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1. DIABETESIN PREGNANCY Devanraj Selvam The Anatomy of a Pregnant Woman Jacques Fabien Gautier D’Agoty (1717-1785)

2. INTRODUCTION DIABETES IN PREGNANCY [1] PREGESTATIONAL (10%) GESTATIONAL (90%) Defined as glucose intolerance of variable severity with onset or first identified during the present pregnancy. Generally occurs in the latter half of the pregnancy; hence there is no effect on organogenesis and does not cause congenital defects. Generally disappears after delivery as the hormonal levels revert back to normal. It is pregnancy in a known or overt diabetic. May either be Type 1 or Type 2 DM. Type 1 occurs in a younger age group and end organ complications are likely to be more in these patients. Type 2 is rare during pregnancy except in those women who are obese or above 35 years old. Buchanan TA, Coustan DR. Diabetes mellitus. In Burrow GN, Ferris TF, eds, Medical Complications in Pregnancy. 4th ed. Philadelphia, Pa: WB Saunders; 1995: 29-61.

3. PATHOPHYSIOLOGY OF GDM

4. GESTATIONAL DIABETES MELLITUS Pregnancy is a diabetogenic state. Maternal metabolism is altered to ensure there is an appropriate supply of glucose to the foetus.

5. GESTATIONAL DIABETES MELLITUS 3. Normal pregnancy is characterised by; a) Mild fasting hypoglycaemia b) Postprandial hyperglycaemia c) Hyperinsulinaemia 4. Due to peripheral insulin resistance which ensures an adequate supply of glucose for the baby.

6. GESTATIONAL DIABETES MELLITUS 5. Maternal insulin does not cross the placenta.

7. GESTATIONAL DIABETES MELLITUS 6. Anti-insulin hormones a) Oestrogen b) Progesterone c) Prolactin d) Cortisol e) Human Placental Lactogen (hPL)

8. GESTATIONAL DIABETES MELLITUS These hormones; a) oppose the action of insulin less effective. b) This subsequently causes a state of insulin resistance. c) There is progressive decline in insulin sensitivity. 8. Further aggravated by increased body weight and caloric intake during pregnancy.

9. HUMAN PLACENTAL LACTOGEN (hPL) Produced by syncytiotrophoblastof the placenta. Affects protein, fat and carbohydrate metabolism. Promotes lipolysis and the available free fatty acids (FFA) are used for the mother’s own metabolism as to ensure adequate glucose supply to the foetus. Primary chorionic vili

10. HUMAN PLACENTAL LACTOGEN (hPL) Elevated FFAs also increase insulin resistance. As a result, the circulatory glucose level is raised to meet the foetal needs.

11. INSULIN In response of these physiological changes, the maternal pancreas increases the production of insulin to maintain a stable carbohydrate metabolism. However, the increase in insulin is ineffective  peripheral resistance of its action by the ‘anti-insulin’ hormones. 3. GDM develops when the pancreas, despite the production of insulin, cannot overcome the effect of these counter-regulatory hormones.

12. PREGNANCY DIABETOGENIC HORMONES PANCREAS Placental hormones Insulin production Cortisol  MATERNAL BLOOD SUGAR Oestrogen Progesterone Prolactin Antagonise insulin action and peripheral resistance Carbohydrate Metabolism hPL  FFAs (used for maternal metabolism ) Lipolysis Glucose spared for foetus

13. TESTING FOR GDM Screening Test Diagnostic Test

14. SCREENING FOR GDM GDM is asymptomatic and hence, the need for screening. However, there is NO CONSENSUS regarding the method or the type of screening tests. Two methods of screening that are commonly practised nowadays are: a) Selective screening b) Universal screening

15. SELECTIVE SCREENING 1. The selective screening protocol is done only in the presence of risk factors [2] Berger H, Crane J, Farine D, Armson A, de la Ronde S, et al. Screening for gestational diabetes mellitus. SOGC Clinical Practice Guideline, No. 121, November 2002.

16. SELECTIVE SCREENING However, if the selective screening alone is adopted, majority of GDM can be missed  Risk factors are only present in 30% of those who develop glucose intolerance in pregnancy [3] 3. Gillmer MDG: Diabetes in Pregnancy, In: Weatherhall DJ, Ledingham JGG, Warrel DA (Eds) Oxford Textbook of Medicine, 3rdEdn, Vol 2, Oxford, Oxford Medical Publications 2: 1752-58, 1996.

