The Pregnant Diabetic. Queenie G. Ngalob, MD, FPCP May 5, 2014

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1 The Pregnant Diabetic Queenie G. Ngalob, MD, FPCP May 5, 2014

2 Outline Classification of diabetes in pregnancy Effect of diabetes and pregnancy on Conceptus Mother Treatment recommendations for pregnant diabetics

3 Classification of DM in pregnancy Preexisting Pregnancy PreGestational Diabetes (Type 1 or Type 2) Gestational Diabetes Overt Diabetes IADPSG. Diabetes Care. 2010; 33(3):

4 Classification of DM in pregnancy Preexisting Pregnancy PreGestational Diabetes (Type 1 or Type 2) Gestational Diabetes Overt Diabetes UNITE for Diabetes (Philippines) Evaluate for risk factors on 1 st prenatal visit 75gm OGTT ASAP if with any risk factor, th week if none Unite for Diabetes.

5 Risk factors for GDM Prior GDM Glucosuria Family history of DM Prior macrosomic (>8lbs) baby Macrosomia in current pregnancy Age 25 years old PCOS Overweight or obese Polyhydramnios in current pregnancy Intake of drugs affecting carbohydrate metabolism Unite for Diabetes.

6 Diagnosis 1 st Prenatal Visit Diagnosis FBS, mg/dl (mmol/l) RBS, mg/dl (mmol/l) HBA1C* % Overt Diabetes** 126 ( 7.0) 200 ( 11.1) 6.5 Gestational Diabetes ( ) na na *NGSP certified & standardized to the DCCT reference assay ** repeated on another day If criteria not met, repeat testing at weeks AOG using 75gm OGTT ADA 2014,WHO 2013, EndoSoc 2013, IADPSG 2010

7 Diagnosis 24 th 75 gm OGTT Diagnosis FBS, mg/dl (mmol/l) to 28 th week AOG using 1 st hour mg/dl (mmol/l) 2 nd hour mg/dl (mmol/l) Overt Diabetes** 126 ( 7.0) na 200 ( 11.1) Gestational Diabetes ( ) 180 ( 10.0) ( ) ADA 2014,WHO 2013, EndoSoc 2013, IADPSG 2010

8 Classification of DM in pregnancy Preexisting Pregnancy PreGestational Diabetes (Type 1 or Type 2) Gestational Diabetes Overt Diabetes IADPSG. Diabetes Care. 2010; 33(3):

9 Effect DM on the conceptus Fetal malformation Spontaneous abortion Perinatal mortality

10 Fetal Malformations fold higher risk 3 rd to 7 th weeks AOG embryogenesis & organogenesis Toxic metabolites may be teratogenic Pathogenesis is poorly understood Rates similar between Type 1 & 2 Boulot P, et al., Diabetes Care 26: , 2003 Lapolla A., et al. Nutr Metab Cardiovasc Dis May;18(4):291-7 Persson M, et al., Diabetes Care Nov;32(11): Eriksson UJ, et al.,. Rev Endocrinol Metabol Dis 2003;4: Kousseff BG. Diabetic embryopathy. Curr Opin Pediatr 1999;11:348 Bell R., et al., BJOG Mar;115(4):

11 Congenital malformations The poorer the glycemic control periconceptionally or early in pregnancy, the greater the risk for congenital anomalies. Towner D, et al., Diabetes Care 1995;18: Langer O, et al., J Mat Fet Med 2000;9: Temple R, et al., BMJ 2002;325: Schaefer-Graf UM, et al., Am J Obstet Gynecol 2000;182: Suhonen L, et al., Diabetologia 2000;43:79 82.

