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Raised uterine artery impedance is associated with increased maternal arterial stiffness in the late second trimester
Placenta 33 (2012) 572e577
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Raised uterine artery impedance is associated with increased maternal arterial stiffness in the late second trimester T.R. Everett a, A.A. Mahendru a, C.M. McEniery b, I.B. Wilkinson b, C.C. Lees a, * a b
Dept. of Fetal Medicine, Box 228, Rosie Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 2SW, UK Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital, CB2 0QQ, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 1 April 2012
Objective: To assess the relationship between uterine artery Doppler pulsatility index (PI) and maternal global arterial stiffness and aortic stiffness in women at high a priori risk of preeclampsia in the late second trimester of pregnancy. Methods: A prospective cohort study was performed. 99 women were recruited from the high-risk obstetric ultrasound clinic in the second trimester; median (IQR) age and gestation were 33 (29e37) years and 23þ6 (23þ3e24þ4) weeks respectively. Transabdominal uterine artery Doppler was performed and mean values recorded. Women returned at a later date, median gestation (IQR) 26þ5 (25þ6e28þ0) weeks, for measurement of blood pressure, augmentation index (AIx) and aortic pulse wave velocity (aPWV). Results: Uterine artery PI is positively associated with both AIx (r ¼ 0.4, P <0.0001, 95% CI: 0.22e0.55) and aPWV (r ¼ 0.22, P ¼ 0.03, 95% CI: 0.02e0.40). No relationship was found between uterine artery PI and mean arterial pressure or pulse pressure. AIx was significantly higher in women with uterine artery PI > 1.45 (P ¼ 0.003, 95% CI: 3.1e14.9) but not aPWV (P ¼ 0.45). AIx, but not aPWV, was significantly higher in women who developed preeclampsia (14% vs 9%, 95% CI: 2.0e8.6, P ¼ 0.0018) or IUGR (11% vs 9%, 95% CI: 0.3e4.2, P ¼ 0.027). AIx showed a negative correlation with birth weight z-score (r ¼ 0.25, 95% CI: 0.43 to 0.06, P ¼ 0.013). Conclusion: Increasing uterine artery Doppler PI reflects impaired placentation and increasing risk of preeclampsia. We show a positive association between uterine artery Doppler PI and both global arterial and aortic stiffness. We also show that increased maternal arterial stiffness is associated with a lower birth weight. These findings may represent evidence of an early effect of impaired placentation on the maternal vasculature. Alternatively, given the association between preeclampsia and later cardiovascular disease, ineffective placentation may result from impaired arterial function. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Uterine artery Doppler Augmentation index Pulse wave velocity Intra-uterine growth restriction
1. Introduction Compared to normal pregnancy, profound differences in maternal cardiovascular function characterize preeclampsia even before the clinical syndrome of hypertension and proteinuria is apparent. These include impaired intravascular volume expansion, a hyperdynamic state [1] in the latent phase and a cross-over to increased peripheral vascular resistance and a decrease in cardiac output as clinical disease develops [2]. Women with pre-existing cardiovascular risk factors are at higher risk of developing preeclampsia [3] and may possess
* Corresponding author. Tel.: þ44 1223 217972; fax: þ44 1223 216185. E-mail address: [email protected] (C.C. Lees). 0143-4004/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.placenta.2012.04.001
a phenotype that gives rise to increased cardiovascular complications, both outside of, and during pregnancy [4]. Further, women who have developed preeclampsia are at subsequent increased risk of long-term cardiovascular complications including hypertension, stroke and ischaemic heart disease [5]. Whether preeclampsia independently predicts this risk, or is an expression in pregnancy of it, remains to be elucidated. Aortic pulse wave velocity (aPWV) and augmentation index (AIx) are measures of aortic stiffness and arterial wave reflection respectively. Higher velocities of the arterial pulse wave result from increased aortic stiffness. Augmentation index is influenced by the tone of small vessels and the stiffness of large and small vessels and is a surrogate marker of endothelial function. Therefore, increased arterial wave reflection and hence increased AIx is seen as tone increases in small and medium arteries and with large vessel stiffening. Outside pregnancy, increased aPWV and AIx are strong
T.R. Everett et al. / Placenta 33 (2012) 572e577
predictors of future cardiovascular events, independent of blood pressure [6,7]. Compared to women with normotensive pregnancies, both aPWV [8] and AIx [9,10] are increased in women with preeclampsia. Altered arterial function in preeclampsia as evidenced by changes in aPWV and AIx, is consistent with endothelial dysfunction that has been demonstrated both in vivo [11] and in vitro [12]. Derangement of nitric oxide availability in the condition has been postulated as a cause [11,13], although the precise underlying mechanism remains unclear. Uterine artery Doppler impedance in the late second trimester provides an indirect non-invasive method of assessing placental implantation, trophoblast invasion and spiral artery remodelling at the maternaleplacental interface [14]. Increased uterine artery impedance is a predictor of risk of IUGR and early-onset preeclampsia [15,16]. Little is known about arterial stiffness in pregnant women prior to the onset of clinically evident preeclampsia. AIx has been proposed as a constituent of predictive models of preeclampsia in the first trimester [17]. However, separate from predictive models, improved understanding of endothelial function and aortic stiffness before the onset of preeclampsia will give an important insight to the underlying pathogenesis. The aim of this study was to investigate the relationship between second trimester uterine artery impedance (pulsatility index) and arterial stiffness (aPWV and AIx) in women at high a priori risk of preeclampsia and associated complications, prior to the onset of clinical disease.
