Pregnancy, t he oﬀspring & Beyond..   The problem   Incidence prevalence   DM I and II   Preconception   Gestational DM   Or is it type-‐II (overt diabetes)?   Intra and post partum   Complicates 3-‐5 8% of all pregnancies   Aﬀecting more than 200,000 women in the US each year   Major cause of perinatal morbidity and mortality, as well as maternal morbidity   Gestational diabetes accounts for 80-‐90% and preexisting diabetes accounts for 10-‐20%   More than 50% of gestational diabetics develop Type 2 diabetes mellitus later in life   Our health care crisis is the development of obesity and DM in oﬀspring DM Type Primary Defect Proposed Etiology Onset Ketosis Type I Insulin Deficient Auto-immune Early life Yes Type II Insulin Resistant Receptor defect Later life No GDM Insulin Resistant Pregnancy hormones Pregnancy No (usually) Class A1 A2 Onset Duration Vasc. Dx Gestational Gestational B C D F R Over 20 10-19 Before 10 Any Any <10 10-19 >20 Any Any H Any Any None None None Nephropathy Proliferative Retinopathy Heart Therapy Diet Insulin/ Glyburide Insulin Insulin Insulin Insulin Insulin Insulin   Perinatal mortality   Stillbirth 10-‐30% (much less currently)   Most after 36 weeks   Perinatal morbidity   IUGR   Macrosomia   Preterm delivery   Preeclampsia   Intrauterine asphyxia   Fetal anomalies Despite advances in maternal morbidity, congenital fetal anomalies remain 4x (up to 10x) as frequent in DM as in non-‐diabetic pregnancy!   Pregnancy characterized by increased insulin resistance and reduced sensitivity to insulin action   Largely a result of placental production of human placental lactogen and progesterone, TNF’s receptors, other unknowns   Other hormones such as prolactin and cortisol may contribute   Diabetes poorly controlled at time of conception and early gestation has higher risk of spontaneous abortion and major congenital abnormalities.   Early in pregnancy, higher levels of estrogen enhance insulin sensitivity and thus risk of maternal hypoglycemia   Insulin resistance most marked in third trimester   2nd trimester, maternal hyperglycemia causes stimulation of fetal β cells and fetal hyperinsulinemia   Insulin is major fetal growth hormone and produces excessive fetal growth, especially in fat, the most insulin sensitive tissue   Fetus of poorly controlled diabetic is more likely to be macrosomic, disproportionately large in shoulders and chest, more than doubling the risk of shoulder dystocia   Macrosomic fetuses at risk for stillbirth in last 4-‐6 weeks of pregnancy   Hyperinsulinemia can increase rate of respiratory distress syndrome   Rate of preeclampsia doubled, especially when maternal nephropathy exists, rates up to 40%.   In setting of hypertension and nephropathy, fetal growth restriction is more than doubled   Long term adverse outcomes include obesity and carbohydrate intolerance/DM Obesity & DM Preventable Pandemic Study Population Prevalence (%) Harris et al, 1997 Native American (Cree) 8.3 Henry et al, 1993 Australian 7.8 Vietnamese 4.3 African American 7.5 Nahum et al, 1993 White 4.7 Asian 4.2 Lopez-‐de la Pena et al, 1997 Mexican 6.9 Yalcin et al, 1996 Turkish 6.6 Rith-‐Najarian et al, 1996 Native American (Chippewa) 5.8 Fraser et al, 1994 Israeli 5.7 Bedouin 2.4 Rizvi et al, 1992 Pakistani 3.5 Miselli et al, 1994 Italian 2.3 Serirat et al, 1992 Thai 2.2 Jang et al, 1995 Korean 2.2 Mazze et al, 1992 White, Minnesota 1.5   Malformations 30-‐50% of PNM   Neonatal deaths from anomalies exceed stillbirths (congenital malformations)   2-‐6X increase in major malformations (up to 10%)   Direct Glucose eﬀect? Old notion   Multifactorial etiology   Hyperglycemia   Ketone excess   Somatomedin inhibition   Arachidonic acid deﬁciency   Free oxygen radical excess   Decrease in antioxidant (HDL)   Altering expression or penetrance   