12 Malformations associated with preexisting diabetes OR CNS All 1.55 anencephalus 1.9 Encephalocoele 3.27 Head Anotia 4.37 GI Omphalocoele 2.32 Urinary Bilateral Renal agenesis 2.43 Musculoskeletal All 1.66 Garne E, et al., Birth Defects Research (Part A) 94: , 2012

13 Malformations associated with preexisting diabetes Congenital heart defects OR All 2.07 Common arterial truncus 2.59 Transposition of great vessels 2.00 Single ventricle 2.57 Ventricular septal defect 1.43 Atrial septal defect 2.15 Atrioventricular septal defect 2.21 Coarctation of the Aorta 1.84 Garne E, et al., Birth Defects Research (Part A) 94: , 2012

14 Spontaneous abortions 4 fold increased risk Risk rises poor glycemic control Temple R., BMJ Nov 30;325(7375):

15 Perinatal mortality 2.3 to 6- fold increased risk Intrauterine stillbirth (>24 weeks AOG) or neonatal death (within 28 days of life) Feig, et al., Diabetes Care Apr 4. [Epub ahead of print] Boulot P, et al., Diabetes Care 26: , 2003 Dunne R, et al., Diabet Med Sep;20(9): Lapolla A., et al. Nutr Metab Cardiovasc Dis May;18(4):291-7 Persson M, et al., Diabetes Care Nov;32(11):2005-9

16 Pregnancy Loss Cundy T, et al., Diabetes Care 30: , 2007

17 Perinatal outcomes MACROSOMIA OR (95% CI ) PRETERM OR 4.86 (95% CI ) FETAL DISTRESS OR (95% CI ) RESPIRATORY DISTRESS SYNDROME OR 4.65 (95% CI ) Perrson M, et al., Diabetes Care 32: , 2009

18 Effect DM on the conceptus Pantalone K, et al., Endocr Pract. 2011;17:

19 Effect of pregnancy on the diabetic mother DM Complications Obstetric Outcomes

20 DM retinopathy No to mild retinopathy Small risk for progression Established retinopathy can rapidly progress during and up to 1 year after pregnancy, more so in poorly controlled (OR 1.63 to 2.48) Effects of pregnancy on retinopathy eventually diminish after the first year. DCCT group. Diabetes Care 23: , 2000 Boulot P, et al., Diabetes Care 26: , 2003 D. Thompson et al., Can J Diabetes 37 (2013) S168eS183 Chew EY, et al., Diabetes Care May;18(5):6

21 Patients with more severe diabetic retinopathy at baseline were more likely to show progression (Χ 2 trend P<0.001) Chew EY, et al., Diabetes Care May;18(5):631-7.

22 Patients with higher levels of HBA1C were at greater risk for progression Chew EY, et al., Diabetes Care May;18(5):631-7.

23 DM nephropathy Normal creatinine albuminuria and creatinine clearance is preserved during pregnancy Microalbuminuria may worsen but typically modest and reversible (BP and blood sugar are wellcontrolled) Moderate to severe can significantly deteriorate and may not be reversible Rossing K, et al., Diabetologica 2002, 45: Miodovnik M, et al., Am J Obstet Gynecol 1996;174: Biesenbach, et al., Nephrol. Dial. Transplant. (1992) 7 (2): Purdy LP, et al., Diabetes Care Oct;19(10):

24 DM nephropathy & pregnancy outcomes Increased risk of preeclampsia, exacerbation of hypertension (OR ) Hypertension leads to increased risk of preterm delivery Placental dysfunction leads to intrauterine growth restriction and fetal distress Sibai BM, et al., Am J Obstet Gynecol Feb;182(2):364-9 Jensen DM, et al., Diabetes Care 33:90 94, 2010 Ekbomm P, et al, Diabetes Care 24: , 2001

25 Obstetric Outcomes PREECLAMPSIA OR 4.47 (95% CI 3.77 to 5.31) CESAREAN SECTION OR 5.31 (95% CI 4.97 TO 5.69) VACUUM EXTRACTION/FORCEP S OR 1.41 (95% CI 1.25 TO 1.58) Perrson M, et al., Diabetes Care 32: , 2009

26 Management of PreGDM

27 Management of PreGDM Preconception During Pregnancy Postpartum Counseling Glycemic control Weight control Co-morbidities

28 Preconception Counseling Should be provided to all diabetic women of childbearing potential or considering pregnancy Start at puberty or on diagnosis Blumer I, et al., J Clin Endocrinol Metab 98: , 2013 ADA, Diabetes Care Jan;37 Suppl 1:S14-80 IDF 2009.

