Diabetes, Obesity and Pregn

University Medical Center, Utrecht, the NL
Diabetes, Obesity and
Pregnancy
- ‘More big babies despite better control’
- GDM or Obesity, which is the problem
- Methformin in case of obesity?
Gerard H.A.Visser
6940 g
3120 g
4480 g
36 weeks
Type-1 diabetes and Pregnancy in the NL
Birth weight centiles
35
30
25
%
20
15
10
5
0
< 2.3
2.3-10
10-25
25-50
50-75
75-90
90-97.7
geboortegewicht in percentielen
(Evers et al, Diabetologia, 2002; BMJ 2002)
>97.7
Birthweight > p 90 in type-1/2 diabetes
country year
n
%
.
.
.
.
.
3809
289
323
1218
3705
51.7
55
56.1
62.5
47.3
UK
02-03
Scot. 98-99
NL
99-00
DK
93-99
Sweden 98-07
Type-1 diabetes and pregnancy
So, nowadays bigger babies??
• Sweden 1982 – 1985
20% > p 97.5
• Sweden 1991 – 2003 31% > p 97.5
(Hanson & Persson, 1993; Persson et al. Diab Care, 2009; n=5.089; Persson et al,Diab Care,2011; n=3.705)
Birth weight distribution
Persson et al. Diab Care 2011;34:1145-1149
Fetal growth profiles in diabetic pregnancies
Head to abdomen circumf. ratio( N. Hammoud et al, UOG 2012)
1,3
Fetal growth profiles in diabetic pregnancies
Head to abdominal circumference ratio (HC/AC ratio)
1,25
IDDM non-macrosomia
1,2
IDDM macrosomia
DM2 non-macrosomia
1,15
DM2 macrosomia
GDM non-macrosomia
1,1
GDM macrosomia
1,05
1
0,95
Birthweight>90th cent
Type-1 AGA
0,9
Type-1-diabetes LGA
0,85
0,8
100
120
140
160
180
Gestational age in days
200
220
240
260
280
Increase in fetal macrosomia
• Increase in maternal Obesity (Klemetti et al, Diabetologia, 2012)
• Lower incidence of maternal vascular
complications
• Better control in early pregnancy, better
placentation, bigger babies?
• Poorer control in the course of pregnancy, since
women are not admitted to hospital anymore?
• Increased weight gain during pregnancy ( due to
easier glucose control) ?
Increase in fetal macrosomia
• Increase in maternal Obesity (Klemetti et al, Diabetolgia, 2012)
• Lower incidence of maternal vascular
complications
• Better control in early pregnancy, better
placentation?
• Poorer control, since women are not admitted
to hospital anymore?
5 reasons and probably all
five hold true !!
Early placental function and birth weight centiles
Log MOM
PAPP-A
Birth weight centiles
Kuc et al, BJOG 2011;118:748-754
data similar for ADAM 12, PP13 and PlGF
So,……. in women with PGDM
poor placentation
normal placentation
normal birthweight
increased birthweight
So,……. in women with PGDM
poor placentation
normal placentation
normal birthweight
increased birthweight
In other words, fetal overgrowth due to
overexposure to glucose, in both instances
IUFD 34 wks; birth weight 60th centile
MUPPITT study ,Kuc et al, in preparation
IUFD 34 wks; birth weight 60th centile
.
MUPPITT study, Kuc et al, in preparation
Type-1 diabetes and PAPP-A
control
• n
36.415
• PAPP-A (Mom)
1.01
• Free B-hcg
0.99
type-1 diabetes
331
0.86
0.98
Significant inverse relation between HbA1c and PAPP-A
Madsen et al, Acta Ob Gyn Scan 2011, June 15 ( Epub ahead of print)
And that closes the circle……
Better periconceptional glucose control,
better placentation,
bigger babies
And that closes the circle……
Better periconceptional glucose control,
better placentation,
bigger babies
• birthweight
•
•
•
•
•
Increasing periconc HbA1c
Later gestation at first visit
Increasing maternal age
Retinopathy/nephropathy
Smoking
N=1.505
birthweight
increasing third trimester HbA1c
increasing maternal BMI
longer maternal height
parity
BMI
Large-for-Gestational age infant:
Lower, less variable glucose in 1st trimester; higher and
more variable glucose in 2nd and 3rd trimester
Law et al, Diab Care, 2015; CGM in 117 women; 46% of infants LGA
Continuous glucose profiles during pregnancy
(type-1 diabetes, n = 46; controls n = 12; Kerssen et al. Diab Care,2007)
Normoglycaemia?? NO !!
> 2mmol/l
>2.5 mmol/l
>1.5mmol/l
(type-1 diabetes, n = 46; controls n = 12; Kerssen et al. Diab Care,2007)
Near Normoglycaemia???
• NO……., not at all
• The struggle towards adequate glucose
control has only just begun
• And will be difficult
Almost good is not good enough
Conclusion
At present we are not capable of
achieving adequate glycemic control.
Nor of reducing maternal BMI.
Almost good is not good at all.
Big babies are therefore going to stay
Obesity and GDM; short term
outcome
independent risk factors with synergistic effects
Adapted from Catalano et al, 2012
Maternal obesity is the main problem
and not GDM
overweight and abdominal obesity in 16 y old adolescents
Risk population
(n=741):
-GDM 84
-Normal OGTT 657
Control 3.427
= mat BMI> 25
Pirkola et al, Diab Care 2010
Mat Diabetes and Childhood obesity
meta-analysis, Philipps et al, Diabetologia 2011
All types of diabetes:
GDM:
Mat Diabetes and Childhood obesity
meta-analysis, Philipps et al, Diabetologia 2011
Adjusted for maternal BMI:
All types of diabetes:
Lawlor and Wright; GDM
So, which infants are likely to
develop obesity/diabetes
•
•
•
•
Genetic predisposition ( thrifty genotype)
High maternal BMI
High weight gain in pregnancy
Macrosomia at birth
Maternal diabetes
• And……excessive weight gain > 2 y of age
Which factors affect outcome in
offspring
•
•
•
•
•
•
•
•
Genetic predisposition
Maternal BMI
Weight gain in pregnancy
(Gestational) diabetes mellitus
Macrosomia at birth
Cesarean Delivery
Excessive weight gain > 2 y of age
Socio-economic circumstances
And which can we change/influence?
