pathology in obstetric

1. Arterial Stiffness in
Predicting Preeclampsia ?
Abarham martadiansyaH

2. • There is emerging evidence that PE is associated
with increased arterial stiffness (AS), which is
itself an important predictor of outcome.
• A recent meta- analysis of 23 relevant studies
showed a significant increase in all AS indices
measured in pre-eclamptic compared with
normotensive pregnant women.
• Aortic stiffness
– reportedly varies throughout normal pregnancy,
reaching its nadir in the second trimester and rising
again in the third
– in pre-eclamptic women it continues to increase
throughout pregnancy.

3. ARTERIAL STIFFNESS

4. Definition
• Arterial Stiffness
–The elasticity (or compliance) of the arteries.
• Arteriosclerosis
–The hardening or stiffening of the arteries.
• The stiffness of arteries influences how hard the
heart has to work to pump blood through the
body.

5. Figure 1. Summary of the multiple causes and locations of arterial stiffness.
Susan J. Zieman et al. Arterioscler Thromb Vasc Biol.
2005;25:932-943
Copyright © American Heart Association, Inc. All rights reserved.

9. Arterial Stiffness and Its clinical
Implications in woman

11. Peter M. Nilsson, Pierre Boutouyrie, Stéphane Laurent
Hypertension. 2009;54:3-10
Arterial stiffness is a cumulative measure of the damaging effects of CV risk factors on the arterial wall
with aging.
Arterial stiffness, which reflects the true arterial wall damage of CV risk factors, increases with aging, whereas
blood pressure (MBP), glycemia, and lipids which are fluctuating along the follow-up of patients, may give a
constant value when combined into a CV risk score if their fluctuations occur in opposite directions.
Thus, measuring “circulating” biomarkers at a certain time may give only a “snapshot” and not the whole history of
arterial wall damage.

12. Conclusion
Women who had iatrogenic PTB, but not those who had
spontaneous PTB, have increased SBPAo and arterial
stiffness that is apparent from as early as the first trimester
of pregnancy.

13. Conclusion
Woman who develop GDM have increased SBP(Ao) and
Arterial stiffness from the 1st TM of pregnancy before the
clinical onset of GDM

14. • The aim of this study was to examine the potential value of assessment of SBPAo,
PWV and AIx at 11–13weeks’ gestation in identifying women who subsequently
develop pre-eclampsia.
• Results :
– In the pre-eclampsia group vs unaffected controls, there was an increase in
Aix-75 (1.13 vs. 1.00 multiples of the median (MoM); P<0.0001), PWV (1.06
vs. 1.00 MoM; P<0.0001) and SBPAo (1.09 vs. 1.00 MoM; P<0.0001)
Conclusion :
Compared with women who remain normotensive,
women who develop pre-eclampsia have higher
SBPAo and arterial stiffness, which is apparent from
the first trimester of pregnancy

16. How can large artery stiffness be measured?

17. • Augmentation index (Aix) :
– Using the shape of the pulse wave to provide measures of
endothelial function
– Primarily reated to the endotheliaal function modulated
vascular tone of the arterioles and small arteries
• Pulse Wave Velocity (PWF) :
– Measuring the time it take for a pressure pulse to travel
between two points in the arterial system, usually the carotid
artery (neck) and femoral artery (groin), and estimating the
length of the artery between these two points.
– Related to the peripherial (brachial) Related to peripheral
(brachial) BP and the Aix (wafe reflection)

18. • Central blood pressure :
–The pressure that the heart acts against, tends
to increase with higher arterial stiffness.
–Related to the peripheral (brachial) BP and the
Aix (wave reflection).
• Carotid, intima-media thickness :
–using an ultrasound scan to gauge the
thickness of the inner distance of the wall of
the carotid artery.

19. • Carotid-femoral pulse wave velocity (cf-PWV),
the most widely validated and universally
accepted measure of AS, is considered the
‘gold-standard’ measurement of AS.
• PWV has not been adequately examined
during pregnancy, and the potential utility of
PWV as a predictor of PE has not yet been
determined.

20. AORTIC PULSE WAVE VELOCITY

21. • A simple method to assess arterial stiffness and
distensibility.
• A long-established and widely used technique.
• Non-invasive, accurate and reproducible.

22. Principles
L.V.Ejection generates a pulse wave which will propagate
along the arterial walls at a certain speed.
Propagation along the arterial tree
Systole
L.V.
Blood = incompressible fluid
Artery = elastic conduit }
The propagation velocity is determined by:
• the elastic and geometric properties of
the arterial wall
• the characteristics of the arterial wall
structure.
Higher velocity = higher stiffness
= lower distensibility.

