1. Pakistan Society Of Chemical Pathologists Distance Learning Programme In Chemical Pathology Lesson No 6 Diabetes Mellitus in Pregnancy By Surg Commodore Aamir Ijaz MCPS, FCPS, FRCP (Edin) Professor of Pathology / Consultant Chemical Pathologist Bahria University Medical & Dental College / PNS SHIFA Karachi

2. : Q 1: A 28 years pregnant lady not a known diabetic underwent OGTT with 75 g glucose. The result was as following: Fasting Plasma Glucose: 6.5 mmol/L (117 mg/dl) 01 Hour Post glucose: 8.9 mmol/L (160 mg/dl) 02 Hour Post glucose: 7.5 mmol/L (135 mg/dl) She will be labelled as: a.Gestational Diabetes Mellitus b.Impaired Fasting Glucose (IFG) c.Impaired Glucose Tolerance (IGT) d.Maturity onset Diabetes of the young e.Pregnancy with Diabetes Mellitus Best Answer: a. Gestational Diabetes Mellitus (GDM)

3. GDM Definition “any degree of glucose intolerance with onset or first recognition during pregnancy” ( ADA-2009) A known diabetic becoming pregnant would not be labeled as GDM

4. Factors for Risk Assessment of GDM (at First Visit) Ethnicity Age BMI History of diabetes in first degree relative History of glucose intolerance History of obstetric complications usually associated with GDM

5. Low Risk Patients Low-risk ethnicity (Caucasian, European) Age < 25 y BMI < 25 No known diabetes in first degree relative No h/o glucose intolerance No h/o obstetric complications usually associated with GDM

6. High Risk Patients Strong family history of diabetes Prior history of GDM Morbid obesity Other manifestations of glucose intolerance

7. Screening For GDM Low risk, no screening required Intermediate risk, screen at 24-28 weeks High risk, should be screened as early as possible and repeated at 24-28 weeks if screening negative

8. Diagnosis of GDM One Step Approach: OGTT with 75 g glucose Two Step Approach: Glucose challenge test with 50 g glucose OGTT with 100 g glucose

9. Diagnosis of GDM by Two Step Approach Screen: 50g glucose 1 hour glucose challenge Non-fasting state (higher or similar values with fast) Diagnosis: 100g, 3 hour glucose tolerance test No smoking prior to test Unrestricted diet i.e. at least 150g carbohydrates/d for at least 3 days prior (to avoid spurious high values) One abnormal value with increased risk for macrosomic infants & associated morbidities

10. Diagnosis of GDM by one Step Approach Screen for undiagnosed type 2 diabetes (Overt DM) at the first prenatal visit in those with risk factors, using same diagnostic criteria as in non-pregnant adults. In pregnant women not previously known to have diabetes, screen for GDM at 24-28 weeks gestation, using 75-g OGTT.

11. Diagnosis of GDM by one Step Approach (cont) GDM diagnosis: One of the following values after a 75-g OGTT must be equalled or exceeded for the diagnosis of GDM : Fasting: < 5.1 mmol/l (92 mg/dl) 1 h : < 10.0 mmol/l (180 mg/dl) 2 h : < 8.5 mmol/l (153 mg/dl)

12. : Q 2: The most prevalent Diabetes Mellitus in pregnancy is: a.GDM b.Gestational Impaired Glucose Tolerance c.Overt DM d.Type 1 DM e.Type 2 DM Best Answer: a. Gestational Diabetes Mellitus (GDM)

13. : Q 3: Prevalence rate of GDM is highest in people from: a.Caribbean b.Europe c.Japan d.Latin America e.Sub-continent Best Answer: e.Sub-continent

14. 4.The most important pathogenic mechanism of GDM is : a.Increased Diabetogenic Hormones b.Increased Maternal Weight c.Failure of Beta cells mass to increase d.Insulin Resistance e.Mal-nutrition Best Answer: c.Failure of Beta cells mass to increase

15. Pathogenesis of GDM Normal pregnancy is a state of physiological IR, and therefore represents a physiological model of beta-cell stress IR stems from placental secretion of diabetogenic hormones including growth hormone, corticotropin releasing hormone, placental lactogen, and progesterone. In normal pregnancy IR emerges in the second trimester and progresses over the late third trimester, thereby increasing maternal glucose, free fatty acids and amino acids in order to provide adequate energy to the fetus

16. Pathogenesis of GDM (cont) These and other endocrinologic and metabolic changes ensure that the fetus has an ample supply of fuel and nutrients at all times. Gestational diabetes occurs in women whose pancreatic function is not sufficient to secrete adequate amounts of additional insulin to overcome the IR created by changes in diabetogenic hormones during pregnancy.

