Dr AA Khalil, Department of Obstetrics & Gynaecology, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. Email email@example.com
Objective To investigate whether first-trimester arterial pulse wave analysis (PWA) can predict pre-eclampsia.
Design This was a prospective screening study.
Setting The Homerton University Hospital, a London teaching hospital.
Population Two hundred and ten low-risk women with a singleton pregnancy were analysed.
Methods Radial artery pulse waveforms were measured between the 11+0 and 13+6 weeks of gestation and the aortic waveform derived by applying a generalised transfer function. Augmentation pressure (AP) and augmentation index at heart rate of 75 beats per minute (AIx-75), measures of arterial stiffness, were calculated. The multiple of the gestation-specific median in controls for AP and AIx-75 were calculated. Logistic regression models were developed and their predictive ability assessed using the area under the receiver operator curve.
Main outcome measures Prediction of pre-eclampsia by AIx-75.
Results Fourteen (6.7%) women developed pre-eclampsia, and 196 remained normotensive. Eight of the 14 women developed pre-eclampsia before 34 weeks of gestation (early-onset pre-eclampsia). For a false-positive rate of 11%, AIx-75 had a detection rate of 79% for all cases of pre-eclampsia and 88% for early-onset pre-eclampsia.
Conclusion First-trimester arterial PWA can play a significant role in understanding the pathophysiology of pre-eclampsia and may play a role in early screening.
Pre-eclampsia remains one of the leading causes of maternal mortality and morbidity worldwide, occurring in 3–5% of all pregnancies.1 Although its aetiology has not yet been precisely defined, we know that failure of adequate trophoblast invasion of the spiral arteries in early pregnancy can lead to changes in the mother, such as impaired angiogenesis, which predate the onset of the clinical manifestations of the disease.2,3 Screening for pre-eclampsia in the first trimester has had limited success. Currently, clinical history, maternal serum biochemistry and uterine artery Doppler sonography before 14 weeks are being investigated.4–7 In the second trimester, uterine artery Doppler can claim a detection rate (DR) of only 63.1% for a high (25%) false-positive rate (FPR).8 First-trimester uterine artery Doppler studies have been shown to have high sensitivity but poor specificity, with a high FPR.9 The combination of first-trimester uterine artery Doppler indices and placental protein 13 (PP13) holds promise in this respect, but further evidence is needed.4 Maternal serum markers, such as inhibin A, activin A, soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin, when used alone have proved poor predictors of pre-eclampsia.10–12
Vascular compliance can be assessed by analysing the peripheral arterial pulse waveform, measured using applanation tonometry. This technique has been widely studied in the nonpregnant population,13–19 but studies in pregnancy are limited.20–24 Pulse wave analysis (PWA) can quantify alterations in vascular compliance associated with conditions that cause endothelial dysfunction, such as diabetes, renal disease and arteriosclerosis. The technique is noninvasive and easy to learn. Information from a distal part of the vasculature, for example the radial artery, can provide information on central haemodynamics, that is in the aorta.
Pre-eclampsia is characterised by endothelial dysfunction, which is likely to begin some considerable time before the onset of clinical disease.25 Recent studies using PWA have confirmed reduced arterial compliance (in other words, increased arterial stiffness) in women with clinically established pre-eclampsia.21,23,24
Our aims were to investigate whether PWA could identify an increase in arterial stiffness in advance of clinically evident pre-eclampsia and to provide preliminary information on whether the technique might be used to predict the disease.
