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(1)

Den gravide med diabetes

Peter Damm, Center for Gravide med

Diabetes, Obstetrisk klinik, Rigshospitalet

(2)

Dagsorden

o  Fokus på type 1 diabetes o  Lidt baggrundsfysiologi

o  Generel, og udvalgte detaljer o  Fokus på blodtryk

o  Lidt om fødslen

o  Langtidseffekter for børnene?

o  Alt primært baseret på danske studier

(3)

Diabetes og graviditet

o   Gestationel diabetes (3-4%) o   Prægestationel diabetes

n   Type 1 – 250/år

n   Type 2 – 150/år

n   MODY – 10-15/år

(4)

Diabetes and pregnancy

Diabetes types in Copenhagen

GDM

T1D T2D

Unknown T2D

30-50 years ago

GDM

T2D T1D

Unknown T2D This millenium

(5)

The Pedersen hypothesis

Glucose

Insulin

Mother Fetus

Pl ace nt a

Fetal

Hyperglycemia

Fetal

Hyperinsulinemia

(6)

The Pedersen hypothesis

Glucose

Insulin

Mother Fetus

Pl ace nt a

Fetal

Hyperglycemia

Fetal

Hyperinsulinemia

?

(7)

BEHAVORIAL

ORGAN ANTHROPOMETRIC

- METABOLIC

Fuel-mediated teratology

INSULIN DEPENDENT DIABETES

GESTATIONAL DIABETES

Weeks of Pregnancy

1980 Banting Lecture: “Of Pregnancy and Progeny”, Diabetes 1980

(8)

Changes in insulin requirement in diabetic women during pregnancy

0 4 8 12 16 20 24 28 32 36 40

week of pregnancy

IU/day

(9)

Perinatal implications of maternal hyperglycemia

-  Congenital malformations ↑ - Perinatal mortality ↑

-  Prematurity ↑

-  Neonatal hypoglycemia ↑ -  Shoulder dystocia ↑

-  Macrosomia ↑

Severe pre-gestational diabetes

Mild GDM

(10)

Maternal complications

Denmark 1993-99 (N=1215)

Type 1 diabetes

Background

population RR Preeclampsia 18% 2.6% 6.9 * Preterm delivery 42% 6% 7.0 *

Caesarean

section 56% 13% 4.3 *

DM Jensen et al Diabetes Care 2005 * P < 0.01

(11)

Maternal complications

Denmark 1993-99 (N=1215)

Type 1 diabetes

Background

population RR Preeclampsia 18% 2.6% 6.9 * Preterm delivery 42% 6% 7.0 *

Caesarean

section 56% 13% 4.3 *

DM Jensen et al Diabetes Care 2005 * P < 0.01

(12)

Maternal complications

Denmark 1993-99 (N=1215)

Type 1 diabetes

Background

population RR Preeclampsia 18% 2.6% 6.9 * Preterm delivery 42% 6% 7.0 *

Caesarean

section 56% 13% 4.3 *

DM Jensen et al Diabetes Care 2005 * P < 0.01

(13)

Neonatal complications

Denmark 1993-99 (N=1215)

Type 1 diabetes

Background

population RR Stillbirth 2.1% 0.45% 4.7 *

Perinatal

mortality 3.1% 0.75% 4.1 * Congenital

malformations 5.0% 2.8% 1.7 *

DM Jensen et al Diabetes Care 2005

* P < 0.01

(14)

Neonatal complications

Denmark 1993-99 (N=1215)

Type 1 diabetes

Background

population RR Stillbirth 2.1% 0.45% 4.7 *

Perinatal

mortality 3.1% 0.75% 4.1 * Congenital

malformations 5.0% 2.8% 1.7 *

DM Jensen et al Diabetes Care 2005

* P < 0.01

(15)

Neonatal complications

Denmark 1993-99 (N=1215)

Type 1 diabetes

Background

population RR Stillbirth 2.1% 0.45% 4.7 *

Perinatal

mortality 3.1% 0.75% 4.1 * Congenital

malformations 5.0% 2.8% 1.7 *

DM Jensen et al Diabetes Care 2005

* P < 0.01

(16)

Planlagt graviditet

(17)

Hvordan sikrer den vordende mor sig at graviditeten forløber så godt som muligt – før graviditeten ?

o  God kontakt til diabetesteam o  God metabolisk kontrol,

n  HbA1c < 53 mmol/l (7%)

o  Folinsyretilskud 400 ug per dag o  Medicinliste gennemgåes:

n  insulin, blodtryksmedicin

Øjne og nyrer undersøges

(18)

Hvordan sikrer den vordende mor sig at graviditeten forløber så godt som muligt – under graviditeten ?

o  God kontakt til fødested og diabetesteam o  God metabolisk kontrol,

n  HbA1c < 48/38 mmol/mol (6,5/5,6%)

o  Blodsukkermåling 7 gange dagligt o  Blodsukker før måltider 4-5,5

o  Blodsukker efter måltider 4-7

o  Hyppige ambulante kontroller (blodtryk m.m.)

o  Insulinføling 2-4 gange ugentligt

accepteres

(19)

Hvordan sikrer den vordende mor sig at graviditeten forløber så godt som muligt – under graviditeten ?

o  Fokus på begrænset vægtstigning o  Brug af insulin analoger

o  Insulinpumper og glukosesensorer?

