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.pdf
In: Advances in Arterial Stiffness Research ISBN: 978-1-63485-838-0
Editor: Becky Chavez © 2016 Nova Science Publishers, Inc.
Chapter 5
AMBULATORY ARTERIAL STIFFNESS INDEX
DURING PREGNANCY IN
TYPE 1 DIABETES MELLITUS
Finn F. Lauszus
1,2,*
, Hanine Fadel Mustafa Al-Far
1
,
Ingvild Tjessem
1
, Ole W. Rasmussen
2
and Jens Fuglsang
3
1
Department of Obstetrics/Gynecology, Herning, Denmark
2
Department of Obstetrics/Gynecology and Medical Department,
Kolding Hospital, Denmark
3
Clinical Institute, Aarhus University Hospital, Denmark
ABSTRACT
The ambulatory arterial stiffness index (AASI) and pulse pressure
(PP) was analyzed during pregnancy and three months after delivery in
type 1 diabetes mellitus (T1DM) compared to non-diabetic, pregnant
controls. The study was performed prospectively in 176 women with
T1DM and 54 control women at a tertiary centre. Blood pressure (BP)
was measured using a portable oscillometry monitor and AASI was
calculated as 1 minus the regression slope of diastolic BP on systolic BP
obtained from 24-hour monitoring. Main outcome measures were AASI
and PP associated with diabetes vasculopathy and blood pressure
measurements during and after pregnancy. We found that AASI and PP
were higher in 2
nd
and 3
rd
trimester during pregnancy in T1DM compared
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Finn F. Lauszus, Hanine Fadel Mustafa Al-Far, Ingvild Tjessem et al.
98
to post partum and significantly associated with albumin excretion rate.
The AASI was positively correlated with night-day ratio during and
outside pregnancy in diastolic BP and in 1
st
trimester and outside
pregnancy in systolic BP. The higher the AASI the lower was the
coefficient of determination. Thus, AASI showed a strong association
with albuminuria, PP, and circadian rhythm during pregnancy in T1DM
women and it seems even more pronounced than after pregnancy. The
diastolic and systolic BP displays non-linear behaviour and increasing
random variability with stiffing arteries measured as AASI.
Keywords: pregnancy, diabetes, arterial stiffness index, pulse pressure,
retinopathy, albumin excretion rate, nocturnal blood pressure,
hypertension
INTRODUCTION
According to an authoritative source the evidence of benefit of treatment
of mild and moderate hypertension is not evidence-based [1]. This statement
may simply indicate that the diagnostic procedures and monitoring of blood
pressure need a quality check, which is the purpose of this review. Relative
few blood pressure (BP) monitors are validated for use in pregnancy and those
most common in use in obstetric wards are semi-automatic monitors; the
majority of these are non-validated. Nevertheless, numerous studies are
published with conclusions based on sub-standard methodology, so one must
not wonder about the meager evidence on treatment. The strategy for safe
conclusions in this study and its brief discussion was chosen with respect to
validated monitors and evaluation of diurnal blood pressure.
The main biological arguments for the importance of the BP methodology
is that even minute increase in BP as well as increase in albuminuria are
forerunners for incipient and overt nephropathy in the non-pregnant, diabetic
women. Antihypertensive treatment is essential and can conserve renal
function, modifying the risk of renal insufficiency. During pregnancy, renal
insufficiency in diabetes leads to termination of pregnancy. As diabetic
pregnancy is complicated with a risk of hypertension/preeclampsia up to 50%,
we presume that detection of minute changes is invaluable to protect the
mother’s kidney function based on reliable measurements in this high-risk
population and, if possible, prolong pregnancy for the benefit of the fetus.
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AASI in Diabetic Pregnancy
99
The ambulatory arterial stiffness index (AASI) and pulse pressure (PP),
both computed from repeated 24-h ambulatory BP recordings, was proposed
as a novel indirect measure of arterial stiffness [2-6]. AASI was shown to
correlate with pulse wave velocity and it can be used to detect arterial
dysfunction at a younger age than is achievable by pulse pressure [2]. AASI
predicts cardiovascular death and stroke more precisely than classical
risk factors [3, 4] and is associated with target organ damage in individuals
with arterial hypertension, i.e., left ventricular hypertrophy, carotid artery
abnormalities and reduced renal function [5, 6].