This was a prospective screening study carried out at The Homerton University Hospital, London, UK, over an 18-month period in 2006 and 2007. This is a hospital with a high incidence of pre-eclampsia due to its large Afro-Caribbean ethnic mix. The study was approved by the Camden and Islington Community Local Research Ethics Committee. Written informed consent was obtained from all participating women. Radial artery pressure waveform was recorded between 11+0 and 13+6 weeks of gestation (gestational age [GA] having first been established on the basis of menstrual date and/or ultrasonographic examination). All ultrasound scans were performed between 11+0 and 13+6 weeks of gestation. For clinical purposes, GA in our unit is calculated based on the crown-rump length (CRL) measurements if the LMP is not reliable or if there is a discrepancy of more than 5 days between the GA calculated by LMP and that determined by CRL measurements. However, for the purposes of calculating multiples of the gestation-specific medians (MoMs) for the PWA parameters in our study, we used CRL measurements to date the pregnancy. In all women, a careful search to exclude fetal abnormalities was performed. Demographic and clinical data including age, body mass index (BMI), parity, blood pressure (BP) and GA were recorded. All women were followed up until after delivery, and fetal and maternal outcomes were obtained from the women’s medical records and labour ward records. Exclusion criteria included multiple pregnancy, fetal anomalies, a history of essential hypertension, previous pre-eclampsia, renal disease, autoimmune disorders or diabetes or women taking low-dose aspirin or medication that could affect BP. Women were managed (and the diagnosis of pre-eclampsia made) by their attending clinicians (midwives and obstetricians), blinded to the results of the PWA examination; none of the women with pre-eclampsia or gestational hypertension was attended by any of the authors. No further PWA measurements was performed.
The primary outcome measure was the prediction of pre-eclampsia with PWA indices. Pre-eclampsia was defined according to the guidelines of the International Society for the Study of Hypertension in Pregnancy (ISSHP). This definition requires two recordings of diastolic BP ≥90 mmHg at least 4 hours apart in a previously normotensive woman and proteinuria ≥300 mg in 24 hours or two readings of at least ++ on dipstick analysis of a midstream or catheter specimen of urine (if no 24-hour urine collection available).26 Severe pre-eclampsia was defined as severe hypertension (diastolic BP ≥110 mmHg) and mild proteinuria or mild hypertension and severe proteinuria (a 24-hour urine sample that contained ≥3.5 g protein or a urine specimen ≥3+ protein by dipstick measurement). Women with an abnormal liver function test (aspartate aminotransferase >70 IU/l) and thrombocytopenia (platelet count <100 000/cm3) were also classified as having severe pre-eclampsia. Gestational hypertension was defined as a diastolic BP ≥90 mmHg on at least two consecutive occasions in the second half of pregnancy, without proteinuria, in a previously normotensive woman.27
All measurements (BP and PWA) were performed in the same room at room temperature. Participants refrained from caffeine intake on the day of the study and rested for at least 10 minutes prior to the measurements. During measurements, the women did not move or speak. Peripheral BP was measured in duplicate in the brachial artery of the nondominant arm using a calibrated standard mercury sphygmomanometer. Brachial artery systolic BP was defined using the first Korotkoff sound and diastolic BP using the fifth Korotkoff sound. Mean arterial pressure was calculated by integration of the radial pressure waveform using the Sphygmocor® system (Atcor Medical, West Ryde, Australia) described below. Pulse pressure (PP) was defined as systolic pressure minus diastolic pressure.
Arterial PWA was performed as follows: the radial artery was gently compressed with the tip of the tonometer at the site of maximal pulsation. This tonometer contains a micromanometer that provides a very accurate recording of the pressure within the radial artery (Millar Instruments, Houston, TX, USA).28 A generalised transfer function was applied to the radial artery waveform to derive the aortic pressure waveform.29–31 From this aortic pressure waveform, the augmentation pressure (AP) and augmentation index (AIx) were calculated. The AP is defined as the height of the late systolic peak above the inflection point on the waveform (Figure 1). The AIx is defined as AP expressed as a percentage of the aortic PP.32,33 AIx is affected by changes in heart rate. An increase in heart rate shortens the duration of systole. As a result, the reflected wave reaches the advancing wave in diastole (rather than the usual systole), resulting in reduced augmentation of the advancing wave, that is reduced AIx. As there is a linear relationship between maternal heart rate and AIx, the AIx was standardised to a heart rate of 75 beats per minute (AIx-75).34 The Sphygmocor system32 was used for the analysis of the radial pressure wave contour.