29 Preconception Counseling Need for pregnancy to be planned, sufficient control of glucose & co-morbidities Risk of malformations & adverse outcomes associated with unplanned pregnancy or poor metabolic control Use of effective contraception Time, commitment and effort is required Blumer I, et al., J Clin Endocrinol Metab 98: , 2013 ADA, Diabetes Care Jan;37 Suppl 1:S14-80 IDF 2009.

30 Preconception Counseling Diabetes Specialist Dietician Patient & partner Diabetes Educator Obstetrictian

31 Improved glycemic parameters Outcome Mean HBA1C decrease in the 1 st trimester No. of Studies Mean Difference (95% CI) % (-2.05, -1.79) Wahabi et al. BMC Public Health 2012, 12:792

32 Decreased risk for congenital malformations OR = 0.25 (0.16, 0.37) Wahabi et al. BMC Public Health 2012, 12:792

33 Decreased Perinatal Mortality OR = 0.34 (0.15, 0.75) Wahabi et al. BMC Public Health 2012, 12:792

34 Preconception Glycemic Control Strive to achieve blood glucose and HBA1C as close to normal as possible when they can be safely achieved without undue hypoglycemia. ideal preconception glucose levels not established Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

35 OR 1.3 (95% CI 1.2, 1.4) for every 1% increase in HBA1C Bell R, et al. Diabetologia Feb 8.

36 Strategies : Insulin-treated Intensified therapy using subcutaneous insulin Provide basal coverage Human insulin : NPH Analogs : Glargine, Detemir Provide prandial coverage Human insulin : regular Analogs : Aspart, Lispro Kitzmiller JL, et al., Diabetes Care May;31(5):

37 Jacobs DM Care 20:1279, 1997

38 Jacobs DM Care 20:1279, 1997

39 Strategies : Insulin-treated Recommend multiple daily doses of insulin or continuous SC insulin infusion over split-dose, premixed insulin Changes should be done well before conception or before withdrawing contraception to allow patient to gain expertise Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

40 Strategies : Insulin-treated Suggest rapid acting insulin analog (aspart or lispro) in preference to regular insulin Basal insulins detemir and glargine : preconceptionally & during pregnancy Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

41 Strategies : OHAS-treated No trials on use of oral hypoglycemics in pregestational DM Shift to insulin Blumer I, et al., J Clin Endocrinol Metab 98: , 2013 Kitzmiller JL, et al., Diabetes Care May;31(5):

42 Overweight & Obese Weight reduction before pregnancy for overweight and obese diabetic women. Increased risk for complications during pregnancy Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

43 OR for maternal outcomes according to antenatal BMI Overweight ( kg/m2) n=2882 Obese ( kg/m2) n=1679 Morbidly obese (>40 kg/m2) n-=248 Hypertensive disorders 1.74 ( ) 3.0 ( ) 4.87 ( ) Gestational Diabetes 1.78 ( ) 2.95 ( ) 7.44 ( ) Caesarean section 1.5 ( ) 2.02 ( ) 2.54 ( ) Callaway LK, et al., Med J Aust 2006; 184 (2):

44 Overweight ( kg/m2) n-=2882 Obese ( kg/m2) N=1679 Birth defects 1.58 ( ) Hypoglycemia 2.57 ( ) Prematurity (<34 wks) Admission to NICU OR for neonatal outcomes according to antenatal BMI Morbidly obese (>40 kg/m2) n-= ( ) 7.14 ( ) 2.13 ( ) 2.77 ( ) Callaway LK, et al., Med J Aust 2006; 184 (2):

45 Ocular care Have a detailed ocular assessment by a suitably-trained and qualified eye care professional in advance of withdrawing contraception or trying to conceive If retinopathy is documented, should be appraised of risk of worsening during pregnancy. Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

46 Ocular care If degree of retinopathy warrants therapy, recommend deferring conception until the retinopathy has been treated and stabilized. The greater the degree of preconception retinopathy, the greater the risk of progression during pregnancy Blumer I, et al., J Clin Endocrinol Metab 98: , 2013 Chew EY, et al., Diabetes Care May;18(5):631-7.