In diabetic pregnancy reno-vascular co-morbidity may be present and is
strongly associated with hypertension, preeclampsia, and pregnancy outcome.
We, therefore, found interest in further evaluating the use of AASI and PP
as it carries the potential to influence outcome on the diabetic status and
co-morbidity. A number of studies on the benefit of measuring AASI in
pregnancy focused on high-risk sub-populations like women with pre-
gestational hypertension, gestational diabetes, and twin pregnancies [7-9].
We present the results of a cohort of pregnant women with type 1 diabetes
mellitus (T1DM), in which (i) AASI and PP were analyzed during pregnancy
compared to non-diabetic women and (ii) the association AASI was evaluated
with vascular events like retinopathy, albuminuria grade and with BP variation
patterns. Pre-pregnant and post partum measurements were compared to
pregnancy values in T1DM women (iii). We hypothesized that the dynamic
changes in diurnal BP measuring the stiffness of the arterial wall would
display the vasculopathy during pregnancy.
MATERIAL AND METHODS
In total 176 T1DM women and 54 non-diabetic women were included and
the study performed in concordance with the Helsinki II declaration and all
women gave their informed consent (Table 1). The study was part of an
evaluation of morbidity in diabetic pregnancy with respect to nephropathy and
retinopathy approved by the local Ethical Committee (jr.nr.1992/2523,
1998/4147, and 2026-99). The blood pressure data were either initially stored
to a data file or manually re-entered from a paper output and further
statistically processed.
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Finn F. Lauszus, Hanine Fadel Mustafa Al-Far, Ingvild Tjessem et al.
100
Table 1. 1
st
trimester clinical and pregnancy data of 176 women with
T1DM and 54 non-diabetic women
Non-
diabetic
women
All T1DM
women
White Group
B
C
D0
D+
R
F+F/R
No.
54
176
57
13
7
70
8
21
Normo-/micro-
/macroalbumin
uria
0
135/22/19
54/3/0
11/2/0
6/1/0
58/12/0
4/4/0
2/0/19
Simplex/prolife
rative
retinopathy
(no.)
-
83/16
0
0
0
70/0
0/8
13/8
Age (yrs)
27 ± 3
§
29 ± 4
29 ± 4
27 ± 5
28 ± 6
29 ± 5
28 ± 3
28 ± 4
BMI (kg/m2)
26 ± 4
§§
24 ± 4
*
24 ± 4
24 ± 6
23 ± 1
25 ± 4
24 ± 2
24 ± 3
Weight (kg)
75 ± 12
§§
68 ± 12
70 ± 15
68 ± 8
63 ± 3
68 ± 11
64 ± 6
66 ± 12
Duration of
diabetes (yrs)
-
13 ± 8
**
4 ± 2
12 ± 4
20 ± 9
17 ± 7
20 ± 5
19 ± 6
Parity
1.3 ±
0.5
§§
1.7 ± 0.8
1.7 ± 1
1.8 ±
0.9
1.9 ±
0.9
1.6 ± 0.8
1.8 ±
0.7
1.4 ± 0.7
HbA1c (%)
4.8 ±
0.3
§§
7.4 ± 1
**
7 ± 1
7.3 ±
0.8
7.2 ±
0.4
7.6 ± 0.4
7.6 ± 1
8.2 ± 1.3
Creatinine
(μmol/l)
-
63 ± 33
**
58 ± 8
58 ± 5
64 ± 6
58 ± 9
49 ± 8
101 ± 94
Creatinine
clearance
(ml/min)
-
128 ± 30
**
133 ± 25
121 ±
21
119 ±
23
131 ± 28
149 ±
29
96 ± 41
Cholesterol
(mmol/l)
4.8 ± 0.9
*
4.7 ± 0.9
4.7 ±
0.7
4.8 ±
0.9
4.8 ± 0.7
4.1 ±
0.7
5.4 ± 1.1
Triglyceride
(mmol/l)
1.2 ± 0.6
1.3 ± 0.7
1.1 ±
0.5
1.2 ±
0.7
1.2 ± 0.6
0.8 ±
0.5
1.3 ± 0.5
HDL (mmol/l)
1.9 ± 0.5
2 ± 0.5
2 ± 0.5
1.9 ±
0.5
1.8 ± 0.5
1 ± 0.6
1.9 ± 0.5
LDL (mmol/l)
2.4 ± 0.8
2.2 ± 0.8
2.2 ±
0.6
2.4 ±
0.6
2.4 ± 0.6
2 ± 0.5
2.9 ± 1
Gestational
week at
delivery
39.5
± 1.7
§§
35.4
± 2.9
**
36.1
± 1.6
36.2
± 1.4
36.3
± 1.7
35.4
± 2.7
35.9
± 1.1
32.3
± 5.3
Birth weight
(g)
3588
± 483
§
3555
± 890
**
3859
± 756
3795
± 674
3905
± 714
3557
± 718
3711
± 676
2401
± 1122
Birth weight
ratio a,b
