Diabetes in Pregnancy Kirstin Woo, MD Palo Alto Foundation Medical Group May 5, 2009.

Diabetes in PregnancyDiabetes in Pregnancy

Kirstin Woo, MDKirstin Woo, MD

Palo Alto Foundation Medical GroupPalo Alto Foundation Medical Group

May 5, 2009May 5, 2009

OutlineOutline

Physiologic changes in pregnancyPhysiologic changes in pregnancy– Organ systems affectedOrgan systems affected– Metabolic changes in pregnancyMetabolic changes in pregnancy

Diabetes in pregnancyDiabetes in pregnancy– Clinical implicationsClinical implications– Epidemiology/TypesEpidemiology/Types– Screening and DiagnosisScreening and Diagnosis– Management Management – Future directionsFuture directions

Physiologic changes in pregnancyPhysiologic changes in pregnancy

Cardiovascular systemCardiovascular system Respiratory systemRespiratory system Gastrointestinal systemGastrointestinal system Urinary systemUrinary system Endocrine systemEndocrine system Genital TractGenital Tract SkinSkin

Physiologic changes in pregnancy:Physiologic changes in pregnancy:CardiovascularCardiovascular

Sodium and water retentionSodium and water retention Reduced systemic blood pressure (mean Reduced systemic blood pressure (mean

105/60 mmHg in 2105/60 mmHg in 2ndnd trimester) trimester) Increased cardiac output (30-50% rise)Increased cardiac output (30-50% rise)

– Increased blood volume (total body water Increased blood volume (total body water increases 40%)increases 40%)

– Reduced systemic vascular resistance Reduced systemic vascular resistance (vasodilitation PLUS high flow, low-resistance (vasodilitation PLUS high flow, low-resistance circuit of the uteroplacental circulation)circuit of the uteroplacental circulation)

– Increased maternal heart rate (up 15-20 Increased maternal heart rate (up 15-20 beats/min)beats/min)

Physiologic changes in pregnancy:Physiologic changes in pregnancy:RespiratoryRespiratory

Mechanical changesMechanical changes– Diaphragm rises 4 cmDiaphragm rises 4 cm– Less negative intrathoracic pressureLess negative intrathoracic pressure– No impairments in diaphragmatic or thoracic No impairments in diaphragmatic or thoracic

muscle motionmuscle motion– Lung compliance remains unaffectedLung compliance remains unaffected

Physiologic changesPhysiologic changes– Oxygen consumption increases 15-20 %Oxygen consumption increases 15-20 %– 50% of this increase is required by the uterus50% of this increase is required by the uterus– Progesterone directly stimulates breathingProgesterone directly stimulates breathing– 70% of women experience dyspnea (increased 70% of women experience dyspnea (increased

desire to breathe) desire to breathe)

Physiologic changes in pregnancy:Physiologic changes in pregnancy:GastrointestinalGastrointestinal

MechanicalMechanical– Pressure from growing uterus on stomach Pressure from growing uterus on stomach

reflux/heartburnreflux/heartburn– Pressure from growing uterus on lower portion Pressure from growing uterus on lower portion

of colon and rectum of colon and rectum constipation constipation PhysiologicPhysiologic

– Relaxation of sphincter muscle between Relaxation of sphincter muscle between esophagus and stomachesophagus and stomach

– Progesterone (a smooth muscle relaxant) Progesterone (a smooth muscle relaxant) causes decreased GI motility and delayed causes decreased GI motility and delayed gastric emptyinggastric emptying

Normal glucose metabolismNormal glucose metabolism Glucose enters Glucose enters

bloodstream from food bloodstream from food sourcesource

Insulin aids in storage of Insulin aids in storage of glucose as fuel for cellsglucose as fuel for cells

Insulin resistance is Insulin resistance is defined as insensitivity defined as insensitivity of cells to insulin, of cells to insulin, therefore resulting in therefore resulting in increased levels of increased levels of insulin and glucose in insulin and glucose in the bloodstreamthe bloodstream