•
•
•
•
•
•
•
•
Genetic predisposition
Maternal BMI
Weight gain in pregnancy
(Gestational) diabetes mellitus
Macrosomia at birth
Cesarean Delivery
Excessive weight gain in infants > 2 y of age
Socio-economic circumstances
Prepregnancy BMI and Gest Weight Gain in
relation to childhood obesity
BBMI
Subcutane
Adipose
Tissue
I
Kaar et al, P Pediatr, 2014
Waist
Circumf
HDL-c
Adequate W gain
Excessive W gain
Optimal weight gain during pregnancy
Birthweight, Infant growth & Type-2 diabetes
Mean Z-score
(Eriksson et al, Diab Care 2003; 26: 2006-10)
Birthweight, Infant growth & Type-2 diabetes
diabetes
Mean Z-score
(Eriksson et al, Diab Care 2003; 26: 2006-10)
Childhood growth of infants of women with
type-1, type-2 and Gest diabetes (Hammoud et al, subm)
Type-2
Childhood growth of infants of women with
type-1, type-2 and Gest diabetes (Hammoud et al, subm)
Type-2
BMI 31
BMI 26
BMI 24
Prevention of impaired outcome
• Prevent overgrowth of the young infant
(2-7 yrs)
GDM and Obesity; practical considerations
• oGTT in all pregnant women around 24-28
wks
• Use strict threshold values for obese women
• And monitor weight gain in obese women
carefully with the help of dietary advices
RCTs metformin in Obese non-diabetic
women, started in 1st trimester
Author
Inclusion N
Carlsen 2012
PCO
258
mean BMI 30
Chiswick 2015 BMI>30
Cauc.only
449
Syngelaki 2016 BMI>35
400
MWG BW
PE Weight at 1y
Carlsen et al, Pediatrics, 2012; Chiswick et al, Lancet July 2015; Syngelaki et al in press JEJM, 2016
RCTs metformin in Obese non-diabetic
women, started in 1st trimester
Author
Carlsen 2012
Inclusion N
PCO
258
mean BMI 30
Chiswick 2015 BMI>30
Cauc.only
449
Syngelaki 2016 BMI>35
400
MWG BW
PE Weight at 1y
-1 kg
-
?
-
-
-
-3 kg
-
+0.5kg
4fold reduction
Carlsen et al, Pediatrics, 2012; Chiswick et al, Lancet July 2015; Syngelaki et al in press JEJM, 2016
Thank you
G1P0, 31 y, DM type 1, GA 9 1/7 weeks
HbA1c 42 mmol/l (6%=2SD)
20,0
Glucose Concentration (mmol/L)
15,0
Meter Value
Paired Meter Value
10,0
Sensor Value
Insulin
Meal
Exercise
Other
5,0
0,0
-5,0
12:00 AM
4:00 AM
8:00 AM
12:00 PM
Tim e
(Kerssen et al, 2003)
4:00 PM
8:00 PM
12:00 AM
Continuous glucose profile, 10 weeks’ gestation
( Kerssen et al, Pren Diagn, 2006)
G2P1, 29 y, DM type 1, GA 10 2/7 weeks
HbA1c 50 mmol/l (6.7%=2-4SD)
20,0
Glucose Concentration (mmol/L)
15,0
Meter Value
Paired Meter Value
10,0
Sensor Value
Insulin
Meal
Exercise
Other
5,0
0,0
-5,0
12:00 AM
4:00 AM
8:00 AM
12:00 PM
Tim e
(Kerssen et al, 2003)
4:00 PM
8:00 PM
12:00 AM
Continuous glucose profiles; abnormal infants
9 wks,HA1c 42,
mild caudal
regression,deviated
position of hands,
extra ear
10 wks,HbA1c 49
bilateral club foot
11 wks,HbA1c 61
unilateral atrophic
kidney
(Kerssen et al, Pren Diagn, 2006)
Two-day continuous glucose profiles
(Kerssen et al, BJOG, 2004)
Two-day continuous glucose profiles
(Kerssen et al, BJOG, 2004)
Real-time continue
subcutane glucose
sensor
. CSII
. Real-time glucose
sensor
. Warning abrupt
changes
RCT real-time CGM
for 6 days at 8, 12, 21, 27 and 33 wks
•
•
•
•
•
CGM
N
79
HbA1c baseline 6.6%
HbA1c 33 wks
6.1%
Severe hypo glyc. 16%
LGA infant
45%
Controls*
75
6.8%
6.1%
16%
34%
A.L.Secher et al, Diab Care online Jan 24, 2013; 123 type-1 and 31 type 2 diabetes; * 7
times daily self monitored plasma glucose; real-time CGM per protocol 49 (64%)
Real-time CGM
during the whole of pregnancy
• N
• HbA1c 1st trim
• LGA
De Valk et al, submitted
CGM
Controls*
55
22
48 mmol/mol
59
61%
46%
RCT real-time CGM in GDM
2nd half of pregnancy; n=236
JCEM 2015
LGA 13.6% vs 25.6%; PE & CSs sign lower
Pickup et al, BMJ 2011
Maternal weight gain and LGA
• Type-1 diabetes, n=175
• Excessive weight gain (65%)
• Recommended weight gain*
LGA
42%
8%
* BMI<18.5: 12.7-18kg; 18.5-25: 11.5-16 kg; 25-30: 6.811.4 kg; >30, 5-9 kg (Inst Med Guidelines weight gain in pregnancy,2009)
Adjusted OR for BMI, gest age at delivery, nulliparity, vascular
complications and HbA1c: 8.9 (95% CI 3-26). Both in normal
weight, overweight and obese women.