17. Pathogenesis of GDM (Cont) Pregnancy is associated with increase in the beta- cell mass and increase in insulin level throughout pregnancy. Certain pregnant women are unable to up-regulate insulin production relative to the degree of IR Consequently they become hyperglycemic, developing gestational diabetes.

18. Q 5: The Biochemical pathway leading to Macrosomia in GDM mothers includes: a. Foetal Hyperinsulinaemia causing lipogenesis b.Foetal Hypoglycaemia causing adrenal hormone secretion c.Human Placental Lactogen causing lipid deposit in foetus d.Maternal Hyperglycaemia causing fluid retention in foetus e.Maternal Hyperinsulinaemia causing lipogenesis in fetus Best Answer: a. Foetal Hyperinsulinaemia causing lipogenesis

19. : Q 6: Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) is a landmark study conducted in 25000 women. The main focus of the study was pregnant women with: a.Gestational Diabetes Mellitus b.Impaired Fasting Glucose c.Impaired Glucose Tolerance d.Normal Plasma Glucose e.Overt diabetes Best Answer: d.Normal Plasma Glucose

20. Hyperglycemia and Adverse Pregnancy Outcomes (HAPO). NEJM. May, 2008. Hypothesis: maternal hyperglycemia less severe than overt DM will still increase risk for adverse pregnancy outcomes 25,505 pregnant women at 15 centers in 9 countries underwent 75-g oral glucose-tolerance testing at 24- 32 weeks gestation

21. Women included with FBS < 105 and 2-hr glucose was < 200 Hyperglycemia and Adverse Pregnancy Outcomes (HAPO). NEJM. May, 2008.

22. BIRTH WEIGHT > 90 TH PERCENTILE Frequency (%) Glucose category HAPO. NEJM. May 2008: Frequency of primary outcomes across the Glucose Categories

23. Frequency (%) Glucose category Primary Cesarean Section HAPO. NEJM. May 2008: Frequency of primary outcomes across the Glucose Categories

24. Frequency (%) Glucose category Clinical Neonatal Hypoglycemia HAPO. NEJM. May 2008: Frequency of primary outcomes across the Glucose Categories

25. : Q 7: A 27 years pregnant lady reported for ante-natal examination at 18 week of gestation. Her fasting blood glucose was advised which was found to be 7.8 mmol/L (140 mg/L). Considering the latest diagnostic criteria what is your opinion and advise to this patient at this glucose level: a.Overt DM requiring intervention b.GDM requiring no intervention c.OGTT with 100 g glucose and three samples d.OGTT with 75 g glucose and two samples e.She should be advised to visit at 24 weeks for OGTT Best Answer: a.Overt DM requiring intervention

26. Overt DM in Pregnancy A newly described entity Women with intermediate to higher risk should undergo blood test at first visit Diagnosed at first visit by FPG or HbA1c before 20 weeks Actually this is previous undiagnosed DM

27. Measure of glycemiaThreshold Fasting glucose> 7.0 mmol/L (126 mg/dl) If Fasting glucose > 5.3 mmol/L, 24 weeks screening should be advised A1C> 6.5% Random glucose> 200 mg/dl Diagnosis of Overt DM

28. SHORT ANSWER QUESTIONS

29. Q 8: A 32 years Pakistani lady, with 16 weeks of pregnancy, has been referred to you for risk assessment of DM. Her BMI is 31 Kg/m2. The weight of her previous baby was 5.5 Kg (12.5 lb). Her mother has type 2 DM. (In this question you can fully use any one of the internationally recommended strategies but mixture of more than one strategies will not be acceptable). a.When you will you like to carry out screening for GDM in this lady? b.What strategy you will adopt for screening and diagnosis of GDM? c.Give the diagnostic criteria you will use for the diagnosis of GDM?

