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Diabetes in Pregnancy Martin L Gimovsky MD Division of Maternal Fetal Medicine Newark Beth Israel Medical Center Learning Points • Importance - 17 million diabetics in US + 6 million undiagnosed, 6 – 8% of population • Pathophysiology - A diabetic has metabolic changes that adversely affect blood vessels • Pregnancy - Accelerates/predisposes these metabolic derangements. • Treatment - Seeks to minimize maternal and fetal/neonatal M&M by correcting/compensating for fluctuations in blood glucose. Overview: Diabetes • Hyperglycemic state fasting and/or postprandial • Due to relative/absolute deficiency of insulin • Results in significant changes in intermediary metabolism with striking clinical effects Beta cells Nucleus Endoplasmic reticulum Storage granules The Islet of a Type 1 Diabetic Beta Cells (Injured and then) Destroyed Islet cells and Isle of Langerhans Beta cells in blue Alpha cells in red Delta cells unmarked Type 2 and GDM • Tissue becomes insulin resistant • Hyperglycemia – – – – – Inhibits glucose uptake Results in inadequate insulin response Disrupts pulsatile insulin release Enhances lipolysis in visceral fat Increases FFA, increases insulin resistance • Impaired glucose tolerance elevated FBS and increases PP hyperglycemia Diabetes alters intermediary metabolism Insulin Effects Glucose, aa glycogen Glycogen glucose Protein synthesis Protein catabolism Glucose, amino acid uptake Fatty acid synthesis Inhibits glucose, amino acid uptake Fatty acid release Comparison of Diabetic Types 1=IDDM Habitus Pathology 2=NIDDM (3=GDM) Normal Obese Chronic Increased Autoimmune Insulin Resist No Yes Family History HLA assoc Yes No Sulfonylurea No response Responsive Insulin Low, absent Varies Diabetes in Pregnancy • Common medical complication • 2-5% (2.6%) of live births • 90% are gestational diabetics, White class A1, A2 (GDM & NIDDM) • 10% are overt diabetics, White class B-H (IDDM) Diabetes and Pregnancy • Pregnancy is a “diabetogenic state.” • Placenta has passive control of glucose to fetus, but is impermeable to insulin. • Maternal intermediary metabolism is under control of hormonal influences that insure fetal needs for glucose are met. Pregnancy as a Diabetogenic State • • • • Increasing glucose (&insulin) demand both maternal and fetal Increasing insulin resistance hormone driven Maternal hyperglycemia fetal excess of nutrients fetal hyperglycemia & insulinemia, neonatal hypoglycemia Teratogenesis Catabolism consumes energy & oxygen and episodic fetal hypoxemia, results in fetal hypertension, cardiac remodeling, polycythemia, increased blood viscosity, heart failure, stillbirth Insulin Resistance in Pregnancy • More insulin demand: Increased basal level and response to blood glucose, increased overall demand for glucose • Insulin is less efficient (resistance) – HCS, Prolactin, E&P – Hyperglycemia • Facilitate a continuous supply of glucose for placental transfer Effect of Pregnancy Hormones on Maternal Carbohydrate Metabolism HCS = decreases glucose tolerance Prolactin = insulin resistance Glucocorticoids = glycogenolysis, gluconeogenesis Overview: Recognition Clinical Preclinical • IDDM, NIDDM (I,II) • GESTATIONAL(III) • Poly-dipsia, uria, phagia, glycosuria • Infections • Vascular damage • FBS > 140 mg/dL • Random BS > 200 • Hyperglycemia first seen in pregnancy • Screening: – 50 gram 1 hr > 140 • Diagnosis: – 100 gram GTT 2 abnormal values, or a single value > 200 Classification of Overt Diabetes (IDDM) in Pregnancy Hare and White, Diabetes Care 3:394 1980 Class Onset Duration Vascular Rx B >20 <10 None Insulin C 10-19 10-19 None Insulin D <10 >20 Insulin F - - Benign Ret Renal R,H,T - - Pro Ret, Heart, Renal T Insulin