Scifres et al, Obstetrics & Gynecology, June 2014
Type-1 diabetes, 32 y, 1.88 m, 88 kg, CSII, HbA1c 9 wks
56 mmol/l, Continuous glucose sensor since 12 wks
19 wks
20 wks
Metabolic syndrome in 175 infants age 711, according to birth weight and GDM
Boney, Pediatrics 2005
Follow-up infants of women with type-1 diabetes
Independent predictors of
childhood overweight:
OR
Rijpert et al,Diab Care 2009
Birthweight>p90
4.4(1.6-11.8)
Maternal weight
2.8(1.2- 6.6)
Maternal obesity during pregnancy and premature mortality
from cardiovascular event in adult offspring; Reynolds et al, BMJ 2013
Adjusted for mat age at delivery, socioeconomic status, birth weight, gestation
at delivery
Pima Indians NIDDM
Incidence of NIDDM in 20-24 y old offspring of:
- nondiabetic women
- women developing NIDDM after pregnancy
- women with NIDDM during pregnancy
1.4 %
8.6 %
45 %
differences persist taking into account paternal diabetes, age at
onset diabetes in parents, birth weight
(Pettitt et al, Diabetes 1988;37:622-8)
Type-2 diabetes or impaired glucose intolerance
in 18-27 y offspring ( total study group 597)
• Women with gest diabetes
• Genet predisposed women
21%
12%
9%
11%
4%
7%
( but no diabetes in pregnancy)
• Women with type-1 diabetes
• Control group
So, diabetes during pregnancy results in a 8%
incidence of diabetes in offspring
Clausen et al, Diab Care 2008;31:340-6
So,
• Genetic and epigenetic predisposition may
differ between populations
• Limitation of both studies: no correction for
maternal BMI
Evolutionary perpectives
”Thrifty genotype”:populations have been
selected for alleles favoring insulin
resistance.
These genes confer advantage in a poor
food/high energy expenditure environment,
by reducing glucose uptake and limiting
body growth
And which can we change/influence?
•
•
•
•
•
•
•
•
Genetic predisposition
Maternal BMI
Weight gain in pregnancy
(Gestational) diabetes mellitus
Macrosomia at birth
Cesarean Delivery
Excessive weight gain > 2 y of age
Socio-economic circumstances
Prevention
-- Healthy diet
-- Excercise
-- Folic acid
(may prevent epigenetic changes)
(Eriksson; Lillycrop et al, 2005)
Fetal Macrosomia
•
•
•
•
1989-93
N
172
BMI
23.1
HbA1C 3rd trim
6.71%
Birthweight>90th cent 48.3%
2004-08
261
24.8
6.94%
52.1%
BMI and 3rd trim HbA1C independent predictors macrosomia; multiple logistic
regression analysis; PM 1st trim HbA1C lower >2004
Klemetti et al, Diabetologia, 2012
Fetal Macrosomia
• ‘good’ glucose control in early
pregnancy
• ‘poorer’ glucose control in 2nd and
3rd trimester
Childhood obesity in relation to maternal
diabetes ( Type-1, Mat BMI 24; Type-2 Mat BMI 31, GDM 26)
Type-2
Type-1
GDM
Hammoud et al, in prep
University Medical Center, Utrecht, the NL
Diabetes and Pregnancy;
or: ‘’Almost good is not good enough’’
Gerard H.A.Visser
Behandeling = glucose controle
• Preconceptie: foliumzuur
• Eerste trimester: preventie hypoglycemie,
onderzoek naar aangeboren afwijkingen?
• 2e/3e trimester: vervolgen foetale groei
• Bevalling: lage risico: circa 39 weken
anderen: -foetaal gewicht > 4000g
-slechte glucose controle
. Keizersnede: foetaal gewicht > 4.250g
Shoulder dystocia and birth weight
birth weight (g)
non diabetic (%) diabetic (%)
UK 2002-2003
2500-3750
0.2
0.5
3750-4000
1.0
1.2
4000-4250
2.6
3.0
22%
4250-4500
5.0
6.9
25%
4500-4750
7.5
21.8
43%
13.0
37.0
>4750
4.7%
(Langer et al, 1991: Texas 1970-1985; 74.390 non diab.+ 1589 diabetics)
(UK, CEMACH, n=3423)
Developmental Origens of Health
and Disease (DOHaD)
Gluckman & Hanson, Science 2004; 305: 1733-6
Type-1 diabetes and Pregnancy in the NL
The price to pay for tight glycemic control:
a two-to threefold increase in severe hypoglycemic
epidoses, involving 41% of patients, with
hypoglycemic coma in 19% during the first
trimester
Maternal death: 1:300-500 (?)
(based on 278 questionnaires; Evers et al, Diabetes Care 2002;25:554)
Type-2 diabetes or impaired glucose intolerance
in 18-27 y offspring ( total study group 597)
• Women with gest diabetes
• Genet predisposed women
21%
12%
( but no diabetes in pregnancy)
• Women with type-1 diabetes
• Control group
Clausen et al, Diab Care 2008;31:340-6
11%
4%
Obesity and GDM; direct perinatal
outcome
independent risk factors with synergistic effects
Adapted from Catalano et al, 2012
More diabetes, more gestational diabetes
75 g OGTT:
fasting => 5.1 mmol/l
1 hour => 10.0
2 hour => 8.5
Diagnostic criteria based on 1.75 fold
increase in LGA infant
(Metzger et al, Diab Care, 2010)
•
•
•
•
•
•
•
•
•
Evaluate diagnostic thresholds associated with an adverse
outcome of 2.0 in the HAPO study as opposed to 1.75
Determine whether women, normal in a two-step strategy and
abnormal in the IADPSG model, benefit from treatment (RCT?)