Fasting BS level vs HgA1C Recommendations Procedure/test Tests Hx, FH, ROS FBS, pp, clarify When to attempt pregnancy, type HbA1c… Phys exam HTN, Retinopathy, Goiter, Neuropathy, Obesity, Proteinuria ECG, ECHO, renal, T-4 TSH, Ab’s Anthypertensives, Opthalmology, Vascular, podiatry, Nephrology, exercise, wt loss DM assessment HbA1c, Home Glycemic control monitoring, Stable profile Occupational & Lifestyle changes Dietician, lifestyle commitments, tight control   Focus on importance of euglycemic control before pregnancy as well as adverse obstetric and maternal outcomes that result from poorly controlled diabetes   Search for underlying vasculopathy   Consider opthalmology evaluation, 24 hour urine for protein & creatinine clearance, EKG   Thyroid function studies   Multivitamin with folic acid   ACE inhibitors discontinued   Oral hypoglycemics converted to insulin   Obesity   Retinopathy   Nephropathy   Neuropathy   Gastropathy   Coronary artery disease   Presence and severity and progression related to poor glycemic control   Rapid institution of strict glycemic control associated with worsening in pregnancy, now thought to be predated by poor control   Pregnancy does not aﬀect long term   Active proliferative retinopathy may worsen in pregnancy   Patients scheduled for screening retinal examination at ﬁrst visit. If retinopathy, F/U visits during pregnancy and postpartum recommended   Increases risk of maternal hypertensive complications, including preeclampsia, preterm birth, fetal growth restriction   Renal dysfunction by decreased creatinine clearance and proteinuria best predictor of poor perinatal outcome   Proteinuria increases in pregnancy, but generally no permanent worsening   Those with advanced renal disease (Cr > 1.5 mg/dL), pregnancy may accelerate progression to end-‐stage renal disease   Baseline 24 hr urine for total protein and creatinine clearance preconceptually or at ﬁrst visit   Those with long-‐standing disease with hypertension and nephropathy highest risk   Hemodynamic changes associated with pregnancy increase myocardial stress   Coronary artery disease potential contraindication to pregnancy   Should undergo preconceptual counseling and understand risks   Baseline echocardiogram and EKG   Nausea and vomiting in pregnancy may be worsened with gastroparesis   Diabetic neuropathy not well studied in pregnancy   FGR   Associated with vascular disease   Macrosomia   Substrate   Body growth   Fetal injury   Stillbirth   IDM   Juvenile & adult risks   Obesity   DM   Mother   End organ disease   Shortened life expectancy   Obesity   Operative morbidity   Clinical management   Obtain euglycemia   Attention to endo-‐organ disease   Constant teaching (once to twice weekly)   Fetal monitoring   Growth   Anomaly screen   Surveillance May be dealing with DM-‐II IGT/IFG   Deﬁned as carbohydrate intolerance of variable severity with onset or ﬁrst recognition during pregnancy   Complicates 5-‐10% of pregnancies   More common in Hispanics, Native Americans, African Americans, Asian Americans   Rate will rise as obesity increases   Improved perinatal outcome with treatment No universal agreement on screening all obstetrical patients for GDM. US Preventative Task Force, & Canadian Health Care Task force “…concludes that the evidence is insuﬃcient to recommend for or against screening for gestational diabetes   Reasons to screen 1.  Identify women with GDM in which treatment will reduce risk of macrosomia and identify women with greater risk of fetal death 2.  Identify women with GDM in which interventions after delivery may delay or prevent the onset of type 2 diabetes mellitus 3.  Improve outcome of oﬀspring 1.  2.  3.  4.  5.  