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2.3. Cardiovascular measurements Blood pressure, AIx and aPWV were measured with the woman lying supine in a 30 left lateral position to avoid aorto-caval compression. Participants were rested for 10 min in a quiet temperature controlled room before readings were taken. Measurements were performed at least twice and a third reading taken if the difference between two consecutive readings was more than 5 units, or 0.5 m/s for aPWV measurements. For waveforms derived using the SphygmoCor device, an operator index of at least more than 80 (quality control contained within the software) was accepted. The average of the two or three readings was used for subsequent analysis. 2.4. Blood pressure Brachial blood pressure, using the left arm, was obtained using an Omron M7 automated sphygmomanometer, a device validated for use in pregnancy [19]. 2.5. Wave reflection Pulse wave analysis was performed at the radial artery by applanation tonometry using a micromanometer (Millar Instruments, Houston, Tex) and SphygmoCor device (AtCor Medical, West Ryde, NSW, Australia) as previously described [20]. The aortic pulse waveform was derived from the radial artery waveform using a validated transfer function [21]. Augmentation index values were calculated from the derived waveform as the difference in the pressures of the second and first systolic peaks expressed as a percentage of the pulse pressure. AIx-75, augmentation index adjusted for a standard heart rate of 75 bpm, is calculated automatically by the SphygmoCor device. 2.6. Pulse wave velocity aPWV analysis was assessed between the carotid and femoral devices using a Vicorder device (Skidmore Medical Ltd, Bristol, UK). Briefly, an inflatable collar was placed around the upper thigh and neck, as described elsewhere [22]. To avoid the gravid uterus potentially overestimating the horizontal path, the suprasternal notch-femoral distance was measured using callipers.
2. Methods 2.7. Statistical analysis 2.1. Study population 99 pregnant women with singleton pregnancies were recruited. Smokers, those taking aspirin, or other thromboprophylaxis, and those with diabetes mellitus were excluded. Approval for the study was obtained from the Research Ethics Committee (REC). All eligible women attending for uterine artery Doppler assessment were provided with information about the study at this time. Women were then contacted after at least 24 h (as requested by the REC) and returned at a mutually convenient time for cardiovascular measurements if they wished to participate. Written informed consent was obtained from all women before taking part. As uterine artery Doppler is not routinely performed in the UK, women underwent uterine artery Doppler screening by virtue of their high a priori risk of preeclampsia or fetal growth restriction based on the clinical criteria in Table 1.
Statistical analyses were performed using MedCalc v11.6 (Mariakerke, Belgium). Multiple regression analysis was performed and AIx was adjusted for maternal heart rate and height as both independently influence AIx [23]. aPWV was adjusted for age and mean arterial pressure (MAP) [23]. Normality was assessed using the KolmogoroveSmirnov test and non-normally distributed values were log10 transformed. Linear regression by the method of ordinary least squares was used to define the correlation between cardiovascular parameter and mean uterine artery Doppler PI, with goodness of fit expressed by Pearson’s correlation coefficient (r). Absolute values were compared using Student’s paired t-tests. Our units previous years’ singleton birth records for gestations 34þ0e42þ0 (n ¼ 5449) and previous 5 years for gestations 24þ0e34þ0 (n ¼ 518) were used to calculate gender specific birth weight z-scores for each week of gestation.
3. Results 2.2. Uterine artery Doppler Transabdominal uterine artery Doppler was performed using a Siemens S2000 (Mountain View, CA) ultrasound machine using a 6C2 transabdominal probe and waveforms were obtained as previously described [18]. Pulsatility index was measured in both uterine arteries and the mean value recorded. Comparison was made in the analyses for women with a mean PI >1.45 and <1.45 (the 95th percentile for transabdominal Doppler PI, as previously reported [18]).
Table 1 Indications for referral for uterine artery Doppler. N Abnormal serum markersa Essential hypertensionb Previous preeclampsiac Previous IUGR (<3rd centile) Previous stillbirth Other a
b c
HCG >4 Multiples of Median (MoM), AFP >3MoM, PAPP-A <0.3MoM. Requiring medication or booking BP >150/90 mmHg. Requiring delivery before 34/40 or MgSO4 treatment.
28 13 21 10 10 17
One hundred and sixty-eight women attending for uterine artery screening were approached for study inclusion. Ninety-nine consented and were recruited for subsequent cardiovascular testing. Demographic data are summarised in Table 2. There was a positive relationship between uterine artery Doppler PI and AIx (r ¼ 0.3, P ¼ 0.003, 95% CI: 0.11e0.47). This relationship strengthened after adjustment for maternal heart rate and height (r ¼ 0.4, P <0.0001, 95% CI: 0.22e0.55) (Fig. 1). AIx-75 was not significantly associated with uterine artery Doppler PI (P ¼ 0.13). Women with a mean uterine artery PI >1.45 (n ¼ 10), demonstrated a higher augmentation index than those with uterine artery Doppler PI <1.45 (17% vs. 8%, P ¼ 0.003, 95% CI: 3.1e14.9) also after adjustment for heart rate and height (14% vs 9%, P <0.0001, 95% CI: 3.0e7.3) (Fig. 2). A positive relationship was found between mean uterine artery Doppler PI and aPWV (adjusted for MAP and age) (r ¼ 0.22, P ¼ 0.03, 95% CI: 0.02e0.40) (Fig. 3). Adjusted aPWV was not different between those women with uterine artery PI >1.45 and those with uterine artery Doppler PI <1.45 (mean aPWV: 5.5 vs 5.4, 95% CI: 0.13e0.30, P ¼ 0.45) (Fig. 4).
