpartum1
Weeks gestation
Total daily dose (TDD) of insulin†
1-13 weeks
(0.7 x weight in kg) or (0.30 x weight [lbs])
14-26 weeks
(0.8 x weight in kg) or (0.35 x weight [lbs])
27-37 weeks
(0.9 x weight in kg) or (0.40 x weight [lbs])
38 weeks to delivery
(1.0 x weight in kg) or (0.45 x weight [lbs])
Postpartum (and lactation)‡
(0.55 x weight in kg) or (0.25 x weight [lbs])
† The
total daily dose (TDD) of insulin should be split, so that 50% is used for basal insulin and
50% is used for premeal rapid-acting insulin boluses
‡ Nighttime basal insulin should be decreased by 50% in lactating women (to prevent severe
hypoglycemia)
• Special notes for T1DM:
• Between 10 and 14 weeks gestation, patients with T1DM undergo a period of increased
insulin sensitivity; insulin dosage may need to be reduced accordingly during this time
frame
• From weeks 14 through 35 of gestation, insulin requirements typically increase steadily
• After 35 weeks gestation, insulin requirements may level off or even decline2
• Obese patients may require higher insulin dosages than non-obese individuals2
Insulin therapy in gestational diabetes mellitus
 Total Insulin dose: 0.7 – 2 units/kg (present pregnant weight)
 If FPG is high : NPH at bedtime with initial dose of 0.2
units/kg
 If PPG is high : NovoRapid®
 Ideally, insulin should be started prior to conception to
optimize glycemic control during the critical period of
organogenesis early in the first trimester. Insulin
requirements during the first trimester are similar to
those prior to pregnancy in women with type 1 and
type 2 diabetes.
POSTPARTUM CARE
 Lactation
 All women should be supported in attempts to nurse
their babies, given immediate nutritional and
immunological benefits of breastfeeding for the baby;
there may also be a longer-term metabolic benefit to
both mother and offspring ,though data are mixed.
 Women with GDM should be screened for
persistent diabetes or prediabetes at 6–12 weeks
postpartum using non-pregnancy criteria and
every 1–3 years thereafter depending on other risk
factors.
Postpartum GDM
Management Checklist
1. Encourage Breastfeeding
2. 75g OGTT between 6 weeks - 6 months postpartum
to detect prediabetes or diabetes
3. Discuss increased long-term risk of diabetes –
Importance of returning to pre-pregnancy weight
79
 Dose : The average insulin requirement in pregnant
women with type 1 diabetes is 0.7 units/kg in the first
trimester, often increasing to 0.8 U/kg for weeks 13 to
28, 0.9 U/kg for weeks 29 to 34, and 1.0 U/kg for weeks
35 to term; however, the range of change in insulin
requirements is broad.
 Meal related insulin lispro and aspart doses are
calculated as 50 percent of the insulin requirement.
For most pregnant women, this dose is approximately
0.15 times their pregnant weight in kilograms .
 As an example, an 80 kilogram pregnant diabetic
woman would take 12 units of lispro or aspart before
each meal.