30. Suggested Answer Q.8 a When you will you like to carry out screening for GDM in this lady? Many risk factors are present in this patient e.g. ethnicity (Sub-continent origin), high BMI, previous h/o large baby, diabetes in first degree relative. So in this lady screening for DM should be carried out at first antenatal (same) visit.

31. Suggested Answer Q.8 b When you will you like to carry out screening for GDM ? 1 step i.e. 75-g OGTT with plasma glucose measurement, at fasting and 1 and at 2h.

32. Suggested Answer Q.8 c Give the diagnostic criteria you will use for the diagnosis of GDM We may use ADA 2013 guidelines i.e. Diagnosis of diabetes in pregnancy (GDM ) is made if any of following plasma glucose value are exceeded Fasting plasma glucose ≥ 5.1mmol/L (92mg/dl) Plasma glucose after 1 h ≥ 10.0mmol/L (180 mg/dl) Plasma glucose after 2 h ≥ 8.5mmol/L (153mg/dl)

33. Q 9:A 29 years female with GDM has reported for monitoring at 32 nd week of pregnancy. Her fundal height is normal for date. a.What test you will advise for monitoring of GDM? b.What are your target glycaemic levels in this patient? c.Name THREE major fetal complications of GDM which will concern you?

34. Suggested Answer Q.9 a What test you will advise for monitoring of GDM? Plasma Fasting and preprandial glucose Postprandial plasma glucose i.e. 2 h after meals

35. Suggested Answer Q.9 b What are your target glycaemic levels in this patient? The goals for glycemic control in GDM: Fasting or preprandial: ≤ 5.3mmol/L (95mg/dL) 1-h postmeal: ≤ 7.8 mmol/L (140mg/dL) 2-h postmeal: ≤ 6.7 mmol/L (120mg/dL) HbA1c < 7.0 %

36. Suggested Answer Q.9 c Name THREE major fetal complications of GDM which will concern you? Adverse birth events related to macrosomia, ie, shoulder dystocia and birth injuries. Neonatal hypoglycemia Hyperbilirubinemia

37. Medical management of GDM Nutritional therapy Exercise Self-monitoring of glucose at home If diet and exercise fail, oral hyperglycemic agent or insulin Metformin is considered safe Short-acting insulin analogs should be standard, and long-acting analogs not far behind, if not already here Goal: Euglycemia!!

38. Q 10: A 22 years girl is known patient of Type 1 DM. She has just conceived and reported for ante-natal care. a.What label you will assign to her DM? b.What type of fetal complications you will anticipate in this patient? c.Write TWO major pillars of treatment in this patient.

39. Suggested Answer of Q.10 a What label you will assign to her DM? Pre-gestation DM Type 1

40. Suggested Answer of Q.10 b What type of fetal complications you will anticipate in this patient? Foetal anomalies and organodysgenesis in addition to Macrosomia and other complications associated with GDM

41. Suggested Answer of Q.10 c Write TWO major pillars of treatment in this patient. Metformin Insulin Lifestyle modification (third pillar)

42. Q 11: A patient with GDM is about to deliver after a week. She is concerned about her Diabetes Mellitus after the pregnancy. a.How will you monitor her for DM after pregnancy b.What advise you will provide her for the management of DM after pregnancy?

43. Suggested Answer to Q.11 a How will you monitor her for DM after pregnancy Assess fasting and/or 2-hr PP in first day or two after delivery – no further treatment necessary if normal (majority of GDM) If fasting and/or 2-hr PP abnormal, continue oral agent or insulin Screen for Type 2 diabetes at 6-week postpartum visit Council patients regarding dietary and behavioral changes necessary to minimize risk of developing overt diabetes later in life

44. Suggested Answer to Q.11 b TimeTestPurpose Post-delivery (1-3 d) Fasting or random glucoseDetect persistent, overt diabetes Postpartum visit 75-g 2-h OGTTPP classification of glucose metabolism per ADA 1 year postpatum 75-g 2-h OGTTAssess glucose metabolism Annually Fasting plasma glucoseAssess glucose metabolism Tri-annually 75-g 2-h OGTTAssess glucose metabolism Prepregnancy 75-g 2-h OGTTAssess glucose metabolism What advise you will provide her for the management of DM after pregnancy?

45. THANK YOU