Macrosomia Hypoglycemia Hyperbilirubinemia Hypocalcemia Erythremia (polycythemia)   The American Diabetes Association propose that women at low risk for GDM need not be screened Less than 25 years of age Normal body weight (BMI < 25) No ﬁrst-‐degree relative with DM Not a member of ethnic group at high risk for Type 2 DM 5.  No history of abnormal glucose metabolism 6.  No history of poor obstetric outcome 1.  2.  3.  4.    One study showed this would only eliminate 10% of screens thus most universally screen   Age older than 35 to 40 years   Obesity (BMI > 30)   History of GDM               Delivery of a previous LGA infant Polycystic ovary syndrome A strong family history of diabetes Previous anomaly Glycosuria? HTN Member of certain ethnic groups *May diagnose 6-‐20% of total GDM if screened on entry   50 gram, 1 hour glucose tolerance test between 24-‐28 weeks (do not need to fast)   Abnormal is > 130 or > 140 and next step is 3 hour glucose tolerance test (overnight fast)   Value of 200 or greater-‐gestational diabetes   If at high risk for GDM, screen at initial visit and repeat between 24-‐28 weeks if negative NDDG (mg/ml) Fasting One hour 105 190 Carpenter/ Coustan (mg/ ml) 95 180 Two hour 165 155 Three hour 145 140   What should be done with one abnormal value?     Women with one abnormal value are more likely to deliver a macrosomic infant and increase risks of PNM and pregnancy complications Reasonable options Place on diabetic diet 2.  Repeat oral GTT in 4 weeks 3.  High index of clinical suspicion 4.  Occasional use of FBS and 2 hr pp 1.    HAPO   NEJM 2008;358:1991-‐2002   Assoc. of maternal glucose tolerance (less than DM)   BW> 90 percentile   Cord blood serum C-‐peptide > 90 percentile   lesser with C-‐delivery & neonatal hypogycemia   Secondary Outcomes, positive assoc. 1.  2.  3.  4.  5.  6.  PTD Shoulder dystocia Birth injury NICU care Hyperbilirubinemia preeclampsia  First Visit  FPG  Hemoglobin A1c  Random plasma BG  All or Only high-‐risk women Guidelines Thresholds   First Visit   FPG   Hemoglobin A1c   Random plasma BG   All or Only high-‐risk women   FPG 126 mg/dl   HgA1c 6.5%   Random BG 200 mg/dl   FPG 126 mg/dl   HgA1c 6.5%   Random BG 200 mg/dl OVERT DIABETES Guidelines Thresholds   First Visit   FPG   Hemoglobin A1c   FPG 92-‐126   HgA1c 5.1-‐7.0 FPG <92 •  Test for GDM at 24-28 weeks •  75 gm OGTT GDM   GDM Screening   Two Hour O/N FASTING, 75 gm OGTT   FPG > 126 mg/dl Overt DM 1 or More of the following:   FPG > 92 mg/dl   1 hr > 180 mg/dl GDM   2 hr > 153 mg/dl   Normal results ALL values on OGTT less than thresholds   Insuﬃcient Data of a beneﬁt to Dx and Rx GDM before window of 24-‐28 weeks GA   All Women with GDM or Overt DM during pregnancy should undergo postpartum glucose testing   Patient seen every 1-‐2 weeks until 36 weeks gestation, then weekly   Diabetic diet is important cornerstone   Generally 2000-‐2200 calories per day   Emphasize complex high-‐ﬁber carbohydrates with exclusion of concentrated sweets   Underweight 35 kcal/kg/day   Normal body weight 30 kcal/kg/day   Overweight 25 kcal/kg/day   Exercise encouraged 20-‐30 minutes/day, 3-‐4 x/ wk   Glucose monitoring-‐Fasting and 1 or 2 hour post prandial   Fasting < 95 mg/dl   1 hour post prandial < 130-‐140 mg/dl   2 hour post prandial < 120 mg/dl   If compliant with diet and > half of BS elevated, then insulin therapy initiated   Starting insulin dose based on pt weight   First trimester 0.8 U/ kg/day   Second trimester 0.9 U/ kg/day   Third trimester 1.0 U/ kg/day   3 shot regimen preferred-‐ NPH @ HS by some   Regular insulin or insulin lispro can be used Total 24-h Dose AM 2/3 Dose 2/3 NPH 1/3 Regular PM 1/3 Dose 1/2 NPH 1/2 Regular   Alternative to insulin therapy is oral hypoglycemic-‐Glyburide   2nd generation sulphonylurea   Does not cross placenta (high protein binding)   Onset of action 4 hours   Duration of action 10 hours   Starting dose 2.5 mg P.O. BID   Maximum dose 