(20)

Pump-treatment is it of value in pregnancy?

o  Theoretically –yes

In practise – may be - no proof

Mathiesen, The Journal of Maternal-Fetal & Neonatal Medicine 2013

(21)

Is intermittent continous glucose monitoring of value in pregnancy

o  Theoretically – Yes

o  In practise – may be

n  One randomized trial with effect

Feig, Lancet 2017;

Secher, Diabetes Care 13

(22)

Fosterovervågning

(23)

Fosterovervågning

o  Ultralydsscanning

n  8, 12, (14), 20, 28, 34, 37 uger

n  Misdannelser, vægt, vand og flow???

o  CTG på vid indikation

o  Opmærksomhed på dagligt liv fra 28-30 uger

o  Insulinbehov

Jørgensen et al AOGS 2019

(24)

Stillbirth

(25)

Audit on stillbirth in type 1 diabetic pregnancy in Denmark 1990-2000

o  Women experiencing stillbirth were characterized by an increased frequency of

n  suboptimal glycemic control

Lauenborg et al. Diabetes Care 2003;26:1385-1389

(26)

Audit on stillbirth in type 1 diabetic pregnancy in Denmark 1990-2000

o  Women experiencing stillbirth were characterized by an increased frequency of

n  suboptimal glycemic control n  diabetic nephropathy

n  smoking

n  low social status n  previous stillbirth

Lauenborg et al. Diabetes Care 2003;26:1385-1389

(27)

Stillbirth in pregnant women with type 1 diabetes

0 1 2 3

Denmark N=1218 1993-1999

RH N=712 2000-2009

Controls

%

0.70 %

0.45 % 2.0 %

Mathiesen ER et al.. Best Pract Res Clin Obstet Gynaecol 2010

(28)

Changes in insulin requirement in diabetic women during pregnancy

0 4 8 12 16 20 24 28 32 36 40

week of pregnancy

IU/day

(29)

Betydning af hypoglykæmi under svangerskabet

o  Fosteret tåler hypoglykæmi utrolig godt.

o  Hypoglykæmi behandles som vanligt o  Ved blodsukker mindre end 5-6 før

sengetid tilrådes ekstra kulhydrater o  Næsten hver anden kvinde har

mindst et svært insulintilfælde i graviditeten.

o  Risiko for død og trafikuheld

Nielsen LR, Diabetes Care 2008;31:9-14

(30)

Er det farligt at have syre i urinen under graviditeten ?

o  Sukkersygen kommer lettere ud af balance når man er gravid.

o  Syre (ketonstoffer) i urinen skal tages alvorligt - fødestedet eller

diabetesteamet skal kontaktes.

o  Syreforgiftning er en alvorlig sag for et foster og skal behandles intensivt.

o  Mål altid blodsukker og urin ketonstoffer

ved ”syge” gravide med diabetes

(31)

Lung maturation -

Glucocorticoid treatment

o  Usual insulin dose is set to 100%

o  Day 1, night insulin dose +25%

o  Day 2, all 4 insulin doses +40%

o  Day 3, all 4 insulin doses +40%

o  Day 4, all 4 insulin doses +20%

o  Day 5, all 4 insulin doses +10%

Mathiesen et al. Acta Obst Gyn Scand 2002

Ved celeston – ring til en ven!

(32)

Er æggehvidestof i urinen farligt ?

o  Nyresygdom tidligt i graviditeten er af betydning for forløbet af graviditeten.

o  Æggehvidestof i urinen og forhøjet

blodtryk senere i graviditeten er tegn på begyndende svangerskabsforgiftning

n  Det kræver tæt kontrol og behandling

n  Fører ofte til for tidlig fødsel

(33)

Diabetes and microalbuminuria

30

0 300

A lb u m in u ri a (m g /2 4 h )

Normoalbuminuria Overt nephropathy

Microalbuminuria

Time (Years)

BP

(34)

Preeclampsia in type 1 diabetic pregnancy in relation to urinary albumin excretion

0 20 40 60 80

100

Preeclampsia

Normal UAE Microalbuminuria Nephropathy

P re ec la m ps ia ( %)

Ekbom

,

Diabetes Care 2002

(35)