1.03
± 0.12
§§
1.3
± 0.27
**
1.35
± 0.22
1.35
± 0.23
1.3
± 0.26
1.31
± 0.28
1.36
± 0.36
1.06
± 0.2
Preterm
delivery < 36
week (no.(%))
2 (4)
§§
60 (32)
12 (21)
4 (27)
1 (13)
27 (39)
2 (25)
14 (67)
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AASI in Diabetic Pregnancy
101
Non-
diabetic
women
All T1DM
women
White Group
B
C
D0
D+
R
F+F/R
No.
54
176
57
13
7
70
8
21
Pre-gravid/
gestational
hypertension
(no./no.)
0/2
§§
23/3
2/1
0/1
0/0
6/1
2/0
13/0
Preeclampsia
(no.(%))
2 (4)
§§
36(20)
8 (14)
0
1
19 (27)
0
8 (38)
D0: white group D without retinopathy; D+: White group D with retinopathy.
a: observed birth weight/expected birth weight for same gestational week and gender.
b: Two twin pregnancies whose birth weights and gestational weeks are excluded from
calculations.
§
: p < 0.05 and
§§
: p < 0.01, test for difference, control vs. all T1DM.
*
: p < 0.05 and
**
: p < 0.01 test for difference between White groups in T1DM women
(ANOVA).
The diabetic women were recruited before pregnancy when possible and
attended the maternity ward for visits every second week during pregnancy
until week 32 and hereafter weekly. BP was measured using a portable
oscillometry monitor providing more than 60 readings per person per 24 h
(SpaceLab 90207, Redmond, WA, USA). The details on validation of
monitors, the recommended clinical setting, and the timing during the day of
BP are found on the British Hypertension Society’s homepage at
www.bhsoc.org [10]. The equipment was programmed for cuff insufflations
every 20 minutes from 0600 to 2300 h, and every hour during the night. At
inclusion and after demonstration of equipment, three auscultatory BP were
measured in the supine position. The average of these three auscultatory
measurements was termed the clinical BP. All auscultatory measurements
were recorded with use of a random zero sphygmomanometer (Hawksley,
Lancing, U.K.). The women followed their normal physical and daily activities
throughout pregnancy and the women stated whether the measurement of BP
took place on a workday or not. The measurement of BP was performed in
gestational week 13, 25, and 33 and three months post partum in women with
T1DM and at week 18 and 33 in the non-diabetic women.
The regression slope of diastolic on systolic BP from unedited 24-h
recordings was computed for each participant at every time point in
pregnancy. AASI was defined as one minus the regression slope of diastolic
BP on systolic BP from the diurnal recording [11]. The regression line for
AASI was not forced through zero. Thus, the stiffer the arterial tree, the closer
the regression slope approaches zero and AASI consequently approaches one.
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Finn F. Lauszus, Hanine Fadel Mustafa Al-Far, Ingvild Tjessem et al.
102
The variation of the AASI measurements was evaluated with the square of the
regression coefficients, also known as the ‘coefficient of determination’, from
the calculation of diastolic BP on systolic BP. This coefficient estimates the
proportion of the variability of diastolic accounted for by the linear
relationship between systolic and diastolic BP. If the coefficient approached 1
the diastole on systole BP has a solid linear association and if it approaches
zero the relation of diastolic with systolic BP is random and highly variable.