17. UNIVERSAL SCREENING Through this protocol, all pregnant mothers are screened. This method may not be cost-effective in populations with a low prevalence (0.5-1%) of GDM. However, since the GDM rate in our Malaysian population is at least 11.4% [4] (another Malaysian study recorded a prevalence of 18.3% [5] for gestational diabetes mellitus in its population-based subjects) the universal screening appears to be superior for the detection of GDM. Tan PC, Ling LP, Omar SZ. Screeninng for gestational diabetes at antenatal booking in a Malaysian university hospital: The role of risk factors and threshold value for the 50g glucose challenge test. Aust N Z J ObstetGynaecol. 2007;47(3):191-7 IdrisN, CheHatikah CH, Murizah MZ, Rushdan MN. Universal versus selective screening for detection of gestational diabetes mellitus in a Malaysian population. Malaysian Family Physician. 2009;4(2&3):83-7

18. SCREENING TEST The screening test that is commonly used is the Glucose Challenge Test (GCT). 50 g of oral glucose is given between 24 to 28 weeks of gestation irrespective of the time or the meal. Blood glucose is determined 1 hour later.

19. SCREENING TEST The ACHOIS trial [6], a large multicentre trial, uses a GCT threshold of 7.8mmol/l. However, it is possible that the sensitivity of GCT can be further improved if the threshold of the glucose level be reduced as suggested by Tan et al who studied 1600 patients at the antenatal clinic in a local university hospital setting. In fact, a value of 7.2 mmol/L (130 mg/dL) will identify 90% of women with GDM [7,8]. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS, for the Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Trial Group: Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 352:2477–2486, 2005 Metzger BE, Coustan DR. Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus.TheOrganizing Committee. Diabetes Care 1998;21(Suppl 2): B161–7. O’Sullivan JB, Mahan CM, Charles D, Dandrow RV. Screening criteria for high-risk gestational diabetic patients. Am J ObstetGynecol1973;116:895–900.

20. SCREENING TEST Hence, in UMMC, a plasma value of  7.2 mmol/L is considered significant to perform the confirmatory diagnostic test. Though this test is generally done in the second trimester, a high risk patient can be tested during the earlier booking visit.

21. DIAGNOSTIC TEST Oral glucose tolerance test (OGTT) is performed for the diagnosis of gestational diabetes mellitus. There are many guidelines that delineate various cut-off values. The two common guidelines that are used nowadays are from the: a) American Diabetes Association (ADA) b) World Health Organisation

22. DIAGNOSTIC TEST The WHO[9] recommends the 2 hour 75 g OGTT while the ADA [10,1112, 13] after the 4th International Workshop-Conference on GDM, uses the 3 hour 100 g OGTT. WHO Consultation: Definition, diagnosis and classification of diabetes mellitus and its complications: report of a WHO consultation. Part 1: Diagnosis and classification of diabetes mellitus. Geneva, WHO/NCD/NCS/99.2,World Health Organization; 1999. O’Sullivan JB, Mahan CM: Criteria for the oral glucose tolerance test in pregnancy. Diabetes 13:278, 1964 Carpenter MW, Coustan DR: Criteria for screening tests for gestational diabetes. Am J ObstetGynecol 144:768–773, 1982 American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2000;23(Suppl. 1):S77–S79. Metzger BE, Coustan DR. Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus.TheOrganizing Committee. Diabetes Care 1998;21(Suppl 2): B161–7.

23. DIAGNOSTIC TEST

24. DIAGNOSTIC TEST In UMMC, the 2 hour 75 g test is employed to pregnant mothers.

25. COMPLICATIONS

26. COMPLICATIONS Pre-eclampsia Pyelonephritis Polyhydromnios Preterm labour Operative delivery Monilialvaginitis

27. COMPLICATIONS Pregestational 1. Difficult sugar control 2. Ketosis 3. Hypoglycaemic state 4. Diabetic vasculopathy IUGR 5. Postpartum thyroiditis

28. COMPLICATIONS

29. COMPLICATIONS Macrosomia Sudden IUD Shoulder dystocia

30. COMPLICATIONS Pregestational 1. Congenital anomalies 2. Abortions

31. COMPLICATIONS

32. COMPLICATIONS Hypoglycaemia Hyaline membrane disease Hypomagnesaemia Hypocalcaemia Hypertrophic cardiomyopathy 6. Hyperviscosity syndrome 7. Transient tachypnoea of the newborn 8. Birth injuries 9. Birth asphyxia

