Transcript Hyperglycemia, Not Diabetes, in Pregnancy

Diabetes in Pregnancy: Antepartum
Considerations and New Perspectives
Amy Rouse, MD
Maternal-Fetal Medicine
Saddleback Memorial Medical Center
31 January 2009
Objectives
After completing this session, the learner should be
able:
1) To identify key considerations in women with diabetes/
insulin resistance who may become pregnant
2) To recognize updated guidelines for identifying women at
risk for gestational diabetes
3) To understand the impact of hyperglycemia below the
threshold of a diagnosis of gestational diabetes
Part I: Preconception
Preconception Issues
Any woman of reproductive age who is
not actively using reliable contraception
may become pregnant
Periconception glycemic control is the
single most influential factor in
embryonic development
Pregnancy Happens . . .
2009, The National Campaign to Prevent Teen and Unplanned Pregnancy
… Even to Women with
Diabetes
St. James PJ et al:
Prospective cohort study of 66 women with
diabetes
1/3 became pregnant within 5 years (n=23)
Only 26 percent of pregnancies were planned
Conclusion: Addressing pregnancy planning in
women with diabetes must improve
Diabetes Care Vol 16, Issue 12 1572-1578; 1993
White’s Classification in Pregnancy
Courtesy of Gabbe Obstetrics: Normal and Problem Pregnancies
Diabetes and Early Pregnancy
Loss
Poor glycemic control is associated with
increased spontaneous abortion
Higher loss rates with long standing disease
or with vasculopathy
Class C, D, and F: SAB rates of 25%, 44%, and
22%, respectively
Jovanovic: Loss rate similar to general
population with excellent glycemic control
Diabetes and Birth Defects
Background rate of major congenital
malformations ~2%
Infants of diabetic mothers: 6-10%,
accounting for 40% of perinatal deaths
in these babies (Reece EA 1996)
Diabetes and Birth Defects
UK data BMJ 2006: 4.6% major
congenital malformation rate in all
pregestational diabetic pregnancies
Neural tube defects increased 4.2 fold
Congenital heart disease increased 3.4 fold
Only 65% of neonatal
anomalies were
identified antenatally
Diabetes and Birth Defects
Miller et al 1981:
3.4% malformation rate if periconception
HbA1c <8.5%
22.4% malformation rate if periconception
HbA1c >8.5%
End-organ damage not modifiable at
time of pregnancy, but control is!
Diabetes and Birth Defects
Lucas et al 1989, n=105:
Overall malformation rate 13.3%
HbA1c range
Rate of
Malformation
>11.2%
25%
9.2-11.1%
23%
7.2-9.1%
14%
<7.2%
0
Why do Birth Defects Happen?
Multifactorial
Clear direct association with hyperglycemia
3-6 weeks after conception
Teratogenic potential of
Inositol
Prostaglandins
Reactive oxygen species
Why do Birth Defects Happen?
Hyperglycemia in embryo increases
oxygen radical production -> inhibits
prostacyclin -> increased
thromboxanes/ prostaglandins ->
abnormal vascularization of developing
tissue
Mouse model demonstrates decreased
defects if prostaglandin inhibitors or
antioxidants given (vitamins C and E)
Preventing Birth Defects
Planned pregnancy/ recognize
potential for pregnancy
Preconception consultation
Achieve glycemic control (more
to follow)
Multivitamins or prenatal
vitamins
Folic acid supplementation
“I don’t have diabetes.”
Increasing concerns in group of
women with
Prediabetes, Impaired Glucose
Tolerance
Polycystic Ovarian Syndrome
(PCOS)
Obesity
We need your help! Screen
and treat!