Conduct cost-benefit analyses
Conduct research to understand patient preferences
Study the impact of GDM treatment on care utilization
Assess lifestyle interventions and effects of obesity
Assess impact that a label of GDM may have on future
reproductive career
Assess long-term outcome of GDM on offspring
Assess interventions to decrease subsequent signs of metabolic
syndrome, diabetes and cardiovascular disease in women with
GDM
Too early to adopt the stringent
IADPSG oGTT criteria for universal
screening
Post partum testing following GDM
• Systemic review; 54 articles
• Postpartum testing on average in 33% of
patients (9-71%)
• With proactive patient contact programs:
60% (14-95%)
Carson MP et al, Prim Care Diabetes, Oct 2013
Cuilin Zhang, Shanghai, Nov 23, 2013
Incidence of diabetes following GDM
NNT 5 and 6 ,respectively
Ratner et al, JCEM 2008
•
•
•
•
•
•
•
•
•
Evaluate diagnostic thresholds associated with an adverse
outcome of 2.0 in the HAPO study as opposed to 1.75
Determine whether women, normal in a two-step strategy and
abnormal in the IADPSG model, benefit from treatment (RCT?)
Conduct cost-benefit analyses
Conduct research to understand patient preferences
Study the impact of GDM treatment on care utilization
Assess lifestyle interventions and effects of obesity
Assess impact that a label of GDM may have on future
reproductive career
Assess long-term outcome of GDM on offspring
Assess interventions to decrease subsequent signs of metabolic
syndrome, diabetes and cardiovascular disease in women with
GDM
MICHELIN MAN DENIES PATERNITY SUIT...... CLAIMS CHILD IS NOT HIS
THANK YOU
Lowest risk of SGA/LGA, preterm delivery
6.500 obese women, California
Weight gain
Class 1 Class 2 Class 3
< 2.2 kg
2.2-5
5-9
9.1-13.5
Bodnar et al, Am J Clin Nutr, 2010
x (Black women)
x ( white women)
x
x
Lowest risk of SGA/LGA, preterm delivery
6.500 obese women, California
Weight gain
Class 1 Class 2 Class 3
With an increase in Preterm delivery in
case of weight loss, in all 3 categories
Bodnar et al, Am J Clin Nutr, 2010
Managing Diabetes
Diabetes care has improved
• various types of insulin
• administration (CSII, pen, multiple injections)
• self control
Managing Diabetes
Diabetes care has improved
• various types of insulin
• administration (CSII, pen, multiple injections)
• self control
With nowadays the possibility to measure
glucose continuously
Fetal Macrosomia
Correlated to 1st, 2nd and 3rd trimester HbA1c,
and to overall mean HbA1c ( 46 versus 42 mmol/l)
But, variance in weight explained by HbA1c & BMI
is limited (<10%; 3rd trimester HbA1c only: 4.7%)
HbA1c is a too insensitive measure of glucose regulation during pregnancy
(Evers et al, Diabetologia, 2002)
Near Normoglycaemia???
Near Normoglycaemia???
• NO……., not at all
• The struggle towards adequate glucose
control has only just begun
Continuous glucose profiles during pregnancy
(type-1 diabetes, n = 46; controls n = 12; Kerssen et al. Diab Care,2007)
RCT off-line continuous glucose monitoring every
4-6 wks
Med BWcentile 93 %
69 %
Med BW (g)
3340 ( 36.6 wks
3630
71 Type-1/2 diabetics. Lower HbA1c>32 wks and birthweight. Murphy et al ,BMJ 2008
Diabetes Care, 2013
Type-1 diabetes, 32 y, 1.88 m, 88 kg, CSII, HbA1c 9 wks
56 mmol/l, Continuous glucose sensor since 12 wks
Insulin (units):
Type-1 diabetes, 32 y, 1.88 m, 88 kg, CSII, HbA1c 9 wks
56 mmol/l, Continuous glucose sensor since 12 wks
19 wks
20 wks
Near Normoglycaemia???
• NO……., not at all
• The struggle towards adequate glucose
control has only just begun
• And will be difficult
• Almost good is not good enough !!
Management (=glucose control)
• Preconception: folic acid
• First trimester: prevention hypoglycemia,
congenital malformations?
