Diabetes in Pregnancy: Antepartum Considerations and New Perspectives Amy Rouse, MD Maternal-Fetal...

Diabetes in Pregnancy: Antepartum Considerations

and New Perspectives

Diabetes in Pregnancy: Antepartum Considerations

and New Perspectives

Amy Rouse, MDMaternal-Fetal Medicine

Saddleback Memorial Medical Center31 January 2009

Amy Rouse, MDMaternal-Fetal Medicine

Saddleback Memorial Medical Center31 January 2009

ObjectivesObjectives

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

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: PreconceptionPart I: Preconception

Preconception IssuesPreconception 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

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 . . .Pregnancy

Happens . . .

2009, The National Campaign to Prevent Teen and Unplanned Pregnancy

… Even to Women with Diabetes

… Even to Women with Diabetes

St. James PJ et al:Prospective cohort study of 66 women with diabetes1/3 became pregnant within 5 years (n=23)

Only 26 percent of pregnancies were planned

Conclusion: Addressing pregnancy planning in women with diabetes must improve

St. James PJ et al:Prospective cohort study of 66 women with diabetes1/3 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

Courtesy of Gabbe Obstetrics: Normal and Problem Pregnancies

White’s Classification in Pregnancy

White’s Classification in Pregnancy

Diabetes and Early Pregnancy Loss

Diabetes and Early Pregnancy Loss

Poor glycemic control is associated with increased spontaneous abortion

Higher loss rates with long standing disease or with vasculopathyClass C, D, and F: SAB rates of 25%, 44%, and 22%, respectively

Jovanovic: Loss rate similar to general population with excellent glycemic control

Poor glycemic control is associated with increased spontaneous abortion

Higher loss rates with long standing disease or with vasculopathyClass 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)

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)



UK data BMJ 2006: 4.6% major congenital malformation rate in all pregestational diabetic pregnanciesNeural tube defects increased 4.2 fold

Congenital heart disease increased 3.4 fold

UK data BMJ 2006: 4.6% major congenital malformation rate in all pregestational diabetic pregnanciesNeural tube defects increased 4.2 fold

Congenital heart disease increased 3.4 fold

Only 65% of neonatal anomalies were identified antenatally



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!

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!



Lucas et al 1989, n=105:Overall malformation rate 13.3%

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?


MultifactorialClear direct association with hyperglycemia 3-6 weeks after conception

Teratogenic potential ofInositolProstaglandinsReactive oxygen species

MultifactorialClear direct association with hyperglycemia 3-6 weeks after conception

Teratogenic potential ofInositolProstaglandinsReactive oxygen species



Hyperglycemia in embryo increases oxygen radical production -> inhibits prostacyclin -> increased thromboxanes/ prostaglandins -> abnormal vascularization of developing tissueMouse model demonstrates decreased defects if prostaglandin inhibitors or antioxidants given (vitamins C and E)

Hyperglycemia in embryo increases oxygen radical production -> inhibits prostacyclin -> increased thromboxanes/ prostaglandins -> abnormal vascularization of developing tissueMouse model demonstrates decreased defects if prostaglandin inhibitors or antioxidants given (vitamins C and E)

Preventing Birth Defects

Preventing Birth Defects

Planned pregnancy/ recognize potential for pregnancy

Preconception consultationAchieve glycemic control (more to follow)

Multivitamins or prenatal vitamins

Folic acid supplementation

Planned pregnancy/ recognize potential for pregnancy

Preconception consultationAchieve glycemic control (more to follow)

Multivitamins or prenatal vitamins

Folic acid supplementation

“I don’t have diabetes.”

“I don’t have diabetes.”

Increasing concerns in group of women with Prediabetes, Impaired Glucose Tolerance

Polycystic Ovarian Syndrome (PCOS)

ObesityWe need your help! Screen and treat!

Increasing concerns in group of women with Prediabetes, Impaired Glucose Tolerance

Polycystic Ovarian Syndrome (PCOS)

ObesityWe need your help! Screen and treat!