All measurements were made by the same observer (A.A.K.). Prior to commencing this study, there was an initial learning period of 25 repeated measurements until satisfactory reproducibility was achieved (<5% variability between duplicate measurements). As a further check, the Sphygmocor software incorporates a quality control feature that is displayed on the screen.
Baseline characteristics were compared using chi-square test (Fisher’s exact test when appropriate) for categorical variables and independent t test for continuous variables. MoMs in controls for AP, AIx and AIx-75 were calculated. MoMs were compared between pre-eclampsia cases and controls with independent t test. Univariate logistic regression analysis was performed to determine the relationship of each demographic variable and each of the PWA parameters for the development of pre-eclampsia. Receiver-operating characteristics (ROC) curve analysis was used to determine the best predictor of pre-eclampsia. P < 0.05 was considered to be statistically significant. All P values were two tailed. Data were analysed using SPSS® (SPSS version 14.0, 2005; SPSS Inc., Chicago, IL, USA).
Women with a singleton pregnancy were recruited (n = 218). One had a second-trimester miscarriage, two had termination for fetal abnormality and two had spontaneous preterm delivery; these five were excluded from further analysis. Of the remaining 213 women, 3 were excluded due to lack of pregnancy outcome data. For this analysis, five women who developed gestational hypertension without proteinuria were included in the control group. In these five women, significant proteinuria >300 mg in 24 hours was excluded with a 24-hour collection; all were followed up postpartum, and none developed postpartum proteinuria or pre-eclampsia. Analysis therefore included 210 women. Fourteen (6.7%) women developed pre-eclampsia, leaving 196 controls. Eight of the 14 women developed pre-eclampsia before 34 weeks of gestation (early-onset pre-eclampsia). Three (21%) women developed severe pre-eclampsia. Five of the 14 women who developed pre-eclampsia also had intrauterine growth restriction. The demographic characteristics, pregnancy outcome, mean brachial BP and heart rate data of the group who subsequently developed pre-eclampsia and the non-pre-eclampsia group are compared in Table 1. There were no significant differences in age, BMI, parity, smoking, GA at recruitment, mean BP or heart rate between controls and subjects who developed pre-eclampsia. As expected, women who developed pre-eclampsia delivered at an earlier GA and had smaller babies.
Table 1. Demographic data: comparison of demographic characteristics in women who developed pre-eclampsia and unaffected controls
Pre-eclampsia (n = 14)
Controls (n = 196)
Values are presented either as mean ± SD or n (%).
Maternal age (years)
32.3 ± 6.0
30.4 ± 6.3
Maternal BMI (kg/m2)
28.3 ± 5.0
26.7 ± 5.2
GA at recruitment (days)
91.2 ± 4.8
89.2 ± 5.4
GA at delivery (days)
232 ± 38
278 ± 10
1757 ± 953
3348 ± 396
Mean blood pressure (mmHg)
86.1 ± 6.1
85.1 ± 13.2
Heart rate at recruitment (beats per minute)
85 ± 11
83 ± 11
The relationship of each of the demographic variables and each of the PWA parameters for the development of pre-eclampsia is shown in Tables 2 and 3, respectively. The incidence of pre-eclampsia in the Caucasian group was 6.1% compared with 6.3% in the Afro-Caribbean group. Figure 2 shows AP and AIx-75 levels in women who developed pre-eclampsia and controls. AIx-75 was significantly higher in the group (n = 3) who developed severe pre-eclampsia (median AIx-75 = 39% in severe pre-eclampsia and 30% in mild pre-eclampsia, P = 0.01). As there was no significant difference (or differences approaching significance) between the groups for any of the demographic variables (Table 2), it was not felt necessary to include them in the logistic regression models. We compared PWA parameters between the two major ethnic groups in our study, that is Caucasian and Afro-Caribbean, and found no statistically significant differences (in women with pre-eclampsia for AIx-75, P = 0.6, and in controls, P = 0.9).
