WHEN HYPERGLYCEMIA STRIKES PREGNANCY: CRITERIA FOR DIAGNOSIS Iris Thiele Isip Tan MD, MSc, FPCP, FPSEM Clinical Associate Professor, UP College of Medicine Section of Endocrinology, Diabetes & Metabolism Department of Medicine, Philippine General Hospital Tuesday, November 8, 11
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When Hyperglycemia Strikes Pregnancy: Criteria for Diagnosis
Presentation at the 2011 annual convention of Diabetes Philippines, Inc.
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WHEN HYPERGLYCEMIA STRIKES PREGNANCY:CRITERIA FOR DIAGNOSIS
Iris Thiele Isip Tan MD, MSc, FPCP, FPSEMClinical Associate Professor, UP College of Medicine
Section of Endocrinology, Diabetes & MetabolismDepartment of Medicine, Philippine General Hospital
Tuesday, November 8, 11
Hyperglycemia Adverse Pregnancy Outcomes (HAPO)
International Association of Diabetes
in Pregnancy Study Groups (IADPSG)
UNITE for Diabetes CPG on screening & diagnosis of GDM
“... the relationship between maternal glucose levels and fetal growth and outcome appear to be a basic biologic phenomenon, and not a clearly demarcated disease state ...”
Tuesday, November 8, 11
International Association of Diabetes in Pregnancy Study Groups IADPSG
Tuesday, November 8, 11
http://www.sxc.hu/photo/358002
IADPSGencourage and facilitate research and advance education
facilitate an international approach to enhancing the quality of care for women with diabetes in pregnancy
Gestational diabetes would be diagnosed if one or morevalues met or exceeded the following levels of glucose:fasting 5.1 mmol/l, 1 h post glucose 10.0 mmol/l and 2 hpost glucose 8.5 mmol/l. Use of these criteria will result in17.8% of the pregnant population being diagnosed withgestational diabetes. A detailed analysis of the same HAPOstudy information and other recent related publicationsraises issues that are worthy of further debate in the widerdiabetes community.
Observational data
HAPO was an international prospective observational studyof 23,316 pregnant women directed to answer the question:‘Is hyperglycaemia during pregnancy, at a level below thatfor overt diabetes, associated with increased risk ofmaternal or fetal complications?’ [2]. The participatingwomen had an OGTT and were divided into seven glucosecategories. The category 3 group encompassed the meanglucose values, i.e. fasting 4.5 mmol/l, 1 h post OGTT7.4 mmol/l and 2 h post OGTT 6.2 mmol/l, while the newproposed cut-offs from IADPSG fall in category 5. Theprimary endpoints were large-for-gestational age infants(LGA), primary Caesarean section rate, neonatal hypogly-caemia and cord C-peptide. The study demonstrated acontinuous relationship between glycaemia (fasting, and 1or 2 h post glucose load) and each of the primary outcomes,having adjusted for field centre and ethnicity. Whilesupporting the Pedersen hypothesis [3], the results did notshow any inflection point indicating clearly increased riskof any of these outcomes with a particular glucose category;rather, risk increased gradually over the glucose range.
A further publication from the group examined the roleof maternal BMI with the same primary outcomes [4]. Thisreport used an adjustment (Model 1) for many of theexpected confounders (age, alcohol, smoking, sex etc.), andalso a model (Model 2) that adjusted for fasting plasma
glucose and mean arterial pressure. The OR for LGA,primary Caesarean section and cord C-peptide increasedsignificantly for increasing categories of BMI, this differ-ence being maintained when adjusted for glucose and meanarterial pressure (reference group BMI <22.6 kg/m2;Fig. 1a). When the plot for LGA vs glucose is added(reference group category 1 glucose as used in the HAPOreport; Fig. 1a), it is apparent that maternal BMI has agreater impact on OR than maternal glucose in all exceptthe highest glucose category. This is also true for theprimary Caesarean section rate (Electronic supplementarymaterial [ESM] Fig. 1a), whereas the glucose level hadmore influence on the OR for cord C-peptide in glucosecategories 5–7 (ESM Fig. 1b). Thus, maternal BMI andglucose both contribute to risk of LGA, but the role of BMIwas more pronounced than that of glucose in determiningLGA incidence, until the highest glucose category wasreached. Using the category BMI 22.6–28.4 kg/m2 (whichincludes overweight women) and category 3 for glucose asthe reference groups (i.e. using reference groups thatinclude the means) shows that BMI and glucose have asimilar impact on the OR (ESM Fig. 2a–c).