Insulin Effects of Diabetes in Pregnancy • • • • • • • • • • Fetal Anomalies Stillbirth Macrosomia Neonatal Resp distress Hypoglycemia Hyperbilirubinemia Hypocalcemia Hypertrophic Cardiomyopathy • Maternal • Infections, DKA, HyperOsm Vascular damage results in – Retinopathy • Benign • Neovascularization – Renal failure • Microalbuminuria <300 • Nephropathy >300 – Myocardial infarction – Neuropathy • Peripheral • Autonomic Monitoring Blood Sugar • Blood glucose levels both fasting and postprandial are the key indicators • AGP ambulatory blood glucose profile • SMBG self monitored blood glucose • HbA1c glycosylated hemoglobin 4-6 week intervals Normal glucose tolerance in pregnancy Mean BS 85, range 70 - 106 120 AGP 70 Relatively flat, narrow limits IDDM in Third Trimester 3 Injection Regimen Mean 137, Range 100 - 165 Wider limits, increase in mean value Overview: Management of Diabetes • Dietary modifications – Caloric content, distribution of food types, frequency of meals, snacks in context of “Glycemic Index, Load” • Interventional Exercise • Insulin • Oral hypoglycemics Dietary Modification Considerations in Diabetic Diet • Kcal/kg/d (30 kcal/kg/d) • CHO=50%, Protein 25%, Fat 25% (ADA 2002) • Decrease kcal for BMI > 30, increase for BMI<25 (ADA 2002) • Low glycemic foods (slow absorption) • Avoid nocturnal hypoglycemia • Avoid ketonemia Glycemic Index •Pro: Measures how rapidly BG is elevated in response to eating a specific food. •Con: Values not necessarily reflective of how foods are really consumed •Total calories may be more important RCT: diet + exercise > diet alone Bung et al, 1993 Glycemic Response to Exercise: Nonpregnant and Pregnant Exercise lowers BG further and faster in pregnancy Nonpregnant Pregnant • Insulin preparations vary by time to peak action and total duration of action • Lispro- 1h/2h • Regular- 2h/4h • NPH- 4h/8h • Ultralente- 8h/20h Insulin pen Oral Hypoglycemics • First generation: Sulfonylureas (diabinase)-freely crossed placenta High level in neonate Severe & prolonged hypoglycemia Sporadic reports of anomalies Oral Hypoglycemics • Second Generation (Pregnancy category B) – Glyburide, Glipizide, Glimepride – Biguanides Metformin • Fast Acting Secretagogues, and Sensitizers Short duration of action Oral Hypoglycemics • Glyburide – – – – Rx of adult onset diabetes Transplacental dose small No known fetotoxicity, teratogenicity Effect is mildly hypoglycemic to gravida and fetus – Dosed by BMI >< 25 2.5mgs, 5 mgs – Similar effect to a 70:30 mix (NPH:Reg) Control: Insulin vs Glyburide Langer et al: Comparison of glyburide and insulin in women with GDM. NEJM 2000;343:1134-8. Insulin N=203 114,104,104 Mean glucose FBS, Pre, Postpr Hba1c 1T 5.7% Hba1c 3T 5.4 Dose 85+/ -48 units Results No difference Glyburide N=201 116,108,107 5.6% 5.5 9 +/- 6 mgs in neonatal or PN outcome Glyburide vs Insulin Langer et al 2000 Glyburide Insulin LGA 12% 13 Anomalous 2 2 > 4 kgs @ delivery 7 4 NN low BS 9 NICU admit 6 RDS/pulmonary 8 6 7 6 Glyburide After ADA Diet Failure Carolinas Medical Center, 2004 • 4/5 gravidas were controlled, 1/5 insulin – Neonatal Outcome – – – – – 23% had hypoglycemic episode 11% had polycythemia 38% were LGA (> 90th centile) 13% were macrosomic (> 4000 gm) 7% needed (any) respiratory support Glycemic Control: Fetal Outcomes Summary, multiple studies Indicator Threshold/Goal Perinatal Mortality Mean BS < 115 mg/dL Spontaneous Abortion HgA1c < 7% Malformations Postprandial < 140 Macrosomia Mean BS < 100 Neonatal Metabolic Problems Mean neonatal BS > 1 SD below the mean Malformations Postprandial BS < 140 mgs/Dl Perinatal Mortality Mean BS < 115 mg/Dl Neonatal Morbidity in Diabetic Pregnancy GDM (III) Type I Type II Hyperbilirubin 29% 55 44 Hypoglycemia 9 29 24 