The HAPO study. ⢠25,505 pregnant women in 9 countries underwent 75-g. OGTT at 24-32 weeks gestation. ⢠Primary outcomes were BW > 90th %tile, primary ...
Gestational Diabetes Mellitus
Eugène SOBNGWI MD, Mphil, PhD Professor of Endocrinology and Diabetes – University of Yaoundé 1 Head, Laboratory of Molecular Medicine and Metabolism, The Biotechnology Centre, University of Yaoundé 1 Consultant Endocrinologist, National Obesity Centre
Gestational Diabetes in 7 Questions 1. What is gestational diabetes? 2. Why focusing on pregnancy? 3. What are the consequences of hyperglycaemia in pregnancy? 4. How to diagnose GDM?
5. How to screen? 6. Impact on prevalence 7. Conclusion
1 WHAT IS GESTATIONAL DIABETES?
Gestational Diabetes
“Any degree of glucose intolerance with onset or first recognition during pregnancy”
2 WHY FOCUSING ON PREGNANCY?
Epidemiological reasons ▪ Despite the young age of pregnant women, diabetes is frequent in pregnancy ▪ Approximately 7% of all pregnancies (1-14%) ▪ Prevalence is higher in non Caucasians ▪ Trends in prevalence of GDM do not parallel trends in type 2 diabetes prevalence
Glucose Metabolism in Pregnancy • First Half of Pregnancy – Pancreatic beta-cell hyperplasia causes hyperinsulinemia – Increased uptake and storage of glucose
• Second Half of Pregnancy – Placental hormones cause insulin resistance (HPL) • Increased lipolysis • Increased gluconeogenesis • Decreased glycogenesis
– Increased glucose and amino acids for the fetus
• Normal pregnancy is a “diabetogenic” state
Insulin sensitivity-secretion relationships in normal women and women with GDM.
Buchanan T A JCEM 2001;86:989-993
3 WHAT ARE THE CONSEQUENCES OF MATERNAL HYPERGLYCAEMIA DURING PREGNANCY?
What are the consequences of maternal hyperglycaemia during pregnancy...
...If hyperglycaemia develops before pregnancy
Consequences of pre-gestational diabetes • • • • • • •
Foetal malformation : 4 to 10%, x 3 if HbA1c>7%. Early spontaneous abortion : 30% if HbA1c > 8%. Stillbirth: 3.5% Premature delivery: 25% Increased risk of Caesarian delivery Macrosomia Neonatal complications: hypoglycaemia, hypocalcaemia, polycythaemia, jaundice, respiratory distress • Pre-eclampsia • Infections (UTI)
Consequences of pregnancy on diabetes • Worsening of preexisting retinopathy • Worsening of preexisiting nephropathy
What are the consequences of maternal hyperglycaemia during pregnancy...
...If hyperglycaemia develops later in pregnancy
The offspring • Pedersen hypothesis (1952)
The offspring 2 • Increased risk of stillbirth • Macrosomia with shoulder dystocia/Birth trauma • Neonatal hypoglycaemia • Hyperbilirubinaemia • Polycythaemia • Hypocalcaemia • Respiratory distress syndrome • No increase in congenital anomalies Cousan 1995, Yang 2002
The offspring 3
Exposure Status
• Long term increase risk of obesity and Type 2 diabetes Exposure
3,7
No Exposure (Reference)
1,0 0
Dabelea D et al. Diabetes 2000
1
2 Odds
3
4
Exposure to maternal diabetes during gestation affects insulin secretion in offspring
Insulin secretion rate (pmol.l-1)
16
y = 0.8497x - 2.0582
14 12
y = -0.0065x 2 + 0.6974x - 1.2287
10 8 y = -0.0123x 2 + 0.7632x - 2.1253
6 4
Controls (all NGT) NGT subjects
2
IGT subjects
0 0
5
10
15
20
25
Early insulin secretion [(I30-I0)/G30-G0]
18
25
p = 0.035
20
p = 0.037
15 10 5 0 NGT Controls
Plasma glucose (mmol.l-1)
Sobngwi et al. Lancet 2003
NGT Subjects
IGT Subjects
The mother • Rates of GDM recurrence ranges between 30 and 84% (Kim C et al. Diabetes Care 2007) • Women with a history of GDM have a high risk of – – – –
Type 2 diabetes mellitus (x 7) Metabolic syndrome (x 2 - 5) Cardiovascular diseases (x 1.7) T2DM may occur from post-partum (5 to 14%) to several years later, up to 25 years
(Verier-Mine, Diabetes Metab 2010)
Increased risk of Type 2 Diabetes in Mothers
Bellamy et al, Lancet 2009
Consequences for the Mothers • About 40% of mothers with gestational diabetes will develop diabetes within 20 years of their pregnancies • Rates may be as high as 70% within 28 years Cousan, Diabetes in America,1995; Kim, et al.Diabetes Care, 2002