The majority of women from the HAPO data hadglucose levels !category 3, i.e. the category encompassingthe mean glucose level (Fig. 1b). Moreover, the number ofLGA increased proportionately with higher glucose levels(Fig. 1b), but when the numbers of mothers with LGA ingiven glucose categories are classed separately (Fig. 1c),the majority (63%) of women with LGA are seen to haveglucose levels from the OGTT at or lower than category 3,the category incorporating the mean glucose level. This isalso true for the 1 and 2 h post-load challenge (ESMFig. 3). It is also noteworthy that at category 5 (equivalentto the IADPSG cut-off criteria, accepting that some cases incategory 5 will lie above these cut-offs within category 5)women below these cut-offs who had LGA represented78% of all women giving birth to LGA.
BMI category (Kg/m2)
Glucose category
Wom
en (
n)
Wom
en (
n)
8,000 700
600
500
400
300
200
100
0
6,000
4,000
2,000
0
<22.6 22.6!28.4
28.5!32.9
33.0!37.4
37.5! 42.041.9
1 2 3 4 5 6 7
Glucose category1 2 3 4 5 6 7
a b c
OR
0
1
2
3
4
5
1 3 52 4 6 7Glucose category
Fig. 1 a Relationship of the OR for an infant of birthweight >90thpercentile vs the BMI in categories (reference group BMI <22.6 kg/m2
[4]) or maternal fasting glucose in categories from HAPO (diamonds;reference group category 1 lowest glucose [2]). a The BMIrelationship is adjusted for model 1 (circles) or model 2 (triangles)
(see text for details). The relationship for maternal fasting glucosecategories is also shown (black diamonds). b Number of participantsin each category of glucose in HAPO (white bars), with number ofmothers with LGA infants (black bars). c Number of participants ineach category of glucose who had LGA infants
Diabetologia (2011) 54:480–486 481
Ryan EA. Diabetologia 2011; 54:480-6
Greater impact of maternal BMI on OR for LGA than maternal glucose except highest glucose category
HAPO
● BMI Model 1▲ BMI Model 2
◆ Maternal FG
Model 1: Adjusted for age, alcohol, smoking, sex, etc.Model 2: Adjusted for mean FG and MAP
Tuesday, November 8, 11
Gestational diabetes would be diagnosed if one or morevalues met or exceeded the following levels of glucose:fasting 5.1 mmol/l, 1 h post glucose 10.0 mmol/l and 2 hpost glucose 8.5 mmol/l. Use of these criteria will result in17.8% of the pregnant population being diagnosed withgestational diabetes. A detailed analysis of the same HAPOstudy information and other recent related publicationsraises issues that are worthy of further debate in the widerdiabetes community.
Observational data
HAPO was an international prospective observational studyof 23,316 pregnant women directed to answer the question:‘Is hyperglycaemia during pregnancy, at a level below thatfor overt diabetes, associated with increased risk ofmaternal or fetal complications?’ [2]. The participatingwomen had an OGTT and were divided into seven glucosecategories. The category 3 group encompassed the meanglucose values, i.e. fasting 4.5 mmol/l, 1 h post OGTT7.4 mmol/l and 2 h post OGTT 6.2 mmol/l, while the newproposed cut-offs from IADPSG fall in category 5. Theprimary endpoints were large-for-gestational age infants(LGA), primary Caesarean section rate, neonatal hypogly-caemia and cord C-peptide. The study demonstrated acontinuous relationship between glycaemia (fasting, and 1or 2 h post glucose load) and each of the primary outcomes,having adjusted for field centre and ethnicity. Whilesupporting the Pedersen hypothesis [3], the results did notshow any inflection point indicating clearly increased riskof any of these outcomes with a particular glucose category;rather, risk increased gradually over the glucose range.
