Diabetes in Pregnancy: Antepartum Considerations and New Perspectives Amy Rouse, MD Maternal-Fetal Medicine Saddleback Memorial Medical Center 31 January 2009 Amy Rouse, MD Maternal-Fetal Medicine Saddleback Memorial Medical Center 31 January 2009

Objectives 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: Preconception

Preconception 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 , The National Campaign to Prevent Teen and Unplanned Pregnancy

… Even to Women with Diabetes  St. James PJ et al:  Prospective cohort study of 66 women with diabetes  1/3 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 diabetes  1/3 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 ; 1993

page 980 Body_ID: P0980 Body_ID: T Table Modified White Classification of Pregnant Diabetic WomenTable Modified White Classification of Pregnant Diabetic Women Body_ID: None CLASSDIABETES ONSET AGE (Y)DURATION (Y)VASCULAR DISEASEINSULIN NEED Body_ID: T Gestational diabetes Body_ID: T A1A1 Any 00 Body_ID: T A2A2 Any 0+ Body_ID: T Pregestational diabetes Body_ID: T B>20 <100+ Body_ID: T C10-19or Body_ID: T D<10or>20++ Body_ID: T FAny ++ Body_ID: T RAny ++ Body_ID: T TAny ++ Body_ID: T HAny ++ Courtesy of Gabbe Obstetrics: Normal and Problem Pregnancies White’s Classification in Pregnancy

Diabetes and Early Pregnancy Loss  Poor glycemic control is associated with increased spontaneous abortion  Higher loss rates with long standing disease or with vasculopathy  Class 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 vasculopathy  Class 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)

Diabetes and Birth Defects  UK data BMJ 2006: 4.6% major congenital malformation rate in all pregestational diabetic pregnancies  Neural 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 pregnancies  Neural tube defects increased 4.2 fold  Congenital heart disease increased 3.4 fold Only 65% of neonatal anomalies were identified antenatally

Diabetes and Birth Defects  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!

Diabetes and Birth Defects  Lucas et al 1989, n=105:  Overall malformation rate 13.3%  Lucas et al 1989, n=105:  Overall malformation rate 13.3% HbA1c rangeRate of Malformation >11.2%25% %23% %14% <7.2%0

Why do Birth Defects Happen?  Multifactorial  Clear direct association with hyperglycemia 3-6 weeks after conception  Teratogenic potential of  Inositol  Prostaglandins  Reactive oxygen species  Multifactorial  Clear direct association with hyperglycemia 3-6 weeks after conception  Teratogenic potential of  Inositol  Prostaglandins  Reactive oxygen species

Why do Birth Defects Happen?  Hyperglycemia in embryo increases oxygen radical production -> inhibits prostacyclin -> increased thromboxanes/ prostaglandins -> abnormal vascularization of developing tissue  Mouse 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 tissue  Mouse model demonstrates decreased defects if prostaglandin inhibitors or antioxidants given (vitamins C and E)

Preventing Birth Defects  Planned pregnancy/ recognize potential for pregnancy  Preconception consultation  Achieve glycemic control (more to follow)  Multivitamins or prenatal vitamins  Folic acid supplementation  Planned pregnancy/ recognize potential for pregnancy  Preconception consultation  Achieve glycemic control (more to follow)  Multivitamins or prenatal vitamins  Folic acid supplementation

“I don’t have diabetes.”  Increasing concerns in group of women with  Prediabetes, Impaired Glucose Tolerance  Polycystic Ovarian Syndrome (PCOS)  Obesity  We need your help! Screen and treat!  Increasing concerns in group of women with  Prediabetes, Impaired Glucose Tolerance  Polycystic Ovarian Syndrome (PCOS)  Obesity  We need your help! Screen and treat!

