A. Introduction

1. Gestational DM is defined as glucose intolerance that is first detected during pregnancy
2. Strong continuous association of maternal glucose levels with increased infant birth weight and cord-blood serum C-peptide levels [2]
3. Classification of Gestational Diabetes
   1. Class A = hyperglycemia restricted to pregnancy (gestational diabetes)
   2. Class B = diabetes during preganancy which continues post-partum
   3. Diabetes present prior to pregnancy is placed in Class B
4. Complicates 3-5% of pregnancies
   1. Remember "Rule of 15's" for gestational diabetes
   2. 15% of women will have abnormal initial glucose tolerance tests (GTT)
   3. 15% of these will have abnormal 3 hour GTT
   4. 15% of these will have diabetes that persists post-partum
5. Risk Factors
   1. Advanced Maternal Age
   2. Family history of diabetes mellitus
   3. Increased maternal body mass index (BMI >25kg/m2 (normal <20kg/m2)
   4. Nonwhite race
   5. Smoking

B. Fetal Problems with Maternal Diabetes

1. Macrosomia (large body habitus): "fat baby" with normal bipyramidal diameter
2. Intrauterine Growth Retardation (IUGR)
   1. Likely due to microvascular insufficiency
   2. Vascular disease is present in mother
   3. Thrombophilia polymorphisms (FVL, MTHFR, prothrombin) do not predispose to IUGR [3]
3. Congenital Abnormalities (4-7X increase over normal)
4. Slowed Lung Maturation (Surfactant Production) - high risk respiratory distress syndrome
5. Stillbirth
6. Birth Trauma - due to large size; shoulder dystocia most common
7. Other
   1. Fetal Hyperinsulinemia leads to hypoglycemia on delivery
   2. Jaundice (polycythemia due to placental insufficiency and hypoxia)
   3. Hypocalcemia
   4. Increased risk of adult obesity
   5. Increased risk of abnormal glucose tolerance
8. Defects in Diabetic Fetus
   1. Caudal Regression
   2. Renal Anomalies (duplex ureters)
   3. Situs inversus
   4. Cardiac Anomalies
9. Risks to fetus increase with increasing maternal glucose levels
   1. Risk for later life insulin resistance
   2. Strong continuous association of maternal glucose levels with increased infant birth weight and cord-blood serum C-peptide levels [2]

C. Problems of Pregnant Diabetic Mothers

1. Microvascular disease
2. Hypertension and/or frank pre-eclampsia (associated with large placental mass)
3. Polyhydramnios (>1000cc at term)
4. Operative delivery often required (macrosomia): C-Section, Forceps, Vacuum Delivery
5. Nephropathy Exacerbation
   1. Increased creatinine clearance rate during pregnancy
   2. Increased risk of urinary tract infection (UTI)
6. Hypoglycemia in First Trimester
7. Acidosis - Third Trimester
8. Five Term pregnancies increases risk of IDDM by 5X in patients <40 years of age
   1. Thus, pregnancy "unmasks" potential IDDM mothers
   2. Estrogen may be a specific pancreatic islet stimulator
   3. Progesterone is anti-insulin
   4. Human Placental lactogen may be major culperate
9. Human Placental Lactogen (HPL)
   1. Anti-insulin
   2. Lipolytic
   3. Causes insulin resistance during later trimesters

D. Screening and Diagnosis

1. Screening recommendations are inconclusive []
   1. Some overall benefits to screening women after 24 weeks' gestation (rather than not screening)
   2. Overall, no benefits to screening at <24 weeks' gestation
2. Initial screening with fasting glucose usually between 24-28 or 24-34 weeks
   1. Women at increased risk of DM should be screened earlier (see above)
   2. Women with symptoms of DM (polyuria, polydipsia, polyphagia) should also be screened
3. Fasting glucose determination
   1. If >140, then Glucose Tolerance Test (GTT) is ordered
   2. GTT (3hr) has 100gm glucose administered orally then 1,2, 3 hour glucose measures
   3. 1hr >190, 2hr>165, or 3hr>145mg/dL are abnormal and suggest (gestational) diabetes
   4. Previously diabetic patients are at increased risk
4. Women with very high GTT glucose results may have frank DM and should be treated as such
5. Chronic diabetics should receive counseling and should increase glucose monitoring