PP was calculated by subtraction of the diastolic value from the systolic
value and a relative PP was set to the systolic and diastolic value, respectively.
Circadian BP was evaluated with night/day ratio (ND-ratio) calculated as a
mean night BP/mean day BP. Night time was defined from 11 p.m. until and
including 6 a.m. An activity diary accompanied the monitor and women with
night work and inverse sleeping rhythms were excluded before further
calculations.
Women were identified as chronic hypertensive if pre-gestational or first
trimester BP confirmed a BP of at least 140 systolic or 90 mmHg diastolic in
diurnal BP based on 50 – 60 readings. Preeclampsia was defined as
systolic/diastolic BP of 140/90 mmHg or greater for individuals that were
normohypertensive before week 20 and, simultaneously, albuminuria in excess
of 300 mg per day in previously normoalbuminuric women. Pregnancy-
induced hypertension was hypertension without signs of preeclampsia.
Albumin excretion rate (AER) was measured by 24-h collection of urine.
AER was divided in normo-, micro- and macroalbuminuria groups if albumin
excretion was <30g, 30-299g, and 300g/24h. A birth weight ratio was
computed by dividing the observed birth weight with the expected birth weight
for the same gestational age and gender. The expected weights were calculated
and distributed by the Danish Health and Medicines Authority based on the
work of Marsál et al. [12].
Statistics was performed with IBM SPSS statistics 20. Difference between
two means was tested with Student's t-test if data followed Gaussian
distribution; otherwise Mann-Whitney’s test was used. For evaluation of the
contingency tables, first the Pearson 2-test for independence was performed
assuming no direction of a trend. Then, the table was tested with the 2-test
for trend.The variable AER was normalized by logarithm computing.
Comparison of the difference between means was tested with analysis of
variance (ANOVA). Newman-Keul’s post-hoc test was applied when the
ANOVA test was p < 0.05. Linear regression analysis was performed with
AASI and PP as dependent variable and preeclampsia, AER, retinopathy, each
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AASI in Diabetic Pregnancy
103
BP variable separately, HbA1c, age, duration of diabetes, and BMI as
independent variables. Repeated measures analysis of variance (two-way-
ANOVA) was used for comparison between groups during and after
pregnancy and co-variants were added. A two-sided p < 0.05 was the level of
significance. Values are given as mean ± SD, unless otherwise stated.
RESULTS
The women with T1DM had lower BMI in 1
st
trimester than non-diabetic
women and HbA1c and the incidence of preeclampsia increased in T1DM
women with AER (Table 1). The birth weight ratio was higher in women with
T1DM suggestive of higher birth weight at all gestational ages.
The prevalence for hypertension was 12% before pregnancy in women
with T1DM. During pregnancy further 2% had gestational hypertension and
19% subsequently developed preeclampsia. At the end of pregnancy, 30% of
the T1DM women displayed hypertension at some stage during pregnancy
and of different severity. During pregnancy 47% of the women had
simplex retinopathy and 9% had proliferative retinopathy; one woman lost
her eye sight unilaterally despite laser treatment. Eleven percent displayed
macroalbuminuria and 13% microalbuminuria. Two women had renal
insufficiency and aborted prematurely in week 21 and 24. The two women
went on dialysis waiting for a renal transplant. Another woman delivered
successfully after her renal transplantation. Two women had pre-gestational
macroalbuminuria and post partum but displayed normoalbuminuria during
pregnancy (Table 1, White group F + F/R).
The BP measurements are shown in Table 2 displaying the highest
values in the T1DM women with macroalbuminuria. AASI and PP were
different during pregnancy with respect to albuminuria groups; this was
neither observed before nor after pregnancy. Similarly, no difference was seen
in diabetic compared to non-diabetic women in AASI during pregnancy; the
control women were close to the normoalbuminuric women’s AASI values. PP
and AASI were higher in 2
nd
and 3
rd
trimester during pregnancy compared to
post partum in women with T1DM (paired analysis, p < 0.01).
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Finn F. Lauszus, Hanine Fadel Mustafa Al-Far, Ingvild Tjessem et al.
