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AASI in Diabetic Pregnancy
107
(lower coefficient of determination). The measurements were affected by the
levels in diurnal systolic BP in all three trimesters and variably in ND-ratio of
systolic BP and diurnal systolic BP. The pattern in the diastolic measurements
was less clear. ND-ratios, diurnal, and clinical BP were not associated with
coefficient of determination post partum, i.e., the variation of measurement
were similar over BP levels and ND-ratios in the non-pregnant T1DM women.
Table 4. Regression coefficients from the analysis on the association of
AASI with blood pressure variables in 176 pregnant 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
Diurnal BP
systole
a
0.22
0.34
**
/0.34
*
0.4
**
0.41
**
/0.34
**
0.21
*
Diurnal BP
diastole
a
0.05
0.17
*
/0.17
0.21
**
0.3
**
/0.17
0.05
Clinical BP
systole
a
-0.09
0.33
**
/0.05
0.3
**
0.27
*
/0.08
0.09
Clinical BP
systole
a
-0.38
0.12/0.04
0.19
*
0.27
**
/0.23
0.1
Heart rate
a
0.02
0.1/0.07
0.11
0.19
*
/0.02
0.25
**
Pulse pressure
a
0.31
0.46
**
/0.37
**
0.48
**
0.47
**
/0.5
**
0.42
**
ND-ratio
systole
a
0.43
**
0.26
**
/0.05
0.16
0.23
**
/0.14
0.26
*
ND-ratio
diastole
a
0.51
**
0.36
**
/0.09
0.26
**
0.3
**
/0.43
**
0.26
*
PP relative to
systole
a
0.17
0.29
**
/0.19
0.24
**
0.15/0.29
0.31
**
PP relative to
diastole
a
0.18
0.29
**
/0.19
0.25
**
0.15/0.29
0.3
**
The 1
st
and 3
rd
trimester data are given as T1DM/control women. PP: Pulse pressure,
BP: Blood pressure, ND: Night/day.
a: Univariate regression analysis i.e., no adjustment variables included in calculation of
regression coefficients.
*
: p < 0.05 and
**
: p < 0.01 in the regression analysis.
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Finn F. Lauszus, Hanine Fadel Mustafa Al-Far, Ingvild Tjessem et al.
108
0.25
0.3
0.35
0.4
0.45
0.5
1st trim 2nd trim 3rd trim
AASI
Figure 1. Ambulatory arterial stiffness index during 1
st
, 2
nd
, and 3
rd
trimester in 125
T1DM women. Repeated measurement analysis of AASI in 125 T1DM women with
complete data by normo- (n = 98, circles with dotted line), micro- (n = 17, squares with
interrupted line), and macroalbuminuria (n = 10, triangles with full line); the
covariates, age, diabetes duration, and HbA1c, are added to the model (2-way
ANOVA, p < 0.001, Newman-Keul’s post hoc test: normo- vs. micro- and
macroalbuminuric women, respectively, both p < 0.05). Error lines indicate ± 1 SEM.
Table 5. Regression coefficients from the analysis on the association of the
coefficient of determination with blood pressure variables in 176 pregnant
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
Diurnal BP systole
a
-0.03
-0.24
**
/-0.2
-0.4
**
-0.28
**
/-0.22
-0.12
Diurnal BP diastole
a
0.1
0.08/0.04
-0.26
**
0.13/-0.1
0.05
Heart rate
a
0.14
-0.09/-0.16
-0.11
-0.13/-0.08
-0.19
*
Pulse pressure
a
-0.17
-0.39
**
/-0.38
**
-0.39
**
-0.38
**
/-0.32
*
-0.4
**
AASI
a
-0.59
**
-0.69
**
/-0.66
**
-0.61
**
-0.7
**
/-0.55
**
-0.77
**
ND-ratio systole
a
-0.4
*
-0.41
**
/-0.3
*
-0.27
**
-0.38
**
/0.05
-0.31
**
ND-ratio diastole
a
-0.26
-0.27
**
/0.01
-0.12
-0.24
**
/-0.14
-0.17
PP relative to systole
a
-0.13
-0.31
**
/-0.32
*
-0.13
-0.23
**
/-0.19
-0.38
**
PP relative to
diastole
a
-0.18
-0.31
**
/-0.37
*
-0.15
-0.23
**
/-0.19
-0.36
**
The 1
st
and 3
rd
trimester data are given as T1DM/control women.