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Table 2 Subject demographic and haemodynamic characteristics. Parameter Age (years) Gestation (weeks) at Ultrasound Mean uterine artery Doppler PI Gestation (weeks) at CV test Height (m) Weight (kg) Body Mass Index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Mean arterial pressure (mmHg) Pulse pressure (mmHg) Heart rate (beats/min) Augmentation index (%)a Augmentation index-75 (%) aPWV (m/s) aPWV (m/s)b Nulliparous/multiparous Ethnic origin White Caucasian Asian/Indian Black Afro-Carribean
33 (29e37) 23þ6 (23þ324þ4) 0.80 (0.65e0.96) 26þ5 (25þ6e28þ0) 166 7 68 13 25 5 106 12 68 8 81 10 38 7 82 9 94 13 8 5.4 1 5.4 0.3 28/71 90 7 2
Values are given as mean SD or as median (Interquartile range) for normally and non-normally distributed data, respectively. a Adjusted for heart rate and height. b Adjusted for MAP and age.
No difference in AIx (9 vs. 9%) or aPWV (5.3 vs. 5.4 m/s) was found between nulliparous and multiparous women. Multiple regression analysis showed that the gestation range within our study cohort was not a significant variable for AIx (P ¼ 0.15) or aPWV (P ¼ 0.27). Neither mean arterial pressure nor central pulse pressure showed a correlation with uterine artery pulsatility index (P-values: 0.06 and 0.25 respectively). Outcome data was available for 96 women. Four women developed preeclampsia prior to 34 weeks. No women developed late-onset preeclampsia. There were 13 (non-preclamptic) cases of IUGR (z-score less than 1.65, equating to <5th centile), 1 requiring delivery before 34 weeks gestation (weighing 820 g at 31þ2 weeks gestation.) A sub-group analysis of these women was performed. In the subgroups, adjusted AIx was higher in both women who developed PET (14% vs 9%, 95% CI: 2.0e8.6, P ¼ 0.0018) and those who delivered babies weighing <5th centile (11% vs 9%, 95% CI:
Fig. 1. Relationship of uterine artery Doppler PI with augmentation index (aadjusted for heart rate and height) (r ¼ 0.4, P ¼ <0.0001).
Fig. 2. Comparison of augmentation index (aadjusted for heart rate and height) in women with uterine artery Doppler PI less than or greater than 1.45 (9% vs 14%). * P ¼ 0.0001.
0.3e4.2, P ¼ 0.027) when compared to those with normal outcome. No difference in adjusted aPWV was found for PET (5.5% vs 5.4%, 95% CI: 0.5e0.2, P ¼ 0.37) or IUGR (5.5% vs 5.4%, 95% CI: 0.3e0.07, P ¼ 0.22) when compared to those with normal outcomes. Fig. 5 shows results of adjusted AIx for a composite of these outcomes. Mean uterine artery Doppler PI was higher for both PET (Mean PI: 1.94, P ¼ <0.0001) and IUGR (Mean PI: 1.3, P ¼ <0.0001) outcomes when compared to normal outcomes (Mean PI: 0.8). Adjusted AIx showed a negative correlation (r ¼ 0.25, 95% CI: 0.43 to 0.06, P ¼ 0.013) with birth weight z-score. No correlation was noted with adjusted aPWV and birth weight. 4. Discussion There is a moderately strong positive association between uterine artery Doppler impedance and arterial wave reflection (AIx) and a weaker positive association with aortic stiffness. This positive
Fig. 3. Relationship of uterine artery Doppler PI with aortic pulse wave velocity (aadjusted for MAP and age) (r ¼ 0.22, P ¼ 0.03).
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Fig. 4. Comparison of aortic pulse wave velocity (aadjusted for MAP and age) in women with uterine artery Doppler PI less than or greater than 1.45 (5.4 vs 5.5 m/s, P ¼ 0.45). NS ¼ not significant.
relationship between augmentation index and uterine artery Doppler PI in the mid-trimester has not previously been reported. That there is a relationship between aPWV and uterine artery Doppler PI is consistent with the findings of others [24]. This study reported that women with raised uterine Doppler PI had higher aPWV than those with uterine artery PI <1.6. However, we have also demonstrated a positive relationship between AIx and uterine artery Doppler PI and higher AIx in women with a uterine artery PI above 95th centile than those with a ‘normal’ uterine artery PI. It is noteworthy that the mean AIx-75 in the high-risk population of our study is considerably higher (13%) than that previously reported in the normal pregnant population (w5%) [25] at similar gestations, although we report similar mid-pregnancy aPWV values (5.4 m/s) [24]. Although we found a positive correlation of aPWV with uterine artery Doppler, we did not find aPWV to be significantly higher in women with PI >1.45. This is most likely due to the relatively smaller number of women with raised PI in our cohort compared to other studies that have shown this relationship [24]. However, this difference may also be due in part to selection of the women; we recruited prospectively from a single population attending for Doppler screening rather than selective recruitment based on the result of normal or abnormal Doppler studies.
Fig. 5. Augmentation index (aadjusted for heart rate and height) by pregnancy outcome: normal or preeclampsia and/or SGA (9% vs 12%). *P ¼ 0.001.
