This study examined whether maternal hemodynamics measured at 11-13 weeks can predict pre-eclampsia (PE). It found that women who developed PE had higher aortic systolic blood pressure, arterial stiffness, and uterine artery pulsatility index compared to unaffected women. These vascular changes were apparent in the first trimester and improved prediction of PE compared to history alone. Arterial stiffness may be promising for predicting late-onset PE, while uterine artery Doppler and biomarkers better predict early-onset PE, suggesting different pathologies.

1. UOG Journal Club: July 2012
Maternal hemodynamics at 11–13 weeks’ gestation and risk
of pre-eclampsia
A. Khalil, R. Akolekar, A. Syngelaki, M. Elkhouli and K. H. Nicolaides
Volume 40, Issue 1, Date: July 2012, pages 28–34
Journal Club slides prepared by Dr Asma Khalil
(UOG Editor for Trainees)

2. Forward flow from cardiac action
Pressure Wave
Reflection
Blood
vessel
Reflected flow from peripheral resistance
Incident pressure wave is generated by the heart.
When the wavefront encounters resistance → Reflected wave
Incident and Reflected waves → Combined waveform

3. Pressure Wave Reflection
Vasodilatation: Vasoconstriction:
 Amplitude of Reflected wave  Amplitude of Reflected wave
And delays its return

4. Pressure Wave Reflection
Vasodilatation
Vasoconstriction

5. Central Blood Pressure
Artery occluded due to
suprasternal cuff pressure
Forward wave
1 2 3
Pressure in Pressure waves
the aorta is travel to the artery The cuff
generated by are transferred to pressure is
the heart the cuff measured
• Aortic blood pressure (BP) ≠ brachial BP
• Better prediction of vascular disease/outcome than brachial BP
• Distinguishes between the effects of different antihypertensive
drugs when brachial BP does not

6. Augmentation index (AIx) and pulse wave velocity
(PWV) are increased in pre-eclampsia (PE)
Author AIx PWV
PE; History of PE; PE vs
gestational hypertension (GH)
Hausvater et al 2012 (meta-analysis)
PE prediction
Khalil et al 2009, Khalil et al 2011
Savvidou et al 2011
Hausvater A et al., J Hypertens 2012
Khalil A et al., BJOG 2009
Khalil A et al., Obstet Gynecol 2010
Savvidou MD et al., Am J Obstet Gynecol 2010

7. Maternal hemodynamics at 11–13 weeks’ gestation
and risk of pre-eclampsia
Khalil et al., UOG 2012
Prospective; 7,084 singleton pregnancies at 11+0 – 13+6 weeks;
2009 – 2011
Objective
To examine the value of maternal hemodynamics measured at
11–13 weeks in the early prediction of PE

8. Maternal hemodynamics at 11–13 weeks’ gestation
and risk of pre-eclampsia
Khalil et al., UOG 2012
Methodology
• Screening for PE at 11 – 13 weeks
• Comparison of history / maternal characteristics, uterine
artery Doppler, PAPP-A and AIx, PWV and central systolic
blood pressure (SBPAo)
n
• Pre-eclampsia 181 (2.6%)
• Gestational hypertension 137 (1.9%)
• Unaffected controls 6,766

9. Methodology
Inclusion criteria Vascular measurements
• Singleton pregnancy and a live • Arteriograph® was used for
fetus identified at 11+0 – 13+6 recording SBPAo (mmHg), PWV
week scan
(m/s) and AIx (%)
Exclusion criteria • Results did not influence the
subsequent management
1) Major fetal abnormalities
2) Termination of pregnancy Statistical Analysis
3) Miscarriage • Multivariate logistic regression
4) Fetal death before 24 weeks analysis → variables that
Outcomes provided a significant
contribution in predicting PE
• Receiver–operating characteristics
• PE (ISSHP definition)
(ROC) analysis to determine the
• GH
performance of screening