23. PULSE WAVE VELOCITY
Intermittent cardiac output
Systole Diastole
Large arteries store a part of the ejection volume
during systole and restore it during diastole.
Arterial Buffering function
Continuous peripheral flow

24. •

26. Speed of the wave is related to
the stiffness of the artery it is
traveling in
The stiffer the artery;
the higher the wave speed
Wave speed is proportional to the square
root of arterial stiffness

27. WHAT ARE THE TOOLS to measure PWV?
• Doppler Ultrasound
• Oscillometric
– Measure the fluctuations observed in an occluding cuff as
the pressure is initially raised and then gradually dropped.
– Mathematically estimates the oscillation
• Tonometric
– Using measurement at radial artery by applanation
tonometry
• Piezo-electronic
– Measuring changes in pressure, acceleration, or force by
converting to an electrical charge

28. Pros and CONS?
• Oscillometric
– Easy to measure
– Non invasive
– Fast & Economic
– Indirect calculation
• Tonometric and Piezoelectric
– Real calculation of the formula
– Non invasive
– Training needed
– Expensive

29. Although the complex pathophysiology underlying the arterial stiffening process is beyond the scope of this review, knowledge of its basic mechanisms
is relevant for better un- derstanding its relationship to sex. The stability and compli- ance of the arterial wall is maintained by a well-regulated balance
between its 2 main extracellular matrix proteins, collagen and elastin. With aging, there is fatigue of the elastin fibres and dysregulation of this balance,
with excessive degradation of its elastic component, elastin, and replacement with tensile collagen fibres, leading to stiffening of the arterial wall. In the
presence of cardiovascular risk factors, an adverse inflammatory and hormonal milieu further exacerbates this process.18 Estrogen has been shown to
directly affect arterial wall remodelling by increasing elastin production and decreasing collagen deposition in human arteries.19
There is compelling evidence suggesting that sex differ- ences in vascular biology are related not only to the type and levels of sex hormones, but also to
tissue and cellular differ- ences responsible for sex-specific responses to various stimuli. For instance, the human aorta has estrogen20 and progester-
one21 receptors, and women have more arterial estrogen re- ceptors than men.22 Although androgen receptors have been identified in primate
vascular tissues,23 there have been no reports of the localization or distribution of androgen re- ceptors in human blood vessels. In addition, it has
been demonstrated that production of the potent vasodilator nitric oxide (NO) is greater in premenopausal women than in men,24 and the endothelial-
dependent, NO-mediated vaso- dilatory effects of estrogen differ between men and women, because intracoronary injections of estradiol improve
endo- thelial function and coronary flow in women with coronary artery disease, but not in men.25 Such vasodilatory effects of estrogen in women
appear to be time-dependent, because they vary inversely with the length of estrogen deprivation.26 Thus, sex differences in arterial estrogen
receptors coupled with a direct effect of endogenous estrogens on endothelial function and arterial stiffness via NO might at least partially underlie the
favourable hemodynamic and risk profile attributed to women of reproductive age; and help explain the adverse hemodynamic and cardiovascular
transitions that often follow menopause.
A potential role for sex hormones in the regulation of arterial function, tone, and elasticity is further suggested by studies that evaluated measures of
arterial stiffness during hormonal transition periods, such as before and after puberty, or throughout the menstrual cycle. Ahimastos and col- leagues27
studied 58 prepubertal and 52 postpubertal healthy children and found that in the prepuberty period, girls had greater cfPWV (a measure of aortic
stiffness) and PP (a global marker of arterial stiffness), than age-matched boys. After puberty, girls’ cfPWV decreased, boys’ cfPWV increased, thereby
dissipating the prepubertal differences; and PP was lower in postpubertal girls than in boys. In addition, stiffness has been shown to vary during the
menstrual cycle in young, healthy women of reproductive age,28-30 although this matter remains debatable because a recent study has challenged this
Canadian Journal of Cardiology Volume 30 2014
concept.31 Use of oral contraceptives among women of reproductive age has been shown to be associated with greater PP and cfPWV,32 corroborating
the notion that suppression of female endogenous sex hormones might have an effect on arterial health and compliance.
In the postmenopausal period, age-related increases in arterial stiffness are observed,33 however, several studies have shown that arterial stiffness is
ameliorated by administration of hormonal therapy (HT) in postmenopausal women,34-40 worsening again after HT withdrawal.41 The aforemen-
tioned findings suggest that female sex hormones (and/or the additional hormonal and metabolic milieu that accompany them) might have a role in the
regulation of large artery compliance. However, the results of the HT studies deserve special interpretation in the context of the Heart and Estro-
gen/Progestin Replacement Study (HERS),42 which showed no difference in the incidence of cardiovascular events in women taking HT vs placebo, and
the Women’s Health Initiative,43 which showed greater risk of nonfatal myocardial infarction and stroke among women taking HT (although absolute
rates of events were low). Interestingly, despite the lack of protection against cardiovascular events, both studies showed a beneficial effect of HT on
cardiovascular risk factors such as blood pressure and lipids, which mirrors the afore- mentioned results of HT in arterial stiffness. Whether these
divergent effects of HT on arterial stiffness/risk factors and cardiovascular events are related to timing of HT adminis- tration, lack of enough follow-up
time for improvement in hard outcomes, or additional thrombogenic mechanisms that are independent of arterial compliance and risk factors is not
the focus of the present review, but remain amenable to further testing and discussion.