33. COMPLICATIONS Later effects 1. Obesity in adulthood 2. Type 2 Diabetes

34. Child with Erb’s Palsy Necrotising enterocolitis Neonatal jaundice IUGR newborn

35. Maternal Hyperglycaemia Hypoglycaemia Placenta blocks maternal insulin Foetal Hyperglycaemia Hypertrophic cardiomyopathy Foetal Islet Hyperplasia HYPERINSULINAEMIA Insulin inhibits acc of surfactant of protein Insulin acts like a growth factor Insulin stimulates EPO and the process also occurs as a response to hypoxia Macrosomia  Foetal metabolism  Lung surfactant Compounded by delayed lung maturity Fat deposition at insulin-dependant areas in the foetal trunk.  Oxygen supply and acidosis Erythropoiesis RDS Disproportionate increase in trunk size Jaundice Hyperviscosity syndrome IUD PEDERSON’S MATERNAL HYPERGLYCAEMIA-FOETAL HYPERINSULINISM HYPOTHESIS Head size remains normal  Intestinal blood flow Slugging of RBC NEC Renal vein thrombosis Shoulder dystocia and birth injuries

36. MANAGEMENT

37. A team approach is ideal for managing women with GDM .The team would usually comprise an obstetrician, diabetes physician, a diabetes educator, dietitian, the midwife and paediatrician. The importance of educating women with GDM (and their partners) about the condition and its management cannot be over-emphasised. Compliance with the treatment plan depends on the patient's understanding of: a) The implications of GDM for her baby and herself; b) The dietary and exercise recommendations; and c) The how and when as well as the goals of self monitoring of blood glucose level. Care should be taken to minimise the anxiety of the women.

39. PRE-CONCEPTION Planning the pregnancy 3 months prior to conception Good diabetic control from the pre-conceptional period decrease the chances of fetal anomalies among pregestational diabetics. During the early antenatal booking HbA1c should ideally be less than 8%. High dose folic acid supplements. Type 1: 4-5 insulin injection/day; long acting at night and short acting after each meal. Type 2: switch from OHA to twice daily mixture of short acting and long acting insulin. 6. Visit fortnightly until Week 32 and once weekly after Week 34.

40. ANTENATAL Dietary therapy is the primary therapeutic strategy for the achievement of acceptable glycaemic control in GDM. This is prescribed to all patients with diabetes and is called medical nutrition therapy. The total calories = 24-30 kcal/kg of present body weight. Carbohydrates should be distributed throughout the day. Eating 3 small-to-moderate sized meals and 3 snacks per day is recommended.

41. ANTENATAL Bedtime snack prevents fasting ketosis. Glycaemic control needs to be monitored. Self monitoring of blood glucose level is the optimal method and is well tolerated by most women. If self monitoring is not possible, fasting and 1 or 2 hour postprandial laboratory capillary blood or venous plasma glucose levels should be investigated regularly (at 1 to 2-weekly intervals).

42. ANTENATAL 9. Self Blood Glucose Monitoring (SBGM): Diet control: Four points fasting, post-breakfast, lunch, dinner On insulin: Seven points pre and post breakfast, pre and post lunch, pre and post dinner and also pre-bedtime 10. ADA recommends the minimum goals for glycaemic control are: • Fasting capillary (venous plasma) blood glucose level <5.8 mmol/L • 2 hour postprandial capillary (venous plasma) blood glucose level <6.7 mmol/L.

43. ANTENATAL Oral hypoglycaemic agents drugs are generally not recommended during pregnancy as they cross the placental barrier and cause foetal hypoglycaemia.

44. INSULIN THERAPY 1. Insulin therapy should be considered if the blood glucose goals have exceeded on two or more occasions within a 1 to 2 week interval, particularly in association with clinical or investigational suspicion of macrosomia. 2. However, the benefit of instituting insulin therapy after 38 weeks of gestation is unproven. 3. Human insulin should be used. No insulin preparations has a pregnancy category listing, except for the new, rapidly-acting insulin analogue Lispro.