10. Maternal hemodynamics and the risk of PE
Results
2.0 1.6 1.5
P<0.0001 P<0.0001 P<0.0001
P=0.051
Central aortic systolic blood pressure (MoM)
P<0.0001 P<0.0001
1.4
Augmentation index-75 (MoM)
1.5 Pulse wave velocity (MoM) 1.25
1.2
1.0 1.0 1.0
0.8
0.5 0.75
0.6
0.0 0.4 0.5
Normal PE GH Normal PE GH Normal PE GH

11. Maternal hemodynamics and the risk of PE
Performance of screening
100
90 Area under
ROC curve P-value
Detection rate at FPR 10%
80
70 History 0.80 (0.79–0.81)
60
61.9% History + vascular- 0.84 (0.83–0.84) 0.005*
50 56.9%
derived risk
40 47.0%
30
History + vascular- 0.85 (0.84–0.86) 0.001*
derived risk + uterine
20
artery PI + PAPP-A
10
0
History + vascular + uterine PI
risk + PAPP-A
* Comparison with performance of screening based on maternal factors

12. Maternal hemodynamics and the risk of PE
Early-onset versus late-onset PE
Early-onset PE Late-onset PE
[History + vascular-derived risk + uterine artery PI Improvement No significant
+ PAPP-A] compared to [History + vascular risk] improvement
No significant association between the vascular-derived risk for PE
(combination log10 MoM of AIx-75, PVW and SBPAo) and gestational age at
delivery of the PE group.
Whereas high uterine artery PI and low PAPP-A were more marked in early-
PE compared to late-PE.

13. Maternal hemodynamics and the risk of PE
Women with chronic hypertension
Superimposed PE No PE
MoMs (n=21) MoMs(n=47)
SBPAo 1.29 1.15*
PWV 1.02 1.00
AIx-75 1.37 1.21
uterine artery PI 1.04 1.07
PAPP-A 0.92 0.84
Even after exclusion of women with chronic hypertension, no significant
change in the results seen in those who developed PE [increased AIx-75,
PWV, SBPao and uterine artery PI, and decrease in PAPP-A].
* p<0.05

14. Maternal hemodynamics and the risk of PE
Discussion
Limitations
Strengths
• Lack of longitudinal data during
•Large number
•Narrow gestational range of 11- pregnancy and assessment of
13 weeks, which is emerging as the patients with PE after
the first clinical visit in pregnancy pregnancy to document
for assessment of patient-specific whether in those with increased
risks for a wide range of arterial stiffness and SBPao
pregnancy complications there was persistence of these
abnormalities

15. Maternal hemodynamics and the risk of PE
Discussion
PE: common phenotypic expression of two distinct processes
Predisposition for Impaired trophoblastic
cardiovascular disease invasion
Late-PE Early-PE

16. Maternal hemodynamics at 11–13 weeks’ gestation
and risk of pre-eclampsia
Khalil et al., UOG 2012
Conclusion
 Women who develop PE have higher aortic systolic blood
pressure and arterial stiffness.
 These findings are apparent from the first trimester of
pregnancy
 The mechanism of association with PE does not appear to
be mediated by impaired placental perfusion and function
 Arterial stiffness appears promising in predicting late-PE

17. Maternal hemodynamics at 11–13 weeks’ gestation and risk of pre-
eclampsia
Khalil et al., UOG 2012
Discussion points
• What is the best screening test for identifying women at high risk of pre
eclampsia?
• Is this test different if the screening is performed in the first trimester or second
trimester?
• Is it justified to screen for pre-eclampsia?
• What are the recommended indications for low-dose aspirin for prevention of
pre-eclampsia?
• How does screening for pre-eclampsia compare to screening for Down
syndrome?
• Discuss whether early-onset and late-onset pre-eclampsia have different
pathologies or simply different degrees of severity of the same pathology.
• Why do most of the screening markers perform better for early-onset than late-
onset pre-eclampsia?
• What are the potential uses of arterial stiffness in obstetrics?