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

2. Outline Physiologic changes in pregnancy Diabetes in pregnancy
Organ systems affected
Metabolic changes in pregnancy
Diabetes in pregnancy
Clinical implications
Epidemiology/Types
Screening and Diagnosis
Management
Future directions
Now that we have considered the general differences between glucose metabolism in the pregnant and non-pregnant state, let us move on to the discussion of when glucose metabolism goes awry – diabetes in pregnancy.

3. Physiologic changes in pregnancy
Cardiovascular system
Respiratory system
Gastrointestinal system
Urinary system
Endocrine system
Genital Tract
Skin
Pregnancy affects nearly all systems in the body
I will focus on the cardiovascular, respiratory and GI effects and then move on to the metabolic changes, since that relates more closely to diabetes in pregnancy

4. Physiologic changes in pregnancy: Cardiovascular
Sodium and water retention
Reduced systemic blood pressure (mean 105/60 mmHg in 2nd trimester)
Increased cardiac output (30-50% rise)
Increased blood volume (total body water increases 40%)
Reduced systemic vascular resistance (vasodilitation PLUS high flow, low-resistance circuit of the uteroplacental circulation)
Increased maternal heart rate (up beats/min)
As a result of increased blood volume and reduced systemic blood pressure, cardiac output increases significantly. In general, the heart is “working harder” through pregnancy, not to mention during labor, which means that women with preexisting heart conditions need to have special consideration when conceiving.

5. Physiologic changes in pregnancy: Respiratory
Mechanical changes
Diaphragm rises 4 cm
Less negative intrathoracic pressure
No impairments in diaphragmatic or thoracic muscle motion
Lung compliance remains unaffected
Physiologic changes
Oxygen consumption increases %
50% of this increase is required by the uterus
Progesterone directly stimulates breathing
70% of women experience dyspnea (increased desire to breathe)
The change in anatomy, especially later in pregnancy influences the shape and function of the thoracic (chest) cavity
With a smaller volume, there is less negative pressure and therefore the volume inhaled with each breath is decreased. The muscle and lung tissue functions themselves remain the same.

6. Physiologic changes in pregnancy: Gastrointestinal
Mechanical
Pressure from growing uterus on stomach  reflux/heartburn
Pressure from growing uterus on lower portion of colon and rectum  constipation
Physiologic
Relaxation of sphincter muscle between esophagus and stomach
Progesterone (a smooth muscle relaxant) causes decreased GI motility and delayed gastric emptying

7. Normal glucose metabolism
Glucose enters bloodstream from food source
Insulin aids in storage of glucose as fuel for cells
Insulin resistance is defined as insensitivity of cells to insulin, therefore resulting in increased levels of insulin and glucose in the bloodstream
Let’s talk about the changes in metabolism that occur during pregnancy, specifically carbohydrate metabolism. First of all, normal glucose metabolism is depicted here.
Glucose is absorbed from the stomach and small intestine and enters the bloodstream, then is transported to various organs. Insulin, secreted by the pancreas is required to permit entry of the glucose into the cell to be used.

8. Metabolic changes in pregnancy
Caloric requirement for a pregnant woman is 300 kcal higher than the non-pregnant woman’s basal needs
Placental hormones affect glucose and lipid metabolism to ensure that fetus has ample supply of nutrients
Later in gestation with increased fetal growth, larger fluctuations in glucose and insulin occur as mother oscillates between fed and fasted states (during fasting, glucose is reserved for fetus)

9. Metabolic changes in pregnancy
Lipid metabolism:
Increased lipolysis (preferential use of fat for fuel, in order to preserve glucose and protein)
Glucose metabolism:
Decreased insulin sensitivity
Increased insulin resistance

10. Metabolic changes in pregnancy
Increased insulin resistance
Due to hormones secreted by the placenta that are “diabetogenic”:
Growth hormone
Human placental lactogen
Progesterone
Corticotropin releasing hormone
Transient maternal hyperglycemia occurs after meals because of increased insulin resistance

11. Metabolic changes in pregnancy
Relative baseline hypoglycemia
Proliferation of pancreatic beta cells (insulin-secreting cells) leads to increased insulin secretion
Insulin levels are higher than in pregnant than nonpregnant women in fasting and postprandial states
Hypoglycemia between meals and at night because of continuous fetal draw
Blood glucose levels are 10-20% lower

12. Metabolic changes in pregnancy
Lipid metabolism
Increased serum triglyceride (300%) and cholesterol (50%) levels
Spares glucose for fetus, since lipids do not cross the placenta
Provides building blocks for increased steroid hormone synthesis

13. Outline Physiologic changes in pregnancy Diabetes in pregnancy
Organ systems affected
Metabolic changes in pregnancy
Diabetes in pregnancy
Clinical implications
Epidemiology/Types
Screening and Diagnosis
Management
Future directions
Now that we have considered the general differences between glucose metabolism in the pregnant and non-pregnant state, let us move on to the discussion of when glucose metabolism goes awry – diabetes in pregnancy.

