nguyen thy khue

Diabetes and pregnancyDiabetes and pregnancy

Nguyen Thy Khue, MD, PhD

Diabetes in pregnancyDiabetes in pregnancy

2-20% of all pregnancies

Pregestational diabetes (approximately

20%)

Gestational diabetes (GDM - approximately

80%)

What is gestational diabetesWhat is gestational diabetes

”Any degree of glucose intolerance

with onset or first recognition during

pregnancy” (1980-2010)

GDM vs ”overt diabetes” detected in

pregnancy (2010)

Metzger et al. Summary and recommendations of the Fourth International Workshop-Conference Diabetes Care 1998

International Association for Diabetes in Pregnancy Study Groups. Recommendations on the diagnosis and classification of hyperglycaemia during pregnancy Diabetes Care 2010

Pathophysiology of GDMPathophysiology of GDM

Increased Insulin resistance

Increased insulin secretion

Adequate in the first trimester

Inadequate as gestation progress

HYPERGLYCEMIA

Inadequate insulin secretion

Buchanan et al. GDM: risks and management during and after pregnancy Nat Rev Endocrinol 2012 Nov;8(11):639-49

Comparison with type 2 diabetesComparison with type 2 diabetes

Increased Insulin resistance

Stumvoll et al. Type 2 diabetes:principles of pathogenesis and therapy Lancet 2005 365(9467):1333-46

Inadequate Insulin secretion

Risk factor of GDMRisk factor of GDM

Obesity or excessive gestational weight gain

Ethnicity associated with higher type 2

diabetes risk

Current glucocorticoid use

Hypertension

Family history of diabetes

Glycosuria

Risk factor of GDMRisk factor of GDM

Previous poor obstetric outcome

Previous GDM

Polycystic Ovarian Syndrome

Age 25 or over

Previous macrosomic baby

Maternal macrosomia or low birth weight

Pedersen Hypothesis

PlacentaPlacenta

Maternal hyperglycemiaMaternal hyperglycemia

Fetal hyperglycemiaFetal hyperglycemiaFetal hyperglycemia

and hyperinsulinemiaFetal hyperglycemia

and hyperinsulinemiaFetal hyperinsulinemiaFetal hyperinsulinemia

1. Congenital anomalies (peri-conceptional)

1. Congenital anomalies (peri-conceptional)

2. Decreased early growth (0-20 weeks gestation)

2. Decreased early growth (0-20 weeks gestation)

3. Hyperinsulinemia(>20 weeks gestation)3. Hyperinsulinemia

(>20 weeks gestation)3. Immature liver

metabolism (neonatal)3. Immature liver

metabolism (neonatal)

2. Surfactant deficiency (neonatal)

2. Surfactant deficiency (neonatal)

1. Neonatal hypoglycemia (0-7 days postnatal)

1. Neonatal hypoglycemia (0-7 days postnatal)

a. Jaundicea. Jaundice

1. Fetal macrosomia(>20 weeks gestation)1. Fetal macrosomia

(>20 weeks gestation)

a. Birth asphyxiab. Cardiomyopathyc. TTN

a. Birth asphyxiab. Cardiomyopathyc. TTN

2. Fetal hypoxia(>30 weeks gestation)

2. Fetal hypoxia(>30 weeks gestation)

a. Polycythemiaa. Polycythemia

c. Iron abnormalitiesc. Iron abnormalities

b. Stroke, RVT

b. Stroke, RVT Poor neurodevelopmental

outcomePoor neurodevelopmental

outcome

Perinatal consequences of GDMPerinatal consequences of GDM

Outcome Odds ratio

Macrosomia 2.66

Large for gestational age 3.28

Caesarean section 1.88

Shoulder dystocia 4.07

Hypoglycemia 10.38

Hyperbilirubinemia 3.87

Erythrocytosis 10.88

Respiratory complications 4.40

Stillbirth 1.91

Langer et al. Gestational diabetes: the consequences of not treating Am J Obst Gynecol 2005 23(3):196-8

Type 2 diabetes Relative risk 7.7 (up to 60% at 16 years)

Metabolic syndrome 3-fold increase (38.4 vs. 13.4%)at 9.8 years

Cardiovascular disease Hazard ratio 1.66 at 12.3 years

Maternal consequences of GDMMaternal consequences of GDM

Impact of GDM on Pregnancy Outcomes

The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study

Rationale:

•Overt diabetes increases the risk of adverse pregnancy outcomes.