• Second/third: fetal growth assessment
• Delivery: low risk: around 39 weeks
others: -fetal weight = 4000g
-poor glucose control
. Caesarean Section: fetal weight > 4-4.5 kg
Type-1 diabetes and Pregnancy in the NL
Congenital malformations and HbA1c
10
9,4
9
8
% CM
7,5
7
6
5
4,2
4
3
2
1
0
4.0-6.0% (2/48)
(Evers et al, BMJ, 2004)
6.1-7.0%
(9/120)
> 7.0%
(6/64)
Stillbirth in type-1 diabetes
• Placental
immaturity
(glucose ↑ + hypoxemia = lactate accumilation)
• Overgrowth of fetal weight in relation to
placental capacity
(Evers et al, Placenta, 2003)
More diabetes, more gestational diabetes
75 g OGTT:
fasting => 5.1 mmol/l
Prevalence of GDM of
1 hour => 10.0
2 hour => 8.5
Diagnostic criteria based on 1.75 fold
increase in LGA infant
(Metzger et al, Diab Care, 2010;33:676-682)
75 g OGTT:
fasting =>5.3 mmol/l
1 hour => 10.6
2 hour => 9.0
Diagnostic criteria based on 2 fold
increase in LGA infant
(E.A.Rian, Diabetologia 2011;54:480-486)
17.8%
Follow-up infants of women with type-1 diabetes
Rijpert et al, Diab Care 2009
Pilot Study; follow-up of infants of
women with type 2 diabetes
(de Valk et al, 2007)
So, which infants are likely to
develop diabetes
• High maternal BMI
• Macrosomia at birth
• And……excessive weight gain > 2 y of age
Continuous glucose monitoring
• Offline, intermittent
• Continuous
Continuous glucose
monitoring system
(CGMS)
G3P1. 34y. DM type 1. GA 12 weeks
HbA1c 7.4%
20,0
Glucose Concentration (mmol/L)
15,0
Meter Value
Paired Meter Value
10,0
Sensor Value
Insulin
Meal
Exercise
Other
5,0
0,0
-5,0
12:00 AM
4:00 AM
8:00 AM
12:00 PM
Tim e
(Kerssen et al, 2003)
4:00 PM
8:00 PM
12:00 AM
Overweight and pregnancy
•
•
•
•
•
•
•
•
•
GDM
Macrosomia
C.section
Hypertension
Preterm delivery
Post operative complications
Congenital malformations
Fetal death
Neonatal morbidity
After Jensen et al, 2003
Odds ratios 2-3
oGTT threshold values
• oGTT threshold values will –by definitionbe arbitrary, given the linear relationship
between glucose values and impaired
outcome
Do you want to become pregnant?
Than first lose weight, and than we will
tell you were your puppy is……..
Obesity and GDM
BMI
Odds ratio
20-25
25-30
>30
>40
1
1.6-1.7
3.6-4
10
Sebire et al, 2001; Baeten et al, 2001, Kumari, 2007
MICHELIN MAN DENIES PATERNITY SUIT...... CLAIMS CHILD IS NOT HIS
Follow-up infants of women with type-1 diabetes
Rijpert et al,Diab Care 2009
Follow-up infants nationwide
Dutch study; n=213
No significant differences:
BMI
Overweight
Diast BP
Fasting glucose
Insulin
HbA1C
HOMA-insulin resistance
HOMA-beta cell function
Cholesterol
HDL
LDL
Trichlycerides
Hs C-reactive protein
1-3 components of MetS
intellectual functioning
Significant differences:
Systolic blood pressure: 100.4 as compared to 96.5 mmHg (p<0.01)
Subtle domains of neurocognitive functioning
Continuous glucose and fECG
monitoring
Continuous glucose
monitoring system
(CGMS)
Fetal ECG monitoring
(fECG)
Fetal response in a case with
fluctuating glucose levels
Figure 8: Variability and glucose levels in a type 1 DM patient (GA 34 wks)
Fetal heart rate variability (ms)
12,0
10,0
8,0
6,0
4,0
2,0
4,0
6,0
8,0
10,0
Glucose (mmol/L)
Decrease in variability with increasing glucose levels
12,0
FHR variability and glucose
levels (n = 15)
Figure 7: FHR Variability and glucose levels for all study-participants (n = 15)
Fetal Heart Rate Variability (ms)
16,0
14,0
12,0
10,0
8,0
6,0
4,0
2,0
2,0
4,0
6,0
8,0
10,0
12,0
Glucose (mmol/L)
Within ‘normal’ glucose ranges no fetal response
14,0
Significantly higher incidene of overweight in
infants of women with diabetes, from 10 y onwards
Birthweight, Infant growth & Mat. diabetes
(Touger et al, Diab Care 2005; 28: 585-9)
RCT induction-expextant management
n=200:
- Insulin dependent (pre) gestational diabetes
(Low risk)
Induction
Expectant
CS
25%
31%
LGA
10%
23%
0%
3%
Shoulder dystocia
(Kjos et al, Am J O&G, 1993. Induction at 38 weeks)
Type-1 diabetes and Pregnancy in the NL
Maternal Outcome
• pre-eclampsia 12%
• preterm birth 32% (of which 20% induced)
• caesarean section 44% (of which 24% elective)
Maternal death (!) n=2
• cardiac arrest following hypoglycemic episode at
17 wks
• amniotic fluid embolism
Type-1 diabetes and Pregnancy in the NL
Maternal Outcome
• pre-eclampsia 12%
12-18%
• preterm birth 32% (of which 20% induced)
• caesarean section 44% (of which 24% elective)
Maternal death (!) n=2
• cardiac arrest following hypoglycemic episode at
17 wks
• amniotic fluid embolism
(Teramo et al, 2000)
UK 5/2776
Finl 5/972
Type-1 diabetes and Pregnancy in the NL
Congenital Malformations:
• Minor
3.4%
• Major
4.9%
• Total
8.3% (ci 5-11.3%)
UK/DK/F/Sc
4.2 - 6.0%
• Major CM in planned and unplanned
pregnancies: 3.8 as compared to 10.4% (p=0.05)
Hba1-c and birth weight (% population mean) and
weight first born
107 second born infants of women with type-1 diabetes; Kerssen et al 2005
Evolutionary perspectives
• ”Thrifty phenotype”:fetus becomes IUGR
in response to adverse environmental
conditions in utero.
• The associated adaptations induce a
phenotype better suited to a deprived
postnatal food/energy environment
Dietary changes and DOHaD
Gluckman & Hanson, Science 2004; 305: 1733-6
Birthweight, Infant growth & Type-2 diabetes
Mean Z-score
(Eriksson et al, Diab Care 2003; 26: 2006-10)
Inverse relation between infectious
diseases and Immune disorders
J.F.Bach, NEJM 2002;347:911-920
Almost good is not good at all !