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Our finding of an association of negative correlation of AIx in the second trimester with birth weight is in close agreement with a previous smaller study [26] and strengthens the argument that sub-clinical global endothelial dysfunction has a deleterious effect on pregnancy. Our data, in contrast to a previous study performed in the third trimester [27], did not find a relationship between aPWV and birth weight. This may be due to the different gestations at which aPWV was studied. AIx has an inverse, linear relationship with heart rate [28]. Therefore AIx standardized to a heart rate of 75 bpm (AIx-75) is particularly useful for inter-individual comparison. In the first trimester of pregnancy others have reported no relationship between AIx-75 and mean uterine artery PI [17], a finding consistent with the current study. However, heart rate rises rapidly to around 82 bpm by the end of the first trimester [29]; adjusting AIx for the actual mean heart rate of the individual or relevant population may be considered more appropriate than applying the generic adjustment to derive AIx-75. Augmentation index has been proposed as a component in first trimester screening models for preeclampsia [17]. We have not aimed to develop a predictive model as this would not be possible in a high-risk population. However, we show that, in the second trimester, there is an association between systemic arterial function and uterine artery Doppler PI. Hence uterine artery PI should be used cautiously in combination with AIx as part of a predictive algorithm as independence cannot be presumed. Further, it seems plausible that the changes in both maternal systemic cardiovascular function and uterine artery impedance that differentiate normal from abnormal pregnancy may not be evident or completed in the first trimester. Another key element of placental implantation and vascular remodelling of the spiral and uterine arteries is that it remains incomplete until the latter stages of the second trimester [30,31]. Indeed this is the underlying rationale on which mid-trimester uterine artery Doppler screening is thought to depend [18]. Women who demonstrate abnormal uterine artery Doppler waveforms in the first trimester, but in whom placentation will ultimately be normal, may well exhibit normal uterine artery waveforms at 22e23 weeks gestation [18]. Given that AIx falls to a mid-pregnancy nadir [25], it is plausible that women who are in fact “low risk” can have a raised uterine artery PI and normal AIx in the first trimester and subsequently have a normal uterine artery PI in the second trimester with the AIx remaining normal. Further, women in whom uterine artery Doppler does not normalise may be those in whom AIx and aPWV either does not fall or indeed rises throughout pregnancy. AIx and aPWV are known to fall from the first trimester to midpregnancy before rising again towards the end of pregnancy [25,32,33]. That the uterine artery Doppler and cardiovascular measurements were not performed at the same visit could be a source of error. However, the gestational range within our study is at the mid-pregnancy nadir for AIx and aPWV, which makes it unlikely that this delay in measurements will have had a significant effect. Further, multiple regression analysis of our data did not show gestation to be a significant variable for AIx or aPWV. This is most likely due to the relatively narrow range of gestation at which our measurements were taken and their being taken at a time of pregnancy when there is little change in AIx and aPWV. Ethnic origin is known to affect AIx [34] and this can be adjusted for in a multiple regression model. Of the cases that we report, >90% are white Caucasian with very small numbers in remaining groups. Hence we have not analysed further nor adjusted for ethnic origin. AIx, a measure of pulse wave reflection, and uterine artery Doppler, a measure of impedance, are both influenced by peripheral vascular resistance (PVR). The findings of our study suggest
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that there may be an underlying systemic increased vascular resistance in the women with higher uterine artery PI. This in turn may lead to an impaired ability of the vasculature, and particularly the uterine element of the utero-placental circulation to respond to the profound changes required for a successful pregnancy. Although increased wave reflection is generally considered deleterious, it may in fact have a protective role [35]. Greater pulse wave reflection will tend to dampen the effects of increased pulse pressure, as seen in preeclampsia [36], and reduce transmission of excessive pulsatile energy to the end-organ, in this case the uteroplacental bed. Women with early-onset preeclampsia have higher AIx postpartum that may persist for at least two years [37]. However, the AIx and aPWV do not differ in our study between nulliparous and multiparous women, suggesting an underlying process of arterial stiffening in “high-risk” women over and above the effect of previous pregnancies. These results provide further evidence that systemic arterial dysfunction is present in women at higher risk of preeclampsia. What remains unclear is whether increased wave reflection and aortic stiffness occurs prior to, or equally plausibly, because of the preeclamptic process. We demonstrate a positive relationship between second trimester uterine artery Doppler PI and both aortic stiffness and arterial wave reflection. It remains to be determined whether our findings are due to a pre-existing, sub-clinical vascular endothelial dysfunction predisposing to impaired placentation and increased risk of preeclampsia, or whether defective placentation itself leads to the increase in arterial stiffness. Author contribution CCL conceived the study design. TRE performed the study. AAM assisted recruitment and performing the measurements. All authors were involved in the analysis and interpretation of the study. TRE wrote the first draft of the manuscript. All authors contributed to the writing of the final manuscript. Funding TRE is funded by the Evelyn Trust. CCL is recipient of an Evelyn Trust research grant. IBW and CMM are both British Heart Foundation Fellows. AAM is supported by Cambridge Fetal Care. CMM and IBW are supported by the Cambridge Biomedical Research Centre (NIHR). IBW has received unrestricted educational support (all <£10,000pa) from AtCor, Vicorder and IEM in the past 5 years. Acknowledgements We wish to thank the women who participated in this study and the research nurses of the Vascular Research Unit. References [1] Easterling T, Benedetti T, Schmucker B, Millard S. Maternal hemodnamics in normal pregnancy and preeclamptic pregnancies: a longitudinal study. Obstetrics & Gynecology 1990;69:1061e9. [2] Bosio PM, McKenna PJ, Conroy R, O’Herlihy C. Maternal central hemodynamics in hypertensive disorders of pregnancy. Obstetrics & Gynecology 1999;94: 978e84. [3] Magnussen EB, Vatten LJ, Lund-Nilsen TI, Salvesen KA, Smith GD, Romundstad PR. Prepregnancy cardiovascular risk factors as predictors of pre-eclampsia: population based cohort study. British Medical Journal 2007;335:978. [4] Romundstad PR, Magnussen EB, Smith GD, Vatten LJ. Hypertension in pregnancy and later cardiovascular risk: common antecedents? Circulation 2010; 122:579e84. [5] Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and metaanalysis. British Medical Journal 2007;335:974.
