Diabetes and pregnancy

Transcription

1 Diabetes and pregnancy Elisabeth R. Mathiesen Professor, Chief Physician, Dr.sci Specialist in Endocrinology Centre for Pregnant Women with Diabetes Rigshospitalet, University of Copenhagen Denmark

2 Gestational diabetes Carbohydrate intolerance of varying degrees of severity, with onset or first recognition during pregnancy

3 Gestational diabetes Non-pregnant Pregnant Insulin secretion Insulin resistance Insulin secretion Insulin resistance Blood glucose

4 Macrosomia and shoulder dystocia High sugars induce fetal insulin production Extra growth of all tissues Extra fat deposition Shoulder areas bigger than the head Shoulder dystocia I

5 Short-term complications Complications in pregnancy Hypertension, pre-eclampsia, preterm delivery Complications during labour Shoulder dystocia, C-section, maternal lesions Neonatal morbidity Hypoglycaemia, prematurity, jaundice, RDS Neonatal mortality - rare macrosomia

6 Screening traditions Universal testing with OGTT (oral glucose tolerance test) Selective testing with OGTT Glucosuria Age BMI Diabetes in first degree relatives Previous GDM

7 ADA 75 g, 3-h OGTT WHO Diagnosis at least 2/3 values (5.3, 10.0 and 8.6 mmol/l) 75 g, 2-h OGTT 2-h value >= 7.8 mmol/l (IGT) DPSG (Europa) 75 g, 2-h OGTT 2-h value >= 9.0 mmol/l

8 Aim HAPO study To clarify unanswered questions on associations of maternal glycemia, less severe than overt diabetes mellitus, with risks of adverse pregnancy outcome Methods Observational multicenter study (N=25.000) Inclusion: FPG<5.8 mmol/l and 2-h PG <11 (75 g OGTT wk 24-32) Blinding of OGTT results Int J Gyn Obstet (1):69-77

9 LGA infants % fasting 1 h 2 h HAPO glucose categories Hapo N Engl J Med 08

10 Diagnose of GDM 75g OGTT Proposed criterias based on HAPO: One of the following: Fasting p-glucose 5,1 mmol/l (92 mg%) 1 hour p-glucose 10,0 mmol/l (180 mg%) 2 hour p-glucose 8,5 mmol/l (153 mg%) Diabetes Care 2010; 33:

11 Diagnose of overt diabetes in early pregnancy First pregnancy visit: Fasting plasma glucose > 7 mmol/l or HbA1c > 6.5% or Random plasma glucose > 11 mmol/l + confirmation Diabetes Care 2010; 33:

12 Management of GDM Diet treatment Exercise Self monitoring of blood glucose (SMBG) Pharmacological treatment Intensified obstetric surveillance

13 SMBG - therapeutic goals ADA American Diabetes Association ACHOIS Australian Carbohydrate Intolerance Study in Pregnant Women BG PG* BG PG* Faste mg% 1h ppr h ppr (9.0**) mg%

14 Therapeutic goal: Hba1c < 5.6% Nielsen RL et al. Diabetes Care 2004;27(5):

15 Dietary treatment Self-management therapy - SMBG Secure micronutrients Energy restriction of 30% in obese women Reduced glucose and TG with no increase in ketonuria (Franz MJ et al. Diabetes Care 17: , 1994) Carbohydrate restriction (35-40% of energy) better glycaemic control, reduced rates of macrosomia and CS (Major CA et al. Obstet Gynecol 91: , 1998

16 Exercise Increase insulin sensitivity Improve maternal glycaemic control (Jovanovic-Peterson AJOG 1989, Brankston AJOG 04) Recent Cochrane review found no effect of exercise alone compared to other regimens (Ceysens G et Al. Cochrane Database Syst Rev Jul 19;3:CD004225) Prevent GDM (Dempsey Am J Epidemiol 04)

17 Obstetric care Treatment of hypertension and preeclampsia Methyldopa, labetalol, ASA Clinical and ultrasonographic surveillance for fetal size and wellbeing Timing of delivery gestational week

18 Does treatment of GDM improve outcome? Intervention group, N=490 informed they had glucose intolerance of pregnancy SMBG, diet, insulin, intensified obstetric surveillance Control group, N=510 informed they did not have gestational diabetes Routine obstetric management Crowther et al. NJEM 2005;352: )