•What level of glucose intolerance during pregnancy, short of diabetes, is associated with the risk of adverse outcomes?

Metzger BE, et al. HAPO Study Cooperative Research Group. N Eng J Med 2008;358:1991-2002.

HAPO Protocol

75 g OGTT 24-32 weeks

Fasting, 1 & 2 hr venous plasma

N = 25,505

Unblinded at field centre ifOGTT fasting >105 &/or 2 hr >200 or random glucose ≥160 ~36 wks

Or <45 mg/dL

1,443 (5.7%) incomplete

23,316Standard care for field centre

Cord glucose & C-peptideNeonatal glucose: 1-2 hr of age

Anthropometrics by 72 hr:Length, head circ, weight, skin folds x3

746 (2.9%) unblindedfor treatment

Metzger BE, et al. HAPO Study Cooperative Research Group. N Eng J Med 2008;358:1991-2002.

• N=23,316 women

• 75g OGTT 24-32 weeks gestation– Fasting glucose ≤ 5.8 mmol/L

– 2-hour glucose ≤ 11.1 mmol/L

• Composite of 4 perinatal outcomes

Hyperglycemia and Adverse Pregnancy Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) studyOutcomes (HAPO) study

HAPO Study Group. Hyperglycemia and Adverse Pregnancy Outcomes NEJM 2008 358:1991–2002

OutcomeOdds Ratio

Fasting glucose

Odds Ratio 1-hour

glucose

Odds Ratio 2-

hourglucose

Birth weight > 90th centile

1.38* 1.46* 1.38*

Cord C-peptide >90th centile

1.55* 1.46* 1.37*

Primary Caesarean Section

1.11* 1.10* 1.08*

Clinical neonatal hypoglycaemia

1.08 1.13* 1.10


*statistically significant


GDM* Overt

diabetes

Fasting plasma glucose –

mg/dl (mmol/l)

≥92

(5.1)

≥126

(7.0)

1-hour glucose- mg/dl

(mmol/L)

≥180

(10.0)

2-hour glucose- mg/dl

(mmol/L)

≥153

(8.5)

≥200

(11.1)

IADPSG Consensus Conference 2010IADPSG Consensus Conference 2010

International Association for Diabetes in Pregnancy Study Groups. Recommendations on the diagnosis and classification of hyperglycaemia during pregnancy Diabetes Care 2010 33(3):676-82

*only one abnormal value required

GDM prevalence IADPSG criteriaGDM prevalence IADPSG criteria

Data from Sacks et al Frequency of Gestational Diabetes Mellitus at Collaborating Centers Based on IADPSG Consensus Panel–Recommended Criteria Diabetes Care 2012 35:526–528

Outcomes of GDM Pregnancies in Urban Vietnam

• Most available data on the pregnancy outcomes of GDM are from high-income countries.

• 2,772 Vietnamese women in Ho Chi Minh City were monitored through routine prenatal care.– 75 g OGTT between 24-32 weeks.– GDM diagnosis using either 2010 ADA criteria

(2 positive results from OGTT), or IADPSG criteria (1 positive result from OGTT)

No GDMBorderline GDM(IADPSG +ve; 2010 ADA -ve)

GDM (2010 ADA +ve)

Prevalence 79.6% 14.5% 5.9%

BMI 20.45 kg/m2 21.10 kg/m2 21.81 kg/m2

Hirst JE, et al. PLoS Med 2012;9(7):e1001272.