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Raised uterine artery impedance is associated with increased maternal arterial stiffness in the late second trimester T.R. Everett a, A.A. Mahendru a, C.M. McEniery b, I.B. Wilkinson b, C.C. Lees a, * a b
Dept. of Fetal Medicine, Box 228, Rosie Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 2SW, UK Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital, CB2 0QQ, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 1 April 2012
Objective: To assess the relationship between uterine artery Doppler pulsatility index (PI) and maternal global arterial stiffness and aortic stiffness in women at high a priori risk of preeclampsia in the late second trimester of pregnancy. Methods: A prospective cohort study was performed. 99 women were recruited from the high-risk obstetric ultrasound clinic in the second trimester; median (IQR) age and gestation were 33 (29e37) years and 23þ6 (23þ3e24þ4) weeks respectively. Transabdominal uterine artery Doppler was performed and mean values recorded. Women returned at a later date, median gestation (IQR) 26þ5 (25þ6e28þ0) weeks, for measurement of blood pressure, augmentation index (AIx) and aortic pulse wave velocity (aPWV). Results: Uterine artery PI is positively associated with both AIx (r ¼ 0.4, P <0.0001, 95% CI: 0.22e0.55) and aPWV (r ¼ 0.22, P ¼ 0.03, 95% CI: 0.02e0.40). No relationship was found between uterine artery PI and mean arterial pressure or pulse pressure. AIx was significantly higher in women with uterine artery PI > 1.45 (P ¼ 0.003, 95% CI: 3.1e14.9) but not aPWV (P ¼ 0.45). AIx, but not aPWV, was significantly higher in women who developed preeclampsia (14% vs 9%, 95% CI: 2.0e8.6, P ¼ 0.0018) or IUGR (11% vs 9%, 95% CI: 0.3e4.2, P ¼ 0.027). AIx showed a negative correlation with birth weight z-score (r ¼ 0.25, 95% CI: 0.43 to 0.06, P ¼ 0.013). Conclusion: Increasing uterine artery Doppler PI reflects impaired placentation and increasing risk of preeclampsia. We show a positive association between uterine artery Doppler PI and both global arterial and aortic stiffness. We also show that increased maternal arterial stiffness is associated with a lower birth weight. These findings may represent evidence of an early effect of impaired placentation on the maternal vasculature. Alternatively, given the association between preeclampsia and later cardiovascular disease, ineffective placentation may result from impaired arterial function. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Uterine artery Doppler Augmentation index Pulse wave velocity Intra-uterine growth restriction
1. Introduction Compared to normal pregnancy, profound differences in maternal cardiovascular function characterize preeclampsia even before the clinical syndrome of hypertension and proteinuria is apparent. These include impaired intravascular volume expansion, a hyperdynamic state [1] in the latent phase and a cross-over to increased peripheral vascular resistance and a decrease in cardiac output as clinical disease develops [2]. Women with pre-existing cardiovascular risk factors are at higher risk of developing preeclampsia [3] and may possess
* Corresponding author. Tel.: þ44 1223 217972; fax: þ44 1223 216185. E-mail address: [email protected] (C.C. Lees). 0143-4004/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.placenta.2012.04.001
a phenotype that gives rise to increased cardiovascular complications, both outside of, and during pregnancy [4]. Further, women who have developed preeclampsia are at subsequent increased risk of long-term cardiovascular complications including hypertension, stroke and ischaemic heart disease [5]. Whether preeclampsia independently predicts this risk, or is an expression in pregnancy of it, remains to be elucidated. Aortic pulse wave velocity (aPWV) and augmentation index (AIx) are measures of aortic stiffness and arterial wave reflection respectively. Higher velocities of the arterial pulse wave result from increased aortic stiffness. Augmentation index is influenced by the tone of small vessels and the stiffness of large and small vessels and is a surrogate marker of endothelial function. Therefore, increased arterial wave reflection and hence increased AIx is seen as tone increases in small and medium arteries and with large vessel stiffening. Outside pregnancy, increased aPWV and AIx are strong
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predictors of future cardiovascular events, independent of blood pressure [6,7]. Compared to women with normotensive pregnancies, both aPWV [8] and AIx [9,10] are increased in women with preeclampsia. Altered arterial function in preeclampsia as evidenced by changes in aPWV and AIx, is consistent with endothelial dysfunction that has been demonstrated both in vivo [11] and in vitro [12]. Derangement of nitric oxide availability in the condition has been postulated as a cause [11,13], although the precise underlying mechanism remains unclear. Uterine artery Doppler impedance in the late second trimester provides an indirect non-invasive method of assessing placental implantation, trophoblast invasion and spiral artery remodelling at the maternaleplacental interface [14]. Increased uterine artery impedance is a predictor of risk of IUGR and early-onset preeclampsia [15,16]. Little is known about arterial stiffness in pregnant women prior to the onset of clinically evident preeclampsia. AIx has been proposed as a constituent of predictive models of preeclampsia in the first trimester [17]. However, separate from predictive models, improved understanding of endothelial function and aortic stiffness before the onset of preeclampsia will give an important insight to the underlying pathogenesis. The aim of this study was to investigate the relationship between second trimester uterine artery impedance (pulsatility index) and arterial stiffness (aPWV and AIx) in women at high a priori risk of preeclampsia and associated complications, prior to the onset of clinical disease.