Big babies……..
• Big babies have an early growth
acceleration from 18 weeks onwards
( Wong et al, Diab Care,2002)
• And all infants with a birth weight> p 97.7
can be identified before 30 wks gestation,
by longitudinal growth assessment
( Kerssen et al, Diab Care, 2007)
HAPO
(NEJM, May 8, 2008)
Type 1/2 diabetes and pregnancy
• How could we ever have thought that 2-4
glucose measurements/day would be
sufficient to assess glucose control ( 10 or
more measurements are necessary)
• Patho-physiology is more complex then
thought before
• The struggle for adequate glucose control
only just has begun.
Type-1 diabetes and Pregnancy in the NL
Perinatal morbidity (2):
• hypoglycemia (< 2.6 mmol/l)
64%
• hypoglycemia (< 2.0 mmol/l)
44%
• hyperbilirubinemia req. treatment
25%
• RDS / wet lung
14%
• cardiomegaly (?)
(Evers et al, BMJ, 2004)
5%
Type-1 diabetes and Pregnancy in the NL
Perinatal morbidity (3):
Hypoglycemia in:
• Macrosomic infants
75%
• Appropriate-for-dates infants
54%
Birthweight, Infant growth & Type-2 diabetes
(Eriksson et al, Diab Care 2003; 26: 2006-10)
Thank you
Follow-up infants of women with type-1 diabetes
• Relationships with maternal glucose control during
pregnancy absent, apart from:
1st trimester maternal HbA1C
<6
6-7
>7
HbA1C offspring
4.98
5.03
5.27 (p<0.01)
Neurocognitive functioning ( HbA1C, neonatal hypoglycemia)
Follow-up infants of women with type-1 diabetes
Conclusions:
- Current care and treatment of pregnant women
with type 1 diabetes result in cardiovascular and
metabolic outcome in the offspring at 6-8 y that is
comparable to controls, despite the impaired
outcome at birth
-These results seem better than those of previous
studies*
-Further follow-up..............
*Plagemann, 1997;Weiss, 2000; Cho, 2000; Buinauskiene, 2004; Manderson, 2002; Tam, 2008
Type-1/2 diabetes and Pregnancy
• Perinatal mortality: 2.8% (n=9)
• Cong. malf. n=4
DK
SC
UK
93-99
98-99
02-03
Perin. mortality 3.2
2.8
3.1
Stillbirth
1.8
2.1
• Stillbirth n=2 (0.6%)
• Preterm n=1
• Asphyxia n=2
(Evers et al, BMJ, 2004)
2.6
Behandeling/preventie
• Dieet en voldoende lichaamsbeweging ( tevoren
beetje (boel) afvallen is een goede zaak)
• Preconceptioneel goede glucose regulatie
• Preconceptionele start met foliumzuur
• Doorgaan met dieet en fysieke activiteit tijdens
zwangerschap
• Medicatie……..
Medicatie
• Geen orale medicatie in de zwangerschap,echter
• Metformine bij PCOS en type-2 diabetes is niet geassocieerd met een
verhoogde incidentie aangeboren afwijkingen. Is in tweede helft
zwangerschap veilig alternatief gebleken voor insuline bij ZwDiab.
Passeert wel de placenta.
• Glibenclamide passeert niet de placenta en blijkt in tweede helft
zwangerschap ook goed alternatief voor insuline.
• Dus: periconceptioneel dieet continueren cq over op
insuline, en metformine en Glibenclamide als
alternatief na circa 12 weken (‘RCT pending’)
Langer, NEJM,2000,Rowan,NEJM 2008
En dan de pasgeborene……
In de baarmoeder
blootgesteld aan een
geheel andere
metabole omgeving
dus,
‘ Diabetische’ intrauterine omgeving
en –waarschijnlijk- overmatige groei
tijdens de kinderjaren leiden tot een
sterke verhoging van de kans op
adipositas en type-2 diabetes
Cafetaria-style diet in rats
Femal Wistar rats
Control or CAF diet from 70 days onwards
Results:
• diet induced obesity
• glucose intolerance during pregnancy
• glucose intolerance offspring
(Holemans et al, Am J O&G 2004;190:858-65)
Thank you for your attention
Other Nationwide studies:
• Denmark 1993-1999
n=1.218
(Jensen et al, Diab.Care, 2004; 27 : 2819-23)
• Scotland 1998-1999
n= 273
(Penney et al, BJOG, 2003; 110 : 966)
Type-1 diabetes and Pregnancy
(Evers et al, Placenta, 2003)
Definition of Macrosomia
- mild macrosomic 4000 – 4500 g
- very macrosomic 4500 – 5000 g
- extremely macrosomic > 5000 g
- or: …… > 10 lb (> 4536 g)
RCT Insulin Aspart
Human
Insulin (n=322)
• Significant lower prandial glucose increments
with Aspart, in first and third trimester
• Tendency towards lower risk of severe
hypoglycaemia (especially at night, RR 0.48, C1
0.20-1.14)
(Mathiesen et al, ADA 2006, Diab Care,2007)
RCT Insulin Aspart
Human
Insulin (n=322)
• No difference in fetal mortality or major
congenital malformations
• Mean birthweight 3438g (at 37.9 wks) and
3555g (at 37.7 wks), respectively
(Hod, Visser et al, ADA 2006, ;AJOG, 2008)
Type-1 diabetes and Pregnancy
The struggle towards adequate blood
glucose control only just has begun
Almost good is not good enough
Population data are of utmost importance to
assess the real effect of current treatment strategies
Type-1 diabetes and Pregnancy
Strict periconceptional control essential
in all women
Strict second-trimester control essential in all
nulliparous women and in multip’s with
an earlier macrosomic child
Follow-up infants nationwide
Dutch study; n=300
- Age 6.5-7 years
-
Psycho-motor development
Metabolic syndrome
Immunology
Epigenetics
- maternal severe
hypoglycaemia
- HbA1c
- birth weight centile
- neonatal hypoglycaemia
(M. Rijpert; Diabetes Foundation, The Netherlands)
Maternal Mortality
100
80
Pre- Insulin
60
40
20
0
1900
’05
’10
’15
’20
’25
’30
’35
’40
Time (years)
’45
’50
’55
’60
’65
’70
’75
’80
’85
Developmental Origins of Health and Disease
• Dutch famine 1944-1945
First publication 1947 (C.Smith)
• Effects of diabetes induced during pregnancy on 2nd
& 3rd generation (Aerts, Van Assche, 1979)
• Fetal origin of cardiovascular disease
(Barker, 1989)
Is gestational diabetes an acquired condition?