4 HOW TO DIAGNOSE GESTATIONAL DIABETES?
The target of GDM definitions • Early Statistical Criteria – 3-hour 100 g OGTT – Abnormal = 2 or more values at, or above, two standard deviations above the mean
• Originally described to identify women at increased risk of type 2 diabetes • Later identified as a group at increased risk of pregnancy complications (Pedersen Hypothesis) O'Sullivan J B, Mahan C M. Diabetes 1964
The diagnostic tests
• 75-g OGTT with samples at 0 and 2 hours • 75-g OGTT with samples at 0, 1, and 2 h • 100-g OGTT with samples at 0, 1, 2 and 3h
Comparison of some criteria ADA
ACOG
WHO/NICE-UK
Load
100-g glucose
100-g glucose
75-g glucose
Samples
plasma glucose
plasma glucose
plasma glucose
Abnormal values
2 or more time points
2 or more time points
1 or more time points
Fasting
>5.3 mmol/l
>5.3 mmol/l;
>7.0 mmol/l;
1-hour
>10.0 mmol/l
>10.0 mmol/l;
-
2-hour
>8.6 mmol/l (only if 75-g glucose used)
>8.6 mmol/l;
> 7.8 mmol/l
3-hour
>7.8 mmol/l
>7.8 mmol/l Simmons D, Diabetes Care 2010
IADPSG Load
75-g glucose
Samples
plasma glucose
Abnormal values
1 or more time points
Fasting
>5.3 mmol/l
1-hour
>10.0 mmol/l
2-hour
>8.6 mmol/l International Association of Diabetes and Pregnancy Study Groups, 2009
Preexisting diabetes To diagnose overt diabetes (preexisting) in pregnancy
Measure of glycemia
Threshold
Fasting glucose
> 126 mg/dl
A1C
> 6.5%
Random glucose
> 200 mg/dl International Association of Diabetes and Pregnancy Study Groups, 2009
How where the criteria decided? The HAPO study • 25,505 pregnant women in 9 countries underwent 75-g OGTT at 24-32 weeks gestation • Primary outcomes were BW > 90th %tile, primary C/S, clinically diagnosed hypoglycemia, and cord-blood serum C-peptide > 90th %tile (fetal hyperinsulinemia) • Secondary outcomes were delivery before 37 wk, shoulder dystocia or birth injury, need for NICU, hyperbilirubinemia, and preeclampsia HAPO study group, New Engl J Med 2008
HAPO study: Methods 7 glucose categories in mg/dl were defined as follows 2-hr
178
1-hr
212
FBS
100
1
2
3
4
5
6
7
HAPO study group, New Engl J Med 2008
HAPO study: Results
HAPO study group, New Engl J Med 2008
HAPO study: Conclusions • The frequency of each primary outcome increased with increasing maternal glucose levels (less for clinical neonatal hypoglycaemia) • Secondary outcomes of preeclampsia, shoulder dystocia or birth injury, premature delivery, NICU admit, and hyperbilirubinaemia were also associated with maternal glycaemia
HAPO study group, New Engl J Med 2008
ACHOIS (Australian Carbohydrate Intolerance Study) • Randomized 1000 women with 2-hr 75 gram glucose values 140-200 to treatment – no treatment (‘normal < 155). • Treatment group: Fewer serious perinatal complications and lower birth weights but more NICU admissions. • Number needed to treat to prevent a ‘serious complication’ (death, shoulder dystocia, bone fracture, nerve palsy) was 34.
• No change in cesarean rate. NEJM 2005;352:2477-86
5 SCREENING FOR GESTATIONAL DIABETES
Why screening? • 2-3 hour OGTT not feasible in all pregnant women worldwide – Capacity – Cost and cost effectiveness – Time
• Does the risk in all women make heavy diagnostic procedure worth?
How to screen?