47 Patients in whom retinopathy was most likely to progress had both the poorest control at baseline and largest improvement during early pregnancy Chew EY, et al., Diabetes Care May;18(5):631-7.

48 Renal Function Have renal function assessed in advance of withdrawing contraception or trying to conceive Urine albumincreatinine ratio Serum Crea egfr Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

49 Renal Function If with significantly reduced GFR, refer to nephrologist before pregnancy baseline renal assessment review the woman s specific risk of worsening renal function in the event of pregnancy Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

50 Address Co-morbidities HYPERTENSION Satisfactory BP control (<130/80) preconception Withdraw ACEI and ARB DYSLIPIDEMIA Withdraw statins VASCULAR RISK Evaluate risk factors screening for CAD treat and counsel Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

51 Preconception During Pregnancy Postpartum Counselling Glycemic control Weight control Co-morbidities Targets SMBG MNT Weight management Pharmacologic Peripartum

52 Glycemic Targets Parameter Fasting & Preprandial Goal mg/dl (mmol/l) 95 ( 5.3) 90 (5.0) if can be achieved without hypoglycemia 1 hour PP 140 ( 7.8) 2 hour PP 120 ( 6.7) HBA1C 7 % (ideally 6.5) Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

53 Self-monitoring of blood glucose (SMBG) Recommend SMBG in all DM pregnant patients Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

54 Self-monitoring of blood glucose (SMBG) Recommend SMBG in all DM pregnant patients Frequency Fasting & Pre-meals Postprandial - 1 or 2 hours after the start of each meal, choosing when is peak bedtime and during the night as indicate. Blumer I, et al., J Clin Endocrinol Metab 98: , 2013 Negrato CA, et al., Diabetol Metab Syndr Dec 22;4(1):54.

55 HBA1C Perform HBA1C at the initial visit and monthly until target levels are achieved, then 2-3 months thereafter. Targets EndoSoc : 7% (6.5% ideal) ADA : <6% Blumer I, et al., J Clin Endocrinol Metab 98: , 2013 Kitzmiller JL, et al., Diabetes Care May;31(5):

56 Medical Nutrition Therapy (MNT) Recommend MNT to help achieve and maintain desired glycemic control while providing essential nutrient requirements Blumer I, et al., J Clin Endocrinol Metab 98: , 2013 Kitzmiller JL, et al., Diabetes Care May;31(5):

57 Medical Nutrition Therapy (MNT) a carbohydrate-controlled meal plan Promotes adequate nutrition and weight gain, normoglycemia and no ketosis Individualized, adjusted as pregnancy progresses CHO : 35-45% of TCR 3 small to moderate-sized meals 2 to 4 snacks Including evening snack Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

58 Weight Management Follow the Institute of Medicine revised guidelines for weight gain during pregnancy Excess weight gain associated with macrosomia (OR 3.58) Blumer I, et al., J Clin Endocrinol Metab 98: , 2013 Kitzmiller JL, et al., Diabetes Care May;31(5):

59 2009 Institute of Medicine Recommendations for total and rate of weight gain in pregnancy, by Prepregnancy BMI Prepregnancy BMI Range (kg) Rates of weight gain in 2 nd & 3 rd trimester Mean (Range), kg/wk Underweight (<18.5 kg/m 2 ) ( ) Normal ( kg/m 2 ) ( ) Overweight ( kg/m 2 ) ( ) Obese ( 30 kg/m 2 ) ( ) Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

60 Pharmacologic Therapy Provide background/ basal coverage Human insulin : NPH Analogs : Glargine, Detemir Provide prandial coverage Match with carbohydrate intake Human insulin : regular Analogs : Aspart, Lispro Blumer I, et al., J Clin Endocrinol Metab 98: , 2013 Kitzmiller JL, et al., Diabetes Care May;31(5):