• 1st generation rats treated with streptozotocin
 mild diabetes in pregnancy
• 2nd generation: abnormal GTT; gestational diabetes
• 3rd generation: impaired glucose tolerance
(Aerts & Van Assche, J. Dev. Physiol 1979;1:219-25)
Transgeneration effect of GDM
(Aerts & Van Assche, 2006)
So,………………………..
• Diabetic environment induces type-2 and
gestational diabetes in offspring ( also in
type-1 diabetes….?)
• Type-1 diabetes: paternal diabetes has a
larger heretary effect than maternal diabetes
Type-1 diabetes and Pregnancy
Dutch Nationwide study
• 118 hospitals
• eligible women
first trimester pregnancy, loss
type-2 or secundary diabetes
lost to follow up
364
23
16
2
included in the study
323
Paradigm Real-Time TM System;
Gardian
•
•
•
•
Continous subcutaneous insulin infusion
Improved bolus calculator
Real-time glucose sensor system
Warning abrupt increase/decrease glucose
level
Paradigm Real-Time TM System;
Gardian
•
•
•
•
Continous subcutaneous insulin infusion
Improved bolus calculator
Real-time glucose sensor system
Warning abrupt increase/decrease glucose
level
Type 1/2 diabetes en Zwangerschap:
bijna goed is niet goed genoeg
Gerard H.A. Visser
UMC
Utrecht, NL
Thank you for your attention
Changing populations
type 1
type 1
type 2
undiagnosed type 2/1
type 2
undiagnosed type 2/1
GDM
GDM
obesity, age, ethnic diversity
Screening more logical
Een 29 jarige patiente met type-2 diabetes,
overgewicht en zwangerschapswens
Gerard H.A.Visser
UMC Utrecht
Predictive Adaptive Response
Gluckman & Hanson, Science 2004; 305: 1733-6
Is gestational diabetes an acquired condition?
• 1st generation rats treated with streptozotocin
 mild diabetes in pregnancy
• 2nd generation: abnormal GTT; gestational diabetes
• 3rd generation: impaired glucose tolerance
(Aerts & Van Assche, J. Dev. Physiol 1979;1:219-25)
St. Vincent Declaration
“To achieve a pregnancy
outcome that
approximates that of
healthy women”
(Diab. Med. 1990; 7:360)
Diabetes care has improved
• various types of insulin
• administration (CSII, pen, multiple injections)
• self control
Type-1 diabetes and Pregnancy in the NL
Risk factors for first trimester hypoglycemia:
• excellent glycemic control (HbA1c < 6%)OR 3.4
• good diabetic control (HbA1c 6-7%)
OR 2.8
• duration of diabetes > 10 years
OR 2.0
• history of SH prior to gestation
OR 8.3
(Evers et al, Diabetes Care 2002;25:554)
November 1, 2010
• We know we have failed thus far, since:
- Maternal morbidity and mortality (type-1: 1/200) remain increased.
-Congenital malformations remain 4-fold increased
-50% of infants are large-for-dates ( >p 90)
-60% of infants have a neonatal hypoglycemia < 2.6 mmol/l
-and since maternal hyperglycemia may induce diabetes/metabolic
syndrome in their offspring
And all of this is due to inadequate glucose control:
Almost good ( HbA1c < 4 SD) is not good enough
i.e. too high for the fetus and too low for the mother
Diabetes and pregnancy
• Pregnancy outcome is identical for type-1
and type-2 diabetes, except for maternal
mortality
Increased risk PCO disease
Resulting in ovulation
induction, overstimulation
and multiples
James Bond
Harold de Valk
Inge Evers
Type 1 = 2767
Type 2 = 1042
Type-1 diabetes and pregnancy
So, bigger babies with better regulation??
• Sweden 1982 – 1985
20% > p 97.5
• Sweden 1991 – 2003 31% > p 97.5
(Hanson & Persson, 1993; Persson et al. Diab Care, 2009; n=5.089)
Early placental function and birth weight centiles
Kuc et al, BJOG, 2011, in press.
Data similar for ADAM-12, PP13, PlGF
The Epidemic of Diabesity, 2000 and 2030
Hossain et al NEJM, 2007
Overexposure is never good
Managing Diabetes
Diabetes care has improved
• various types of insulin
• administration (CSII, pen, multiple injections)
• self control
And nowadays the possibility to measure
glucose continuously
And since oral anti-diabetic medication seems not to
be contra-indicated anymore…………….
Accuracy of CGMS in pregnancy
and diabetes
(Kerssen, et al, 2004)
Reproducibility of CGMS
(Kerssen et al, 2005)
Near Normoglycaemia???