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 prematurity  Did 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 prematurity  Did not observe change in rate of malformation

Part II: Early Identification of Gestational Diabetes

Gestational Diabetes Maternal Risks  Excessive weight gain  Preeclampsia  Cesarean section  Future gestational diabetes  Subsequent type 2 diabetes and heart disease Maternal Risks  Excessive weight gain  Preeclampsia  Cesarean section  Future gestational diabetes  Subsequent type 2 diabetes and heart disease Risks to Offspring  Macrosomia  Birth trauma  Hypoglycemia  Delayed lung maturation  Hypocalcemia  Polycythemia  Stillbirth  Childhood disease

Neonatal Morbidity - Delayed Lung Maturation Moore TM et al AJOG 2003

Neonatal Morbidity - Shoulder Dystocia Nesbitt TS et al AJOG 1998

Neonatal Morbidity - Birth Trauma  Brachial plexus injury  Facial nerve injury  Fractures of humerus or clavicle  Cephalohematoma  Brain injury  Death  Brachial plexus injury  Facial nerve injury  Fractures of humerus or clavicle  Cephalohematoma  Brain injury  Death

Neonatal Morbidity - Birth Trauma  Athukorala et al: positive relationship between maternal fasting hyperglycemia and incidence of shoulder dystocia  Risk 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 dystocia  Risk doubled with each 1 mmol increase in fasting glucose value on OGTT

Screening 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  Overweight before pregnancy (BMI > 25)  1 st degree relative with diabetes  Previous glucose intolerance/ GDM  Previous macrosomia or large for gestational age baby  Overweight before pregnancy (BMI > 25)  1 st degree relative with diabetes  Previous glucose intolerance/ GDM  Previous macrosomia or large for gestational age baby  PCOS  Age > 25 yrs  Members of certain ethnic groups  Multiparous women (13%)  Left column are HIGH RISK factors

Universal Screening v. Selective Screening for GDM  Cosson et al compared universal to selective screening  Universal group had more favorable fetal outcomes  Williams et al studied following ADA guidelines (not screening low risk)  10 to 11% would not have been screened  Missed 4% who would have been diagnosed with GDM  Cosson et al compared universal to selective screening  Universal group had more favorable fetal outcomes  Williams et al studied following ADA guidelines (not screening low risk)  10 to 11% would not have been screened  Missed 4% who would have been diagnosed with GDM

Screening for GDM  High risk patient requires screening earlier in pregnancy, before 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 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 wks

ADA Position Statement 50–G oral glucose tolerance screen for GDM 140mg cutoff -- 80% sensitivity 130mg cutoff -- 90% sensitivity Alternatively, patients with high risk factors can go directly to diagnostic testing instead of initial screening 140mg cutoff -- 80% sensitivity 130mg cutoff -- 90% sensitivity Alternatively, patients with high risk factors can go directly to diagnostic testing instead of initial screening

Screening for GDM 50-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 %90%

Diagnosis of GDM Using 3-hour 100 g OGTT  KEEP IN MIND PATIENT MAY BE:  undiagnosed type 2  mild 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 2  mild 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 100-gADA 75-gWHO 75-g Fasting (mg/dl) hour (mg/dl) hour (mg/dl) hour (mg/dl) Two or more values must be met or exceeded for dx of GDM with 100 g OGTT

Part III: Hyperglycemia, Not Diabetes, in Pregnancy Whattoexpect.com

HAPO Study – Purpose  NEJM May 8, 2008  Hyperglycemia 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, 2008  Hyperglycemia 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  1952: Maternal hyperglycemia causes fetal hyperglycemia, which leads to exaggerated fetal response to insulin

HAPO Study Cooperative Research Group  Cohort study  Fifteen centers in nine countries  25,505 pregnant women underwent 75 g oral GTT at weeks gestation  Patients and providers blinded to results unless unsafe:  Fasting >105 mg/ dL  2 hour glucose > 200 mg/ dL  Any glucose 160 mg/ dL  Cohort study  Fifteen centers in nine countries  25,505 pregnant women underwent 75 g oral GTT at weeks gestation  Patients and providers blinded to results unless unsafe:  Fasting >105 mg/ dL  2 hour glucose > 200 mg/ dL  Any glucose 160 mg/ dL