30. Hypertensive Complications of Pregnancy
It is estimated that approximately 10% of pregnant women experience hypertensive complications,80 including
gestational hypertension, pre-eclampsia and eclampsia. Hypertensive complications can have devastating
consequences to women and their families, including fetal loss and maternal death.81,82 Moreover, women who
develop pre-eclampsia or eclampsia during gestation have a significantly greater risk of developing CVD later in
life,83-85 with hazard ratios as high as 5.36 for women with severe pre-eclampsia/eclampsia.84
Because of the significant health burden associated with hypertensive complications of pregnancy, increasing
efforts have been devoted to understanding its pathophysiology and identifying markers for risk stratification. It
is well recognized that greater arterial stiffness is a common characteristic of women who develop
hypertensive emergencies of pregnancy.86-90 In a meta-analysis of 9 studies, Hausvater and colleagues at McGill
University found that cfPWV and AIx were significantly greater among women who had a history of pre-
eclampsia than women with normotensive pregnancies.88 What remains unclear is whether arterial stiffness is
implicated in the pathogenesis of hypertensive complications of pregnancy, or is simply a marker of increased
risk. Endothelial dysfunction, inflammation, and changes in the renin-angiotensin-aldosterone system are
abnormalities described in arterial stiffness and pre-eclampsia,88 and as such, increased arterial stiffness might
be a simple marker of the physiologic and metabolic derangements that lead to hypertensive complications of
pregnancy. By leading to the delivery of (deleterious) highly pulsatile energy to the end organs, it is also
possible that arterial stiffness might promote endothelial dysfunction and vascular damage, which in turn
trigger the cascade that culminates in pre-eclampsia or eclampsia. Further basic science and prospective
studies are needed to disentangle the complex associations of arterial stiffness and hypertensive complications
of pregnancy.
Although measures of arterial stiffness appear to have a role in predicting future development of pre-
eclampsia/eclampsia, its role as a therapeutic or preventative target remains unknown. Khalil et al.
demonstrated that, among women with pre-eclampsia, arterial stiffness was significantly decreased by
treatment with a-methyldopa.91 However, clinical trials are needed to determine whether therapeutically
decreasing arterial stiffness will be efficacious in preventing hypertensive emergencies in pregnant women
identified as having high risk of developing pre-eclampsia/eclampsia (Fig. 3).

31. • Augmentation Index
• The augmentation index (A-Ix) is defined as the difference
between the second and first systolic peaks expressed as a
percentage of the pulse pressure, is a measure of systemic
arterial stiffness and wave reflection.
• Pulse wave velocity
• The carotid-femoral PWV (cf-PWV) is calculated as the
quotient of the distance traveled by the pulse wave and the
foot-to-foot time delay between the pulse waves.
• The carotid-radial PWV (cr-PWV), the method of calculation
was the same; however the distal distance was measured
from the sternal notch to the radial artery

32. Augmentation Index

33. Mills et al 2008

36. PULSE WAVE VELOCITY

39. Objective:
• To assess arterial stiffness in pregnancies complicated by
hypertensive disorders: preeclampsia and chronic hypertension.
Results:
• Significantly higher PP and PWV and lower SI/PP were observed
in preeclamptic compared to uncomplicated pregnancies.
Preeclamptic pregnancies also differed from chronic
hypertensive pregnancies by higher PP and lower SI/PP. Women
with chronic hypertension had significantly higher PWV than the
control group, but PP and SI/PP were not different. In both
hypertensive groups SVRI was exceptionally high.