Metabolic changes in pregnancyMetabolic changes in pregnancy

Caloric requirement for a pregnant Caloric requirement for a pregnant woman is 300 kcal higher than the woman is 300 kcal higher than the non-pregnant woman’s basal needsnon-pregnant woman’s basal needs

Placental hormones affect glucose Placental hormones affect glucose and lipid metabolism to ensure that and lipid metabolism to ensure that fetus has ample supply of nutrientsfetus has ample supply of nutrients


Lipid metabolism:Lipid metabolism:– Increased lipolysis (preferential use of Increased lipolysis (preferential use of

fat for fuel, in order to preserve fat for fuel, in order to preserve glucose and protein)glucose and protein)

Glucose metabolism:Glucose metabolism:– Decreased insulin sensitivity Decreased insulin sensitivity – Increased insulin resistance Increased insulin resistance


Increased insulin resistanceIncreased insulin resistance– Due to hormones secreted by the Due to hormones secreted by the

placenta that are “diabetogenic”: placenta that are “diabetogenic”: Growth hormoneGrowth hormoneHuman placental lactogenHuman placental lactogenProgesteroneProgesteroneCorticotropin releasing hormoneCorticotropin releasing hormone

– Transient maternal Transient maternal hyperglycemiahyperglycemia occurs after meals because of increased occurs after meals because of increased insulin resistanceinsulin resistance


Relative baseline hypoglycemiaRelative baseline hypoglycemia– Proliferation of pancreatic beta cells Proliferation of pancreatic beta cells

(insulin-secreting cells) leads to (insulin-secreting cells) leads to increased insulin secretionincreased insulin secretion

Insulin levels are higher than in pregnant Insulin levels are higher than in pregnant than nonpregnant women in fasting and than nonpregnant women in fasting and postprandial statespostprandial states

– HypoglycemiaHypoglycemia between meals and at between meals and at night because of continuous fetal night because of continuous fetal drawdraw

Blood glucose levels are 10-20% lowerBlood glucose levels are 10-20% lower


Lipid metabolismLipid metabolism– Increased serum triglyceride (300%) and Increased serum triglyceride (300%) and

cholesterol (50%) levels cholesterol (50%) levels – Spares glucose for fetus, since lipids do Spares glucose for fetus, since lipids do

not cross the placentanot cross the placenta– Provides building blocks for increased Provides building blocks for increased

steroid hormone synthesissteroid hormone synthesis

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Diabetes in Pregnancy:Diabetes in Pregnancy: Clinical Implications Clinical Implications

Obstetric complications:Obstetric complications:– Increased incidence of miscarriageIncreased incidence of miscarriage– Congenital malformationsCongenital malformations

Incidence 4X higher than in general population Incidence 4X higher than in general population Most significant remaining cause of fetal death is Most significant remaining cause of fetal death is

congenital malformation congenital malformation

– Association with hypertensive disorders of Association with hypertensive disorders of pregnancypregnancy

Gestational hypertensionGestational hypertension Preeclampsia Preeclampsia

Diabetes in Pregnancy:Diabetes in Pregnancy:Clinical implicationsClinical implications

Fetal macrosomiaFetal macrosomia

Shoulder dystociaShoulder dystocia


Obstetric complications (cont’d.):Obstetric complications (cont’d.):– Preterm deliveryPreterm delivery– Intrauterine fetal demiseIntrauterine fetal demise– Traumatic delivery (e.g., shoulder Traumatic delivery (e.g., shoulder

dystocia)dystocia)– Operative vaginal delivery Operative vaginal delivery

vacuum-assistedvacuum-assisted forceps-assistedforceps-assisted


Fetal macrosomiaFetal macrosomia– Disproportionate amount of adipose tissue concentrated Disproportionate amount of adipose tissue concentrated

around shoulders and chestaround shoulders and chest Respiratory distress syndromeRespiratory distress syndrome Neonatal metabolic abnormalities:Neonatal metabolic abnormalities:

– HypoglycemiaHypoglycemia– Hyperbilirubinemia/jaundiceHyperbilirubinemia/jaundice– OrganomegalyOrganomegaly– PolycythemiaPolycythemia