Depends on who you ask!! – – – – – – – – –
ADA ACOG WHO NICE 4th International Workshop-Conference on GDM National Diabetes Data Group United States Preventive Services Task Force 5th International Workshop-Conference on GDM …
Who is at risk of GDM? •Maternal age >25 •Family history of diabetes •Glycosuria •Prior macrosomia •Previous unexplained stillbirth •Ethnic group: non Caucasians •Obesity
Strategies • (1) step – 75-g OGTT in all pregnant women or in all high risk women
• 2 steps – Fasting blood glucose or Random blood glucose or 50-g Glucose challenge test followed by – OGTT if abnormal values
Current recommendations for screening for GDM • Do risk assessment at first visit, with no screening for low risk – – – – – –
Low-risk ethnicity (Caucasian, European) Age < 25 BMI < 25 No known diabetes in first degree relative No h/o glucose intolerance No h/o obstetric complications usually associated with GDM 4th International Workshop-Conference on Gestational Diabetes Mellitus, ADA, ACOG
Current recommendations for screening for GDM • High risk patients should be screened as early as possible and repeated at 24-28 weeks if screening negative – Strong family history of diabetes – Prior history of GDM – Morbid obesity – Other manifestations of glucose intolerance 4th International Workshop-Conference on Gestational Diabetes Mellitus, ADA, ACOG
Screening for GDM (24 - 28 weeks) • ACOG Recommendations (2001): – Risk based approach – States that “...since so few people have no risk factors, a universal screening program may be more practical...”
• United States (50-g glucose – venous glucose at 1 hour thereafter) – Threshold = 130 – 140 mg/dl
• UK (NICE) – In High risk women
• WHO – Universal
The Cameroon GDM study In 1000 pregnant women at 24-28 weeks of gestation • Capillary – Fasting blood glucose – Random blood glucose
• • • •
50-g glucose challenge test Risk factors Urine glucose 75-g OGTT with 0 and 2-hour glucose levels
Definitions of gestational diabetes WHO definition 2h post lad Glucose (G-2h) > 140 mg/dl
Frequency (%)
47 (4.8)
ADA definition Fasting glucose > 95 mg/dl G-2h > 155 mg/dl FG > 95 mg/dl AND G-2h > 155 mg/dl GDM (FG > 95 mg/dl OR G-2h > 155 mg/dl)
131 (13.4) 14 (1.4) 5 (0.5) 140 (14.3)
IADPSG definition Fasting glucose > 92 mg/dl G-2h > 153 mg/dl FG > 92 mg/dl AND G-2h > 153 mg/dl GDM (FG > 92 mg/dl OR G-2h > 153 mg/dl)
162 (16.6) 17 (1.7) 8 (0.8) 171 (17.5)
Performance of screening tests in Cameroon Sensitivity
Specificity
PPV (%)
AUC
53.2 (43.6 – 69.0)
65.7 (63.0 – 69.1)
7.3 (5.0 – 9.7)
0.59 (0.52 – 0.67)
> 110 mg/dl
38.3 (22.9 – 55.6)
80.9 (79.8 – 83.5)
9.2 (4.1 – 14.0)
0.60 (0.52 – 0.67)
Our cut point (107mg/dl)
48.9 (34.3 – 63.2)
75.5 (73.0 – 76.3)
9.2 (5.0 – 10.1)
0.61 (0.53 – 0.68)
53.2 (43.6 – 69.0)
65.7 (63.0 – 69.1)
7.3 (5.0 – 9.7)
0.59 (0.52 – 0.67)
> 92 mg/dl
38.3 (22.9 – 55.6)
80.9 (79.8 – 83.5)
9.2 (4.1 – 14.0)
0.60 (0.52 – 0.67)
Our cut point (86 mg/dl)
48.9 (34.3 – 63.2)
75.5 (73.0 – 76.3)
9.2 (5.0 – 10.1)
0.61 (0.53 – 0.68)
1h 50g Glucose post load > 130 mg/dl
59.8 (43.2–64.7)
77.6 (74.7 – 79.0)
12.0 (10.6 – 12.9)
0.69 (0.61 – 0.76)
> 140 mg/dl
44.7 (30.6 – 50.0)
87.7 (84.8 – 89.8)
15.7 (10.7 – 23.1)
0.66 (0.59 – 0.73)
Our cut point (122 mg/dl)
83.0 (74.0 – 87.8)
62.3 (59.5 – 64.6)
10.1 (7.9 – 11.3)
0.72 (0.67 – 0.78)
WHO definition GDM Random blood glucose > 100 mg/dl
Fasting blood glucose > 90 mg/dl
Sobngwi E et al, unpublished
The proposed screening strategy in Cameroon FBG 90 mg/dl
OGTT
Measure capillary glucose
RBG 110mg/dl
OGTT
Last meal >8h = FBG
Last meal