19 Serious perinatal outcome: Perinatal death and shoulder dystocia Intervention (N 506) Routine care (N 526) Serious 7 (1%) 23 (4%) perinatal outcome NNT =34 Death 0 5 (1%) NJEM 2005;352:

20 Infant outcome Int. group (N 506) Rout.Gr. (N 526) Adj. Treatment effect or RR (95% CI) Birth weight (g) (-219 to -70) LGA 13% 22% 0.62 ( ) 4000g 10% 21% 0.47 ( ) SGA 7% 7% 0.88 ( ) Apgar 5<7 1% 2% 0.57 ( ) Hypoglyc. 7% 5% 1.42 ( ) RDS 5% 4% 1.52 ( ) Mean±SD, median (IQ range), % NJEM 2005;352:

21 Summary Diagnosis and treatment of GDM: Reduces the risk of serious perinatal complications by 75% Reduces the risk of macrosomia by 50% NJEM 2005;352:

22 Pharmacological treatment SAFE Insulin (human and fast acting analogues) MAYBE SAFE Glyburide (glibenclamide) Metformin Arcabose NOT SAFE Most sulfonylureas (prolonged neonatal hypo) Thiazolidinediones TZD (teratogenicity)

23 Insulin regimens Basal-bolus regimen 4 times daily Premixed insulin 2 times dialy Other regimens

24 Twice vs. four times daily insulin in gestational diabetes Insulin * 2 Insulin * 4 Number HbA1c (%) 5,8 5,5* Adequate control (%) 74 91* Macrosomia (>4000 g) Neonat- hypoglycaemia 8 1* Overall neonat morbidity 40 24* Nachum BMJ 1999

25 Rationale for glyburide Potential risk of SU in pregnancy Prolonged neonatal hypoglycemia Teratogenecity Placental passage of glyburide minimal in perfusion studies Insulin more expensive

26 Glyburide vs. insulin Outcome Glyburide Insulin P-value N=201 N=203 LGA (%) 24 (12) 26(13) 0.76 Hypoglycaemia (%) 18 (9) 12 (6) 0.25 Stillbirth (%) 1 (0.5) 1 (0.5) 0.99 HbA1c (%) 5.5 ± ± * Means ± SD Langer et al. NEJM 2000, 343;

27 Metformin in pregnancy Potential risks: Teratogenity or less malformations Lactic acidosis Still birth (Helmuth, Diab Med 2000) Neonatal hypoglycemia

28 Metformin versus insulin in GDM Metformin Insulin Number Composite poor outcome Insulin suplemented 32 % 32 % 46% 100 % Women prefere metformin Rowan, N Engl, J Med 08

29 Long-term complications Mother Diabetes up to 70 % Obesity Cardiovascular disease Offspring-importance of the intrauterine milioe Glucose intolerance incl. GDM Other metabolic risk factors Other morbidity

30 Born big is not necessarily better Intra uterine excess foot intake Risk of future obesity Risk of future diabetes

31 Intrauterine milieu and the next generation - Type 2 diabetes and prediabetes in young adults % 21% 12% 11% 4% O-BP O-Type1 O-NoGDM O-GDM 0 Type 1 diabetes Type 2 Prediabetes Type 2/ diabetes Prediabetes Clausen TD et al. Diabetes Care 08

32 Diabetes present before pregnancy

33 Adverse events in diabetic pregnancy Major hypoglycaemia Proliferative retinopathy Fetal loss Malformations Preterm delivery Macrosomia

34 Outcome in Type 2 DM Type 2 Type 1 RR Perinatal mortality (o/1ooo) Malformations (o/1ooo) Preterm delivery (%) LGA (>90% percentile,%) >50 >50? 5 CEMACH 2005, N=2356

35 Weeks Timing of congenital malformations Ovulation Caudal regression Spina bifida, anencephalus Transposition, renal abnormalities Ventricular septal defect, anal atresia weeks after ovulation correspond to gestation week 8

36 Glycemic control Elevated plasma glucose in the mother gives High glucose suply to the fetus Increased oxygen need Obese fetus Immature organs Insulin does not pass placenta Modificded after Pedersen hypotesis

37 Perinatal mortality - Stillbirth High glucose Increased metabolism Increased oxygen need Low oxygen Lactate acid production Stimulation of EPO