RDS 3 8 4 Cardiomyopathy 1 2 1 Polycythemia 1 3 3 Neonatal hypoglycemia = Neonatal BG > 1 SD below the mean Maternal Morbidity Class DM A1, A2 B, C D,F,R PIH 10% 8 16 Chronic HBP DKA 10% 8 17 8% 7 9 C/S 12% 44 57 Guidelines for Diabetic Pregnancy Preconception 1st Trimester 2nd Trimester 3rd Trimester Optimal glycemic control Folic acid x 3 months, GC Fetal Viability CRL Fetal Development Level 2 scan Fetal growth baseline 24 weeks MMS Fetal Growth and Well-being Kick count @ 28wks NST/BPP 36 weeks EFW, Deliver at 37-38.5 with amnio, 38.5-40 without Preconception Counseling Maternal medical risks Fetal and neonatal risks Obstetric complications Family/social supports Economic Diabetes and Obesity Fetal surveillance first 28 weeks • • • • 1st Trimester Dx: up to 20% GDM Fetal viabilty Accurate dates • 2nd Trimester • Mult marker screen • Level 2 scan, Fetal cardiac echo • 24 weeks fetal growth • 28 fetal kick counts Diabetic Ketoacidosis • • • • • Type 1 diabetic, 2nd trimester Infections Limited prenatal care Unrecognized new onset of diabetes Inadequate insulin excessive hepatic glucose production Diabetic Ketoacidosis Treatment of DKA • Recognition: hyperventilation, dehydration, hypotension, fruity odor to breathe, elevated BS, + serum ketones 1:4 • Infection, poor compliance, unrecognized onset of DM • Treatment: Vigorous fluid resuscitation (NS) until base deficit is < -4; anion gap is < 12 • Small bolus (10u) then continuous infusion of low dose insulin 5u/hr; Potassium 20 meq/hr, bicarbonate replacement < 1 amp, pH < 7.2 rd 3 • • • • • • Trimester Fetal growth by 32 week scan, Fetus may be IUGR or LGA, EFW Fetal Testing: 28-32 wks BPP, NST 2X Comorbidity with PIH, Chronic HBP Timing of delivery: term or close Confirmation of fetal lung maturity Fetal Demise in-Utero • Increased glucose is catabolized consumes energy & oxygen. • The greater the fluctuation in BS, the more fetal hyperglycemia & hyperinsulinemia • Decrease testing intervals in A2 or >, test twice weekly after 30-32 weeks • Can reduce the risk Comorbidity with Hypertension Blood Pressure during Gestation Fetal Growth Abnormalities in Diabetic Pregnancy by White Class California Diabetes Project, 1991 GDM Class A,B,C Class D,F,R Total >90th% 22% 31 22 24 <10th% 5 5 4 4 Big Babies • Macrosomia – > 4500 gms ACOG, >4250 Langer • Infants of diabetics (IDM) – 15-45% macrosomic • Large for Gestational Age (LGA) > 90th% 30% diabetes in pregnancy, 70% are constitutional • Hard to predict fetal weight, easy to measure neonatal weight Traumatic Birth & Shoulder Dystocia • Risk is > for diabetic fetus/neonate, at any EGA • Suspected macrosomia- size>dates by FH, EFW> 4500 gms (Tech Bull # 30, 2001) • Induction or prophylactic C/S unlikely to reduce the rate of permanent injury • By ultrasound EFW above 4500, actual bwt for ½ is within 10% of estimate • At EFW 4500 gms, then estimate 333 – 1667 C/S to prevent a single permanent Erb’s palsy Respiratory Distress Syndrome • Abnormal timing of phospholipid production delay in PG+ • Higher levels of myoinositol persistence of PI+ • PG/PI less favorable at same EGA • Effect is magnified with mean plasma glucose > 110 mgs • < 38.5 wks w/amnio; >38.5 with > 3% PG Intrapartum Decisions @ 40 wks with good control @ 38 with PG:PI Active phase must be adequate • Protracted descent best managed by C/S • Avoid mid-pelvic operative delivery absolutely • Outlet/low pelvic delivery with great care • Liberal use of C/S Conclusions • Regulation of blood glucose needs to begin prior to conception for best result. • Treatment includes diet, exercise, oral hypoglycemics and insulin. • Comorbidities- Obesity, HBP, CAD • Fetal growth and well being, timing of delivery require attention in 3rd trimester.