45. INSULIN THERAPY HOW TO START INSULIN THERAPY? The daily insulin requirement is 0.5-0.7 units/kg/day Q: How do we tailor the insulin regime for a 60kg pregnant lady with GDM? A: Since her daily requirement is 30 units/day, we can calculate the amount that should be given via the formulae below. 1) BD Dosage: (2/3 Day + 1/3 Night) Day Amount : 2/3 x 30 =20 units (Short Acting-13 units & Long Acting-7 units) Night Amount : 1/3 x 30 = 10 units Short Acting-7 units & Long Acting-3 unit *Roughly divide 2/3 of each dosage :SHORT ACTING whereas 1/3 of it for LONG ACTING. 2)QID Dosage : (30 Units/4 times) Hence, it is 8 units per jab Prior to the 3 main meals : 8 units of Short Acting Prior going to bed : 8 units of Long Acting

46. INSULIN THERAPY It is important to note that insulin requirements fall dramatically after delivery of the placenta and insulin doses will need to be reduced.

47. ANTENATAL Foetal surveillance and investigations: Maternal serum alpha-fetoprotein Ultrasound Doppler of the umbilical artery

48. OBSTETRIC MANAGEMENT The decision to deliver is based on the degree of diabetes, nature of control, superimposed risk factors and foetal well-being. Pregnancy is not allowed to go beyond due dates even in well-controlled diabetics. There are high chances of a Caesarean Section in a diabetic mother due to pregnancy complications or macrosomia. However, a C-Sec is not indicated for diabetes alone.

49. IN LABOUR In women in labour, maintaining good glucose control (blood glucose levels between 4 and 10 mmol/l) with s/c insulin may be possible throughout the labour. HOWEVER if the labour is prolonged / the women vomits / is not keen to eat / unable to eat due to risk factors precluding eating in labour (eg. the risk under GA) then intravenous insulin will be necessary IV insulin using the sliding scale is necessary for Type 1 women if: a) the blood glucose exceeds 10 mmol/L; or b) if she is unable to eat; or c) vomiting and not later than 6 hours after their last short-acting insulin injection IV insulin using the sliding scale is necessary for Type 2 women or women with GDM if: a)the blood glucose exceeds 10 mmol/l during labour

50. DIK REGIME Used for spontaneous labour/C-Sec On the day of delivery, no breakfast or s/c insulin. Hourly blood sugar on admission (RBS)  if <4 mmol/L or >10 mmol/L : take venous blood for lab blood glucose. Start DIK Regime: a) Dextrose infusion: 500mL 10% Dextrose with 10 mmol/L KCl (potassium chloride; start at 100 mL/h) * Amount of K+ added depends on serum K+

51. DIK REGIME b) Insulin infusion-use the 50 mL syringe pump: 50 units soluble insulin in 50 mL normal saline. Adjust insulin dose according to blood sugar level.

52. DIK REGIME Maintain blood sugar : 5-10 mmol/L When placenta is delivered,  For all patients, discontinue the DIK Regime .  Check BS and adjust insulin accordingly. 7. Do a reassessment of the blood sugar profile.

53. SHOULDER DYSTOCIA Call for help McRoberts’ Manoeuvre  Increase Outlet Diameter  Decrease Pelvic Angle Episiotomy  Increase AP Diameter 4. Give Suprapubic Pressure 5. Delivery of posterior shoulder 6. Cockscrew Manoeuvre 7. Fracture the clavicle. 8. Reversal of process  Push the head back in and shift to OT

54. FOLLOW-UP It is important that women with GDM be counseled with regards to their increased risk of developing permanent diabetes. They should be made aware of the symptoms of hyperglycaemia. Advice should be given about the importance of healthy eating and exercise patterns. Contraceptive advice should be given in the puerperium, and women should be advised to plan future pregnancies and be reviewed medically by their general practitioner before conception (a pre-conception OGTT should be considered). All women with previous GDM to be offered testing for diabetes with a 75 g OGTT 6-8 weeks after delivery;

55. FOLLOW-UP Repeat testing should be performed every 1-2 years among women with normal glucose tolerance and the potential for further pregnancies. If pregnancy is not possible, follow-up testing should be performed every 3 years, with more frequent re-testing, depending on clinical circumstances (eg, ethnicity, past history of insulin treatment in pregnancy, recurrent episodes of GDM). Impaired glucose tolerance merits careful follow-up, which should include at least twice-yearly checks for frank diabetes in addition to assessment of other risk factors for macrovascular disease.

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