PCOS and Pregnancy Outcome

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 prematurityDid not observe change in rate of malformation

Thatcher SS 2006:Retrospective analysis in suburban REI practice, n=237 pregnancies

Pts used metformin +/- clomid, gonadotropins, or ART

Increased GDM and prematurityDid not observe change in rate of malformation

Part II: Early Identification of

Gestational Diabetes

Part II: Early Identification of

Gestational Diabetes

Gestational DiabetesGestational Diabetes

Maternal RisksExcessive weight gain

PreeclampsiaCesarean sectionFuture gestational diabetes

Subsequent type 2 diabetes and heart disease

Maternal RisksExcessive weight gain

PreeclampsiaCesarean sectionFuture gestational diabetes

Subsequent type 2 diabetes and heart disease

Risks to OffspringMacrosomiaBirth traumaHypoglycemiaDelayed lung maturationHypocalcemiaPolycythemiaStillbirthChildhood disease

Neonatal Morbidity - Delayed Lung Maturation

Neonatal Morbidity - Delayed Lung Maturation

Moore TM et al AJOG 2003Moore TM et al AJOG 2003

Neonatal Morbidity - Shoulder Dystocia

Neonatal Morbidity - Shoulder Dystocia

Nesbitt TS et al AJOG 1998Nesbitt TS et al AJOG 1998

Neonatal Morbidity - Birth Trauma


Brachial plexus injuryFacial nerve injuryFractures of humerus or clavicleCephalohematomaBrain injuryDeath

Brachial plexus injuryFacial nerve injuryFractures of humerus or clavicleCephalohematomaBrain injuryDeath



Athukorala et al: positive relationship between maternal fasting hyperglycemia and incidence of shoulder dystociaRisk doubled with each 1 mmol increase in fasting glucose value on OGTT

Athukorala et al: positive relationship between maternal fasting hyperglycemia and incidence of shoulder dystociaRisk doubled with each 1 mmol increase in fasting glucose value on OGTT

Screening for GDMScreening 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

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

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

Overweight before pregnancy (BMI > 25)

1st degree relative with diabetes

Previous glucose intolerance/ GDM

Previous macrosomia or large for gestational age baby

PCOSAge > 25 yrsMembers of certain ethnic groups

Multiparous women (13%)

Left column are HIGH RISK factors

PCOSAge > 25 yrsMembers of certain ethnic groups

Multiparous women (13%)

Left column are HIGH RISK factors

Universal Screening v. Selective Screening

for GDM

Universal Screening v. Selective Screening

for GDMCosson et al compared universal to selective screeningUniversal group had more favorable fetal outcomes

Williams et al studied following ADA guidelines (not screening low risk)10 to 11% would not have been screenedMissed 4% who would have been diagnosed with GDM

Cosson et al compared universal to selective screeningUniversal group had more favorable fetal outcomes

Williams et al studied following ADA guidelines (not screening low risk)10 to 11% would not have been screenedMissed 4% who would have been diagnosed with GDM

Screening for GDMScreening 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 pre-existing overt diabetes (type 1 or type 2) or insulin resistance

High risk patient requires screening earlier in pregnancy, before 24-28 weeks, ideally at first prenatal visit

First trimester glucose intolerance triggers suspicious pre-existing 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 Statement50–G oral glucose tolerance

screen for GDM

ADA Position Statement50–G oral glucose tolerance

screen for GDM

140mg cutoff -- 80% sensitivity


Alternatively, patients with high risk factors

can go directly to diagnostic testing instead of initial

screening



Alternatively, patients with high risk factors

can go directly to diagnostic testing instead of initial

screening

Screening for GDM50-g oral glucose

challenge

Screening for GDM50-g oral glucose

challenge

Serum glucose cut-off point

Proportion with positive test

Sensitivity for GDM

> 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

Diagnosis of GDM Using 3-hour 100 g

OGTT KEEP IN MIND PATIENT MAY BE:

undiagnosed type 2mild 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)

KEEP IN MIND PATIENT MAY BE:undiagnosed type 2mild 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 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

Part III: Hyperglycemia, Not

Diabetes, in Pregnancy

Whattoexpect.com

HAPO Study – PurposeHAPO Study – Purpose

NEJM May 8, 2008Hyperglycemia and Adverse Pregnancy Outcomes

To clarify risks of adverse outcomes associated with degrees of maternal glucose intolerance not meeting criteria for gestational diabetes mellitus

NEJM May 8, 2008Hyperglycemia 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

Background – Pedersen Hypothesis

1952: Maternal hyperglycemia causes fetal hyperglycemia, which leads to exaggerated fetal response to insulin

1952: Maternal hyperglycemia causes fetal hyperglycemia, which leads to exaggerated fetal response to insulin

HAPO Study Cooperative Research Group

HAPO Study Cooperative Research Group

Cohort studyFifteen centers in nine countries25,505 pregnant women underwent 75 g oral GTT at 24-32 weeks gestation

Patients and providers blinded to results unless unsafe:Fasting >105 mg/ dL2 hour glucose > 200 mg/ dLAny glucose < 45 mg/ dL or > 160 mg/ dL

Cohort studyFifteen centers in nine countries25,505 pregnant women underwent 75 g oral GTT at 24-32 weeks gestation