10 mg P.O. BID   5-‐10% failure higher with BMI   Antepartum testing   Diet controlled-‐NST 2x/wk at 40 weeks   Insulin/Glyburide controlled-‐NST 2x/wk at 32 weeks   Clinical estimation and US used to detect macrosomia   If EFW > 4500 grams, cesarean section should be considered to decrease shoulder dystocia   Patients with GDM-‐Diet followed until 40-‐41 weeks   Patients with GDM well controlled with insulin/ glyburide may be followed to due date   Patients with GDM not well controlled, consideration of delivery 37-‐39 weeks with documented lung maturity by amniocentesis   In labor, patients with GDM-‐Insulin/Glyburide should have glucose levels checked every 1-‐2 hrs   Rarely require insulin therapy to maintain glucose level below 120 mg/dl   After delivery, infant should be observed for hypoglycemia, hypocalcemia, and hyperbilirubinemia   Breast feeding should be encouraged   Patient should be evaluated postpartum for diabetes   3-‐15% will be diabetic at that time   >50% will develop diabetes during their life   ADA recommends evaluation by 75 gram oral GTT done 6-‐8 weeks after delivery   Fasting glucose may be alternative   If negative for DM, screen every 3 yrs suggested   Low dose estrogen and progesterone OCP can be used for contraception   Dietary management   Monitorng   Exercise   Fetal Surveillance   Medical treatment   Insulin   Oral agents   Fasting and postprandial monitoring   FBS <95, 2hr pp <130   Nutritional counseling   Complex CHO   Diet based on BMI   Moderate exercise   Signiﬁcant decrease in BS   Q 3-‐4 month HgA1C(feedback)   None for diet controlled DM A1   Begin at 32-‐34 weeks for   Any treatment/intervention group   Glyburide   Insulin   2x/week NST, weekly AFI   Weekly BPP or CST   Deliver at term or amniocentesis if lack of control   Cardiovascular conditioning   Improves glycemic control   Increased tissue sensitivity to insulin   Improves health   Creates healthy habits   Pregnancy (in absence OB-‐contraindications)   Swimming, bicycles, walking   20-‐30min/day up to FHR 140 bpm   Euglycemia   Prevent ketosis   Adequate weight gain   Improve fetal well-‐being   Improve maternal well-‐being   Improve habits for future   Better maternal Health   Improved oﬀspring health   Lower incidence of LGA infants   Lower C-‐delivery rate   Normal body weight 30-‐35 kcal/kg/day   < 90% body weight 30-‐40 kcal/kg/day   > 120% body weight 24 kcal/kg/day   Caloric composition   40-‐50% Carbohydrates   20% Protein   30-‐40% Fats   Calorie distribution   10-‐20% Breakfast   20-‐30% Lunch   30-‐40% Dinner   Up to 30% Snacks, especially bedtime snack with this intervention & compliance 70-‐80% will achieve euglycemia   Emphasis on the total carbohydrate (“carb”) grams eaten throughout the day at each meal and snack   The total “carbs” are balanced with insulin and activity   Each “carb” choice is equal to 15 grams of carbohydrate   Allows more ﬂexibility with diet Insulin & Glyburide (GDM only)   Starting doses Trimester Insulin 1st 0.8 Units/kg/day 2nd 0.9 Units/kg/day 3rd 1.0 Units/kg/day   Goals   Fasting glucose < 95 mg/dL   Premeal glucose < 100 mg/dL   1 hour postprandial < 140 mg/dL   2 hour postprandial < 120 mg/dL   During night glucose > 60 mg/dL TIMING OF HOME CAPILLARY GLUCOSE MONITORINGCapillary Glucose Assessment + Preprandial BS Permits prospective adjustment of food intake, supplementation of preprandial insulin -‐ Preprandial or fasting glucose levels correlate poorly with fetal morbidity. Signiﬁcant postprandial hyperglycemia may go undetected. + Postprandial Permits supplementation of insulin to reduce postprandial glucose overshoots; improved postprandial control correlates with improved fetal or neonatal outcome -‐ Postprandial Results are obtained after food intake. + Bedtime BS Permits adjustment of calories at bedtime