14. Diabetes in Pregnancy: Clinical Implications
Obstetric complications:
Increased incidence of miscarriage
Congenital malformations
Incidence 4X higher than in general population
Most significant remaining cause of fetal death is congenital malformation
Association with hypertensive disorders of pregnancy
Gestational hypertension
Preeclampsia
It has long been recognized that poorly controlled diabetes causes a multitude of obstetric complications

15. Diabetes in Pregnancy: Clinical implications
Shoulder dystocia
Fetal macrosomia

16. Diabetes in Pregnancy: Clinical Implications
Obstetric complications (cont’d.):
Preterm delivery
Intrauterine fetal demise
Traumatic delivery (e.g., shoulder dystocia)
Operative vaginal delivery
vacuum-assisted
forceps-assisted

17. Diabetes in Pregnancy: Clinical Implications
Fetal macrosomia
Disproportionate amount of adipose tissue concentrated around shoulders and chest
Respiratory distress syndrome
Neonatal metabolic abnormalities:
Hypoglycemia
Hyperbilirubinemia/jaundice
Organomegaly
Polycythemia
Perinatal mortality
Long term predisposition to childhood obesity and metabolic syndrome
Other perinatal complications involve both long and short term exposure to high levels of serum glucose.

18. Outline Physiologic changes in pregnancy Diabetes in pregnancy
Organ systems affected
Metabolic changes in pregnancy
Diabetes in pregnancy
Clinical implications
Epidemiology/Types
Screening and Diagnosis
Management
Future directions
Now that we have considered the general differences between glucose metabolism in the pregnant and non-pregnant state, let us move on to the discussion of when glucose metabolism goes awry – diabetes in pregnancy.

19. Diabetes in Pregnancy: Epidemiology
Preexisting diabetes complicates
~1 % of pregnancies in US (>8 million women)
154,000 (4%) of all pregnancies are affected by diabetes
135,000 (88%) due to GDM
12,000 (8%) due to Type 2 DM
7,000 (4%) due to Type 1 DM

20. Diabetes in Pregnancy: Epidemiology
Geographic disparities exist in the state of California with the highest rates of GDM reported in the counties of Alameda, Amador, Colusa, Glenn, Monterey, Santa Clara and Yolo

21. Diabetes in Pregnancy: Classification
Criterion
White Classification
gestational diabetes, insulin not required A1
gestational diabetes, insulin required A2
age of onset >= 20 years (maturity onset diabetes) B1
duration < 10 years, no vascular lesions B2
age of onset years of age C1
duration years, no vascular lesions C2
age of onset < 10 years of age D1
duration >= 20 years D2
benign retinopathy D3
calcified arteries of legs D4
calcified arteries of pelvis (no longer sought) E
nephropathy F
many failures G
cardiopathy H
proliferating retinopathy R
renal transplant T
Priscilla White developed this classification system to assess maternal and fetal risk and differentiate between preexisting diabetes and gestational diabetes

22. Diabetes in Pregnancy: Types
Gestational Diabetes Mellitus (GDM)
Type A1: abnormal oral glucose tolerance test (OGTT) but normal blood glucose levels during fasting and 1-2 hours after meals; diet modification is sufficient to control glucose levels
Type A2: abnormal OGTT compounded by abnormal glucose levels during fasting and/or after meals; additional therapy with insulin or other medications is required
Pregestational Diabetes Mellitus
Type 1: autoimmune process that destroys pancreatic b cells
Type 2 (“lifestyle diabetes”): acquired insulin resistance related to obesity

23. Pregestational Diabetes: Types 1 and 2
Type 1 is characterized by lack of insulin (a production problem)
Type 2 is characterized by plentiful insulin that is not able to do its job effectively (a function problem – i.e., lack of response, hence the term “insulin resistance”)