PP: Pulse pressure, BP: Blood pressure, ND: Night/day.
a: Univariate regression analysis i.e., no adjustment variables included in calculation of regression
coefficients.
*
: p < 0.05 and
**
: p < 0.01 in the regression analysis.
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AASI in Diabetic Pregnancy
109
DISCUSSION
AASI showed a strong association with albuminuria, PP, and circadian
rhythm throughout pregnancy and it seems that it is even more pronounced
than after pregnancy. The variation of measurements is dependent on the
AASI level irrespective of pregnancy but the absolute levels of BP and ND-
ratio display variation during pregnancy, which is not found in non-pregnant
T1DM women.
The preeminent vasculopathy in terms of retinopathy and incipient/overt
nephropathy can be detected in the AASI, too. It was found that hypertensive
disorders during pregnancy were associated with a flattened circadian blood
pressure response and was restored after delivery [7]. We and others were not
able to differentiate in AASI between gestational hypertension, chronic
hypertension or preeclampsia [7]. Despite having lower BP and lower risk of
hypertension, the non-diabetic women did not differ in their AASI from the
T1DM women, so we may not expect to be able to differentiate BP modalities
on AASI alone. The preeclamptic and pre-gestational hypertensive women
may overlap considerably based on data on non-diabetic patients [7-9, 13].
Applying terms like ‘dippers’ and ‘non-dippers’ to the pregnant situation has
proved of little value in estimating prognosis [14]. High level of estrogen or
some other factors may influence elasticity of vessel walls that mask the
influence nocturnal dipping may have on AASI during pregnancy [7, 9, 13].
However, circadian rhythm in terms of ND-ratio correlated well with AASI at
all time points. The change from pregnancy to post partum displayed the
pregnancy adaptation but also that the change in night blood pressure had the
strongest association with AASI. Kärkkäinen et al. found a strong inverse
association of AASI with both systolic and diastolic dipping postpartum in
hypertensive pregnancies suggesting that the two risk factors for later
cardiovascular diseases were connected [7]. In previous studies, AASI was
strongly and inversely dependent on the degree of nocturnal blood pressure
fall and, thus, heralding a risk for cardiovascular disease later in life [3-5, 14-
16].
Our indices in diabetic women are significantly different during pregnancy
compared to post partum. We do not corroborate the suggestion put forward
by Kärkäinen et al. that the same AASI reference values are valid for pregnant
women that are used for the general young population [9]. Our results suggest
that non-pregnant adaptation took place, even though the relatively short time
since delivery and continued lactation may have influenced the findings.
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Moreover, AASI did not vary between the AER groups post partum. Though,
women recovering from hypertensive pregnancies may have subtle vascular
changes, which may need attention in future evaluations.
There are some weaknesses in our study, which was performed
prospectively but obviously has difficulties in obtaining complete data on BP
at all time points. Nevertheless, the number of participants is rather high for
the methodology applied but does not take into account the antihypertensive
treatment of some of women. The clinical applicability, however, was little
changed by including the full cohort of our tertiary center. Despite a few
neglectors the majority consented to participate in the study and could be more
motivated to continue also after delivery, even in the most problematic cases.
Some selection bias has occurred due to referral to our tertiary center. Despite
being a study over six years the same BP methodology was used; however, we
cannot preclude that medical treatment did change over time, affecting
antihypertensive as well as glycemic regulation. The addition of a small
control group helped creating a contrast to the mix of hypertensive disorders in
T1DM pregnancy, which in itself poses a high-risk situation with several
obstetrical and medical issues. However, it is unlikely that the usefulness of
AASI during pregnancy would be dramatically better in a subgroup as few
pregnancies have higher risk of BP disorders,
Vasodilatation during pregnancy and stroke volume may influence AASI,
so one may argue that it is not reflecting stiffness of the vessels but rather
pregnancy adaptation and regression post partum. In normal pregnancy
changes in the arterial and venous sides of the circulation occur independently
of pressure alterations with increase in venous tone, i.e., preload, and decrease
in aortic stiffness, thus reducing afterload, which tend to optimize cardiac
function until delivery [13]. We confirm these observations in the changes
from 3
rd
trimester to post partum but the findings may be biased by our high
risk setting with a considerable number of women with preeclampsia and
hypertension.