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2.3. Cardiovascular measurements Blood pressure, AIx and aPWV were measured with the woman lying supine in a 30 left lateral position to avoid aorto-caval compression. Participants were rested for 10 min in a quiet temperature controlled room before readings were taken. Measurements were performed at least twice and a third reading taken if the difference between two consecutive readings was more than 5 units, or 0.5 m/s for aPWV measurements. For waveforms derived using the SphygmoCor device, an operator index of at least more than 80 (quality control contained within the software) was accepted. The average of the two or three readings was used for subsequent analysis. 2.4. Blood pressure Brachial blood pressure, using the left arm, was obtained using an Omron M7 automated sphygmomanometer, a device validated for use in pregnancy [19]. 2.5. Wave reflection Pulse wave analysis was performed at the radial artery by applanation tonometry using a micromanometer (Millar Instruments, Houston, Tex) and SphygmoCor device (AtCor Medical, West Ryde, NSW, Australia) as previously described [20]. The aortic pulse waveform was derived from the radial artery waveform using a validated transfer function [21]. Augmentation index values were calculated from the derived waveform as the difference in the pressures of the second and first systolic peaks expressed as a percentage of the pulse pressure. AIx-75, augmentation index adjusted for a standard heart rate of 75 bpm, is calculated automatically by the SphygmoCor device. 2.6. Pulse wave velocity aPWV analysis was assessed between the carotid and femoral devices using a Vicorder device (Skidmore Medical Ltd, Bristol, UK). Briefly, an inflatable collar was placed around the upper thigh and neck, as described elsewhere [22]. To avoid the gravid uterus potentially overestimating the horizontal path, the suprasternal notch-femoral distance was measured using callipers.
2. Methods 2.7. Statistical analysis 2.1. Study population 99 pregnant women with singleton pregnancies were recruited. Smokers, those taking aspirin, or other thromboprophylaxis, and those with diabetes mellitus were excluded. Approval for the study was obtained from the Research Ethics Committee (REC). All eligible women attending for uterine artery Doppler assessment were provided with information about the study at this time. Women were then contacted after at least 24 h (as requested by the REC) and returned at a mutually convenient time for cardiovascular measurements if they wished to participate. Written informed consent was obtained from all women before taking part. As uterine artery Doppler is not routinely performed in the UK, women underwent uterine artery Doppler screening by virtue of their high a priori risk of preeclampsia or fetal growth restriction based on the clinical criteria in Table 1.
Statistical analyses were performed using MedCalc v11.6 (Mariakerke, Belgium). Multiple regression analysis was performed and AIx was adjusted for maternal heart rate and height as both independently influence AIx [23]. aPWV was adjusted for age and mean arterial pressure (MAP) [23]. Normality was assessed using the KolmogoroveSmirnov test and non-normally distributed values were log10 transformed. Linear regression by the method of ordinary least squares was used to define the correlation between cardiovascular parameter and mean uterine artery Doppler PI, with goodness of fit expressed by Pearson’s correlation coefficient (r). Absolute values were compared using Student’s paired t-tests. Our units previous years’ singleton birth records for gestations 34þ0e42þ0 (n ¼ 5449) and previous 5 years for gestations 24þ0e34þ0 (n ¼ 518) were used to calculate gender specific birth weight z-scores for each week of gestation.
3. Results 2.2. Uterine artery Doppler Transabdominal uterine artery Doppler was performed using a Siemens S2000 (Mountain View, CA) ultrasound machine using a 6C2 transabdominal probe and waveforms were obtained as previously described [18]. Pulsatility index was measured in both uterine arteries and the mean value recorded. Comparison was made in the analyses for women with a mean PI >1.45 and <1.45 (the 95th percentile for transabdominal Doppler PI, as previously reported [18]).
Table 1 Indications for referral for uterine artery Doppler. N Abnormal serum markersa Essential hypertensionb Previous preeclampsiac Previous IUGR (<3rd centile) Previous stillbirth Other a
b c
HCG >4 Multiples of Median (MoM), AFP >3MoM, PAPP-A <0.3MoM. Requiring medication or booking BP >150/90 mmHg. Requiring delivery before 34/40 or MgSO4 treatment.
28 13 21 10 10 17
One hundred and sixty-eight women attending for uterine artery screening were approached for study inclusion. Ninety-nine consented and were recruited for subsequent cardiovascular testing. Demographic data are summarised in Table 2. There was a positive relationship between uterine artery Doppler PI and AIx (r ¼ 0.3, P ¼ 0.003, 95% CI: 0.11e0.47). This relationship strengthened after adjustment for maternal heart rate and height (r ¼ 0.4, P <0.0001, 95% CI: 0.22e0.55) (Fig. 1). AIx-75 was not significantly associated with uterine artery Doppler PI (P ¼ 0.13). Women with a mean uterine artery PI >1.45 (n ¼ 10), demonstrated a higher augmentation index than those with uterine artery Doppler PI <1.45 (17% vs. 8%, P ¼ 0.003, 95% CI: 3.1e14.9) also after adjustment for heart rate and height (14% vs 9%, P <0.0001, 95% CI: 3.0e7.3) (Fig. 2). A positive relationship was found between mean uterine artery Doppler PI and aPWV (adjusted for MAP and age) (r ¼ 0.22, P ¼ 0.03, 95% CI: 0.02e0.40) (Fig. 3). Adjusted aPWV was not different between those women with uterine artery PI >1.45 and those with uterine artery Doppler PI <1.45 (mean aPWV: 5.5 vs 5.4, 95% CI: 0.13e0.30, P ¼ 0.45) (Fig. 4).
