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Insulin in Pregnancy

Insulin in Pregnancy. Prof. Dr. Sarma VSN Rachakonda M.D., M.Sc., (Canada ), FCGP, FIMSA , FRCP (Glasgow), FCCP (USA) Visiting Professor of Internal Medicine, SBMC, FLL, iDRF Consultant Physician and Cardio-metabolic Specialist, Chennai. Screening Test. Glucose Challenge Test (GCT)

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Insulin in Pregnancy

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  1. Insulin in Pregnancy Prof. Dr. Sarma VSN Rachakonda M.D., M.Sc., (Canada), FCGP, FIMSA, FRCP (Glasgow), FCCP (USA) Visiting Professor of Internal Medicine, SBMC, FLL, iDRF Consultant Physician and Cardio-metabolic Specialist, Chennai

  2. Screening Test Glucose Challenge Test (GCT) An excellent screening test is to obtain plasma glucose level one hour after a 50 g glucose load administered at any time of the day without regard to the time since the last meal. It is a well validated and widely applied screening procedure for women between 24 -28 weeks of gestation. Cut-off value > 140 mg/dl identifies 80% women with GDM Cut-off value > 130 mg/dl identifies 90% women with GDM GCT is elevated, do a diagnostic oral glucose tolerance test

  3. Diagnostic Test – OGTT 2 or more values must be abnormal; for at least 3 days prior to the test, the patient should have an unrestricted diet and unlimited physical activity. The patient should fast for 8 hours before the test. The CC criteria detects 54% more women with GDM than NDDG criteria Diabetes 1979;28:1039–1057; Am J OBG. 1982;144:768-73

  4. OGTT –100g –3 hour Test Two abnormal values are enough

  5. Glycemic Control Targets Tight glycemic control can reduce fetal risk. But, stringent glycemic control puts the mother at increased risk of hypoglycemic events and the fetus at risk of being small-for-gestational age. American Diabetes Association (ADA) Recommendations: These are venous plasma targets, not glucometer targets

  6. Glycemic Targets • HbA1C – not ideal for screening of GDM • May used for screening of T2DM • Patients with excessive fetal growth - Insulin • Those who don’t achieve targets in 1w- Insulin • Target values • Hb A1c < 6%; Pre pregnancy Hb A1c < 7% • Fasting – < 95 mg% • Post prandial 1 hour – < 120 mg % • Post prandial 2 hours – < 140 mg% • Urine ketones should be negative Diabetes Care 21(2):B161–B167, 1998, Diabetes Care 2010; 33: 676–682

  7. Freinkel Hypothesis Uterine At Birth After Birth Placenta Macrosomia Obesity Hypoglycemia Metabolic Syndrome Maternal DM  Insulin IGT/DM AA, Fat CHO Fetus CVD

  8. IUGR & Macrosomia Optimal Nutrition + Optimal Glycemic Control Results in optimal birth weight of 3–3.5 kg.

  9. Glucose Metabolism in Pregnancy • First Half of Pregnancy (Anabolic) • Pancreatic beta-cell hyperplasia  hyper insulinemia • Increased uptake and storage of glucose • Second Half of Pregnancy (Catabolic) • Placental hormones block glucose receptors and cause insulin resistance • Increased lipolysis • Increased gluconeogenesis • Decreased glycogenesis • Increased glucose and amino acids for the fetus

  10. Pathogenesis of GDM • Pregnancy is Diabetogenic condition • A Wonderful Metabolic Stress Test • Placental Diabetogenic Hormones • Progesterone, Cortisol, GH • Human Placental Lactogen (HPL), Prolactin • Insulin Resistance (IR), ↑  cell stimulation • Reduced Insulin Sensitivity up to 80% • Impaired 1st phase insulin, Hyperinsulinemia • Islet cell auto antibodies (2 to 25% cases) • Glucokinase mutation in 5% of cases