Our evaluation of the variation of AASI by the coefficient of
determination indicates loss of linearity when AASI is high in pregnancy; this
was, however, similar in pregnant T1DM women compared to non-pregnant
T1DM women as well as pregnant T1DM women compared to non-diabetic,
pregnant women (Table 2, Figure 2). Only classic diabetic and vascular
co-morbidity variables affected the measurements systematically and, in
particular, during pregnancy. The post partum results show evaluations with
similar direction as in pregnancy. However, the low number disallow safe
conclusions in the non-pregnant state as for the associations of AASI with
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AASI in Diabetic Pregnancy
111
AER, PP, age, and BMI, which are not as consistent as in other studies [5, 6,
14, 17]. Within the physiological range, AASI also appears to lack significant
associations to obstetrical outcome, but given the number of included women
sparse results were expected. As for reproducibility we previously found that
assessment of BP was improved by repeated measurement in terms of
precision, reproducibility and lesser trend of association over the scale of
measurement [18]. Consistency of measurements, however, depended much
more on the quality of the BP monitor with its purpose to perform satisfactory
for prediction of hypertension or preeclampsia in T1DM [7, 14, 18]. In the
non-pregnant T1DM patient, AASI has a low repeatability compared with PP,
which questions the potential implementation of AASI as a therapeutic target
in clinical practice to measure of arterial stiffness [15, 19]. Though the
methodology for measuring AASI is inexpensive and simple, it may measure
similar physiological phenomena as PP and AASI correlates significantly with
PP at all measured time points (Table 4).
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
-0.40 -0.20 0.00 0.20 0.40 0.60 0.80 1.00
AASI
Coefficient fo determination
Figure 2. Ambulatory arterial stiffness index and coefficient of determination in 1
st
trimester in 166 women with T1DM and 54 control women.
AASI on coefficient of determination for T1DM (filled circles) and control women
(hollow squares), r
2
= 0.48 and r
2
= 0.44 respectively, both p < 0.001, regression lines
added (T1DM women: full line, control women: interrupted line).
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Finn F. Lauszus, Hanine Fadel Mustafa Al-Far, Ingvild Tjessem et al.
112
We hint at the reason for the failure to diagnose and monitor blood
pressure disorders properly during pregnancy with substandard methods. The
variation of BP measurements is significantly dependent on the level of BP
and from that fact stems the reduced capability to detect and reproduce BP
changes, too. This phenomenon expands to methods of BP evaluation by ND-
ratio, PP or AASI. The validation and use of adequate BP methodology for
pregnancy is, therefore, a must before entering trials on the benefit of
detecting, treating, and monitoring BP disorders during pregnancy.
CONCLUSION
AASI showed a strong association with albuminuria, PP, and circadian
rhythm during pregnancy in T1DM women and it seems that it is even more
pronounced than after pregnancy. The higher the AASI the lower was the
coefficient of determination, indicating that with stiffing arteries diastolic and
systolic BP display non-linear relation and increase their random variability.
ACKNOWLEDGEMENTS
The laboratory technician Hanne Petersen and Merete Møller are kindly
acknowledged for technical assistance.
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BIOGRAPHICAL SKETCH
Name: Finn Friis Lauszus
Affiliation: Dept. of Gynecology & Obstetrics, Herning Hospital, Denmark
ORCID: 0000-0003-3274-690X at: http://orcid.org/0000-0003-3274-690X
Researcher-ID: J-9823-2015 at: http://www.researcherid.com/rid/J-9823-
2015
Education: M.D. 1987 from Aarhus University, Denmark, Specialist of
Obstetrics & Gynaecology since 1999 in Denmark later recognized in
Norway and Sweden.
Address: Gynecology Dept. Herning Hospital, Gl. Landevej 61, DK-7400
Herning, Denmark. E-mail: finlau@rm.dk
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AASI in Diabetic Pregnancy
115
Research and Professional Experience: Ph.D. "Dietary Treatment of
Gestationel Diabetes Mellitus", 1997 at Aarhus University Training in
Internal Medicine at the Dept. of Medical Endocrinology, Internal
Medicine, and Dept of Infectious Diseases, all Aarhus University
Hospital. Research fellow at the Institute for Experimental Clinical
Research at Aarhus University, April 92 to June ’94.
Fields of research is Endocrinology, Operative Quality, and Perinatal Care.
Post-graduate courses and exams in the subjects Genetic Epidemiology, SPSS
in medical research, Clinical Cancer Research, Evaluation of preventive-
and treatment programs, Biostatistics, Advanced Epidemiology, Statistical
Analysis of Survival data in Clinical Research, and Analysis of Variance
and Regression for Health Researchers at the Universities of Aarhus and
Copenhagen.