24. Gestational Diabetes (GDM)
Definition:
Insulin resistance/ glucose intolerance first diagnosed during pregnancy
Prevalence: 1-14% of all pregnancies
Indicates predisposition to later development of Type 2 Diabetes
Chance of recurrence in future pregnancies:
30-84%
Within years after delivery, approximately 50% of women who had gestational diabetes will develop type 2 diabetes
Varies by ethnicity – in the Hispanic population, up to 50% develop type 2 diabetes within 5 years of diagnosis of gestational diabetes
Prevalence is wide-ranging and variable depending on ethnic makeup of the population.
Also, patients’ first presentation may be during pregnancy

25. GDM: Risk factors Maternal age >25 years
Body mass index >25 kg/m2
Race/Ethnicity
Latina
Native American
South or East Asian, Pacific Island ancestry
Personal/Family history of DM
History of macrosomia

26. Gestational Diabetes (GDM)
Risk factors play into increased pre-conception insulin resistance
Adding on insulin resistance of pregnancy because of estrogen/progesterone and placental hormones creates a hyperinsulinemic state

27. Outline Physiologic changes in pregnancy Diabetes in pregnancy
Organ systems affected
Metabolic changes in pregnancy
Diabetes in pregnancy
Clinical implications
Epidemiology/Types
Screening and Diagnosis
Management
Future directions
Now that we have considered the general differences between glucose metabolism in the pregnant and non-pregnant state, let us move on to the discussion of when glucose metabolism goes awry – diabetes in pregnancy.

28. GDM: Screening Screening test Screening thresholds
50 gm 1-hour glucose challenge test (GCT)
Screening thresholds
130mg/dL: 90% sensitivity
(23% screen positive)
140mg/dL: 80% sensitivity
(14% screen positive)
If patient screens positive, she goes on to take a 3-hour glucose tolerance test (GTT)
50 grams of glucola are drunk, followed by a serum measurement of glucose one hour later
2/3 of obgyns use 140 cutoff
1/3 of obgyns use cutoff

29. National Diabetes and Data Group
GDM: Diagnosis
Fasting blood glucose >126mg/dL or random blood glucose >200mg/dL
100 gm 3-hour glucose tolerance test
(GTT) with 2 or more abnormal values
Carpenter and Coustan
National Diabetes and Data Group
Fasting
95 mg/dL
105 mg/dL
1 hour
180 mg/dL
190 mg/dL
2 hour
155 mg/dL
165 mg/dL
3 hour
140 mg/dL
145 mg/dL
C/C criteria capture 54% more patients than NDDG criteria

30. Outline Physiologic changes in pregnancy Diabetes in pregnancy
Organ systems affected
Metabolic changes in pregnancy
Diabetes in pregnancy
Clinical implications
Epidemiology/Types
Screening and Diagnosis
Management
Future directions
Now that we have considered the general differences between glucose metabolism in the pregnant and non-pregnant state, let us move on to the discussion of when glucose metabolism goes awry – diabetes in pregnancy.

31. Management: Glycemic control
Significant benefit of insulin therapy
Prior to insulin use, perinatal mortality was 65%
After introduction of insulin therapy, perinatal mortality declined to 5%

32. Management: Glycemic control
Glycosylated Hemoglobin A1C (Hgb A1C) level should be less than or equal to 6%
Levels between 5 and 6% are associated with fetal malformation rates comparable to those observed in normal pregnancies (2-3%)
Goal of normal or near-normal glycosylated hemoglobin (Hgb A1C) level for at least 3 months prior to conception
Hgb A1C concentration near 10% is associated with fetal anomaly rate of 20-25%
In the normal 120-day life span of the red blood cell, glucose molecules join hemoglobin, forming glycated hemoglobin. In individuals with poorly controlled diabetes, increases in the quantities of these glycated hemoglobins are noted.
Once a hemoglobin molecule is glycated, it remains that way. A buildup of glycated hemoglobin within the red cell reflects the average level of glucose to which the cell has been exposed during its life cycle. Measuring glycated hemoglobin assesses the effectiveness of therapy by monitoring long-term serum glucose regulation. The HbA1c level is proportional to average blood glucose concentration over the previous four weeks to three months. Some researchers state that the major proportion of its value is related to a rather short term period of two to four weeks.