PCOS and Pregnancy Outcome
Thatcher SS 2006:
Retrospective analysis in suburban REI
practice, n=237 pregnancies
Pts used metformin +/- clomid,
gonadotropins, or ART
Increased GDM and prematurity
Did not observe change in rate of
malformation
Part II: Early Identification of
Gestational Diabetes
Gestational Diabetes
Maternal Risks
Excessive weight
gain
Preeclampsia
Cesarean section
Future gestational
diabetes
Subsequent type 2
diabetes and heart
disease
Risks to Offspring
Macrosomia
Birth trauma
Hypoglycemia
Delayed lung maturation
Hypocalcemia
Polycythemia
Stillbirth
Childhood disease
Neonatal Morbidity - Delayed
Lung Maturation
Moore TM et al AJOG 2003
Neonatal Morbidity - Shoulder Dystocia
Nesbitt TS et al AJOG 1998
Neonatal Morbidity - Birth
Trauma
Brachial plexus injury
Facial nerve injury
Fractures of humerus or clavicle
Cephalohematoma
Brain injury
Death
Neonatal Morbidity - Birth
Trauma
Athukorala et al: positive relationship
between maternal fasting
hyperglycemia and incidence of
shoulder dystocia
Risk doubled with each 1 mmol increase in
fasting glucose value on OGTT
Screening for GDM
First step: Early identification of risk factors
Second step: One hour 50 g glucose screen
Third step: Three hour 100 g OGTT for
diagnosis
Risk Factors for GDM: Assess
at First Prenatal Visit
 Overweight before
pregnancy (BMI >
25)
 1st degree relative
with diabetes
 Previous glucose
intolerance/ GDM
 Previous macrosomia
or large for
gestational age baby
PCOS
Age > 25 yrs
Members of certain
ethnic groups
Multiparous women
(13%)
 Left column are HIGH
RISK factors
Universal Screening v.
Selective Screening for GDM
Cosson et al compared universal to selective
screening
Universal group had more favorable fetal outcomes
Williams et al studied following ADA guidelines
(not screening low risk)
10 to 11% would not have been screened
Missed 4% who would have been diagnosed with
GDM
Screening for GDM
 High risk patient requires screening earlier in pregnancy,
before 24-28 weeks, ideally at first prenatal visit
 First trimester glucose intolerance triggers suspicious preexisting overt diabetes (type 1 or type 2) or insulin resistance
*First OB appt*
Risk Factors Assessed
High risk-do 50 g screen
Low risk-screen at 24-28 wks
ADA Position Statement
50–G oral glucose tolerance screen
for GDM
140mg cutoff -- 80% sensitivity
130mg cutoff -- 90% sensitivity
Alternatively, patients with high
risk factors can go directly to
diagnostic testing instead of initial
screening
Screening for GDM
50-g oral glucose challenge
Serum glucose cut-off Proportion
Sensitivity
point
with positive for GDM
test
> 140 mg/dl
14-18% 80%
> 130 mg/dl
Recommendations as
proposed by Metzger et
al
20-25 % 90%
Diagnosis of GDM
Using 3-hour 100 g OGTT
 KEEP IN MIND PATIENT MAY BE:
undiagnosed type 2
mild abnormal glucose tolerance prior to
pregnancy that worsens with gestation
normal glucose tolerance before pregnancy
that becomes abnormal with advancing
gestation
undiagnosed type 1 (symptoms but no
diagnosis)
ADA and WHO Criteria for the Diagnosis of
Gestational Diabetes Mellitus
ADA 100-g
ADA 75-g
WHO 75-g
Fasting (mg/dl)
95
95
126
1-hour (mg/dl)
180
180
----
2-hour (mg/dl)
155
155
140
3-hour (mg/dl)
140
----
----
Two or more values must
be met or exceeded for
dx of GDM with 100 g
OGTT
Part III: Hyperglycemia, Not
Diabetes, in Pregnancy
Whattoexpect.com
HAPO Study – Purpose
NEJM May 8, 2008
Hyperglycemia and Adverse Pregnancy
Outcomes
To clarify risks of adverse outcomes
associated with degrees of maternal
glucose intolerance not meeting criteria
for gestational diabetes mellitus