104
Table 2. Blood pressure measurements – clinical and 24-h BP and derived
calculations in 176 T1DM women before, during and, after pregnancy and
54 non-diabetic women in 1st and 3
rd
trimester
Status for type 1 diabetes mellitus
All T1DM
Non-diabetic
controls
Normo-
albumi-
nuria
Micro-
albumi-
nuria
Macro-
albumi-
nuria
No.
135
22
19
176
54
Clinical sys 1
st
trim(mmHg)
110 ± 10
116 ± 14
136 ± 22
114 ± 14
**
108 ± 11
§
Clinical dia 1
st
trim(mmHg)
69 ± 8
73 ± 8
83 ± 10
71 ± 9
**
69
Diurnal sys 1
st
trim
(mmHg)
116 ± 9
125 ± 8
137 ± 14
120 ± 11
**
113 ± 7
§§
Diurnal dia 1
st
trim
(mmHg)
70 ± 6
75 ± 5
85 ± 9
72 ± 8
**
65 ± 6
§§
Daytime sys 1
st
trim
(mmHg)
118 ± 9
126 ± 8
139 ± 14
121 ± 11
**
115 ± 8
§§
Daytime dia 1
st
trim
(mmHg)
72 ± 6
77 ± 6
86 ± 9
74 ± 8
**
68 ± 6
§§
Night sys 1
st
trim
(mmHg)
107 ± 9
117 ± 9
127 ± 14
110 ± 12
**
103 ± 6
§§
Night dia 1
st
trim
(mmHg)
59 ± 7
67 ± 6
75 ± 9
62 ± 9
**
56 ± 7
§§
ND-ratio sys 1
st
trim
0.90
0.93
0.92
0.91
0.91
ND-ratio dia 1
st
trim
0.83 ± 0.07
0.87 ± 0.05
0.87 ±
0.07
0.84 ± 0.07
**
0.84
Heart rate 1
st
trim
(beats/min)
84 ± 10
91 ± 6
92 ± 11
86 ± 10
**
83
Heart rate 2
nd
trim
(beats/min)
87 ± 9
93 ± 9
92 ± 10
89 ± 10
*
-
Heart rate 3
rd
trim
(beats/min)
88
93
89
89
88
Heart rate 3 mths pp
(beats/min)
80 ±
91 ±
91 ±
83 ± 10
**
-
PP 1
st
trim (mmHg)
47 ± 5
49 ± 4
52 ± 9
48 ± 6
**
47
PP 2
nd
trim (mmHg)
47 ± 5
49 ± 6
54 ± 9
48 ± 6
**
-
PP 3
rd
trim (mmHg)
46 ± 5
51 ± 9
52 ± 9
47 ± 6
**
48
PP 3 mths pp (mmHg)
44
44
46
44
-
PP relative to sys 1
st
trim
(%)
0.40 ±
0.03
0.40 ±
0.02
0.38 ±
0.03
0.40 ±
0.03
**
0.42 ±
0.03
§§
PP relative to dia 1
st
trim
(%)
0.68 ±
0.08
0.66 ±
0.06
0.62 ±
0.09
0.68 ±
0.08
**
0.72 ±
0.08
§§
AASI pregravid
0.26
0.34
0.32
0.28
-
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AASI in Diabetic Pregnancy
105
Status for type 1 diabetes mellitus
All T1DM
Non-diabetic
controls
Normo-
albumi-
nuria
Micro-
albumi-
nuria
Macro-
albumi-
nuria
No.
135
22
19
176
54
AASI 1
st
trim
0.29 ±
0.15
0.35 ± 0.16
0.39 ±
0.16
0.31 ± 0.16
**
0.27
AASI 2
nd
trim
0.27 ±
0.15
0.37 ± 0.14
0.43 ±
0.18
0.30 ± 0.16
**
-
AASI 3
rd
trim
0.31 ±
0.17
0.36 ± 0.21
0.45 ±
0.13
0.33 ± 0.18
*
0.28
AASI 3 mths pp
0.23
0.27
0.32
0.25
-
r2 1
st
trim
0.57
0.49
0.51
0.55
0.53
r2 2
nd
trim
0.59 ±
0.14
0.50 ± 0.17
0.52 ±
0.19
0.57 ± 0.15
*
-
r2 3
rd
trim
0.52
0.44
0.48
0.50
0.53
r2 3 mths pp
0.57
0.54
0.53
0.56
-
Sys: systole, dia: diastole, PP: Pulse pressure, ND: Night/day, trim: trimester, 3 mths pp: 3
months post partum, wk: week; r2 = squared regressions coefficient from AASI calculation
(coefficient of determination).