• NO……., not at all
• The struggle towards adequate glucose control
has only just begun
• CGM seems only feasible in a restricted highly
motivated subpopulation
• A closed loop system seems necessary for the
majority to reach the required ‘normoglycaemia’
Fetal growth profiles in diabetic pregnancies
Head to abdomen circumf. ratio( N. Hammoud et al, UOG,2012)
1,3
Fetal growth profiles in diabetic pregnancies
Head to abdominal circumference ratio (HC/AC ratio)
1,25
IDDM non-macrosomia
1,2
IDDM macrosomia
DM2 non-macrosomia
1,15
DM2 macrosomia
GDM non-macrosomia
1,1
GDM macrosomia
1,05
1
0,95
Birthweight>90th cent
GDM macrosomic non-macrosomic
0,9
0,85
0,8
100
120
140
160
180
Gestational age in days
200
220
240
260
280
Almost good is not good
enough
Follow-up infants of women with type-1 diabetes
Rijpert et al, Diab Care 2009
Pilot Study; follow-up of infants of
women with type 2 diabetes
(de Valk et al, 2007)
Prioriteiten mbt GDM
•
•
•
•
Initieer universele screening, gebaseerd op een oGTT
bij 24-28 wk
Hanteer strikte normaalwaarden bij obese zwangeren
Initieer goede follow-up GDM, met lifestyle en dieet
adviezen
Bestudeer veiligheid orale ADiabetica
Obesitas and GDM
• Beide hebben een synergistisch effect op de
direkte perinatale uitkomst
• Obesitas heeft het meest uitgesproken effect
op de lange termijn uitkomst van de
kinderen
Type-1 diabetes and Pregnancy in the NL
The price to pay for tight glycemic control:
a two-to threefold increase in severe hypoglycemic
epidoses, involving 41% of patients, with
hypoglycemic coma in 19% during the first
trimester
With maternal death in 1 of 200 to 500 pregnancies
(based on 278 questionnaires; Evers et al, Diabetes Care 2002;25:554)
Type 1 and 2 diabetes in the Netherlands
Nationwide study
Type-1
y ear 2000
• n
323
•
•
•
•
8.3%
44 %
56%
2.8%
Cong malf
CS
LGA
PNM
Evers et al BMJ,2004;
Type 1
UMC Utrecht
Type 2
7 large hosp in NL
Type 1 and 2 diabetes in the Netherlands
Nationwide study
Type-1
year 2000
Type 1
UMC Utrecht
• n
323
185
• Cong malf
8.3%
44 %
56%
2.8%
8.2%
66 %
40 %
1.1%
• CS
• LGA
• PNM
Evers et al BMJ,2004; Hoeks et al in prep;
Type 2
7 large hosp in NL
Near Normoglycaemia???
• NO……., not at all
• The struggle towards adequate glucose
control has only just begun
RCT real-time CGM
why didn’t it work?
• Women were too well controlled
• Compliance is too difficult ( full compliance
64%); near-continuous real-time CGM throughout pregnancy ( at
least 60% of the time) was only chosen by 7% of women
• Prevention of hypoglycaemia
• Too little and too late
• CGM may only work in selected highly motivated
patients
No data on maternal BMI
Alternatives for insulin; type-2; gest diabetes
-Glibenclamide (glyburide)
( Langer et al, NEJM 2000)
-Metformin ( Rowan et al, NEJM 2008)
Glibenclamide; FDA Category C
Metformin crosses the placenta ( fetal concentration
50% of maternal). It has been used in women with
PCOS and/or type-2-diabetes in the first half of
pregnancy and there is thus far no evidence that it
may induce congenital malformations.
However, long term follow-up data are lacking,
especially in IUGR infants and……
Metformin a new drug to kill the
‘dandelion root’
Martin-Castello et al, Cell Cycle 2010
Tumor- initiating stem cells
Weight gain during pregnancy in obese
glucose tolerant women (BMI>30 ; multivariate analysis)
< 5kg
Hypertension
CS
Ind.labour
LGA
SGA
Jensen et al, Diab Care 2005
1
1
1
1
5-10
10-15
2.1
3.6
2.4
3.0
2.7
2.8
2.4
2.1
no difference
>15
4.8
3.6
3.7
4.7
GDM en foetaal geslacht; RR1.03 ( CI 1.01-106)
Jaskolka et al, Diabetologia, 2015
Childhood obesity in relation to
macrosomia at birth and diabetes type
Hammoud et al, in preparation
Toename foetale macrosomie
• Toename maternale Obesitas (Klemetti et al, Diabetologia, 2012)
• Afname maternale vasculaire complicaties
• Betere controle in vroege zwangerschap, betere
placentatie?
• Slechtere glucose controle 3e trimester, aangezien
vrouwen niet meer opgenomen worden
• Grotere gewichtsstijging tijdens de zwangerschap
Toename foetale macrosomie
• Increase in maternal Obesity (Klemetti et al, Diabetolgia, 2012)
• Lower incidence of maternal vascular
complications
• Better control in early pregnancy, better
placentation?
• Poorer control, since women are not admitted
to hospital anymore?
5 redenen en waarschijnlijk
spelen alle vijf een rol !!
Type-1 diabetes and Pregnancy Croatia vs the NL
Country
n
Croatia 2000-2012 557
Netherlands 2000
323
HbA1c(%)
BW>90thc
7.42
31%
70%<7
56%
(Evers et al, Diabetologia, 2002; Ivanisevic & Djelmis, 2013))
So,………………..
Better control: Bigger Babies ??
Type 1 and 2 diabetes in the Netherlands
Nationwide study
Type-1
Type 1
year 2000
UMC Utrecht
• n
323
185
•
•
•
•
8.3%
44 %
56%
2.8%
8.2%
66 %
40 %
1.1%
Cong malf
CS
LGA
PNM
Evers et al BMJ,2004; Hoeks et al in prep; Groen et al, 2013
Type 2
7 large hosp in NL
272
7.1%
41 %
32 %
4.8%