Table 2. Demographic variables and pre-eclampsia: univariate logistic regressions used to determine the relationship of each of the demographic variables to pre-eclampsia
OR (95% CI)
Caucasian was used as the reference category as it represented the largest group.
Table 3. AP and AIx in pre-eclampsia: univariate logistic regressions used to determine the relationship of each of the AP or AIx MoM variables to pre-eclampsia
OR (95% CI)
Both AP MoM and AIx-75 MoM had a significant negative correlation with GA at delivery and with birthweight (Pearson correlation, r =−0.2 for both, P = 0.02).
The results of the ROC curve analyses are shown in Figures 3 and 4 and Table 4. Figure 3 shows the model-predicted ROC curves for the MoMs of AP, AIx and AIx-75. For an 11% FPR, the DR of all pre-eclampsia was 79% by AIx-75. The diagnostic indices, predictive values and likelihood ratios for developing pre-eclampsia at different cutoff values are shown in Table 5. The positive predictive value (PPV) varies according to the cutoff chosen; however, for each of these measurements, PPV was less than 25%. Figure 4 shows the model-predicted ROC curves for early-onset pre-eclampsia. For a 11% FPR, the DR of early-onset pre-eclampsia was 88% using AIx-75.
Table 4. Prediction of pre-eclampsia: performance of arterial PWA indices in the prediction of pre-eclampsia
Test result variables
Area (95% CI)
Table 5. Prediction of all pre-eclampsia and early-onset pre-eclampsia: multiple of median (MoM) cutoff values for AP, AIx and AIx-75 and the corresponding sensitivities and specificities, PPV and NPVs and likelihood ratios for all women with pre-eclampsia and for early-onset pre-eclampsia
NPV, negative predictive value.
In the five women who developed gestational hypertension, AIx-75 was similar to that in the rest of the control group (P = 0.8) and significantly lower than that in the group who developed pre-eclampsia (P < 0.0001).
There is a marked increase in vascular compliance in normal pregnancy so as to accommodate the major cardiovascular changes taking place within the mother as a whole and within the uterus in particular. In the small group (n = 5) of women who developed gestational hypertension, the PWA values were similar to those the normotensive group and significantly lower than those in the women who developed pre-eclampsia. This suggests that the aetiology and pathophysiological changes that occur in gestational hypertension are different from those of pre-eclampsia. We know that there is little or no difference in vascular compliance between women with established pre-eclampsia and nonpregnant women. Pre-eclampsia is in essence a vascular endothelial disorder, so investigating vascular compliance has the potential to provide answers about the pathophysiology of this condition as well as to identify early in pregnancy women at risk.
In this small study, we have found encouraging results that we believe warrant further investigation. We found that both AP and AIx-75 had a significant negative correlation with GA at delivery and birthweight. AIx-75 was significantly higher in the small group (n = 3) who developed severe pre-eclampsia compared with those women with mild pre-eclampsia. For a FPR of 11%, PWA predicted 79% of women who went on to develop pre-eclampsia and 88% of those who developed the more severe early-onset pre-eclampsia. There was a high incidence of pre-eclampsia in our population, and it is likely that this screening test would perform less well in populations with a lower incidence of the disease.
One potential limitation of our study is the fact that the transfer function used to derive the aortic waveform from the measured radial artery waveform has not been validated for use in pregnancy. However, it has been extensively validated in the nonpregnant population under different conditions, including age, disease, physiologic manoeuvres such as Valsalva and various medications.29,31 The transfer function has also been validated in individuals treated with high doses of nitric oxide, which was associated with marked vasodilatation similar to or greater than that seen in pregnancy. Given its remarkable consistency in a wide variety of subjects in a wide variety of clinical situations, it seems likely (although not yet proven) that the transfer function also holds true in pregnant women. Pregnancy is associated with major haemodynamic changes such as increased cardiac output and heart rate and the presence of placental fistulae. However, the transfer function that is used to derive the central pressure waveform from the radial waveform does not depend on central haemodynamics but depends on the aorto-radial arterial path properties. Age and pregnancy have very little effect on the arm arteries, so the transfer function should be expected to remain valid in pregnancy. Nevertheless, we emphasise that future research should address validation of this technique in pregnancy before any clinical applications might be considered.
