GESTATIONAL DIABETES MELLITUS - CURRENT CONCEPTS

1. Dr.Vivek Sundaram.MD.DNB.MRCP(UK) Consultant – Internal Medicine,Diabetes & Critical Care Sundaram Hospital,Trichy. GESTATIONAL DIABETES MELLITUS - CURRENT CONCEPTS

2. Watching TV for 2 hours/day increases Risk of diabetes by 20%....JAMA,June 2011

3. ARETAEUS(200 A.D.) “….wonderful affliction with melting down of flesh and limbs into urine…..patient never stops making water ..……illness is chronic but the patient shortlived”

4. Gestational Diabetes Mellitus (GDM) is defined as -“carbohydrate intolerance with recognition or onset during pregnancy, irrespective of the treatment with diet or insulin.” The importance of GDM is that two generations are at risk of developing diabetes in the future. Definition

5. The maternal metabolic adaptation is to maintain the mean FBG of 74.5 ± 11 mg/dl and the PPG peak of 108.7 ± 16.9mg/dl.1 Compensatory hyperinsulinaemia due to insulin resistance. • Failure of beta cells secretion to overcome the insulin resistance leads to GDM.

6. Hyperglycaemia during pregnancy is associated with high risk of maternal and perinatal morbidity and mortality Diagnosis of GDM identifies women at high risk of future diabetes, offers opportunity of primary prevention Maternal hyperglycaemia is associated with development of type 2 diabetes in the offspring Diabetes and Pregnancy – Why it is relevant?

7. GDM……… Pregnancy – diabetogenic condition (metabolic stress test) Unmasks a compensated metabolic abnormality A direct consequence of the altered maternal metabolism stemming from the changing hormonal milieu.

8. IGT GDM 2% Agarwal S, Gupta AN. Gestational Diabetes. J Assoc Physicians India 1982;30:203 2% Ramachandran A, et .al., High prevalence of diabetes in an urban population in south India. BMJ 1988;3; 297(6648):587-90 GDM prevalence linked to background IGT rates 1980s 7.6% Narendra J, Munichoodappa C, et al, Prevalence of glucose intolerance during pregnancy. Int J Diab Dev Countries 1991;11:2-4 8.2% Ramachandran A, Snehalatha c, Dharmaraj D, Viswanathan M. Prevalence of glucose intolerance in Asian Indians. Diabetes Care 1992; 15:1348-55 1990s 14.5% Ramachandran A, Snehalatha C, Kapur A, Vijay V, Mohan V,Das AK, Rao PV, Yajnik CS, Prasanna Kumar KM, Nair JD.For the Diabetes Epidemiology Study Group in India (DESI).Diabetologia 2001;44:1094-1101. 16.6% V Seshiah, V Balaji, Madhuri S Balaji, CB Sanjeevi, A. Green. Gestational Diabetes Mellitus in India. J Assoc Physicians India 2004;52:707 2000s

9. Uterine At Birth After Birth FREINKEL HYPOTHESIS placenta Macrosomia Obesity Hypoglycemia Maternal DM Metabolic syndrome IGT/DM Amniotic Fluid Insulin Fetus A.A Fat CHO CVD

10. Pathophysiology • Human Placental Lactogen (HPL) • Produced by syncytiotrophoblasts of placenta. • Acts to promote lipolysis  increased Free fatty acids contributing to tissue insulin resistance. • Estrogen and Progesterone • Interfere with insulin-glucose relationship. • Insulinase • Placental product that may play a minor role.

11. Pathophysiology Normal pregnancy : - Mild fasting hypoglycemia – increased lipolysis and FFAs become the main fuel substrate for the mother ( Mediated by human placental growth harmone)-”accelerated starvation” - Postprandial hyperglycemia – insulin resistance aids glucose transfer to the fetus –”facilitated anabolism”

12. GDM –POSTPRANDIAL HYPERGLYCEMIA IS MORE RELEVANT

13. Age  35 years • Obesity (BMI  30 kg/m2) • Family history • Previous delivery of a macrosomic infant • Member of a high-risk population • Polycystic ovarian syndrome • Previous abnormal glucose tolerance Risk Factors INDIAN - ETHNICITY

14. Early or late sreening? • WHO or ADA criteria • One step or twostep? • 75 or 100 gm? • 1 hour or 2 hour? • To treat or not ? • Insulin or pills? • Early or late delivery? • C section or normal? • Breast feed or not? GDM dilemmas

15. UNIVERSAL • First booking – Differentiates pre GDM from GDM • 24-28 weeks [ Repeat - GTT] • 32 -34 weeks [ Repeat -GTT] Who & When to screen?