41. Objective :
• To evaluate the effect of the menstrual cycle, normal pregnancy, and
preeclampsia on central and systemic arterial stiffness.
Result :
• In normal pregnancy, pulse wave velocity and augmentation index
increased from 24 weeks over the third trimester (P 0.01 for both).
• All of the measures were increased in women with preeclampsia (P
0.01), with augmentation index and carotid-femoral pulse wave
velocity remaining elevated 7 weeks postpartum (P 0.02).

42. Objective :
• To compare the maternal wave reflections and arterial stiffness in women
with established PE and those with normotensive pregnancies, after
systematic adjustment for known confounders.
Result :
• In the PE group, compared with controls, there was an increase in the
median pulse wave velocity of both the carotid to femoral [1.1,
interquartile rage (IQR) 1.0–1.3 MoM vs. 0.9, IQR 0.9–1.0 MoM; P 0.0001]
and carotid to radial (1.0, IQR 0.9 –1.1 MoM vs. 0.9, IQR 0.9 –1.0 MoM; P
0.01) parts of the arterial tree.
• In contrast, there were no significant differences between the two groups
in the median augmentation index (0.9, IQR 0.7–1.1 MoM vs. 1.0, IQR
0.5–1.8 MoM; P 0.46).

45. Objective:
• Investigate the association between PE and arterial stiffness. 23 relevant
studies were included.
Results:
• A significant increase in all arterial stiffness indices combined was
observed in PE vs. control [SD 1.62, 95% CI : 0.73–2.50]
• cfPWV and AIx were also significantly increased (weighted mean
difference, WMD cfPWV 1.04, 95% CI 0.34–1.74; WMDAIx 15.10, 95% CI
5.08–25.11), whereas crPWV increase did not reach significance (WMD
crPWV 0.99, 95% CI S0.07 to 2.05).
• Significant increases in arterial stiffness measurements were noted in
women with preeclampsia compared with those with gestational
hypertension. Arterial stiffness measurements may also be useful in
predicting preeclampsia and may play a role in the increased risk of future
cardiovascular complications seen in women with a history of PE
A systematic review and meta-analysis was conducted using MEDLINE, EMBASE, and
the Cochrane Library

53. Objective:
• To evaluated the diagnostic utility of pulse wave velocity (PWV) alone or in combination with other
diagnostic markers in predicting pre-eclampsia (PE) in high-risk women.
Result:
• Of 118 women recruited, 11 and 10 women developed early-onset PE (<34 weeks) and late-onset PE (>34
weeks), respectively.
• Of the five diagnostic markers tested, PWV showed the highest detection rate for all cases (21) of PE (81%)
and for early-onset PE (82%) at a fixed 10% false-positive rate (FPR), and when combined with sFlt-1, these
figures increased to 90% and 92%, respectively.
• Despite the reduced ability of PWV to predict late-onset PE (detection rate 20%), the combination of PWV
with sFlt-1 achieved a detection rate of 50% at a fixed 10% FPR.
• A suggested cutoff value of 9 m/s for PWV resulted in optimal sensitivity (91%) and specificity (86%) for
predicting early-onset PE.
• This study is the first to show that PWV may be a potentially promising predictor of early-onset PE in
women at high risk for PE. The combination of PWV with sFlt-1 may further improve the screening efficacy
for predicting PE.

54. Figure 2. PWV (m s 1) and sFlt-1 (pg ml 1) the non-PE and PE
groups. at 22–26 weeks of gestation in

59. DISCUSSION
• These findings suggest that pre-existing maternal
subclinical endothelial dysfunction and atherosclerosis
may render pregnant women more sensitive to
maladaptive hemodynamic responses including
increased AS, and thus placing them at high risk for
developing PE.
• PWV was significantly higher in the early-onset PE
group compared with the late-onset, and that are
compatible with the concept that early- and late-onset
PE may be two different disorders where early-onset
PE is related to reduced placental perfusion and late-
onset PE is associated with maternal factors.

60. • Screening for PE is believed to be most relevant during
the first trimester because preventive interventions are
more likely to be effective if initiated early in
pregnancy when pathogenic mechanisms may be
modified.
• PWV, a simple, low-cost noninvasive method for
assessing AS, measured during the second trimester,
may prove useful in predicting PE, particularly early-
onset PE, in high-risk women.
• The predictive characteristics of PWV were further
improved when it was used in concert with sFlt-1. T

61. FUTURE STUDY

64. THANK YOU