61 Strategies Recommend multiple daily doses of insulin or continuous SC insulin infusion over split-dose, premixed insulin Suggest rapid acting insulin analog (aspart or lispro) in preference to regular insulin Suggest use of basal insulins for pregnancy: Detemir or glargine Blumer I, et al., J Clin Endocrinol Metab 98: , 2013 Kitzmiller JL, et al., Diabetes Care May;31(5):

62 Pharmacologic Therapy Suggest that Detemir be initiated in 1. Require basal insulin 2. NPH insulin, in appropriate doses, has previously resulted in, or thought that may result in problematic hypoglycemia 3. Successfully taking detemir before pregnancy. Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

63 Detemir in pregnancy P I O M 310 T1DM women planning to be or pregnant at 8-12 weeks AOG, A1C 8% on confirmation or pregnancy 17 countries Detemir vs NPH insulin Primary: HBA1C at 36 wks AOG Secondary: A1C at 8-12, 14 and 24 wks AOG, # attaining 6%, FPG, SMBG Maternal : hypoglycemia, deterioration of retinopathy, AE, weight gain Open-labelled, randomized trial, noninferiority Mathiesen ER, et al., Diabetes Care 35: , 2012

64 Results Glycemic outcomes Parameter at 36 weeks AOG Detemir (n=152) NPH (n=158) significance HBA1C 6.27% 6.33% (95% CI-0.21 to 0.08) HBA1C 6% 41% 32% P=0.28 Estimated mean FPG Mean PG from 8-point SMPG 85.7 mg/dl 97.4 mg/dl P=0.017* 119 mg/dl 123 mg/dl P=0.082 Mathiesen ER, et al., Diabetes Care 35: , 2012

65 Results Maternal tolerability Parameter at 36 weeks AOG Detemir (n=152) NPH (n=158) significance Major hypoglycemia 16% 21% P=0.615 Weight gain 11.5kg 11kg NS Adverse Events (AE) Reported as same ~90% Serious AE 40% 31% * To be Reported in another paper Mathiesen ER, et al., Diabetes Care 35: , 2012

66 Results Maternal tolerability Outcome Detemir n=152 NPH n=158 Serious Adverse Events 40 % 31 % Pregnancy, puerperium, perinatal conditions 25.7 % 16.5 % Few events were considered by the investigator to be possibly or probably related to one or both investigational products (between 8-12% of the mothers) Infection & infestation 4.6 % 1.3 % Reproductive system & breast 2.0 % 3.2 % Nervous system 2.6 % 1.3 % Metabolism and nutrition disorders 11.2 % 8.2 % Hypoglycemia unawareness 2 pts 7 pts Diabetes inadequate control 5 pts 1 pts DKA 3 pts 0 pts Mathiesen ER, et al., Diabetes Care 35: , 2012

67 Detemir in Pregnancy Perinatal and Obstetric Outcomes P I O M 310 T1DM women planning to be or pregnant at 8-12 weeks AOG, A1C 8% on confirmation or pregnancy 17 countries Detemir vs NPH insulin Composite pregnancy outcome GA Sample at delivery, size computed SGA or LGA, based birthweight, on primary macrosomia, live births, early fetal death, perinatal mortality and induced abortions, detect perinatal neonatal and hypoglycemia, obstetric congenital outcomes malformations, preterm delivery, preeclampsia, AE (fetal & Maternal outcome (HBA1C at 36 weeks) and NOT to Open-labelled, randomized trial, noninferiority Hod M, et al., J Matern Fetal Neonatal Med, 2014; 27(1): 7 13

68 Results perinatal & obstetric outcomes Parameter- Detemir (n=152) NPH (n=158) significance Composite outcome 62.7% 66.2% OR 0.86 (95% CI 0.53, 1.40) GA at delivery (wks) 38.2 (SD 1.9) 37.8 (SD 1.5) P=0.012 Live births 90.1% 93.8% P=0.284 Preterm delivery 20.3% 26.5% P=0.238 Early fetal death 7.7% 6.2% - Perinatal death Neonatal death SGA 2.3% 0.7% - LGA Macrosomia Neonatal hypoglyc Hod M, et al., J Matern Fetal Neonatal Med, 2014; 27(1): 7 13