A further publication from the group examined the roleof maternal BMI with the same primary outcomes [4]. Thisreport used an adjustment (Model 1) for many of theexpected confounders (age, alcohol, smoking, sex etc.), andalso a model (Model 2) that adjusted for fasting plasma
glucose and mean arterial pressure. The OR for LGA,primary Caesarean section and cord C-peptide increasedsignificantly for increasing categories of BMI, this differ-ence being maintained when adjusted for glucose and meanarterial pressure (reference group BMI <22.6 kg/m2;Fig. 1a). When the plot for LGA vs glucose is added(reference group category 1 glucose as used in the HAPOreport; Fig. 1a), it is apparent that maternal BMI has agreater impact on OR than maternal glucose in all exceptthe highest glucose category. This is also true for theprimary Caesarean section rate (Electronic supplementarymaterial [ESM] Fig. 1a), whereas the glucose level hadmore influence on the OR for cord C-peptide in glucosecategories 5–7 (ESM Fig. 1b). Thus, maternal BMI andglucose both contribute to risk of LGA, but the role of BMIwas more pronounced than that of glucose in determiningLGA incidence, until the highest glucose category wasreached. Using the category BMI 22.6–28.4 kg/m2 (whichincludes overweight women) and category 3 for glucose asthe reference groups (i.e. using reference groups thatinclude the means) shows that BMI and glucose have asimilar impact on the OR (ESM Fig. 2a–c).
The majority of women from the HAPO data hadglucose levels !category 3, i.e. the category encompassingthe mean glucose level (Fig. 1b). Moreover, the number ofLGA increased proportionately with higher glucose levels(Fig. 1b), but when the numbers of mothers with LGA ingiven glucose categories are classed separately (Fig. 1c),the majority (63%) of women with LGA are seen to haveglucose levels from the OGTT at or lower than category 3,the category incorporating the mean glucose level. This isalso true for the 1 and 2 h post-load challenge (ESMFig. 3). It is also noteworthy that at category 5 (equivalentto the IADPSG cut-off criteria, accepting that some cases incategory 5 will lie above these cut-offs within category 5)women below these cut-offs who had LGA represented78% of all women giving birth to LGA.
BMI category (Kg/m2)
Glucose category
Wom
en (
n)
Wom
en (
n)
8,000 700
600
500
400
300
200
100
0
6,000
4,000
2,000
0
<22.6 22.6!28.4
28.5!32.9
33.0!37.4
37.5! 42.041.9
1 2 3 4 5 6 7
Glucose category1 2 3 4 5 6 7
a b c
OR
0
1
2
3
4
5
1 3 52 4 6 7Glucose category
Fig. 1 a Relationship of the OR for an infant of birthweight >90thpercentile vs the BMI in categories (reference group BMI <22.6 kg/m2
[4]) or maternal fasting glucose in categories from HAPO (diamonds;reference group category 1 lowest glucose [2]). a The BMIrelationship is adjusted for model 1 (circles) or model 2 (triangles)
(see text for details). The relationship for maternal fasting glucosecategories is also shown (black diamonds). b Number of participantsin each category of glucose in HAPO (white bars), with number ofmothers with LGA infants (black bars). c Number of participants ineach category of glucose who had LGA infants
Diabetologia (2011) 54:480–486 481
Ryan EA. Diabetologia 2011; 54:480-6
HAPO☐ Participants■ Participants with LGA infants
Majority of women had glucose levels < Cat. 3 (mean glucose level)
Most cases of LGA occur in normal maternal glycemia
Tuesday, November 8, 11
Proposed IADPSG diagnostic criteria are based on LGA, cord-C peptide and fetal adiposity.
Treatment reduces perinatal morbidityACHOIS
Crowther et al. NEJM 2005; 352:2477-86.
Landon et al NEJM 2009; 361:1339-48.
Tuesday, November 8, 11
ACHOISCrowther et al. NEJM 2005; 352:2477-86.
