Gestational Diabetes

Dr Hala Mosli PGY-4 February 25 th , 2009

Objectives

• Definition of gestational diabetes • Pathophysiology of GDM • Diagnosis • Rationale behind treatment • Treatment of GDM • Complications of GDM • Prognosis

Definition

 Hyperglycemia of varying severity with first diagnosis during pregnancy.

 Usually resolves within 6 weeks of delivery.

• Regardless of whether insulin is used for treatment or the condition persists after pregnancy. • Does not exclude the possibility of pre pregnancy unrecognized glucose intolerance.

Prevalence In Canada

• Non-Aboriginal, multiethnic population: 3.7% • Aboriginal populations: 8-18%

CDA 2008 CPG

Pathophysiology

• Pregnancy is an insulin-resistant state.

• Thought to relate to hPL, progesterone, cortisol, prolactin and FFA. • TNF-α is involved as well.

• Defects at the post-insulin receptor level in hepatic and muscle cells.

• Regulation of glucagon is also impaired.

Greenspan’s Basic and Clinical Endocrinology

• Increase in insulin secretion starting from the first trimester and continuing into the third trimester, when it reaches its maximum.

• Increase in first-phase insulin secretion in response to IV glucose in pregnancy, found to be significantly reduced in patients with GDM.

• Second phase response similarly increased in both normal pregnancies and in GDM

Etiology and pathogenesis of gestational diabetes Claus Kuhl. Diabetes Care . Aug 1998 . Vol. 21

• The insulin response per unit of glycemic stimulus (i.e., the insulinogenic index) is significantly higher in pregnant women with NGT than in women with GDM, being increased by approximately 90% and 40% in late NGT and GDM pregnancies, respectively

Etiology and pathogenesis of gestational diabetes Claus Kuhl. Diabetes Care . Aug 1998 . Vol. 21

BUCHANAN, 2001, J. Clin.Endocrinol. Metab

• Post-receptor mechanisms also contribute to the insulin resistance and are multi-factorial.

• These are exerted in the skeletal muscle at the β-subunit of the insulin receptor and at the level of insulin receptor substrate-1

Summary and Recommendations, Fifth International Workshop-Conference on Gestational Diabetes Mellitus

,

Diabetes Care, Vol 30 suppl. July 2007

THEORIES 1. The physiological insulin resistance of late pregnancy. 2. Chronic insulin resistance anteceding pregnancy and exacerbated by the physiological changes causing insulin resistance during pregnancy.

3. A subtype of women may have autoimmune β-cell dysfunction.

Summary and Recommendations, Fifth International Workshop-Conference on Gestational Diabetes Mellitus

,

Diabetes Care, Vol 30 suppl. July 2007

Screening and Diagnosis

• Screening for GDM still a large area of controversy.

• Who to screen and what numbers to use are the main areas of debate.

• Multiple risk factors vs universal screening are the two main approaches.

• Screening is through a 50-g glucose load with a 1hr pc blood sugar (GDS)

Risk Factors: • Previous diagnosis of GDM or • Delivery of a macrosomic infant, • High-risk population (Aboriginal, Hispanic, South Asian, Asian, African), • Age >35 years, • BMI >30 kg/m2, • PCOS, • Acanthosis nigricans • Corticosteroid use.

• 75g OGTT is the diagnostic tool.

• If screening is inconclusive, proceed to 75-g OGTT.

• Aim of the study was to clarify the risks of adverse outcomes associated with various degrees of maternal glucose intolerance less severe than that in overt diabetes.

• Reasoning was that the current criteria were established over 40 years ago with minor modifications over the years.

• Some data suggest that current criteria are too restrictive and lesser degrees of hyperglycemia also increase risk of adverse outcomes.

• No uniform international standards are available for the screening and diagnosis of gestational diabetes:

WHO:

Diagnosis

• Standard OGTT is done at 24-28 weeks after an overnight fast (fasting plasma glucose and a plasma glucose 2 hours after 75g glucose drink is done). • A 2 hour level >=7.8 mmol/L (or 140 mg/dL) is diagnostic of gestational diabetes. • If fasting and postprandial blood sugars are elevated in the first trimester, this may indicate pre-existing diabetes mellitus (which is considered a different condition, with different implications).

HAPO

• A total of 25,505 pregnant at 15 centres in nine countries underwent 75-g oral glucose testing at 24 to 32 weeks gestation.

• 2189 women were later excluded.