Neonatal Outcomes of GDM Pregnancies in Urban Vietnam


GDM(2010 ADA +ve)

Gestation at birth (weeks) 1.48% 1.67% 1.70%

Preterm delivery (<37 weeks) 6.55% 9.59%* 14.02%*

>90th percentile for gestational age

11.76% 16.06% 18.90%

<10th percentile for gestational age

8.04% 6.99% 6.10%

Clinical neonatal hypoglycemia

0.70% 2.33%* 14.02%*

Jaundice requiring phototherapy

3.02% 4.15% 4.27%

Intensive neonatal care 4.0% 4.40% 5.49%

Perinatal death 0.4% 0.8% 0% Hirst JE, et al. PLoS Med 2012;9(7):e1001272.


GDM(2010 ADA +ve)

Preeclampsia 1.63% 2.59% 0.61%

Primary caesarean section 33.46% 31.35% 40.85%

Induction of labour 2.84% 3.88% 7.64%*

Severe perineal trauma 2.81% 3.06% 2.78%

Postpartum hemorrhage(>500 mL)

4.32% 4.15% 3.66%

Maternal Outcomes of GDM Pregnancies in Urban Vietnam

Hirst JE, et al. PLoS Med 2012;9(7):e1001272.

International Recommendations on

Screening for GDM

GDM: Clinical Risk Assessment

Risk category Clinical characteristics

High risk ObesityFamily historyPersonal history IGTPrior macrosomic infantCurrent glycosuria

Average risk Neither low or high risk

Low risk <25 yrsLow-risk ethnicityNo family historyNormal pre-pregnancy weight and pregnancy weight gainNo personal history of abnormal glucose levelsNo prior poor obstetrical outcomes

ADA. Therapy for Diabetes Mellitus and Related Disorders. 5 th Edition. 2009.

When to screen for GDM?

For women at high risk:

• Screen for undiagnosed T2DM at firstprenatal visit.

• Diabetes detected during this visit constitutes a diagnosis of overt, not gestational, diabetes.

ADA. Standards of Medical Care in Diabetes. Diabetes Care 2014;37(suppl 1):S14-S80.

When to screen for GDM?

For women at average risk:

• Screen for GDM at 24-28 weeks gestation.

• Due to increasing global rates of diabetes,ADA recommends:

– 2-hr 75 g OGTT.

– Consider a single abnormal value as diagnostic.


Screening and Diagnosis of GDM

Criteria Diagnosis

ADA (2014) GDM defined when any of the following values are exceeded:Fasting ≥92 mg/dL (5.1 mmol/L)1-h ≥180 mg/dL (10.0 mmol/L)2-h ≥153 mg/dL (8.5 mmol/L)

IADPSG GDM defined as at least one value meeting the threshold:Fasting plasma glucose ≥5.1 mmol/L1-h plasma glucose ≥10.0 mmol/L2-h plasma glucose ≥8.5 mmol/L

WHO GDM defined as diabetes or impaired glucose tolerance. Diabetes defined as at least one value meeting the threshold: •Fasting plasma glucose ≥7.0 mmol/L•2-h plasma glucose ≥11.1 mmol/LImpaired glucose tolerance defined as:•Fasting plasma glucose <7.0 mmol/L•2-h plasma glucose ≥7.9 mmol/L

ADIPS GDM defined as at least one value meeting the threshold:Fasting plasma glucose ≥5.5 mmol/L2-h plasma glucose ≥8.0 mmol/L

Screening for GDM (ADA 2014)

• Perform a 75 g OGTT, with plasma glucose measurement fasting, and at 1 and 2 hrs, at 24-28 weeks gestation in women not previously diagnosed with overt diabetes.

• Perform OGTT in the morning after an overnight fast of at least 8 hrs.


GDM Diagnosis

• Plasma glucose values:– Fasting ≥92 mg/dL

– 1 hr ≥180 mg/dL

– 2 hr ≥153 mg/dL

• Women found to meet criteria at first prenatal visit should receive a diagnosis ofovert diabetes.


Selection of a Screening Strategy in Low-/Middle-Income Countries

• In resource-poor settings, screening must be optimized to reduce cost.1

• A 2013 study of Vietnamese patients found that:• Using a risk-threshold of 3%, the ADA 2010 criteria

had a sensitivity of 93% for GDM patients.