16. One Step Approach – Validated in the indian population • 2 hrs value >140 mg/dl with 75g oral glucose -GDM ( irrespective of the time last meal was consumed) Definitive test: 75gm 2 hour OGTT ( ADA Criteria) • If negative rescreen at 24 weeks /32 weeks • If positive proceed to treatment How to screen?

17. Gestational DM-Revised ADA criteria (2011)75 g OGTT at 24-28 wks of gestation _ _ _ ANY 1 ABNORMAL VALUE - GDM 100 g OGTT – O,I,2,3 hr values …. 95,180,155,140 …2 abnormal values

18. “Abnormal” Plasma Glucose during Pregnancy Occurrence of birth weight of new born > 90th percentile was continuum as FPG increased from 80 mg/dl and was significant above 90 mg/dl(adjusted odds ratio 2.08 [ 95% CI 1.24 – 3.48], P = 0.005]) The occurrence of macrosomia was continuum as the 2 hr plasma glucose increased from 120 mg/dl(adjusted odds ratio 3.02 [ 95% CI 1.30 – 7.00], P < 0.05]) Balaji V, Balaji MS, Seshiah V, Mukundan S, Datta M.Diabetes Res Clin Pract. 2006 Aug;73(2):223-4. V Seshiah, V Balaji,Madhuri S Balaji, A Paneerselvam. Abnormal Fasting Plasma Glucose during Pregnancy. Diabetes Care vol 31 (12): e92, December 2008 Abnormal : FPG > 90 & PPG > 120 mg/dl

19. TARGET BLOOD GLUCOSE LEVELS Balaji V, Balaji MS, Seshiah V, Mukundan S, Datta M.Diabetes Res Clin Pract. 2006 Aug;73(2):223-4. V. Seshiah, AK Das, Balaji V, Shashank Joshi, MN Parikh, Sunil Gupta for DIPSI. GDM- Guidelines. JAPI vol 54, 2006, 622-28 Oded Langer. Maternal glycemic criteria for insulin therapy in GDM. Diabetes care, vol 21 (2), August 1998. B91-98. Birth weight between 2.5 and 3.5 Kg Vinod K Paul, Ashok K Deorari, Meharban Singh. Management of Low Birth Weight Babies. In: IAP Textbook of Pediatrics. 2nd ed. A. Parthasarathy, editor. Jaypee publications, 2002, p60.

20. GDM – Fetal Morbidity • Macrosomia of the baby • CPD – Shoulder Dystocia • Intrapartum Trauma – Feto-maternal • Neonatal Hypoglycemia • Neonatal Hypocalcemia • Neonatal Hyperbilirubinemia • Respiratory Distress Syndrome (RDS) • Polycythemia (secondary) in the new born

21. Fetal Morbidity

22. Maternal Morbidity • Hypertension/Preeclampsia and Eclampsia • Cesarean delivery; Pre term labour • Polyhydramnios – fluid > 2000 ml • Post-partum uterine atony • Abruptio placenta • 40-60% risk of DM (screen 6 wk/6 mths after delivery)

23. AimTo maintain plasma glucose values as to that of non diabetic pregnancy MANAGEMENT

24. Medical nutrition therapy (MNT) • Exercise • Insulin How to treat?

25. MNT • 2 wk trial – if uncontrolled switch over to insulin • 30 kcal/kg/day for 60 kg • BMI>30- 25kcal/kg/day • 300 extra calories for 2 & 3 trimester • 3 meals & 3 snacks - avoid hypoglycemia • 40 – 50% of calories as CHO,25% each as fat and protein

26. Exercise • Women with GDM often need regular, moderate physical activity to help control their blood sugar levels by allowing insulin to work better. • Examples include: • Walking • Prenatal aerobics classes • Swimming Keep in mind that it may take 2 to 4 weeks before physical activity has an effect on blood sugar levels.

27. Safe ,Effective, time tested • Human Insulin preferred • Short acting analogues – good option • May need short term hospitalization • Monitoring fasting, premeals & post meal Insulin therapy

29. Insulin secretion defect in diabetes Normal Diabetes Plasma-immunoreactive Insulin (µU/mL) Plasma-immunoreactive Insulin (µU/mL) 1ste fase (acute afgifte) 120 120 100 100 80 80 60 60 40 40 2e fase 20 20 0 0 -30 0 30 60 90 120 -30 0 30 60 90 120 Time (min) Time (min) Fonseca V. Curr Med Res Opin 2003;19:635–641.