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39 Percentage of preterm delivery vs. third trimester HbA 1c 213 women with type 1 diabetes Preterm delivery ra ate (%) Upper normal limit (HbA 1c ) Old target (HbA 1c ) < >7.4 HbA 1c in third trimester (%) Ekbom

40 167 events of severe hypoglycaemia in 108 pregnant women with type 1 diabetes Number of events Gestational week LR Nielsen, unpublished

41 Major hypoglycemia during pregnancy 2.5 p= % lower risk IAsp HI 2.0 p=0.660 Rate (episodes/ye ear) p= % lower risk 15% lower risk h Nocturnal Daytime N=322N=322

42 Frequency of preterm delivery p=0.05 n=41 % of all deliveries n=28 IAsp n=138 HI n=134

43 Clinical experience of insulin analoges in pregnancy 2010 Insulin Lispro (1996) Several observational trials Approved for use in pregnancy Insulin Aspart (1999) One large randomized trial Approved for use in pregnancy Insulin Glargine (2000) Several observational studies no concerns Insulin Detemir (2004) Ongoing large randomized trial no concerns

44 Hypertension-diabetespreeclampsia Brain Eye Heart Kidney Arteries

45 Preterm delivery in relation to urinary albumin excretion Preterm delivery (%) 100 Pre-eclampsia Other causes Normal UAE Microalbuminuria Nephropathy Ekbom, Diabetes Care 2002

46 Effect of early antihypertensive treatment in pregnant women with microalbuminuria Cohort- year AH- treatment protocol Methyldopa first choice BP>140/95 AH-pause Number 26 HbA1c at 28 wks (%) 6.3 Preeclampsia (%) 42% Delivery < 34 wks 23% Delivery < 37 wks 62% Nielsen et al, Diabetes Care 2009

47 Effect of early antihypertensive treatment in pregnant women with microalbuminuria Cohort- year AH- treatment protocol Methyldopa first choice BP>140/95 AH-pause U-alb>2000 BP>140/90 AH-shift Number HbA1c at 28 wks (%) 6.3 Preeclampsia (%) 42% Delivery < 34 wks 23% Delivery < 37 wks 62% Nielsen et al, Diabetes Care 2009

48 Effect of early antihypertensive treatment in pregnant women with microalbuminuria Cohort- year AH- treatment protocol BP>140/95 AH-pause U-alb>2000 BP>140/90 AH-shift U-alb>300 Methyldopa first choice AH-shift BP>135/85 Number HbA1c at 28 wks (%) 6.3 Preeclampsia (%) 42% 20% Delivery < 34 wks 23% 0 Delivery < 37 wks 62% 40% Nielsen et al, Diabetes Care 2009

49 Effect of early antihypertensive treatment in pregnant women with microalbuminuria Cohort- year AH- treatment protocol BP>140/95 AH-pause U-alb>2000 BP>140/90 AH-shift U-alb>300 Methyldopa first choice AH-shift BP>135/85 Number HbA1c at 28 wks (%) Preeclampsia (%) 42% 20% 0 Delivery < 34 wks 23% 0 0 Delivery < 37 wks 62% 40% 20% Nielsen et al, Diabetes Care 2009

50 Drugs compatible with breast-feeding Insulin Metformin Glyburide Glipizide Methyldopa Labetalol Dihydropyridine Aspirin Captopril, enalapril

51 Prevention of poor outcome in diabetic pregnancy Strict metabolic control Aim for blood glucose 4-6 mmol/l preprandially and 4-8 mmol/l postprandially measured 7-8 times daily HbA1c <5,6 % measured 1-2 times monthly avoid severe hypoglycaemia. self-adjustment of insulin treatment and frequent clinic visits. Modern insulin treatment focusing on pre and postprandial blood glucose Early and strict treatment of micro- and macroalbuminuria with antihypertensive drugs. E Mathiesen 2005

52 Stillbirth in type 1 diabetes % % 0.60 % 0.45 % 1 0 Denmark N= Our clinic N= Background population

53 Preterm delivery in type 1 DM background HbA1c: 6,3% HbA1c: 5,9% HbA1c: 5.0%

54 It is possible to obtain better outcome within a short time period We have to strive for better outcome in diabetic pregnancies

55 Extra slides