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Table 2 Subject demographic and haemodynamic characteristics. Parameter Age (years) Gestation (weeks) at Ultrasound Mean uterine artery Doppler PI Gestation (weeks) at CV test Height (m) Weight (kg) Body Mass Index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Mean arterial pressure (mmHg) Pulse pressure (mmHg) Heart rate (beats/min) Augmentation index (%)a Augmentation index-75 (%) aPWV (m/s) aPWV (m/s)b Nulliparous/multiparous Ethnic origin White Caucasian Asian/Indian Black Afro-Carribean
33 (29e37) 23þ6 (23þ324þ4) 0.80 (0.65e0.96) 26þ5 (25þ6e28þ0) 166 7 68 13 25 5 106 12 68 8 81 10 38 7 82 9 94 13 8 5.4 1 5.4 0.3 28/71 90 7 2
Values are given as mean SD or as median (Interquartile range) for normally and non-normally distributed data, respectively. a Adjusted for heart rate and height. b Adjusted for MAP and age.
No difference in AIx (9 vs. 9%) or aPWV (5.3 vs. 5.4 m/s) was found between nulliparous and multiparous women. Multiple regression analysis showed that the gestation range within our study cohort was not a significant variable for AIx (P ¼ 0.15) or aPWV (P ¼ 0.27). Neither mean arterial pressure nor central pulse pressure showed a correlation with uterine artery pulsatility index (P-values: 0.06 and 0.25 respectively). Outcome data was available for 96 women. Four women developed preeclampsia prior to 34 weeks. No women developed late-onset preeclampsia. There were 13 (non-preclamptic) cases of IUGR (z-score less than 1.65, equating to <5th centile), 1 requiring delivery before 34 weeks gestation (weighing 820 g at 31þ2 weeks gestation.) A sub-group analysis of these women was performed. In the subgroups, adjusted AIx was higher in both women who developed PET (14% vs 9%, 95% CI: 2.0e8.6, P ¼ 0.0018) and those who delivered babies weighing <5th centile (11% vs 9%, 95% CI:
Fig. 1. Relationship of uterine artery Doppler PI with augmentation index (aadjusted for heart rate and height) (r ¼ 0.4, P ¼ <0.0001).
Fig. 2. Comparison of augmentation index (aadjusted for heart rate and height) in women with uterine artery Doppler PI less than or greater than 1.45 (9% vs 14%). * P ¼ 0.0001.
0.3e4.2, P ¼ 0.027) when compared to those with normal outcome. No difference in adjusted aPWV was found for PET (5.5% vs 5.4%, 95% CI: 0.5e0.2, P ¼ 0.37) or IUGR (5.5% vs 5.4%, 95% CI: 0.3e0.07, P ¼ 0.22) when compared to those with normal outcomes. Fig. 5 shows results of adjusted AIx for a composite of these outcomes. Mean uterine artery Doppler PI was higher for both PET (Mean PI: 1.94, P ¼ <0.0001) and IUGR (Mean PI: 1.3, P ¼ <0.0001) outcomes when compared to normal outcomes (Mean PI: 0.8). Adjusted AIx showed a negative correlation (r ¼ 0.25, 95% CI: 0.43 to 0.06, P ¼ 0.013) with birth weight z-score. No correlation was noted with adjusted aPWV and birth weight. 4. Discussion There is a moderately strong positive association between uterine artery Doppler impedance and arterial wave reflection (AIx) and a weaker positive association with aortic stiffness. This positive
Fig. 3. Relationship of uterine artery Doppler PI with aortic pulse wave velocity (aadjusted for MAP and age) (r ¼ 0.22, P ¼ 0.03).
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Fig. 4. Comparison of aortic pulse wave velocity (aadjusted for MAP and age) in women with uterine artery Doppler PI less than or greater than 1.45 (5.4 vs 5.5 m/s, P ¼ 0.45). NS ¼ not significant.
relationship between augmentation index and uterine artery Doppler PI in the mid-trimester has not previously been reported. That there is a relationship between aPWV and uterine artery Doppler PI is consistent with the findings of others [24]. This study reported that women with raised uterine Doppler PI had higher aPWV than those with uterine artery PI <1.6. However, we have also demonstrated a positive relationship between AIx and uterine artery Doppler PI and higher AIx in women with a uterine artery PI above 95th centile than those with a ‘normal’ uterine artery PI. It is noteworthy that the mean AIx-75 in the high-risk population of our study is considerably higher (13%) than that previously reported in the normal pregnant population (w5%) [25] at similar gestations, although we report similar mid-pregnancy aPWV values (5.4 m/s) [24]. Although we found a positive correlation of aPWV with uterine artery Doppler, we did not find aPWV to be significantly higher in women with PI >1.45. This is most likely due to the relatively smaller number of women with raised PI in our cohort compared to other studies that have shown this relationship [24]. However, this difference may also be due in part to selection of the women; we recruited prospectively from a single population attending for Doppler screening rather than selective recruitment based on the result of normal or abnormal Doppler studies.
Fig. 5. Augmentation index (aadjusted for heart rate and height) by pregnancy outcome: normal or preeclampsia and/or SGA (9% vs 12%). *P ¼ 0.001.