Patients and providers blinded to results unless unsafe:Fasting >105 mg/ dL2 hour glucose > 200 mg/ dLAny glucose < 45 mg/ dL or > 160 mg/ dL

HAPO Study – Exclusions

HAPO Study – Exclusions

< 18 y/oDelivering outside of study facilityUnknown dating/ poor datingMultiple gestationConception by IVF or gonadotropin use

Prior dx of GDM or DMPrior glucose testing this pregnancyInfection with HIV, Hep B, Hep C

< 18 y/oDelivering outside of study facilityUnknown dating/ poor datingMultiple gestationConception by IVF or gonadotropin use

Prior dx of GDM or DMPrior glucose testing this pregnancyInfection with HIV, Hep B, Hep C

HAPO Study – Primary Outcomes

HAPO Study – Primary Outcomes

Birth weight > 90th percentile for gestational age

Primary cesarean deliveryClinical neonatal hypoglycemia

Cord-blood serum C-peptide level above 90th percentile

Birth weight > 90th percentile for gestational age

Primary cesarean deliveryClinical neonatal hypoglycemia

Cord-blood serum C-peptide level above 90th percentile

HAPO Study – Secondary Outcomes

HAPO Study – Secondary Outcomes

Delivery < 37 weeks gestationShoulder dystocia or birth injury

Need for admission to NICUHyperbilirubinemiaPreeclampsia

Delivery < 37 weeks gestationShoulder dystocia or birth injury

Need for admission to NICUHyperbilirubinemiaPreeclampsia

HAPO – StatisticsHAPO – 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

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

HAPO – Data Analysis, Categorical

Glycemic values categorized into seven levels for fasting, 1- and 2-hour valuesEx] fasting subsets included:

100-104 (105 unblinded) – 99th percentile95-99 – 97th percentile90-9485-8980-8475-79<75

Glycemic values categorized into seven levels for fasting, 1- and 2-hour valuesEx] fasting subsets included:

100-104 (105 unblinded) – 99th percentile95-99 – 97th percentile90-9485-8980-8475-79<75

HAPO – Data Analysis, Continuous

HAPO – Data Analysis, Continuous

Odds ratios calculated for a 1 standard deviation increaseFasting1-hour2-hour

Logistic regression modelsAdjusted for confounders

BMIAgeSmokingHypertensionFamily history of DM, etc.

Odds ratios calculated for a 1 standard deviation increaseFasting1-hour2-hour

Logistic regression modelsAdjusted for confounders

BMIAgeSmokingHypertensionFamily history of DM, etc.

Mean values were recorded as fasting 81, 1 hr 134, 2 hr 111

Summary of HAPO Findings

Summary of HAPO Findings

Associations between increasing fasting, 1-hour, and 2-hour glucose values andBirthweight > 90th percentileCord blood serum C-peptidePrimary cesarean (weaker)Neonatal hypoglycemia (weaker)Premature deliveryShoulder dystocia/ birth injuryNICU admissionHyperbilirubinemiaPreeclampsia

All in patients who are below criteria for GDM

Associations between increasing fasting, 1-hour, and 2-hour glucose values andBirthweight > 90th percentileCord blood serum C-peptidePrimary cesarean (weaker)Neonatal hypoglycemia (weaker)Premature deliveryShoulder dystocia/ birth injuryNICU admissionHyperbilirubinemiaPreeclampsia

All in patients who are below criteria for GDM

Future StudyFuture StudyInstead 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?

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?

Will More Treatment Mean Better Outcomes?

ACHOIS Trial: Evaluated neonatal outcomes in women with gestational diabetesNNT to avoid one adverse outcome: 43

HAPO demonstrated fewer IUGR/ SGA babiesProblems if aggressively treat mild hyperglycemia?

Associations not tested, may not be causally mediated

ACHOIS Trial: Evaluated neonatal outcomes in women with gestational diabetesNNT to avoid one adverse outcome: 43

HAPO demonstrated fewer IUGR/ SGA babiesProblems if aggressively treat mild hyperglycemia?

Associations not tested, may not be causally mediated

What to do Today: Don’t Forget Postpartum TestingWhat to do Today: Don’t Forget Postpartum TestingAll women with diagnosis of gestational diabetes should be offered screening in the nonpregnant stateFasting glucose2-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%

All women with diagnosis of gestational diabetes should be offered screening in the nonpregnant stateFasting glucose2-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%

SummarySummaryThe optimal time to positively influence pregnancy outcome is before the patient gets pregnantRole 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

The optimal time to positively influence pregnancy outcome is before the patient gets pregnantRole 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

Diabetes in Pregnancy: Antepartum Considerations and New Perspectives Amy Rouse, MD Maternal-Fetal...

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