Our work supports the hypothesis that the pathophysiology of pre-eclampsia starts early in pregnancy and results from a failure of the mother to adapt adequately to the invading trophoblast. Our data support the idea that inadequate maternal adaptation (represented by less vascular compliance) may contribute for the development of pre-eclampsia later in pregnancy. Early-onset pre-eclampsia is the most severe end of the spectrum, carrying the greatest risk for mother and fetus. In this study, PWA predicted early-onset disease better than all pre-eclampsia, suggesting that the worse the maternal adaptation in the first trimester, the more severe the subsequent disease. The PPV varies according to the cutoff values chosen (Table 5). However, the best predictor (AIx-75) had a PPV of less than 25% and therefore is potentially useful as a negative, rather than positive, predictive test. We acknowledge that the number of participants in the study is too small to draw firm conclusions, and confirmation from larger studies will be required.
The search for a clinically useful test for predicting pre-eclampsia has continued for many years, but a solution remains elusive. Studies using first-trimester9,35,36 or second-trimester37–39 Doppler sonography alone or combined with maternal serum markers4,40–43 have had some success, but sensitivity and PPVs are low, or the tests were expensive or invasive. Accurate identification of women at risk, particularly those at risk of early-onset disease, would have real clinical benefits. While there is currently no effective preventative measure, a recent meta-analysis has suggested that low-dose aspirin may reduce the incidence of pre-eclampsia by 10%.44,45 Early identification of women at risk of pre-eclampsia facilitates targeted surveillance and intervention.46,47 There are likely to be significant advantages in predicting pre-eclampsia in the first, as opposed to the second trimester; given that the disease process (failure of adequate trophoblastic invasion) is already established by the mid-second trimester, it seems likely that any successful preventative measure will need to be instituted as early in pregnancy as possible. Early prediction will also facilitate the investigation of prophylactic interventions in the future—it is possible that the earlier intervention is started the more likely it is to be effective.
PWA has been shown in nonpregnant individuals to accurately evaluate arterial stiffness in cardiovascular disorders. Pre-eclampsia is a disorder of vascular endothelium, and recent studies have shown that PWA can successfully assess the increased arterial stiffness that results.21 In recent years, it has been shown that serum and placental levels of angiogenic factors such as sFlt1 and soluble endoglin are altered in women with pre-eclampsia not just at the time of the clinical manifestations of the disease but often many weeks prior its clinical onset.12,27,33,34,40 This led us to hypothesise that the increase in arterial stiffness might occur in advance of the clinical disease, that this might be measurable using arterial PWA and that, if so, these observations might allow us to identify early those women who subsequently developed pre-eclampsia.
Currently, the combination of first-trimester uterine artery Doppler and maternal serum PP13 holds the greatest promise, with a DR of 90% for an FPR of 9%.4 However, this combination needs further supporting evidence and, for the moment at least, remains expensive and invasive. In contrast, arterial PWA is inexpensive, noninvasive, easy to learn and apply and seems to predict pre-eclampsia as early as the first trimester. It may be that combining PWA with another method or methods, such as first-trimester uterine artery Doppler, PP13 or other maternal serum markers, may improve the DR still further.