• Selective screening of patients results in 27% fewer glucose tolerance tests than systematic screening.2

• The study authors concluded that the ADA 2010 strategy may be a reasonable approach in conditions of limited resources.2

1.Gupta Y, Gupta A. Diabetes Care 2013;36(10):e185.2.Tran TS, et al. Diabetes Care 2013;36(3):618-24.

15-04-23 29

Outcome Routine care(n=510)

Intervention(n=490)

p value

Hypoglycaemia 15.4% 16.3% 0.75

Perinatal death 0.0% 0.0% N/A

Elevated cord C-peptide 22.8% 17.7% 0.07

Birth trauma 1.3% 0.6% 0.33

Neonatal jaundice 12.9% 9.6% 0.12

Birth weight>4kg 14.3% 5.9% <0.001*

Large for gestational age 14.5% 7.1% <0.001*

Treatment of mild GDM Landon et alTreatment of mild GDM Landon et al

*p<0.05

Landon et al. A multicentre, randomized trial of treatment for GDM NEJM 2009 361(14):1339-48

Outcome Routine care(n=510)

Intervention(n=490)

p value

Caesarean section 33.8% 26.9% 0.02*

Shoulder dystocia 4.0% 1.5% 0.02*

Preeclampsia 5.5% 2.5% 0.02*

Treatment of mild GDM Landon et alTreatment of mild GDM Landon et al

*p<0.05*p<0.05

Landon et al. A multicentre, randomized trial of treatment for GDM NEJM 2009 361(14):1339-48Landon et al. A multicentre, randomized trial of treatment for GDM NEJM 2009 361(14):1339-48

Glycemic Targets During Pregnancy: AACE & ADA Guidelines1,2

Glucose Increment

Patients with GDM Patients with

Preexisting T1DM or T2DM

Preprandial, premeal

≤95 mg/dL (5.3 mmol/L) Premeal, bedtime, and overnight glucose:60-99 mg/dL (3.4-5.5 mmol/L)

Postprandial, post-meal

1-hour post-meal: ≤140 mg/dL (7.8 mmol/L) or 2-hour post-meal: ≤120 mg/dL (6.7 mmol/L)

Peak postprandial glucose 100-129 mg/dL(5.5-7.1 mmol/L)

A1C A1C ≤6.0%

1. AACE. Endocr Pract. 2011;17(2):1-53. 2. ADA. Diabetes Care. 2013;36(suppl 1):S11-66.

Glycemic Targets During Pregnancy: Expert Recommendations

Glucose Increment

Patients With Gestational Diabetes Mellitus (GDM)1

Patients With Preexisting T1DM or

T2DM1,2

Preprandial, premeal

≤90 mg/dL (5.0 mmol/L)1,2

Postprandial, post-meal

1-hour post-meal: ≤120 mg/dL (6.7 mmol/L)1,2

A1C A1C <5.0%3 A1C <6.0%4

1. LeRoith D, et. al. Endocrinol Metab Clin N Am. 2011;40(1): xii-919. 2. Castorino K et al. Curr Diab Rep, 2012;12:53-59.

3. L. Jovanovic; personal communication.4. AACE. Endocr Pract. 2011;17(2):1-53.

Some experts recommend more stringent goals (in particular, for patients on insulin therapy) to prevent maternal and fetal complications1,2

Glucose Monitoring in GDM:Self-Monitoring of Blood Glucose

• Self-monitoring of blood glucose (SMBG) is the cornerstone of diabetes management in gestational diabetes mellitus (GDM)1

• ADA guidelines for pregnant patients requiring insulin:– SMBG ≥3 times daily– More frequent SMBG may be required, including:2

• Morning fasting • Premeal (breakfast, lunch, and dinner)• 1-hour postprandial (breakfast, lunch, and dinner)• Before bed3

1. Jovanovic L, et al. Diabetes Care. 2011;34(1):53-54. 2. ADA. Diabetes Care. 2013;36(suppl 1):S11-S66. 3. Castorino K, Jovanovic L. Clin Chem. 2011;57(2):221-30. .