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Our finding of an association of negative correlation of AIx in the second trimester with birth weight is in close agreement with a previous smaller study [26] and strengthens the argument that sub-clinical global endothelial dysfunction has a deleterious effect on pregnancy. Our data, in contrast to a previous study performed in the third trimester [27], did not find a relationship between aPWV and birth weight. This may be due to the different gestations at which aPWV was studied. AIx has an inverse, linear relationship with heart rate [28]. Therefore AIx standardized to a heart rate of 75 bpm (AIx-75) is particularly useful for inter-individual comparison. In the first trimester of pregnancy others have reported no relationship between AIx-75 and mean uterine artery PI [17], a finding consistent with the current study. However, heart rate rises rapidly to around 82 bpm by the end of the first trimester [29]; adjusting AIx for the actual mean heart rate of the individual or relevant population may be considered more appropriate than applying the generic adjustment to derive AIx-75. Augmentation index has been proposed as a component in first trimester screening models for preeclampsia [17]. We have not aimed to develop a predictive model as this would not be possible in a high-risk population. However, we show that, in the second trimester, there is an association between systemic arterial function and uterine artery Doppler PI. Hence uterine artery PI should be used cautiously in combination with AIx as part of a predictive algorithm as independence cannot be presumed. Further, it seems plausible that the changes in both maternal systemic cardiovascular function and uterine artery impedance that differentiate normal from abnormal pregnancy may not be evident or completed in the first trimester. Another key element of placental implantation and vascular remodelling of the spiral and uterine arteries is that it remains incomplete until the latter stages of the second trimester [30,31]. Indeed this is the underlying rationale on which mid-trimester uterine artery Doppler screening is thought to depend [18]. Women who demonstrate abnormal uterine artery Doppler waveforms in the first trimester, but in whom placentation will ultimately be normal, may well exhibit normal uterine artery waveforms at 22e23 weeks gestation [18]. Given that AIx falls to a mid-pregnancy nadir [25], it is plausible that women who are in fact “low risk” can have a raised uterine artery PI and normal AIx in the first trimester and subsequently have a normal uterine artery PI in the second trimester with the AIx remaining normal. Further, women in whom uterine artery Doppler does not normalise may be those in whom AIx and aPWV either does not fall or indeed rises throughout pregnancy. AIx and aPWV are known to fall from the first trimester to midpregnancy before rising again towards the end of pregnancy [25,32,33]. That the uterine artery Doppler and cardiovascular measurements were not performed at the same visit could be a source of error. However, the gestational range within our study is at the mid-pregnancy nadir for AIx and aPWV, which makes it unlikely that this delay in measurements will have had a significant effect. Further, multiple regression analysis of our data did not show gestation to be a significant variable for AIx or aPWV. This is most likely due to the relatively narrow range of gestation at which our measurements were taken and their being taken at a time of pregnancy when there is little change in AIx and aPWV. Ethnic origin is known to affect AIx [34] and this can be adjusted for in a multiple regression model. Of the cases that we report, >90% are white Caucasian with very small numbers in remaining groups. Hence we have not analysed further nor adjusted for ethnic origin. AIx, a measure of pulse wave reflection, and uterine artery Doppler, a measure of impedance, are both influenced by peripheral vascular resistance (PVR). The findings of our study suggest
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that there may be an underlying systemic increased vascular resistance in the women with higher uterine artery PI. This in turn may lead to an impaired ability of the vasculature, and particularly the uterine element of the utero-placental circulation to respond to the profound changes required for a successful pregnancy. Although increased wave reflection is generally considered deleterious, it may in fact have a protective role [35]. Greater pulse wave reflection will tend to dampen the effects of increased pulse pressure, as seen in preeclampsia [36], and reduce transmission of excessive pulsatile energy to the end-organ, in this case the uteroplacental bed. Women with early-onset preeclampsia have higher AIx postpartum that may persist for at least two years [37]. However, the AIx and aPWV do not differ in our study between nulliparous and multiparous women, suggesting an underlying process of arterial stiffening in “high-risk” women over and above the effect of previous pregnancies. These results provide further evidence that systemic arterial dysfunction is present in women at higher risk of preeclampsia. What remains unclear is whether increased wave reflection and aortic stiffness occurs prior to, or equally plausibly, because of the preeclamptic process. We demonstrate a positive relationship between second trimester uterine artery Doppler PI and both aortic stiffness and arterial wave reflection. It remains to be determined whether our findings are due to a pre-existing, sub-clinical vascular endothelial dysfunction predisposing to impaired placentation and increased risk of preeclampsia, or whether defective placentation itself leads to the increase in arterial stiffness. Author contribution CCL conceived the study design. TRE performed the study. AAM assisted recruitment and performing the measurements. All authors were involved in the analysis and interpretation of the study. TRE wrote the first draft of the manuscript. All authors contributed to the writing of the final manuscript. Funding TRE is funded by the Evelyn Trust. CCL is recipient of an Evelyn Trust research grant. IBW and CMM are both British Heart Foundation Fellows. AAM is supported by Cambridge Fetal Care. CMM and IBW are supported by the Cambridge Biomedical Research Centre (NIHR). IBW has received unrestricted educational support (all <£10,000pa) from AtCor, Vicorder and IEM in the past 5 years. Acknowledgements We wish to thank the women who participated in this study and the research nurses of the Vascular Research Unit. References [1] Easterling T, Benedetti T, Schmucker B, Millard S. Maternal hemodnamics in normal pregnancy and preeclamptic pregnancies: a longitudinal study. Obstetrics & Gynecology 1990;69:1061e9. [2] Bosio PM, McKenna PJ, Conroy R, O’Herlihy C. Maternal central hemodynamics in hypertensive disorders of pregnancy. Obstetrics & Gynecology 1999;94: 978e84. [3] Magnussen EB, Vatten LJ, Lund-Nilsen TI, Salvesen KA, Smith GD, Romundstad PR. Prepregnancy cardiovascular risk factors as predictors of pre-eclampsia: population based cohort study. British Medical Journal 2007;335:978. [4] Romundstad PR, Magnussen EB, Smith GD, Vatten LJ. Hypertension in pregnancy and later cardiovascular risk: common antecedents? Circulation 2010; 122:579e84. [5] Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and metaanalysis. British Medical Journal 2007;335:974.
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