Perinatal mortalityPerinatal mortality Long term predisposition to childhood obesity and Long term predisposition to childhood obesity and

metabolic syndromemetabolic syndrome

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Diabetes in Pregnancy: Diabetes in Pregnancy: EpidemiologyEpidemiology

Preexisting diabetes complicates Preexisting diabetes complicates ~1 % of pregnancies in US (>8 million ~1 % of pregnancies in US (>8 million women)women)

154,000 (4%) of all pregnancies are 154,000 (4%) of all pregnancies are affected by diabetesaffected by diabetes– 135,000 (88%) due to GDM135,000 (88%) due to GDM– 12,000 (8%) due to Type 2 DM12,000 (8%) due to Type 2 DM– 7,000 (4%) due to Type 1 DM7,000 (4%) due to Type 1 DM

Diabetes in Pregnancy: Diabetes in Pregnancy: EpidemiologyEpidemiology

Geographic disparities Geographic disparities exist in the state of exist in the state of California with the California with the highest rates of GDM highest rates of GDM reported in the counties reported in the counties of Alameda, Amador, of Alameda, Amador, Colusa, Glenn, Colusa, Glenn, Monterey, Monterey, Santa ClaraSanta Clara and Yolo and Yolo

Diabetes in Pregnancy: ClassificationDiabetes in Pregnancy: ClassificationCriterionCriterion White ClassificationWhite Classification

gestational diabetes, insulin not requiredgestational diabetes, insulin not required A1A1

gestational diabetes, insulin requiredgestational diabetes, insulin required A2A2

age of onset >= 20 years (maturity onset diabetes)age of onset >= 20 years (maturity onset diabetes) B1B1

duration < 10 years, no vascular lesionsduration < 10 years, no vascular lesions B2B2

age of onset 10-19 years of ageage of onset 10-19 years of age C1C1

duration 10-19 years, no vascular lesionsduration 10-19 years, no vascular lesions C2C2

age of onset < 10 years of ageage of onset < 10 years of age D1D1

duration >= 20 yearsduration >= 20 years D2D2

benign retinopathybenign retinopathy D3D3

calcified arteries of legscalcified arteries of legs D4D4

calcified arteries of pelvis (no longer sought)calcified arteries of pelvis (no longer sought) EE

nephropathynephropathy FF

many failuresmany failures GG

cardiopathycardiopathy HH

proliferating retinopathyproliferating retinopathy RR

renal transplantrenal transplant TT

Diabetes in Pregnancy: TypesDiabetes in Pregnancy: Types Gestational Diabetes Mellitus (GDM)Gestational Diabetes Mellitus (GDM)

– Type A1: abnormal oral glucose tolerance test (OGTT) Type A1: abnormal oral glucose tolerance test (OGTT) but normal blood glucose levels during fasting and 1-2 but normal blood glucose levels during fasting and 1-2 hours after meals; diet modification is sufficient to hours after meals; diet modification is sufficient to control glucose levels control glucose levels

– Type A2: abnormal OGTT compounded by abnormal Type A2: abnormal OGTT compounded by abnormal glucose levels during fasting and/or after meals; glucose levels during fasting and/or after meals; additional therapy with insulin or other medications is additional therapy with insulin or other medications is required required

Pregestational Diabetes MellitusPregestational Diabetes Mellitus– Type 1: autoimmune process that destroys pancreatic Type 1: autoimmune process that destroys pancreatic

cellscells– Type 2 (“lifestyle diabetes”): acquired insulin resistance Type 2 (“lifestyle diabetes”): acquired insulin resistance

related to obesity related to obesity

Pregestational Diabetes: Pregestational Diabetes: Types 1 and 2Types 1 and 2

Gestational Diabetes (GDM)Gestational Diabetes (GDM)

Definition: Definition: Insulin resistance/ Insulin resistance/ glucose intolerance first glucose intolerance first diagnosed during diagnosed during pregnancy pregnancy

Prevalence: 1-14% of all Prevalence: 1-14% of all pregnanciespregnancies

Indicates predisposition Indicates predisposition to later development of to later development of Type 2 DiabetesType 2 Diabetes