33. Management: Overview Home self glucose monitoring
Nutrition therapy
Home self glucose monitoring
Medical therapy if glycemic control not achieved with diet/exercise
Subcutaneous insulin
Oral hypoglycemic agents (Glyburide, Metformin)
Antenatal monitoring
Main goal is glycemic control, first by lifestyle adjustments (diet and exercise) and then by medication if necessary

34. Management: Glycemic Control
Blood glucose goals during pregnancy
Fasting < 95mg/dL
1-hr postprandial < mg/dL
2-hr postprandial am < 120mg/dL
2 am < 120mg/dL
Nocturnal glucose level should not go below 60 mg/dL
Abnormal postprandial glucose measurements are more predictive of adverse outcomes than preprandial measurements

35. Management: Nutrition
Caloric requirements:
Normal body weight kcal/kg/day
Distributed 10-20% at breakfast, 20-30% at lunch, 30-40% at dinner, up to 30% for snacks (to avoid hypoglycemia)
Caloric composition:
40-50% from complex, high-fiber carbohydrates
20% from protein
30-40% from primarily unsaturated fats

36. Management: Subcutaneous Insulin Therapy
Insulin requirements increase rapidly, especially from 28 to 32 weeks of gestation
1st trimester: U/kg/d
2nd trimester: U/kg/d
3rd trimester: U/kg/d
Recall that the introduction of insulin therapy significantly reduced perinatal mortality

37. Management: Subcutaneous Insulin Therapy
Recall that the introduction of insulin therapy significantly reduced perinatal mortality
“Regular” insulin = Humalog, Novalog

38. Management: Oral Hypoglycemic Agents
Glitazones (Avandia, Actos)
Sensitize muscle and fat cells to accept insulin more readily
Decrease insulin resistance
Sulfonylureas
Augment insulin release
1st generation
Concentrated in the neonate  hypoglycemia
2nd generation (Glyburide)
Low transplacental transfer
Biguanide (Metformin, aka Glucophage)
Increases insulin sensitivity
Crosses placenta
Recall that the introduction of insulin therapy significantly reduced perinatal mortality

39. Management Summary: Pregestational Diabetes
Referral to perinatologist and/or endocrinologist
Multidisciplinary approach
Regular visits with nutritionist
Hgb A1C every trimester
Fetal Echocardiogram
Level II ultrasound
Opthamologist
Baseline kidney and liver function tests

40. Management Summary: Pregestational Diabetes
Optimize glycemic control – frequent insulin dose adjustments
Type 1: often have insulin pump
Type 2: subcutaneous insulin
Fetal monitoring starting at weeks, depending on glycemic control
Ultrasound to assess growth at 36 weeks
Delivery at weeks
Practice varies by institution, but the general principle of detecting fetal macrosomia and avoiding IUFD applies

41. Management Summary: GDM
Begin with diet / walk after each meal
If borderline/mild elevations, consider metformin (start at 500 mg daily)
Counsel about increased PTD rates
Unlikely pre-existing DM
If elevations start out moderate to severe or metformin fails, proceed to subcutaneous insulin therapy
NPH (long acting)
Humalog/Novalog (short acting)

42. Management Intrapartum
Attention to labor pattern, as cephalopelvic disproportion may indicate fetal macrosomia
Careful consideration before performing operative vaginal delivery
Hourly blood glucose monitoring during active labor, with insulin drip if necessary
Notify pediatrics if patient has poorly controlled blood sugars antepartum or intrapartum

43. Management Postpartum
For patients with pregestational diabetes, halve dose of insulin and continue to check blood glucose in immediate postpartum period
For GDM patients who required insulin therapy (GDMA2), check fasting and postprandial blood sugars and treat with insulin as necessary
For GDM patients who were diet controlled (GDMA1), no further monitoring nor therapy is necessary immediately postpartum

44. Management Postpartum
For all GDM patients, perform 75 gram 2-hour OGTT at 6 week postpartum visit to rule out pregestational diabetes
Most common recommendation is for primary care physician to repeat
2-hour OGTT every three years

45. Diabetes in Pregnancy: Future directions
ACOG recommendations on oral hypoglycemic agents will be updated as more safety and efficacy data become available
Further development of programs for patient and provider education
Example: California Diabetes and Pregnancy Program (CDAPP) consultants develop, update and disseminate Sweet Success: Guidelines for Care which provides standards of practice for diabetes and pregnancy

46. References
ACOG practice bulletin. Gestational Diabetes. Obstet Gynecol 2001;93:525-34
ADA position statement. Standards of Medical Care in Diabetes. Diabetes Care 2006;29:S4-42
Crowther CA et al. N Engl J Med 2005;352:
Casey BM et al. Obstet Gynecol 1997;90:867-73
Yang X et al. Diabetes Care 2002;9:
UpToDate.com
Thanks to Dr. Bertha Chen and Dr. Aaron Caughey
for sharing their slides