Crowther CA et al. Effect of Treatment of Gestational Diabetes Mellitus on Pregnancy Outcomes. NEJM 2005; 352:2477-86.
PI
MO
GDM24-28 wks AOG
Intervention (n=490)
diet CBG insulin vs
routine care (n=510)
Serious perinatal
complications death
shoulder dystociabone fracturenerve palsy
Randomized controlled
trial
Tuesday, November 8, 11
ACHOISCrowther et al. NEJM 2005; 352:2477-86.
Crowther CA et al. Effect of Treatment of Gestational Diabetes Mellitus on Pregnancy Outcomes. NEJM 2005; 352:2477-86.
PI
MO
GDM24-28 wks AOG
Intervention (n=490)
diet CBG insulin vs
routine care (n=510)
Serious perinatal
complications death
shoulder dystociabone fracturenerve palsy
Randomized controlled
trial
Any serious perinatal complication Adj RR 0.33 (95% CI 0.14-0.75), p=0.01
Tuesday, November 8, 11
Landon et al NEJM 2009; 361:1339-48.
PI
MO
Intervention (n=485)
diet CBG insulin vs
routine care (n=473)
Composite of stillbirth/perinatal
death and neonatal
complications
Randomized controlled
trial
“mild” GDM24-31 wks AOG
Landon MB et al. A multicenter, randomized trial of treatment for mild gestational diabetes. NEJM 2009; 361:1339-48.
hyperbilirubinemia hypoglycemia
hyperinsulinemia birth trauma
Tuesday, November 8, 11
Landon et al NEJM 2009; 361:1339-48.
PI
MO
Intervention (n=485)
diet CBG insulin vs
routine care (n=473)
Composite of stillbirth/perinatal
death and neonatal
complications
Randomized controlled
trial
“mild” GDM24-31 wks AOG
Landon MB et al. A multicenter, randomized trial of treatment for mild gestational diabetes. NEJM 2009; 361:1339-48.
hyperbilirubinemia hypoglycemia
hyperinsulinemia birth trauma
Composite endpoint RR 0.87 (95% CI 0.72-1.07), p=0.14
Tuesday, November 8, 11
Landon et al NEJM 2009; 361:1339-48.
PI
MO
Intervention (n=485)
diet CBG insulin vs
routine care (n=473)
Randomized controlled
trial
“mild” GDM24-31 wks AOG
Landon MB et al. A multicenter, randomized trial of treatment for mild gestational diabetes. NEJM 2009; 361:1339-48.
Composite endpoint RR 0.87 (95% CI 0.72-1.07), p=0.14
Tuesday, November 8, 11
Landon et al NEJM 2009; 361:1339-48.
PI
MO
Intervention (n=485)
diet CBG insulin vs
routine care (n=473)
Randomized controlled
trial
“mild” GDM24-31 wks AOG
Landon MB et al. A multicenter, randomized trial of treatment for mild gestational diabetes. NEJM 2009; 361:1339-48.
Composite endpoint RR 0.87 (95% CI 0.72-1.07), p=0.14
1.All pregnant women should be screened for GDM by patient history, clinical risk factors or a 50-g, 1-hour loading test to determine blood glucose levels.
ACOG Committee on Obstetric Practice. Screening & Diagnosis of Gestational Diabetes Mellitus. Obstetrics & Gynecology 2011; 118(3):751-3
3.Diagnosis of GDM based on the 1-step screening and diagnosis test outlined in the IADPSG guidelines is not recommended at this time because there is no evidence that diagnosis using these criteria leads to clinically significant improvement in maternal or newborn outcomes, and it would lead to a significant increase in healthcare costs.
ACOG Committee on Obstetric Practice. Screening & Diagnosis of Gestational Diabetes Mellitus. Obstetrics & Gynecology 2011; 118(3):751-3
Family history of diabetes (OR 7.1 [95%CI 5.6, 8.9]1; OR 2.74 [95%CI 1.47, 5.11]3)
First-degree relative with type 2 diabetes (PPV 6.7%)4
First-degree relative with type 1 diabetes (PPV 15%)4Prior macrosomic baby (OR 5.59 [95%CI 2.68, 11.7])3
Age >25 years old (OR 1.9 [95%CI 1.3, 2.7]1; OR 3.37 [95%CI 1.45, 7.85]3)
! !1 Davey RX, Hamblin PS. Selective versus universal screening for gestational diabetes mellitus:
an evaluation of predictive risk factors. Medical Journal of Australia 2001;174(3):118–21.