Chance of recurrence in Chance of recurrence in future pregnancies: future pregnancies: 30-84%30-84%

GDM: Risk factorsGDM: Risk factors

Maternal age >25 yearsMaternal age >25 years Body mass index >25 kg/mBody mass index >25 kg/m22

Race/EthnicityRace/Ethnicity– LatinaLatina– Native AmericanNative American– South or East Asian, Pacific Island ancestrySouth or East Asian, Pacific Island ancestry

Personal/Family history of DMPersonal/Family history of DM History of macrosomiaHistory of macrosomia

Gestational Diabetes (GDM)Gestational Diabetes (GDM)

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GDM: ScreeningGDM: Screening

Screening testScreening test– 50 gm 1-hour glucose 50 gm 1-hour glucose

challenge test (GCT)challenge test (GCT)

Screening thresholdsScreening thresholds– 130mg/dL: 90% sensitivity 130mg/dL: 90% sensitivity

(23% screen positive)(23% screen positive)– 140mg/dL: 80% sensitivity 140mg/dL: 80% sensitivity

(14% screen positive)(14% screen positive) If patient screens If patient screens

positive, she goes on to positive, she goes on to take a 3-hour glucose take a 3-hour glucose tolerance test (GTT)tolerance test (GTT)

GDM: DiagnosisGDM: Diagnosis

Fasting blood glucoseFasting blood glucose >126mg/dL or >126mg/dL or random blood glucose >200mg/dLrandom blood glucose >200mg/dL

100 gm 3-hour glucose tolerance test 100 gm 3-hour glucose tolerance test (GTT) with (GTT) with 2 or more abnormal 2 or more abnormal

valuesvalues

Carpenter and Coustan

National Diabetes and Data Group

Fasting 95 mg/dL 105 mg/dL

1 hour 180 mg/dL 190 mg/dL



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Diabetes in pregnancyDiabetes in pregnancy– Clinical implicationsClinical implications– Epidemiology/TypesEpidemiology/Types– Screening and DiagnosisScreening and Diagnosis– ManagementManagement – Future directionsFuture directions

Management:Management:Glycemic controlGlycemic control

Significant benefit of insulin therapySignificant benefit of insulin therapy– Prior to insulin use, perinatal Prior to insulin use, perinatal

mortality was 65%mortality was 65%– After introduction of insulin After introduction of insulin

therapy, perinatal mortality therapy, perinatal mortality declined to 5%declined to 5%

Management:Management:Glycemic controlGlycemic control

Glycosylated Hemoglobin A1C (Hgb A1C) Glycosylated Hemoglobin A1C (Hgb A1C) level should be less than or equal to 6%level should be less than or equal to 6%– Levels between 5 and 6% are associated with Levels between 5 and 6% are associated with

fetal malformation rates comparable to those fetal malformation rates comparable to those observed in normal pregnancies (2-3%)observed in normal pregnancies (2-3%)

– Goal of normal or near-normal glycosylated Goal of normal or near-normal glycosylated hemoglobin (Hgb A1C) level for at least 3 hemoglobin (Hgb A1C) level for at least 3 months prior to conceptionmonths prior to conception

Hgb A1C concentration near 10% is Hgb A1C concentration near 10% is associated with fetal anomaly rate of 20-associated with fetal anomaly rate of 20-25%25%

Management:Management:OverviewOverview

Nutrition therapyNutrition therapy Home self glucose monitoringHome self glucose monitoring Medical therapy if glycemic control Medical therapy if glycemic control

not achieved with diet/exercisenot achieved with diet/exercise– Subcutaneous insulinSubcutaneous insulin – Oral hypoglycemic agents (Glyburide, Oral hypoglycemic agents (Glyburide,

Metformin)Metformin) Antenatal monitoringAntenatal monitoring

Management: Management: Glycemic ControlGlycemic Control

Blood glucose goals during pregnancyBlood glucose goals during pregnancy – Fasting < 95mg/dLFasting < 95mg/dL– 1-hr postprandial < 130-140mg/dL1-hr postprandial < 130-140mg/dL– 2-hr postprandial am < 120mg/dL2-hr postprandial am < 120mg/dL– 2 am < 120mg/dL2 am < 120mg/dL