Glucose Monitoring in GDM: HbA1C

• Provides valuable supplementary information for glycemic control

• To safely achieve target glucose levels, combine A1C with frequent self-monitoring of blood glucose (SMBG)1,2

• Recent research suggests weekly HbA1C during

pregnancy:1

– SMBG alone can miss certain high glucose values

– SMBG + HbA1C = more complete data for glucose control

– Clinicians can further optimize treatment decisions with weekly HbA1C

1. Jovanovic L, et al. Diabetes Care. 2011;34(1):53-54.2. Castorino K, Jovanovic L. Clin Chem. 2011;57(2):221-30.

Traditionally carbohydrate restriction to

approximately 40% of total intake

Limited evidence

Appropriate weight gain

Maximum 9kg if obese

Exercise plus diet lower glucose /HbA1c

High level of exercise in studies

Evidence for perinatal outcome measurements lacking

Diet/Exercise

Carbohydrate Source Exchange

1 Exchange : 175 calorie, 4 g protein, 40 g CHO

Management of GDMManagement of GDM

• Medical nutrition therapy (MNT) and lifestyle

changes can effectively manage 80% to 90%

of mild GDM cases1,2

• As pregnancy progresses, glucose intolerance

typically worsens; patients may ultimately

require insulin therapy1,3

1. Chitayat, L, et al. Diabetes Technology & Therapeutics. 2009;11:S105-111. 2. ADA. Diabetes Care. 2013;36(suppl 1):S11-66.3. ADA. Diabetes Care. 2004;27(suppl 1):S88-90. 4.

Most experience with human insulin Regular insulin, NPH

Insulin aspart and lispro appear safe and

effective

Insulin detemir appears safe and effective

Insulin glargine is likely to be safe, but less

evidence to date

Insulin

Glucose Levels for Insulin Initiation in GDM1

Fasting plasma glucose ≤105 mg/dL (5.8 mmol/L)

1-hour postprandial plasma glucose ≤155 mg/dL (8.6 mmol/L)

2-hour postprandial plasma glucose ≤130 mg/dL (7.2 mmol/L)

Gestational Diabetes Mellitus (GDM): Initiation of Insulin

1. ADA. Diabetes Care. 2004;27(suppl 1):S88-90.

Choice of Insulin

Insulin Options Shown to Be Safe During Pregnancy1

Name Type OnsetPeak Effect

DurationRecommended Dosing Interval

AspartRapid-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

Intermediate-acting

60 min 2-4 hrs 6 hrs60-90 minutes before meal

NPH Intermediate-acting (basal)

2 hrs 4-6 hrs 8 hrs Every 8 hours

Detemir Long-acting

(basal) 2 hrs n/a 12 hrs Every 12 hours

1. Castorino K, Jovanovic L. Clin Chem. 2011;57(2):221-30.2. Kitzmiller JL, et al. Diabetes Care. 2008;31(5):1060-79.

Insulin Use During Pregnancy

1. Jovanovic L, et al. Mt Sinai J Med. 2009;76(3):269-80. 2. AACE. Endocr Pract. 2011;17(2):1-53.3. Castorino K, Jovanovic L. Clin Chem. 2011;57(2):221-30. 4. ADA. Diabetes Care. 2004;27(suppl 1):S88-90.

Women with GDM History

80-90% of women with mild GDM can be managed by lifestyle changes alone


Summary

• It is important to screen pregnant patients at

risk of GDM to achieve an early diagnosis.

• Diagnostic criteria (based on HAPO findings)

aim to decrease the risk of hyperglycemia in

both mothers and infants.

Summary (cont.)

• Women at high risk should be screened for TD2M at their first prenatal visit.

• Women at average risk should be screened for GDM at 24-28 weeks gestation.• 2 hr 75 g OGTT should be used with a single abnormal

value qualifying as diagnostic.

• 80-90% of mild GDM cases could be managed by lifestyle changes and medical nutrition therapy

nguyen thy khue

Documents

pregnancy diabetes care

diabetes relative risk

gdm vs overt diabetes

gestational age

fetal hypoxia2

birth asphyxiab

higher type

low birth weight