HAPO Study – Exclusions  < 18 y/o  Delivering outside of study facility  Unknown dating/ poor dating  Multiple gestation  Conception by IVF or gonadotropin use  Prior dx of GDM or DM  Prior glucose testing this pregnancy  Infection with HIV, Hep B, Hep C  < 18 y/o  Delivering outside of study facility  Unknown dating/ poor dating  Multiple gestation  Conception by IVF or gonadotropin use  Prior dx of GDM or DM  Prior glucose testing this pregnancy  Infection with HIV, Hep B, Hep C

HAPO Study – Primary Outcomes  Birth weight > 90 th percentile for gestational age  Primary cesarean delivery  Clinical neonatal hypoglycemia  Cord-blood serum C-peptide level above 90 th percentile  Birth weight > 90 th percentile for gestational age  Primary cesarean delivery  Clinical neonatal hypoglycemia  Cord-blood serum C-peptide level above 90 th percentile

HAPO Study – Secondary Outcomes  Delivery < 37 weeks gestation  Shoulder dystocia or birth injury  Need for admission to NICU  Hyperbilirubinemia  Preeclampsia  Delivery < 37 weeks gestation  Shoulder dystocia or birth injury  Need for admission to NICU  Hyperbilirubinemia  Preeclampsia

HAPO – 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  Glycemic values categorized into seven levels for fasting, 1- and 2-hour values  Ex] fasting subsets included:  (105 unblinded) – 99 th percentile  – 97 th percentile      <75  Glycemic values categorized into seven levels for fasting, 1- and 2-hour values  Ex] fasting subsets included:  (105 unblinded) – 99 th percentile  – 97 th percentile      <75

HAPO – Data Analysis, Continuous  Odds ratios calculated for a 1 standard deviation increase  Fasting  1-hour  2-hour  Logistic regression models  Adjusted for confounders  BMI  Age  Smoking  Hypertension  Family history of DM, etc.  Odds ratios calculated for a 1 standard deviation increase  Fasting  1-hour  2-hour  Logistic regression models  Adjusted for confounders  BMI  Age  Smoking  Hypertension  Family history of DM, etc.

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

Summary of HAPO Findings  Associations between increasing fasting, 1- hour, and 2-hour glucose values and  Birthweight > 90 th percentile  Cord blood serum C-peptide  Primary cesarean (weaker)  Neonatal hypoglycemia (weaker)  Premature delivery  Shoulder dystocia/ birth injury  NICU admission  Hyperbilirubinemia  Preeclampsia  All in patients who are below criteria for GDM  Associations between increasing fasting, 1- hour, and 2-hour glucose values and  Birthweight > 90 th percentile  Cord blood serum C-peptide  Primary cesarean (weaker)  Neonatal hypoglycemia (weaker)  Premature delivery  Shoulder dystocia/ birth injury  NICU admission  Hyperbilirubinemia  Preeclampsia  All in patients who are below criteria for GDM

Future Study  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?  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?  ACHOIS Trial: Evaluated neonatal outcomes in women with gestational diabetes  NNT to avoid one adverse outcome: 43  HAPO demonstrated fewer IUGR/ SGA babies  Problems if aggressively treat mild hyperglycemia?  Associations not tested, may not be causally mediated  ACHOIS Trial: Evaluated neonatal outcomes in women with gestational diabetes  NNT to avoid one adverse outcome: 43  HAPO demonstrated fewer IUGR/ SGA babies  Problems if aggressively treat mild hyperglycemia?  Associations not tested, may not be causally mediated

What to do Today: Don’t Forget Postpartum Testing  All women with diagnosis of gestational diabetes should be offered screening in the nonpregnant state  Fasting glucose  2-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 state  Fasting glucose  2-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%

Summary  The optimal time to positively influence pregnancy outcome is before the patient gets pregnant  Role 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 pregnant  Role 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