Background – Pedersen
Hypothesis
1952: Maternal hyperglycemia causes
fetal hyperglycemia, which leads to
exaggerated fetal response to insulin
HAPO Study Cooperative
Research Group
Cohort study
Fifteen centers in nine countries
25,505 pregnant women underwent 75 g oral
GTT at 24-32 weeks gestation
Patients and providers blinded to results
unless unsafe:
Fasting >105 mg/ dL
2 hour glucose > 200 mg/ dL
Any glucose < 45 mg/ dL or > 160 mg/ dL
HAPO Study – Exclusions
< 18 y/o
Delivering outside of study facility
Unknown dating/ poor dating
Multiple gestation
Conception by IVF or gonadotropin use
Prior dx of GDM or DM
Prior glucose testing this pregnancy
Infection with HIV, Hep B, Hep C
HAPO Study – Primary
Outcomes
Birth weight > 90th percentile for
gestational age
Primary cesarean delivery
Clinical neonatal hypoglycemia
Cord-blood serum C-peptide level above
90th percentile
HAPO Study – Secondary
Outcomes
Delivery < 37 weeks gestation
Shoulder dystocia or birth injury
Need for admission to NICU
Hyperbilirubinemia
Preeclampsia
HAPO – Statistics
Continuous variables – mean and standard
deviation
Categorial data – number and percentage
Glucose measurements evaluated as both
continuous and categorical for primary
outcomes
For secondary outcomes, only continuous
HAPO – Data Analysis,
Categorical
Glycemic values categorized into seven levels
for fasting, 1- and 2-hour values
Ex] fasting subsets included:
100-104 (105 unblinded) – 99th percentile
95-99 – 97th percentile
90-94
85-89
80-84
75-79
<75
HAPO – Data Analysis,
Continuous
Odds ratios calculated for a 1 standard
deviation increase
Fasting
1-hour
2-hour
Logistic regression models
Adjusted for confounders
BMI
Age
Smoking
Hypertension
Family history of DM, etc.
Mean values were recorded as fasting 81, 1 hr 134, 2 hr 111
Summary of HAPO Findings
Associations between increasing fasting, 1hour, and 2-hour glucose values and
Birthweight > 90th percentile
Cord blood serum C-peptide
Primary cesarean (weaker)
Neonatal hypoglycemia (weaker)
Premature delivery
Shoulder dystocia/ birth injury
NICU admission
Hyperbilirubinemia
Preeclampsia
All in patients who are below criteria for GDM
Future Study
Instead of screening for glucose intolerance,
screening for hypoglycemia? (Everyone at risk goes
on the diet)
Screening and treating for macrosomia? For
“diabetogenic pregnancies”?
Establishment of new thresholds for diagnosing
gestational diabetes or gestational glucose
intolerance? (Ex] One abnormal value on 3 hr GTT?
One SD above the mean?)
Stronger evidence that treatment improves (clinically
relevant) outcomes?
Will More Treatment Mean Better
Outcomes?
ACHOIS Trial: Evaluated neonatal outcomes
in women with gestational diabetes
NNT to avoid one adverse outcome: 43
HAPO demonstrated fewer IUGR/ SGA babies
Problems if aggressively treat mild hyperglycemia?
Associations not tested, may not be causally
mediated
What to do Today: Don’t Forget
Postpartum Testing
All women with diagnosis of gestational
diabetes should be offered screening in
the nonpregnant state
Fasting glucose
2-hour 75 g OGTT
Cohort study demonstrated 58% risk of
overt DM within 8 years (previously
quoted 15 yrs)
Weight loss and lifestyle changes can reduce
risk by 50%
Summary
The optimal time to positively influence
pregnancy outcome is before the patient gets
pregnant
Role of primary care physicians and educators is
critical (this means you!)
Gestational diabetes can be identified in the
first trimester in a cohort of high risk patients
Small differences in blood glucose translate to
significant differences in pregnancy outcomes