30. Basal needs: Intermediate-/long-acting insulins (NPH, ILPS, detemir, glargine) Bolus needs: Rapid-/short-acting insulins given with meals (lispro, aspart, glulisine, human regular insulin) Insulin Therapy- Physician Expectations Insulin therapy should closely mimic normal insulin physiology Meal Meal Meal Expected insulin changes during the day for individuals without diabetes Insulin effect images are theoretical representations and are not derived from clinical trial data. • Normal insulin physiology is matched by multiple insulin injections

31. Comparison of Human insulins/Analogs Insulin Onset Peak Duration Short acting Regular 30-60 min 2-4 h 4-6 h Lispro/aspart 5-15 min 1-2 h 3-4 h Glulisine Intermediate acting NPH 1-4 h 4-8 h 10-20 h Long acting Glargine 1-2 h Flat ~24 h Detemir 1-4 Flat 12-20

32. So, Why Modern Insulins ?

33. Peak time 2-4 hr Peak time 1 hr Dissociation of Insulins Regular Human Insulin 10-3 M 10-3 M 10-5 M 10-8 M Û Û Û Formulation Capillary membrane Analogs 10-3 M 10-3 M 10-3 M Û Û Formulation Transient

34. Limitations of conventional soluble human insulin • Inability of s.c. injected soluble insulin to mimic the physiological pattern • Delayed onset of action (30-60 min after injection) i.e. should be injected 30-60 min prior to a meal • Prolonged duration of action (6-8 hrs after injection) • Inadequate insulin when in need • Insulin when not needed Presentation title

35. Presentation title • Regular insulin fails to match normal insulin peak Fails to match the physiology The shortcomings of conventional insulin (regular) • Physiological insulin profile: • basal component • meal-related peaks

36. Presentation title • Mixtard fails to re-create the physiological insulin profile Shortcomings of human insulin • Physiological insulin • profile: basal component • meal-related peaks Period of unwanted hyperglycemia Period of unwanted hypoglycemia

37. What is premixed insulin? Premixed is a suspension of: Soluble insulin analogue 30% 30% Soluble human insulin Protamine-crystallised insulin NPH Presentation title

38. INSULIN TACTICS Twice-daily Split-mixed Regimens Regular NPH Insulin Effect B L S HS B 6-23

39. Lispro Lispro NPH NPH Insulin Effect Insulin Effect B L S HS B B L S HS B INSULIN TACTICS Multiple Daily Injections (MDI):NPH + Mealtime Lispro NPH at AM and HS + Lispro AC NPH at HS + Lispro AC 6-29

40. Insulin Regimen • If MNT fails after 2 wks of trial initiate Insulin • Dose: 0.7, 0.8 and 0.9 u/kg – 1, 2 & 3 trim. • Eg. 1st trim – 64 kg = 0.7 x 64 = 45 units • Give 2/3 before BF = 30 units of 30:70 mix • Give 1/3 before supper = 15 u of 30:70 mix • Increase total dose by 2-4 units based on BG

41. Oral agents -GDM ADVANTAGES Easy to take Need far less education Affordable No social stigma Glibenclamide ( Currently not recommended) Metformin – Select group ( pre GDM/PCOS) Not endorsed by any formal recommendations apart from NICE Guidelines

43. Original ArticleMetformin versus Insulin for the Treatment of Gestational Diabetes Janet A. Rowan, M.B., Ch.B., William M. Hague, M.D., Wanzhen Gao, Ph.D., Malcolm R. Battin, M.B., Ch.B., M. Peter Moore, M.B., Ch.B., for the MiG Trial Investigators N E J M.358(19):2003-2015 May 8, 2008

44. HbA1c in early pregnancy - differentiates between a pre gestational diabetic and GDM. If the HbA1c level is more than 6%, she is likely to be a pre GDM. • HbA1c is useful in monitoring the glucose control during pregnancy, but not for the day to day management. Estimation of fructosamine during pregnancy is less frequently used. Monitoring HbA1c Levels

45. Universal screening ideal for our women • 2 hour 75 gm screening is cost effective • 2 hour 75 gm – GTT ( Definitive test) • Diet and exercise provides good control in many • Insulin analogues are safe and very effective • Oral agents are an alternative – in select situations • Postpartum follow-up is an integral part of GDM management Conclusions

46. Remember how fortunate we are to be included in the lives of our patients at the most precious times of their lives Richard S. Hollis President ACOG

47. ILLNESS WELLNESS

48. THANK YOU