Nocturnal glucose level should not go below Nocturnal glucose level should not go below 60 mg/dL60 mg/dL

Abnormal postprandial glucose Abnormal postprandial glucose measurements are more predictive of measurements are more predictive of adverse outcomes than preprandial adverse outcomes than preprandial measurementsmeasurements

Management:Management:NutritionNutrition

Caloric requirements:Caloric requirements:– Normal body weight - 30-35 kcal/kg/dayNormal body weight - 30-35 kcal/kg/day– Distributed 10-20% at breakfast, 20-30% at Distributed 10-20% at breakfast, 20-30% at

lunch, 30-40% at dinner, up to 30% for snacks lunch, 30-40% at dinner, up to 30% for snacks (to avoid hypoglycemia)(to avoid hypoglycemia)

Caloric composition:Caloric composition:– 40-50% from complex, high-fiber 40-50% from complex, high-fiber

carbohydratescarbohydrates– 20% from protein20% from protein– 30-40% from primarily unsaturated fats30-40% from primarily unsaturated fats

Management:Management:Subcutaneous Insulin TherapySubcutaneous Insulin Therapy

Insulin requirements increase Insulin requirements increase rapidly, especially from 28 to 32 rapidly, especially from 28 to 32 weeks of gestationweeks of gestation– 11stst trimester: 0.7-0.8 U/kg/d trimester: 0.7-0.8 U/kg/d– 22ndnd trimester: 0.8-1 U/kg/d trimester: 0.8-1 U/kg/d– 33rdrd trimester: 0.9-1.2 U/kg/d trimester: 0.9-1.2 U/kg/d

Management:Management:Subcutaneous Insulin TherapySubcutaneous Insulin Therapy

“Regular” insulin = Humalog, Novalog

Management:Management:Oral Hypoglycemic AgentsOral Hypoglycemic Agents

Glitazones (Avandia, Actos)Glitazones (Avandia, Actos)– Sensitize muscle and fat cells to accept insulin more Sensitize muscle and fat cells to accept insulin more

readilyreadily– Decrease insulin resistanceDecrease insulin resistance

SulfonylureasSulfonylureas– Augment insulin releaseAugment insulin release– 11stst generation generation

Concentrated in the neonate Concentrated in the neonate hypoglycemia hypoglycemia– 2nd generation (Glyburide)2nd generation (Glyburide)

Low transplacental transferLow transplacental transfer Biguanide (Metformin, aka Glucophage)Biguanide (Metformin, aka Glucophage)

– Increases insulin sensitivityIncreases insulin sensitivity– Crosses placentaCrosses placenta

Management Summary:Management Summary:Pregestational DiabetesPregestational Diabetes

Referral to perinatologist and/or Referral to perinatologist and/or endocrinologistendocrinologist

Multidisciplinary approachMultidisciplinary approach– Regular visits with nutritionistRegular visits with nutritionist– Hgb A1C every trimesterHgb A1C every trimester– Fetal EchocardiogramFetal Echocardiogram– Level II ultrasoundLevel II ultrasound– OpthamologistOpthamologist– Baseline kidney and liver function testsBaseline kidney and liver function tests

Management Summary:Management Summary:Pregestational DiabetesPregestational Diabetes

Optimize glycemic control – frequent Optimize glycemic control – frequent insulin dose adjustmentsinsulin dose adjustments– Type 1: often have insulin pumpType 1: often have insulin pump– Type 2: subcutaneous insulinType 2: subcutaneous insulin

Fetal monitoring starting at 28-32 weeks, Fetal monitoring starting at 28-32 weeks, depending on glycemic controldepending on glycemic control

Ultrasound to assess growth at 36 weeksUltrasound to assess growth at 36 weeks Delivery at 38-39 weeksDelivery at 38-39 weeks

Management Summary:Management Summary:GDMGDM

Begin with diet / walk after each mealBegin with diet / walk after each meal If borderline/mild elevations, consider If borderline/mild elevations, consider

metformin (start at 500 mg daily)metformin (start at 500 mg daily)– Counsel about increased PTD ratesCounsel about increased PTD rates– Unlikely pre-existing DMUnlikely pre-existing DM