  11. Fundamental Defect in GDM • The hormones of pregnancy cause IR • They also cause direct hyperglycemia • But, the basic defect is • The maternal pancreatic  cells are unable to compensate for this increased demand • Plasma Glucose in pregnancy hangs on a delicate balance • If the Mean Plasma Glucose (MPG) is • Less than 87 mg% - IUGR of fetus • More than 104 mg% - LGA of fetus • It is important to screen for hypothyroidism

  12. Questions in GDM • Does GDM pose serious risks to offspring? • Does treatment reduce those risks? • Does treatment reduce other risks associated with GDM (obesity/diabetes in offspring)? • Does reducing hyperglycemia reduce risks? (macrosomia & cesarean delivery)

  13. Diabetes in PregnancyWhy is it so important?

  14. Look at the impact of GDM

  15. Congenital Anomalies - DM Control Maternal HbA1c levels < 7.2 Nil 7.2-9.1 14% 9.2-11.1 23% > 11.2 25% Critical periods - 3-6 weeks post conception Need preconception metabolic care

  16. Complications & Glycemic Thresholds

  17. Insulin therapy remains the main stay of treatment and it is being increasingly used.

  18. Physiological Insulin Profile

  19. Insulin Release in Normal Persons

  20. Time Line of Insulins • 1922- Insulin discovery by Banting and Best • 1923- Commercial insulin with impurities • 1975- Higher quality Bovine and Porcine Insulin • 1978- Synthetic Human Insulin • 1982- Synthetic human insulin approved • 1983- Synthetic recombinant human insulin • 1985- Sequencing the human insulin receptor • 1996- Lispro insulin (Lilly) analogue • 2003- Glargine insulin (Sanofi Aventis) analogue • 2004- Glulisine (Sanofi Aventis) analogue • 2006- Detemir insulin (Novo Nordisk) analogue

  21. Ideal Insulin in Pregnancy • Mimic physiological control • No adverse effect upon maternal and fetal outcome. • No interfere with antenatal, perinatal & post natal care • IgG bound insulin can cross placenta. So insulin should not induce antibody generation • Insulin Analogues fulfills all the criteria • Mimic physiological insulin secretion • Does not cross placenta • No mitogenic potential

  22. Analogue Insulins (rDNA)

  23. Analogue Insulins (rDNA)

  24. Advantages of Analogs • Batch to Batch consistency • No allergy, antibody formation • No immune mediated lipoatrophy • Glucose control is similar in endogenous insulin production • Pre prandial hypoglycemia and postprandial hyperglycemia are well controlled. • Mealtime flexibility is possible with analogues.

  25. Benefits of Insulin Analogues

  26. FPG and Insulin Response Brunzell JD et al. J Clin Endocrio Metab. 1976; 42:222-229

  27. Action Profiles of Insulins

  28. Pharmacokinetics of Insulins Barnett AH, Owens DR, Lancet 1977; 349:97-99 and 1997,101:60-70

  29. Insulin Regimens

  30. Dosage of Insulin Therapy • Two parameters – Weight and Gestational age • The level of blood sugar is not the criterion • Insulin requirements increase rapidly, especially from 28 to 32 weeks of gestation • 1st trimester: 0.7-0.8 U/kg/day • 2nd trimester: 0.8-1.0 U/kg/day • 3rd trimester: 0.9-1.2 U/kg/day • Increase every 3 days by 2 units based on BGM

  31. Insulin Titration in GDM Titrate insulin based on SMBG values: • Fasting 60-90 • Pre-meal <95 • 2 hour post-meal <120 • Bedtime <120

  32. Insulin Regimens

  33. Basal-Bolus Insulin Rx.

  34. Multiple Injection Regimen NICE Clinical Guideline 63 March 2008

  35. During Delivery In GDM Insulin requirement precipitously drops after placental expulsion

  36. Total 24 hour Insulin requirement in 60 kg 1st Trimester 60 x 0.7 = 42 units – 2/3 pre BF = 28 U, 1/3 = 14 U evening Of the 28U – 2/3 NPH and 1/3 Regular = (19 + 9) in one inj. Of the 14U – ½ Regular pre supper (7U) and ½ NPH at bed