• Data was unblinded if the FPG was less than 2.5 mmol/L or exceeded 5.8 mmol/L, or the 2-hr post-load level exceeded 11.1 mmol/L

HAPO

• Patient characteristics:

Criteria for exclusion

1. Age -18 years.

2. Planning to deliver at another hospital or location.

3. Date of last menstrual period not certain and no ultrasound estimation from 6 –24 weeks of gestational age available.

4. Unable to complete OGTT within 32 weeks of gestation.

5. Known multiple pregnancy.

6. Became pregnant with assistance of advanced reproductive technology such as in-vitro fertilization or superovulation with gonadotropins.

7. Any unblinded blood glucose testing and/or diagnosis of GDM during this pregnancy prior to enrolment.

8. Previous diagnosis of diabetes requiring treatment with medication outside of pregnancy.

9. Currently receiving treatment with oral glucocorticoids, thiazide diuretics, b blockers, ACE inhibitors, oral b mimetics, dilantin, or antiretroviral agents.

10. Participation in another study which may interfere with HAPO.

11. Known to be HIV positive or to have Hepatitis B (or be B surface antigen positive) or C.

12. Participation in HAPO during a previous pregnancy.

13. Inability to converse in language(s) used in field center forms without the aid of an interpreter.

• Primary outcomes: • Birth weight above the 90 th percentile for GA • Primary c-section • Clinical neonatal hypoglycemia • Fetal hyperinsulinemia (cord-blood serum C peptide above the 90 th percentile)

• Secondary outcomes: • Premature delivery (before 37 wks gestation) • Shoulder dystocia or birth injury • Need for intensive neonatal care • Hyperbilirubinemia • Preeclampsia.

• For the 23,316 participants with blinded data, the adjusted odds ratios for adverse pregnancy outcomes associated with an increase in FPG of 1-SD (0.4 mmol/L), an increase in the 1-hr PG of 1-SD (1.7 mmol/L) and an increase in the 2-hr PG of 1-SD (1.3 mmol/L) were calculated.

• For categorical analysis, each level of glycemia was divided into seven categories where the 1- and 2-hr PG measures reflected data for approx. the same number of women in each category as did the FPG measure.

Fasting Category 1 < 4.2

Category 2 4.2-4.4

Category 3 4.5-4.7

Category 4 4.8-4.9

Category 5 5-5.2

Category 6 5.3-5.5

Category 7 >=5.6

1-hr 2-hr =<5.8

5.9-7.3

7.4-8.6

8.7-9.5

9.6-10.7

10.8-11.7

>=11.8

=<5.0

5.1-6.0

6.1-6.9

7.0-7.7

7.8-8.7

8.8-9.8

>=9.9

HAPO

Conclusion: •Maternal hyperglycemia less severe than currently used to define diabetes is related to clinically important perinatal outcomes.

•Maternal glucose measured at a single point is predictive of birth outcomes.

•Maternal glucose influences the primary outcomes in a continuous manner across all levels of glucose.

HAPO

• These outcomes can be reduced by treating the hyperglycemia.

• The threshold for the need for treatment is not established.

Why Do We Treat?

• Maternal hyperglycemia is associated with adverse outcomes in both mother and fetus.

• Uncontrolled diabetes has profound effects on embryogenesis, organogenesis, and fetal and neonatal growth. • Some of these effects are lifelong and may contribute to adult obesity. Barnes-Powell, Neonatal Netw. 2007 Sep Oct;26(5):283-90

ACHOIS

• RCT to determine if treating maternal hyperglycemia reduces the risk of perinatal outcomes.

• Effect of treatment on maternal outcome, mood and quality of life were also assessed.

• Eligible women underwent a 75-g oral glucose test at 24 to 34 weeks gestation.

• Classified as having glucose

intolerance

of pregnancy according to the old WHO definition.

“If they were assigned to the intervention group, they received a slip indicating a diagnosis of glucose intolerance of pregnancy and the plan for intervention, whereas if they were assigned to routine care, they received a slip indicating that they did not have gestational diabetes. This approach was continued throughout the trial, because there remained uncertainty as to the level of glucose impairment associated with adverse perinatal outcomes”

ACHOIS

• Primary outcomes among the infants were a composite measure of: • Serious perinatal complications (defined as one or more of the following: death, shoulder dystocia, bone fracture, and nerve palsy).

• Admission to the neonatal nursery.

• Jaundice requiring phototherapy.