2 Schytte T, Jorgensen LG, Brandslund I, et al. The clinical impact of screening for gestational diabetes. Clinical Chemistry and Laboratory Medicine 2004;42(9):1036–42.
3 Ostlund I, Hanson U. Occurrence of gestational diabetes mellitus and the value of different screening indicators for the oral glucose tolerance test. Acta Obstetricia et Gynecologica Scandinavica 2003;82(2):103–8.
4 Griffin ME, Coffey M, Johnson H, et al. Universal vs. risk factor-based screening for gestational diabetes mellitus: detection rates, gestation at diagnosis and outcome. Diabetic Medicine 2000;17(1):26–32.
Tuesday, November 8, 11
Risk Factors for Gestational Diabetes
Diagnosis of polycystic ovary syndrome (OR 2.89 [95%CI 1.68, 4.98])5
Overweight or obese before pregnancy
(BMI >27 kg/m2 OR 2.3 [95%CI 1.6, 3.3]1; BMI>30 kg/m2 OR 2.65 [95%CI 1.36, 5.14]3
Macrosomia in current pregnancy (PPV 40% 4)Polyhydramnios in current pregancy (PPV 40% 4)Intake of drugs affecting carbohydrate metabolism
3 Ostlund I, Hanson U. Occurrence of gestational diabetes mellitus and the value of different screening indicators for the oral glucose tolerance test. Acta Obstetricia et Gynecologica Scandinavica 2003;82(2):103–8.
1 Davey RX, Hamblin PS. Selective versus universal screening for gestational diabetes mellitus: an evaluation of predictive risk factors. Medical Journal of Australia 2001;174(3):118–21.
4 Griffin ME, Coffey M, Johnson H, et al. Universal vs. risk factor-based screening for gestational diabetes mellitus: detection rates, gestation at diagnosis and outcome. Diabetic Medicine 2000;17(1):26–32.
5 Toulis KA, Goulis DG, Kolibiankis EM, Venetis CA, et al. Risk of gestational diabetes mellitus in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Fertil Steril 2009;92(2):667–77.
Tuesday, November 8, 11
For pregnant women, when should screening be done?
Recommendations:2. High-risk women should be tested at the soonest possible time (Level 3, Grade B).
6.2
Tuesday, November 8, 11
For pregnant women, when should screening be done?
Recommendations:3. Routine testing for gestational diabetes is recommended at 24-28 weeks age of gestation for women with no risk factors (Level 3, Grade B).
6.2
Tuesday, November 8, 11
For pregnant women, when should screening be done?
Recommendations:4. Testing for gestational diabetes should still be carried out in women at risk, even beyond 24 to 28 weeks age of gestation (Level 3, Grade C).
6.2
Tuesday, November 8, 11
Which tests should be used to screen pregnant women for gestational diabetes?
Recommendation:An oral glucose tolerance test (OGTT), preferably the 75-g OGTT, should be used to screen for gestational diabetes (Level 3, Grade B).
6.3
Tuesday, November 8, 11
What criteria will be used to interpret the 75-g OGTT?
Recommendation:
The criteria put forth by the International Association of Diabetes & Pregnancy Study Groups (IADPSG) will be used to interpret the 75-g OGTT (Level 3, Grade B).
6.4
International Association of Diabetes and Pregnancy Study Groups Consensus Panel. IADPSG Recommendations on the Diagnosis and Classification of Hyperglycemia in Pregnancy. Diabetes Care 2010; 33(3):676-82.
Tuesday, November 8, 11
Hyperglycemia Adverse Pregnancy Outcomes (HAPO)
International Association of Diabetes
in Pregnancy Study Groups (IADPSG)
UNITE for Diabetes CPG on screening & diagnosis of GDM
Tuesday, November 8, 11
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