snack, adjustment of bedtime insulin + 3-‐4 AM BS Enables detection of nocturnal hypoglycemia -‐ 3-‐4 AM BS Interrupts sleep, may increase stress Type Name Very Shortacting Lispro NovoLog Short-acting Regular Onset Peak 5-15 min 45-75 min Duration 2-4 h 30 min 2-4 h 5-8 h Intermediate- NPH acting Lente 2h 6-10 h 18-28 h Long-acting Ultralente 4h 10-20 h 12-20 h Lantus 2h No peak 20-24 h   Advantages   Variable basal rates   Patient ﬂexibility   Uniformity   Disadvantages   Constant pump attachment   Pump malfunction   Pregnancy   Equivalent to split dose         and long acting insulin Higher incidence of insulin reactions Lower lows Practitioner/patient preference More frequent site changes in later pregnancy   Mechanism   Stimulate pancreatic β-‐cells to secrete more insulin in basal and postprandial states   Can decrease overnight hepatic glucose output   Candidates   Gestational A2DM with relatively normal fasting blood glucose levels   ? Type II DM with residual β-‐cell function* *Caution in pregnancy   Mechanism   Increase insulin-‐mediated glucose utilization in peripheral tissues   Suppress hepatic glucose output   Antilipolytic eﬀects to lower serum free fatty acid concentrations   Candidates   Polycystic ovarian syndrome (PCOS)   OK in ﬁrst trimester   Type II DM and GDM? Verdict not yet out* *Caution in pregnancy, crosses placenta, ? preeclampsia   Early studies and later reviews suggest equal eﬃcacy of glyburide when compared to insulin for GDM   Metformin demonstrate improved ovulation rates and decreased spontaneous abortions in patients with PCOS   Caution is advised when using oral agents alone for patients with pre-‐existing Type II DM in pregnancy   Metformin may be equal to Glyburide us of Metformin in pregnancy guarded.   Barriers   Implantable devices   IUD   Progesterone   Combination OCP’s   DMPA   Surgery   Decreased needs   Breast feeding (decreases type-‐2-‐DM 15%)   Both mother and infant   Honeymoon   Decreased pregnancy resistance Test (6-‐12 weeks pp) Diabetes Impaired Fasting Glucose Impaired Glucose Tolerance Fasting Plasma glucose >126 100-‐125 N/A 75 g 2 hr GTT Fasting >126 or 100-‐125 140-‐199 2 hr >200 1.  Normal result screen every three years 2.  IFG or IGT implement testing or Rx/referral as needed, including wt loss management, lifestyle changes, ? Metformin????   Combination of diet, exercise, and insulin   Patient seen every 1-‐2 weeks during ﬁrst two trimesters and weekly after 28-‐30 weeks gestation   Carbohydrate counting increases dietary ﬂexibility and useful as long as total daily caloric intake is considered to avoid excessive weight gain   Dietary consultation useful Oﬀer MSAFP to screen for neural tube defects Level II Ultrasound at 18-‐20 weeks Fetal Echocardiogram 22-‐24 weeks Antepartum testing 2x/wk starting at 32 weeks with weekly AFI   Consider ultrasounds for growth   If steroids administered, monitor BS closely-‐may need Insulin drip   Well controlled patients can deliver 39-‐40 weeks   Uncontrolled patients deliver at 37-‐38 weeks with documented mature fetal lung studies   Consider cesarean section for EFW > 4500 grams           During labor, insulin drip to maintain BS < 120 mg/dL   Restart insulin at half pregnancy dose when starting regular food intake   For patients after C-‐Section, sliding scale can be used until regular food intake   Breast feeding encouraged   Discuss family planning   Preconceptual   Conceptual   Control baseline   Teaching   End-‐organ involvement   Surveillance   Disease progression   Compliance   Associated   Psycho/social complications   Expectations   Surveillance   “letting go”   Engage in care   Overt diabetes   FBS > 126, A1C >6.5, Random BS >200   Gestational DM   FBS >92 but <126 at ﬁrst visit   2 hr 75gm OGT 24-‐28 weeks at least one abnormal result THANK YOU!