Each heartbeat generates a pulse wave that travels away from the heart along the arterial tree. This waveform is reflected from bifurcations within the arterial tree and from the junctions of the preresistance and resistance vessels. The reflected wave travels back towards the heart and meets the advancing wave. Thus, the height of the pulse wave at any point in the arterial tree is the net combination of the advancing and reflected waves (Figure 1). Generally, the reflected wave reaches the aorta during diastole, boosting the height of the diastolic portion of the wave. This also helps to maintain coronary artery perfusion. When arterial wall stiffness is increased (as in pre-eclampsia), the arterial pulse wave travels more rapidly away from the heart and the reflected wave returns more rapidly. As a result, the reflected wave reaches the advancing wave in systole, resulting in significant augmentation of the systolic peak. This can be measured as raised AP and AIx. Previous studies have demonstrated that, in normal pregnancy, aortic stiffness falls and remains low until delivery.20
This is the first study to show that arterial PWA has potential use as a predictive test for subsequent development of pre-eclampsia. Our data suggest that the pathophysiological changes associated with pre-eclampsia occur early in pregnancy (as early as the first trimester), long before the development of the clinical disease. It may be that early changes in angiogenic factors lead to modifications in vessel structure or behaviour at this early stage. These findings may lead to the development of a robust screening model that would be invaluable in the development of an early therapeutic strategy for the prevention of pre-eclampsia.
Conflict of interests
None of the authors has any conflict of interest.
Contribution to authorship
A.A.K. designed the study, recruited and studied the participants, analysed the data and wrote the paper. D.J.C. analysed the data and reviewed the paper. K.F.H. designed the study and reviewed the paper. All authors approved the final version of the manuscript.
Details of ethics approval
This study was approved by the Camden and Islington Community Local Research Ethics Committee on 24 February 2006. Ethics approval number: 06/Q0511/2. Written informed consent was obtained from all participating women.
Commentary on ‘Pulse wave analysis: a preliminary study of a novel technique for the prediction of pre-eclampsia’
In this article, Dr Khalil et al. elegantly demonstrate that pulse wave analysis of waveforms obtained from radial artery applanation tonometry at 11–14 weeks can predict the subsequent development of pre-eclampsia. The earlier the onset of pre-eclampsia the better the sensitivity of the test. However, these promising initial results need further scrutiny and more studies are needed.
In cardiovascular disease, a series of linked changes in the vasculature, the most important of which is increased central arterial stiffness, can lead to both isolated systolic and combined systolic–diastolic hypertension. The propagative and reflective properties of the arterial tree (intensity of wave reflections and timing of incident and reflected pressure waves), dependent on arterial stiffness, can be assessed using noninvasive methods such as pulse wave analysis. Pulse wave analysis obtained from recordings of the peripheral arteries—such as the radial artery—allows quite an accurate estimate of central vascular pressure and is probably superior to traditional ‘cuff’ blood pressure measurements in predicting cardiovascular end-points and in evaluating the response to drug treatment (Nichols et al. Am J Hypertens 2005;18:3S–10S).
Not only have we been aware for some time that that maternal chronic hypertension greatly increases the risk of pre-eclampsia (Chappell et al. Hypertension 2008;51:1002–9), but it is also becoming evident that, even in apparently normotensive women, blood pressure levels at 11–14 weeks are an independent risk factor for the later development of pre-eclampsia (Poon et al. Hypertension 2008;51:1027–33). The data from Khalil et al. suggest that the augmentation index derived by pulsed wave analysis is a more sensitive test than traditional blood pressure measurements in screening for pre-eclampsia at 11–14 weeks. This might be explained by the simple fact that the estimate of central vascular pressure by pulse wave analysis is a better predictor of clinical end-points. Alternatively, changes in central vascular pressure in the late first trimester may already reflect abnormalities in endothelial function directly involved in the pathophysiological pathways of pre-eclampsia. Future research should aim to clarify the mechanisms affecting arterial stiffness in pregnancy, as well as to
investigate the screening potential of radial artery pressure wave measurements in larger populations. Furthermore, the introduction of a new technology such as pulse wave analysis, however innovative and exciting it promises to be, must be accompanied by a clear understanding of its limitations (Hope et al. J Hypertens 2008;26:4–7) and undergo validation in pregnant women.
F Prefumo Department of Obstetrics and Gynaecology, Maternal-Fetal Medicine Unit, University of Brescia, Brescia, Italy