If elevations start out moderate to If elevations start out moderate to severe or metformin fails, proceed to severe or metformin fails, proceed to subcutaneous insulin therapy subcutaneous insulin therapy – NPH (long acting) NPH (long acting) – Humalog/Novalog (short acting)Humalog/Novalog (short acting)

Management IntrapartumManagement Intrapartum

Attention to labor pattern, as Attention to labor pattern, as cephalopelvic disproportion may indicate cephalopelvic disproportion may indicate fetal macrosomia fetal macrosomia

Careful consideration before performing Careful consideration before performing operative vaginal deliveryoperative vaginal delivery

Hourly blood glucose monitoring during Hourly blood glucose monitoring during active labor, with insulin drip if necessaryactive labor, with insulin drip if necessary

Notify pediatrics if patient has poorly Notify pediatrics if patient has poorly controlled blood sugars antepartum or controlled blood sugars antepartum or intrapartumintrapartum

Management PostpartumManagement Postpartum

For patients with pregestational diabetes, For patients with pregestational diabetes, halve dose of insulin and continue to halve dose of insulin and continue to check blood glucose in immediate check blood glucose in immediate postpartum periodpostpartum period

For GDM patients who required insulin For GDM patients who required insulin therapy (GDMA2), check fasting and therapy (GDMA2), check fasting and postprandial blood sugars and treat with postprandial blood sugars and treat with insulin as necessaryinsulin as necessary

For GDM patients who were diet controlled For GDM patients who were diet controlled (GDMA1), no further monitoring nor (GDMA1), no further monitoring nor therapy is necessary immediately therapy is necessary immediately postpartumpostpartum

Management PostpartumManagement Postpartum

For all GDM patients, perform 75 For all GDM patients, perform 75 gram 2-hour OGTT at 6 week gram 2-hour OGTT at 6 week postpartum visit to rule out postpartum visit to rule out pregestational diabetes pregestational diabetes

Most common recommendation is for Most common recommendation is for primary care physician to repeat primary care physician to repeat 2-hour OGTT every three years2-hour OGTT every three years

Diabetes in Pregnancy:Diabetes in Pregnancy:Future directionsFuture directions

ACOG recommendations on oral ACOG recommendations on oral hypoglycemic agents will be updated as hypoglycemic agents will be updated as more safety and efficacy data become more safety and efficacy data become availableavailable

Further development of programs for Further development of programs for patient and provider educationpatient and provider education– Example: California Diabetes and Pregnancy Example: California Diabetes and Pregnancy

Program (CDAPP) consultants develop, update Program (CDAPP) consultants develop, update and disseminate and disseminate Sweet Success: Guidelines for Sweet Success: Guidelines for CareCare which provides standards of practice for which provides standards of practice for diabetes and pregnancydiabetes and pregnancy

ReferencesReferences ACOG practice bulletin. Gestational Diabetes. ACOG practice bulletin. Gestational Diabetes.

Obstet Gynecol 2001;93:525-34Obstet Gynecol 2001;93:525-34 ADA position statement. Standards of Medical ADA position statement. Standards of Medical

Care in Diabetes. Diabetes Care 2006;29:S4-42Care in Diabetes. Diabetes Care 2006;29:S4-42 Crowther CA et al. N Engl J Med 2005;352:2477-Crowther CA et al. N Engl J Med 2005;352:2477-

8686 Casey BM et al. Obstet Gynecol 1997;90:867-73Casey BM et al. Obstet Gynecol 1997;90:867-73 Yang X et al. Diabetes Care 2002;9:1619-24Yang X et al. Diabetes Care 2002;9:1619-24 UpToDate.comUpToDate.com

Thanks to Dr. Bertha Chen and Dr. Aaron Caughey Thanks to Dr. Bertha Chen and Dr. Aaron Caughey for sharing their slides for sharing their slides

Diabetes in Pregnancy Kirstin Woo, MD Palo Alto Foundation Medical Group May 5, 2009.

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