Development of preeclampsia in women with type 1 diabetes is preceeded by presence of

o  Higher blood pressure

o  Increased urinary albumin excretion

o  Decreased maximal vasodilatory capacity o  Signs of endothelial dysfuncion

o  All which theoretically can be modulated by antihypertenisve treatment

o  Placenta function is often well preserved

Clausen P et al., J Diab. Compl. 2007

(36)

Consensus of treatment of hypertension

in pregnancy when BP ≥ 150/100 mmHg

(37)

Antihypertensive drugs used during pregnancy

o  Methyldopa

o  Labetalol

o  Calcium antagonists o  Diuretics

(38)

Effect of early antihypertensive treatment in pregnant women with microalbuminuria

Cohort- year 1995-99 2000-2003 2004-2006 AH- treatment protocol

Methyldopa first choice

BP>140/95 AH-pause

Number 26

AH- treatment 35%

AH-treatment onset

(week) 29 (20-34)

HbA1c at 28 wks (%) 6.3 Preeclampsia (%) 42%

Delivery < 34 wks 23%

Delivery < 37 wks 62%

Nielsen et al, Diabetes Care 2009

(39)

Effect of early antihypertensive treatment in pregnant women with microalbuminuria

Cohort- year 1995-99 2000-2003 2004-2006 AH- treatment protocol

Methyldopa first choice

BP>140/95

AH-pause U-alb>2000 BP>140/90

AH-shift

Number 26 20

AH- treatment 35% 50%

AH-treatment onset

(week) 29 (20-34) 13 (0-34)

HbA1c at 28 wks (%) 6.3 Preeclampsia (%) 42%

Delivery < 34 wks 23%

Delivery < 37 wks 62%

Nielsen et al, Diabetes Care 2009

(40)

Effect of early antihypertensive treatment in pregnant women with microalbuminuria

Cohort- year 1995-99 2000-2003 2004-2006 AH- treatment protocol

Methyldopa first choice

BP>140/95

AH-pause U-alb>2000 BP>140/90

AH-shift

Number 26 20

AH- treatment 35% 50%

AH-treatment onset

(week) 29 (20-34) 13 (0-34)

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

(41)

Effect of early antihypertensive treatment in pregnant women with microalbuminuria

Cohort- year 1995-99 2000-2003 2004-2006 AH- treatment protocol

Methyldopa first choice

BP>140/95

AH-pause U-alb>2000 BP>140/90

AH-shift

AH-shift U-alb>300 BP>135/85

Number 26 20 10

AH- treatment 35% 50% 50%

AH-treatment onset

(week) 29 (20-34) 13 (0-34) Before - 14 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

(42)

Effect of early antihypertensive treatment in pregnant women with microalbuminuria

Cohort- year 1995-99 2000-2003 2004-2006 AH- treatment protocol

Methyldopa first choice

BP>140/95

AH-pause U-alb>2000 BP>140/90

AH-shift

AH-shift U-alb>300 BP>135/85

Number 26 20

10

AH- treatment 35% 50% 50%

AH-treatment onset

(week) 29 (20-34) 13 (0-34) Before - 14

HbA1c at 28 wks (%) 6.3 5.6

Preeclampsia (%) 42% 20%

Delivery < 34 wks 23% 0 Delivery < 37 wks 62% 40%

Nielsen et al, Diabetes Care 2009

(43)

Effect of early antihypertensive treatment in pregnant women with microalbuminuria

Cohort- year 1995-99 2000-2003 2004-2006 AH- treatment protocol

Methyldopa first choice

BP>140/95

AH-pause U-alb>2000 BP>140/90

AH-shift

AH-shift U-alb>300 BP>135/85

Number 26 20

10

AH- treatment 35% 50% 50%

AH-treatment onset

(week) 29 (20-34) 13 (0-34) Before - 14

HbA1c at 28 wks (%) 6.3 5.6

Preeclampsia (%) 42% 20% 0

Delivery < 34 wks 23% 0 0

Delivery < 37 wks 62% 40% 20%

Nielsen et al, Diabetes Care 2009

(44)

Preeclampsia

o  Hypertension in diabetic pregnancy is prevalent

o  Hypertension is associated with increased risk of preeclampsia and preterm delivery o  Early antihypertensive treatment may

reduce the risk

o  Safe drugs must be used and avoid

blockers of the renin angiotensin system

(45)

The Copenhagen recommendations for

antihypertensive treatment in diabetic pregnancy

o  BP > 135/85

o  U-albumin> 300 mg/24h

o  If antihypertensive treatment is given prior to pregnancy then shift to drugs approved for use in pregnancy

o  Low dose aspirin

o  Seems safe for the fetus

Pedersen BW et al. J Mat Fetal Neonat 2016

(46)

Should we be even more aggressive or are we treating too many

o  White coat hypertension

(47)

o  0-3 weeks before term after individual judgement

o  Induction of labor

n  medical

o  prostaglandins o  oxytocin

n  physical

o  rupture of the membranes o   balloon catheter

o  Elective Cesarean Section

Delivery

(48)

Treatment during delivery

o  Aim for blood glucose: 4-7 mmol/l

o  Normal insulin and food until regular contractions or rupture of the

membranes

o  Hereafter fasting, and infusion of 5%

glucose in water, 60 ml/h, plus insulin

in reduced doses (25-50%) at regular

hours

(49)

Hvor kommer det fra?