ACHOIS

•Primary clinical outcomes among the women: • Induction of labor • Cesarean section. •Maternal health status was assessed by means of the Medical Outcomes Study 36 Item Short-Form General Health Survey (SF 36)

ACHOIS

• Secondary outcomes among the infants included: • Components of the composite primary outcome, • Gestational age at birth, • birth weight, • Other measures of health.

ACHOIS

• Secondary outcomes among the women included: • The number of prenatal visits to a health professional, • Mode of birth, • Weight gain during pregnancy, • Number of antenatal admissions, • Pregnancy-induced hypertension (defined as a blood pressure of at least 140/90 mm Hg on two occasions four or more hours apart), • Other complications.

Interventions

• Ongoing care by OB team.

• Individualized dietary advice from a qualified dietitian.

• SMBG, QID • BG targets: FBG 3.5-5.4 mmol/L AC meal <5.5 mmol/L 2-hr PC =<7 mmol/L

• Insulin added if: » FBG >=5.5 mmol/L, or » 2-hr PC >=7 mmol/L at 35 wks GA, or » 2-hr PC >=8 mmol/L after 35 wks GA, or » Any one CBG >=9 mmol/L

Results

• Treatment of gestational diabetes reduces the rate of serious perinatal complications, without increasing the rate of cesarean delivery.

• It was also shown to improve the woman’s health-related QOL.

Treatment

•

Non-pharmacological:

• Counselling. • Education.

• Dietician.

• SMBG.

• Trial of diet controlX2 weeks.

• Monitor fetal growth parameters clinically and by early third trimester ultrasound.

Treatment

• Target glucose values: • Fasting/preprandial PG: 3.8 to 5.2 mmol/L • 1h postprandial PG: 5.5 to 7.7 mmol/L • 2h postprandial PG: 5.0 to 6.6 mmol/L • Must avoid ketosis

Treatment

•

Pharmacological:

• Glyburide: • Metformin: • Insulin.

Treatment

• The use of insulin to achieve glycemic targets has been shown to reduce fetal and maternal morbidities.

• A variety of protocols can be used, with multiple injections being the most effective.

• Continuous adjustment needed.

CDA 2008 CPG

Treatment

• What kind of insulin?

• Regular and NPH best studied.

• Rapid-acting insulin analogues widely used.

• No significant difference in HbA1c (

CMAJ

2009;180(4):385-97).

• No evidence for long-acting insulin analogues.

Post-Partum

• Fasting plasma glucose is done once the mother has had a full meal. • Breastfeeding is encouraged.

• Healthy eating habits and exercise are also encouraged.

Post-partum

• FPG alone will miss many women with some degree of abnormal glucose tolerance. • A 75-g OGTT should be done between 6 weeks and 6 months postpartum.

CDA 2008 CPG

Prognosis

• Women with previous GDM are at high risk for developing type 2 DM and should screened.

• These women should be also be screened for type 2 diabetes when planning another pregnancy.

• Normoglycemia should be achieved prior to conception.

• Folic acid 0.4-1 mg supplementation is recommended.

CDA 2008 CPG

Prognosis

• A longitudinal study of 91 GDM women showed a relatively reduced insulin secretion to oral glucose in pregnancy, postpartum as well as 5-11 years later. • It was also shown that even non-obese glucose tolerant women with previous GDM are characterized by the metabolic profile of NIDDM i.e. insulin resistance and impaired insulin secretion. • The combination of this finding together with the significantly increased risk for development of diabetes indicates that all women with previous GDM should have a regular assessment of their glucose tolerance in the years after pregnancy.

Damm P

., Dan Med Bull. 1998 Nov;45(5):495-509

• Evidence that offspring exposed to GDM are at increased risk of obesity and IGT, especially if large for gestational age and born to obese mothers.

• In a Canadian cohort of children exposed to GDM, 7% had IGT at age 7 to 11 years.

CDA 2008 CPG

• In the Pima Indian population, as many as 70% of offspring exposed to diabetes in utero had type 2 diabetes at age 25 to 35 years.

Franks et al, Diabetes 55:460-465, 2006

• Breastfeeding may lower the risk. • The importance of tight glycemic control during pregnancy to prevent these outcomes is not clearly established.

• HAPO: Associations with Neonatal Anthropometrics

.

• Validates the basic principles of the Pedersen hypothesis.

• Main outcomes were: – Sum of skin folds >90 th percentile – Individual skin folds >90 th percentile – Percent body fat >90 th – Birth weight >90 th percentile percentile

• Results: – Glycemia less severe than diabetes is associated with fetal overgrowth, specifically adiposity

Thank you.