*
: p < 0.05 and
**
: p < 0.01 test for difference between albuminuria groups in T1DM women
(ANOVA).
§
: p < 0.05 and
§§
: p < 0.01 in all T1DM vs. control women.
AASI was associated with AER during pregnancy and retinopathy
(Table 3). Within the BP variables AASI was closely associated ND-ratio and
PP during and after pregnancy (Table 4). The AASI was positively correlated
with ND-ratio during and outside pregnancy. Interestingly, the association of
AASI with absolute BP values, which was present during pregnancy, was lost
after pregnancy.
Analysis with repeated measurement in 1
st
, 2
nd
, and 3
rd
trimester showed
that AASI was significant associated with the AER groups and followed
different patterns during the trimesters (p < 0.001), also when adjusting for
age, duration of diabetes, and glycemic regulation measured by HbA1c (Figure
1, p < 0.001).
After pregnancy, the association of AASI with PP and ND-ratio persisted
in the T1DM women (Table 4). Adjustment for AER, age, duration of
diabetes, HbA1c did not change this finding (p < 0.001). The change in BP
was significant associated with the change in AASI from 3
rd
trimester to post
partum, in particular with the night BP (r = 0.35, r = 0.32, r = 0.21, and
r = 0.13, for systolic, diastolic night BP, for systolic and diastolic day BP,
respectively, p < 0.01, p < 0.01, p < 0.05, not significant).
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106
Table 3. Association of AASI with clinical variables in 176 women with
T1DM and 54 non-diabetic control women
Time of BP
measurement
Pre-
gravid
1
st
Trimester
2
nd
trimester
3
rd
trimester
3 months
post partum
No.
34
166/54
150
138/46
110
Age
a
0.12
0.18
*
/0.1
0.25
**
0.12/0.07
-0.05
BMI
a
0.28
0.22/0.04
0.18
*
0.19/0.42
**
0.1
Duration of
diabetes
a
-0.11
0.16
0.18
*
0.18
*
0.11
AER
a,c
-0.13
0.22
**
0.32
**
0.31
**
0.03
Creatinine
clearance
(ml/min)
a
-0.14
0.12
0.08
-0.15
-0.18
HbA1c
a
0.07
0.07/0.03
0.02
0.05/0.12
0.07
Cholesterol
(mmol/l)
a
-
-0.04
0.08
0.2
*
-0.08
Triglyceride
(mmol/l)
a
-
0.11
0.07
0.21
*
0.02
Birth weight
ratio
a,d
-0.09
-0.03/0.1
-0.15
-0.02/0.01
0.06
Gestational age
a,d
-0.05
-0.19
*
/0.03
-0.19
*
-0.09/0.01
0.06
Retinopathy
b
0.03
0.16
*
0.17
*
0.22
**
0.02
Preeclampsia
b
0.01
0.01/0.01
0.06
0.07/0.02
0.01
Preterm
delivery
b,d
0.04
0.02
0.01
0.02
0.01
Data in 1
st
and 3
rd
trimester are given as T1DM/control when available data in control
women. AER: albumin excretion rate.
a: Univariate regression analysis i.e., no adjustment variables included in calculation of
regression coefficients.
b: Sum of squares between groups (one-way ANOVA).
c: AER: log transformed 24-h albumin excretion rate.
d: Two twin pregnancies’ birth weights and gestational weeks were excluded from
calculations.
*
: p < 0.05,
**
: p < 0.01.
The variation of the AASI measurements was analyzed with the
coefficient of determination (Table 2 and 5, Figure 2). It showed that the
higher the AASI the lower was the coefficient of determination; thus
indicating that with stiffening arteries the diastolic and systolic BP display a
non-linear relation with increasing random variability. Similar was found in
the non-diabetic women during pregnancy (Figure 2) and the non-pregnant
T1DM women (Table 5). Similarly, the larger PP showed larger variation
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