E. Clinical Evaluation

1. Euglycemia checks with Hemoglobin A1c level
2. Urine Check
   1. Ketones and Glucose
   2. Creatinine (Clearance calculation) and Protein (Preeclampsia)
   3. 25% of Diabetic Patients with Bactiuria will develop Pyelonephritis
   4. Bactiuria should be treated in nearly all pregnant women
3. Non-Stress Test (NST) at 36 weeks performed every week
4. Biophysical Profile (BPP) with Sonogram to follow size and anomaly scan
5. Delivery Recommendations
   1. Deliver at 40 weeks (42 weeks for Diet Controlled Diabetics)
   2. Delivery earlier if estimated fetal weight is near 4000gm
   3. May need to do amniocentesis to check for lung maturity
   4. Glucose will often drop precipitously with delivery, even in Type 1 DM
   5. Patients must be monitored closely
   6. Combination iv glucose (5-10%) with low dose insulin drip may be required
6. Ophthalmology Consultation
7. ECG - silent infarctions
8. Alpha Fetoprotein (AFP) in second trimester

F. Treatment

1. Antipartum treatment focuses on dietary and adjunctive control to normalize glucose
   1. Active intervention in women with pregnancy associated diabetes is highly beneficial
   2. Blood glucose monitoring + insulin therapy associated with 1% severe complications compared with 4% severe complications with routine care alone [7]
2. Levels of Hemoglobin (Hb) A1c are used as a marker for control of diabetes
   1. Hb A1c is the fraction of glycosylated hemoglobin in the blood
   2. Hb A1c levels <7%
3. Nutritional Counseling is crucial
   1. First, diet of 30-35 cal/kg/day is used for 1 week
   2. Then, Glucose Tolerance Test is repeated
   3. Diet consists of 110gm protein, 65-70gm fat, remainder in carbohydrate
4. Recommend splitting meals into 4-7 smaller meals a day
5. Tight control of glucose within first 3 weeks of pregnancy decreases anomalies ~4 fold
   1. Decreased perinatal morbidity and mortality
   2. Birth defects rate positively correlated with HbA1c level
   3. Glucose should be monitored in fasting state, and on 2-3 additional occasions per day
   4. Insulin therapy is strongly recommended to achieve adequate glucose control [7]
   5. Metformin (Glucophage®) is about as effective as insulin, preferred by patients, and is well tolerated; about 50% of women added insulin to their metformin to achieve good control [6]
   6. Therefore, metformin is a reasonable first line therapy for gestational DM
6. Insulin and Sulfonylureas
   1. Previoulsy believed that only insulin should be used for glucose control
   2. Insulin dose should be adjusted based on post-prandial, not pre-prandial, glucose levels
   3. Sulfonylureas were believed to be contraindicated in pregnancy
   4. However, glyburide 2.5-20mg/day in gestionational diabetes showed good effects [8]
   5. Glyburide was not detected in fetal blood, and was equivalent to thrice daily insulin [8]
   6. Therefore, glyburide may be considered in gestational diabetes

References

1. Kjos SL and Buchanan TA. 1999. NEJM. 341(23)1749
2. HAPO Study Cooperative Group. 2008. NEJM. 358(19):1991
3. Infante-Ri vard C, Rivard GE, Yotov WV, et al. 2002. NEJM. 347(1):19
4. US Preventive Services Task Force. 2008. Ann Intern Med. 148(10):759
5. Hillier TA, Vesco KK, Pedula KL, et al. 2008. Ann Intern Med. 148(10):766
6. Rowan JA, Hague WM, Gao W, et al. 2008. NEJM. 358(19):2003
7. Crowther CA, Hiller JE, Moss JR, et al. 2005. NEJM. 352(24):2477
8. Langer O, Conway DL, Berkus MD, et al. 2000. NEJM. 343(16):1134