  37. Barriers for Insulin Rx. • Patient Resistance: (Psychological Insulin Resistance) • Compliance issues, Needle phobia • Fear of scarring, Fear of wrong dosage • Financial, Difficulties in administration • Physician Resistance (Clinician Inertia) • Lack of resources and knowledge of Insulins • Lack of time to plan/follow/educate intensive regimen • Perceived and real adverse effects • Weight gain; Hypoglycemia • Optimal control requires multiple injections

  38. GDM Trials • Crowther et al – Multicenter – 1000 pts. • Langer et all – 1100 GDM, 1100 Normal • HAPO: 28,000 women (Hyperglycemia And Adverse Pregnancy Outcome) • ACHOIS (Australian Carbohydrate Intolerance Study) • MFMU Maternal and Fetal Medicine Unit (NICHD) GDM Trial Int J Gynecology & Obstetrics. 2002,78, (1);69-77

  39. Langer et al – Glyburide Study Langer et al - NEJM 2000: 1343-1138, Oct 19

  40. OAD in Pregnancy: The Other Alternative, O. Langer,

  41. Algorithm for Rx of GDM OAD in Pregnancy: The Other Alternative, O. Langer,

  42. Glibenclamide – Class B, may be other SUs Metformin – Class B ( No statins, No ACEi, ARB) TZD – Not to be used, AGI – Class B GLP-1, DPP IV Inhibitors – More studies needed Current Diabetes Reviews, 2009, 5, 252-258

  43. OADs in Pregnancy • New generation of oral hypoglycemic agents glyburide does not cross the placenta and may be used to replace insulin between 11-33 wks. • Metformin can be used in P.C.O. patients during the whole pregnancy. It showed that it reduces miscarriages and the incidence of GDM • TZDs not studied in pregnancy – not a choice • AGIs – weak drugs – GI side effects -local action • GLP-1 and DPP IV Inhibitors not studied yet

  44. Selective v/s Universal screening Single 50g GCT v/s 100g OGTT OADs – Poor Women’s Insulin Expert Rev. Endocrinol. Metab. 7(2), 165–167 (2012)

  45. Abstract Diabetes in pregnancy is associated with risks to the woman and to the developing fetus. Miscarriage, pre-eclampsia, preterm labour and congenital malformations in fetus are more common in women with pre-existing diabetes. Insulin requirement increases with each trimester of pregnancy in diabetic females. Treatment of gestational diabetes consists of medical nutrition therapy but insulin treatment forms the mainstay of the therapy. Monitoring glycemic control is essential in treatment of gestational diabetes. HbA1c level is helpful to differentiate between a pre-GDM and GDM. Majority of pregnant women with diabetes fail to achieve optimum glycemic control, mostly the postprandial plasma glucose with conventional insulin. In them, the best option is to administer ultra-short-acting analogs, insulin Lispro or insulin Aspart. These analogs improve the postprandial glucose control during pregnancy in both type 1 and type 2 diabetes and are considered safe and effective. Supplement to JAPI • April 2011 • VOL. 59

  46. NICE Clinical Guideline 63 March 2008

  47. Insulin Pumps

  48. Continuous Subcutaneous Insulin Infusion (CSII) • Blood glucose levels monitored continuously • Pre specified insulin dose is s/c delivered by pump • This minimized timing and dosing errors. Continuous Glucose Monitoring System (CGMS) • Blood glucose is assessed periodically • Insulin dose is calculated • CGMS is integrated with a delivery device – blue tooth • Hence round the clock blood glucose is controlled.

  49. Artificial Sweeteners When used within ADI • Aspartame (NutraSweet) • does not cross placenta; • No adverse effects • Sucralose (Equal) – acceptable • Acesulfame K (Sunnet) – acceptable • Saccharin (Nectra Sweet, Sweet Twin) – Crosses placenta; not acceptable • Cyclamate (Sucril) – not acceptable

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