(50)

Treatment during delivery

o  Close fetal surveillance (CTG, STAN)

o  Be prepared for shoulder dystocia

(51)

Skulderdystoci

(52)

Fødselsmåde hos gravide med

type 1 diabetes – 2004-2006 - RH

0 10 20 30 40 50 60

% 70

Vaginalt Sectio

Vaginalt Sectio

Bytoft et al. unpublished

2012-2014 – 45 % føder ved kejsersnit

(53)

Et par erfarne jordemødre ved vagtskifte

(54)

Changes in insulin requirement in diabetic women during pregnancy

0 4 8 12 16 20 24 28 32 36 40

week of pregnancy

IU/day

(55)

Insulin treatment post partum

o  Insulin dosis is reduced to around 70%

of the prepregnancy dose to avoid

hypoglycemia

(56)

Recent data – 2012-16 Rigshopsitalet

Type 1 DM (n=307)

Type 2 DM (n=187)

HbA1c, last visit, mmol/mol (%)

43±6 (6.1±0.5)

42±7

(6.0±0.6)

Gestational hypertension 9% 6%

Preeclampsia 9% 7%

Preterm delivery 17% 16%

LGA 42% 29%

Cesarean section 44% 43%

Nørgaard S et al, Diabetes Res Clin Pract. 2018

(57)

Recent data – 2012-16

Type 1 DM (n=307)

Type 2 DM (n=187)

HbA1c, last visit, mmol/mol (%)

43±6 (6.1±0.5)

42±7

(6.0±0.6)

Gestational hypertension 9% 6%

Preeclampsia 9% 7%

Preterm delivery 17% 16%

LGA 42% 29%

Cesarean section 44% 43%

Nørgaard S et al, Diabetes Res Clin Pract. 2018

(58)

Recent data – 2012-16

Type 1 DM (n=307)

Type 2 DM (n=187)

HbA1c, last visit, mmol/mol (%)

43±6 (6.1±0.5)

42±7

(6.0±0.6)

Gestational hypertension 9% 6%

Preeclampsia 9% 7%

Preterm delivery 17% 16%

LGA 42% 29%

Cesarean section 44% 43%

Nørgaard S et al, Diabetes Res Clin Pract. 2018

(59)

Recent data – 2012-16

Type 1 DM (n=307)

Type 2 DM (n=187)

HbA1c, last visit, mmol/mol (%)

43±6 (6.1±0.5)

42±7

(6.0±0.6)

Gestational hypertension 9% 6%

Preeclampsia 9% 7%

Preterm delivery 17% 16%

LGA 42% 29%

Cesarean section 44% 43%

Nørgaard S et al, Diabetes Res Clin Pract. 2018

(60)

o  Intended for pregnant women with diabetes and those planning

pregnancy

o  Features quick, convenient and easily accessible information o  Based on the treatment

recommendations at the Center for Pregnant Women with Diabetes in Copenhagen

App on diabetes in pregnancy - free

http//:www.pregnantwithdiabetes.com

(61)

The obstetricians dream

However this is a much to simplistic view What happens during pregnancy might have

longterm consequenses for both mother and offspring

Exposure to maternal diabetes

(62)

Maternal type 1 diabetes and offspring longterm health

Summary

o  Increased risk of type 2 diabetes/pre-diabetes, overweight and the metabolic syndrome

o  Lower cognitive scores

n  More leaning difficulties in school

n  But similar school grades finishing primary school

o  Offspring longterm complications might be prevented by optimal treatment of maternal hyperglycemia – solid evidence is currently lacking

Clausen T et al Diabetes Care 2008, Vlachova Z et al. Diabetologia 2015, Knorr S et al. Diabetes Care 2015, Bytoft et al. Diabetes Care 2016

(63)

Take home message

o  Planlagt graviditet

o  God diabetes - og blodtryksregulation er alt afgørende

o  Tæt obstetrisk kontrol o  Obs ved Celeston

– Ring til en ven!

o  Outcome af graviditeterne bedres, men

er stadig et stykke fra det normale

(64)

Tak for opmærksomheden

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