69 Results Congenital Malformations based on treatment during organogenesis Parameter Detemir (n=84) NPH (n=154) Significance Congenital 4.8% 7.1% - malformation Minor malformation 1.2% 5.2% - Major malformation 3.6% 1.9% - Hod M, et al., J Matern Fetal Neonatal Med, 2014; 27(1): 7 13

70 Results Adverse Events in Children Parameter Detemir (n=84) NPH (n=154) significan ce AE 36.8% 34.8% - Serious AE Severe AE AE possibly/probably related to basal insulin Detemir is well-tolerated Further reassurance will be provided with the collection of longterm observational data from a large cohort. Hod M, et al., J Matern Fetal Neonatal Med, 2014; 27(1): 7 13

71 Glargine Suggest that pregnant women successfully using glargine before pregnancy may continue it during pregnancy Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

72 Glargine Increased affinity to IGF-1 receptors mitogenicity Role of IGF-1 in fetal tissues Placenta perfusion study showed that glargine does not cross the placenta Kurtzhals P, et al., Diabetes 2000; 49: Chisalta SI, et al., Am J Physiol Endocrinol Metab 286: E896 E901, Pollex E, et al., Diabetes Care 33:29 33, 2010

73 Glargine Maternal outcomes Outcome 1 st Trimester HBA1C Severe Hypoglycemia # of studi es Gl N I 2 Effect (OR) 95% CI NPH % (Mean Diff) , % , 3.79 Preeclampsia % , 1.32 Gestational/ New Onset HPN % , 1.2 Lepercq J, et al., Obstet Gynecol Int. 2012;2012:649070

74 Glargine Neonatal outcomes Outcome Neonatal hypoglycemia # of studie s Gl N I 2 Effect (OR) 95% CI NPH % , 1.56 NICU admission % , 1.38 Congenital malformations % , 1.59 Macrosomia % , 2.02 Lepercq J, et al., Obstet Gynecol Int. 2012;2012:649070

75 Glargine Current available data from retrospective studies and one prospective cohort show that glargine does not result in increased risk for the mother and fetus. Lepercq J, et al., Obstet Gynecol Int. 2012;2012:649070

76 Pharmacologic Therapy NO randomized clinical trials regarding the use of non-insulin antihyperglycemics in pregestational diabetes Blumer I, et al., J Clin Endocrinol Metab 98: , 2013 Kitzmiller JL, et al., Diabetes Care May;31(5):

77 Pharmacologic Therapy NO randomized clinical trials regarding the use of non-insulin antihyperglycemics in pregestational diabetes Shift OHAS to insulin once pregnancy confirmed Blumer I, et al., J Clin Endocrinol Metab 98: , 2013 Kitzmiller JL, et al., Diabetes Care May;31(5):

78 Blumer I, et al., J Clin Endocrinol Metab 98: , 2013 ADA 2014 Standards of Care. Diab Care (37) : S14-80, 2014 Labor & Delivery Suggested targets during labor & delivery : mg/dl ( mmol/l)

79 Labor & Delivery Hyperglycemia during labor and delivery increases risk of neonatal hypoglycemia fetal distress birth asphyxia abnormal heart rate Method: No evidence on single best way of maintaining target BG No recommendation and at discretion of practitioner Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

80 Preconception During Pregnancy Postpartum Counselling Glycemic control Weight control Co-morbidities Targets SMBG MNT Weight management Pharmacologic Peripartum Lactation

81 Lactation Recommend whenever possible, women with diabetes should breastfeed their infants. Blumer I, et al., J Clin Endocrinol Metab 98: , 2013

82 Lactation Oral agents with data on transfer to breastmilk 1. Metformin - <1% 2. Glyburide, Glipizide <1.5% Blumer I, et al., J Clin Endocrinol Metab 98: , 2013 Feig DS, et al., Ann Pharmacother Jul;41(7): Glueck CJ, et al., J Pediatr May;148(5):

83 Preconception During Pregnancy Postpartum Counselling Glycemic control Weight control Co-morbidities Targets SMBG MNT Weight management Pharmacologic Peripartum Lactation

84 Thank you.

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