Professional Appointments:
1. Senior Consultant at the Gynaecology Dept., Herning Hospital since
2004 with 50 % allocated to a position as Research Specialist since
1999. Head of section for Infertility and Endocrinology 2005-2014.
2. Senior Lectureship for Aarhus University since 2004
3. External Censor at the Medical Faculty at the Universities of
Copenhagen and Odense since 2005
4. Research Coordinating Lectureship at the Western Region Hospitals
2008-12
Honors: Organon’s Gynecology Award 2001 for the project “Metformin-
treatment of women with PCOS”.
Publications: Total no. 92 in the subject of Diabetes (n = 37), Surgical
Rehabilitation (n = 13), Gynecological Endocrinology (n = 13), Oncology
(n= 9), Obstetrics (n = 10), Sexual behavior (n = 6) Research facilitation
(n = 4).
Publications Last 3 Years:
1. Nielsen A, Frost L, Nielsen GL, Lauszus FF, Lederballe O, Rasmussen
R, Djurhuus JC, Kjellberg PK. [Research at regional hospitals in
Denmark can be reinforced].Forskning på regionshospitaler – fra strategi
til implementering. Ugeskr f Laeger 2013; 175/6: 336-9. PMID:
23402237.
2. Lauszus FF, Nielsen GL, Petersen LJ, Rasmussen C, Frost L, Fedder J,
Lederballe O, Hornung N. [Research in regional hospitals in two Danish
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Finn F. Lauszus, Hanine Fadel Mustafa Al-Far, Ingvild Tjessem et al.
116
regions] Forskning på regionshospitaler i Region Midt- og Nordjylland.
Ugeskr f Laeger 2013; 175/6: 339-41. PMID: 23402238.
3. Lauridsen AH, Bannason J, Lauszus FF. Second trimester rupture in
a retroflexed, scarred uterus: a case report. J Obstet Gynaecol 2013
Aug;33(6):629. doi: 10.3109/01443615.2013.795135.
4. Lauszus FF, Fuglsang J, Rosgaard A, Lousen T, Klebe JG. Ambulatory
arterial stiffness index in type 1 diabetes mellitus: Any different during
pregnancy? Eur J Obstet Gynecol Reprod Biol. 2013;169:234-8. doi:
10.1016/j.ejogrb.2013.04.010.
5. Greibe E, Trolle D, Bor MV, Lauszus FF, Nexo E. Metformin lowers
serum cobalamin without changing other markers of cobalamin status:
A study on women with polycystic ovary syndrome. Nutrients. 2013;
5:2475-82. doi: 10.3390/nu5072475.
6. Lauridsen AH, Lauszus FF, Petersen AC. Ovarian granulosa cell tumor
and increased risk of breast cancer. Acta Obstet Gynecol Scand. 2013;
92:1422-5. doi: 10.1111/aogs.12252.
7. Rasmussen AL, Lauszus FF. Umbilical pulsatility index is associated
with fetal acidemia in type 1 diabetic pregnancies. J Gynecol Obstet
2013; 3:149. doi:10.4172/2161-0932.1000149.
8. Lauszus FF. Blood pressure and diabetes pregnancy: Diurnal
blood pressure methodology and preeclampsia prediction in type 1
diabetes mellitus. In: Type 1 Diabetes: Causes, Treatment and Potential
Complications. Page 25-40. Nova Science Publishers, Inc. 400 Oser
Avenue, Suite 1600, Hauppauge, NY 11788. 2013. Editor: Zachary
Pearce. ISBN: 978-1-63117-000-3.
9. Lauszus FF, Petersen AC, Neumann G, Cleemann L, Rosgaard
A, Jørgensen A, Vandborg M, Jakobsen A. Less extensive surgery
compared to extensive surgery: Survival seems similar in young women
with adult ovarian granulosa cell tumor. Eur J Obstet Gynecol Reprod
Biol. 2014;177:61-6. doi: 10.1016/j.ejogrb.2014.02.037.
10. Rasmussen AL, Frostholm GT, Lauszus FF. Curettage after medical
induced abortions in second trimester. Sex Reprod Healthc. 2014;5
(3):156-7. doi: 10.1016/j.srhc.2014.06.002.
11. Viftrup-Lund M, Gade M, Lauszus FF. Pregnancy in PCOS women and
their history of diabetes. J Metabolic Synd 2014; 4 (3): 163. doi:10.
4172/2167-0943.1000163.
12. Lauszus FF, Viftrup-Lund M, Gade M. Metformin exposure in early
pregnancy and spontaneous abortions in women with polycystic ovary
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