Do maternal cerebral vascular changes assessed by transcranial Doppler antedate pre-eclampsia?

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Ultrasound Obstet Gynecol 2004; 23: 254–256 Published online 3 February 2004 in Wiley InterScience ( DOI: 10.1002/uog.955

Do maternal cerebral vascular changes assessed by transcranial Doppler antedate pre-eclampsia? K. P. WILLIAMS* and J. M. MOUTQUIN† *Yale University School of Medicine, New Haven, CT, USA and †CUSE, Hopital Fleurimont, Sherbrooke, Quebec, Canada ˆ

K E Y W O R D S: cerebrovascular resistance; maternal cerebral blood flow; middle cerebral artery; pre-eclampsia; second trimester; third trimester; transcranial Doppler

ABSTRACT Objective To determine whether maternal transcranial Doppler (TCD) evaluation of the middle cerebral artery identifies changes in the cerebral circulation prior to the development of pre-eclampsia. Methods In a nested, case-controlled study developed from a previous prospective cohort study, 20 preeclamptic and 40 normotensive pregnancies, matched for maternal age, were assessed with the traditional middle cerebrovascular Doppler parameters (pulsatility index, mean cerebral blood flow velocity), together with non-traditional Doppler parameters including time taken to achieve end systole (EST) and percentage time to achieve end systole (% EST). Assessments done at 20–24 and 28–32 weeks’ gestational age were compared using Student’s t-tests. Significance was set at the P < 0.05 level. Results In the second trimester (20–24 weeks) there were no significant differences in any of the Doppler waveform characteristics in either group. In the third trimester (28–32 weeks) there was a significant increase in the % EST in the group who subsequently developed preeclampsia (45.2 ± 4.2 vs. 42.3 ± 4.1; P < 0.01). Conclusions Patients who subsequently develop preeclampsia show a significant lengthening in the EST in the third trimester as a late finding, which indicates an increase in the cerebrovascular resistance. Earlier prediction of pre-eclampsia using TCD waveform analysis will require more provocative testing (i.e. hand grip and CO2 reactivity). Copyright  2004 ISUOG. Published by John Wiley & Sons, Ltd.

INTRODUCTION In a previous report, middle cerebral blood flow velocities were measured in the mid-second trimester and in

the early third trimester in a cohort of 1400 normal pregnancies in order to assess whether early changes in cerebral blood flow velocity (CBFV), estimated cerebral perfusion pressure or cerebrovascular resistance could predict pre-eclampsia. Some changes in these parameters occurred but the differences were not significant1 . Other reports have identified in other vascular beds, several parameters derived from the Doppler waveform related to the duration of systole such as systolic acceleration and percentage systolic acceleration time that may demonstrate better predictive discrimination than traditional measurements in the detection of downstream vascular resistance2,3 . Subsequently, we decided to determine in a nested, case-controlled study whether Doppler parameters derived from the duration of systole in the second trimester and early third trimester can be used to detect early changes in cerebrovascular resistance and predict the development of pre-eclampsia.

METHODS From our original cohort of 1400 primigravid women who were assessed at 20–24 and 28–32 gestational weeks we identified 20 pregnancies that developed pre-eclampsia and matched one pre-eclamptic pregnancy with two controls that remained normotensive. Cases and controls were matched for maternal age within 2 years. Maternal characteristics and neonatal outcomes were obtained from both the study database and patients’ hospital records. Pre-eclampsia was diagnosed in the presence of hypertension, with blood pressure (BP) ≥ 140/90 on at least two occasions 6 h apart, proteinuria (> 0.3 g/day) or 1+ protein on dipstick test on at least two occasions 6 h apart after 20 weeks with normotensive BP levels verified at 6 weeks postpartum4 . All maternal demographics were reviewed from the patients’ antenatal records. The Doppler waveforms from the middle cerebral artery

Correspondence to: Dr K. P. Williams, Yale University School of Medicine, 333 Cedar Street, PO Box 208063, New Haven, CT 6520-8063, USA (e-mail: [email protected]) Accepted: 20 August 2003

Copyright  2004 ISUOG. Published by John Wiley & Sons, Ltd.


Maternal cerebral vascular changes and pre-eclampsia (MCA) previously performed at 20–24 and 28–32 weeks and stored on computer tape were retrieved and reanalyzed. Maternal MCA CBFV assessment was done according to the following protocol. The ultrasound probe (Medasonics CDS, Freemont, CA, USA) is placed over the temporal window, and the depth of the ultrasound beam is set at 55–66 mm. At this distance, Doppler signals from the MCA can be found. From the velocity wave, the maximum systolic velocity (velocity of the fastest moving red blood cells), the minimum diastolic velocity (the velocity of the moving red blood cells during the diastolic phase of the cardiac cycle), the mean velocity (calculated as the average velocity of the red blood cells) and the pulsatility index (PI) (maximum systolic velocity minus minimum diastolic velocity divided by mean velocity) are recorded. In addition to the traditional Doppler parameters of systolic, diastolic and mean velocity, we also assessed the following parameters derived from the duration of systole: end systolic time (EST), the time from the beginning of the systolic wave to end systole, and percentage end systolic time (% EST), the percentage time taken to achieve end systole, which is the EST divided by the time taken for a full cardiac cycle (Figure 1). For the purpose of this study, Doppler parameters were assessed in the sitting position with the head of the bed raised to 90◦ . After insuring normality of the data, mean and standard deviations were calculated and the measurements were compared between pre-eclamptic and normotensive pregnancies. Statistical differences were calculated using the unpaired Student’s t-test and significance was set at P < 0.05.

RESULTS Maternal age in pre-eclamptic and normotensive women was similar at about 27 years (Table 1). Pregnancy duration was decreased by 4 weeks in pre-eclampsia compared to control pregnancies (35 ± 2 vs. 39 ± 1 weeks; P < 0.0001) while birth weight displayed a deficit of about 800 g (2670 ± 165 vs. 3450 ± 200 g; P < 0.0001). The mean arterial blood pressure was significantly elevated from 28 weeks’ gestational age S




Figure 1 Middle cerebral artery waveform parameters. D, diastolic velocity; EST, end systolic time; M, mean velocity; S, systolic velocity; T, time of one cycle. % EST = EST/T × 100.

Copyright  2004 ISUOG. Published by John Wiley & Sons, Ltd.


onwards in the pregnancies destined to develop preeclampsia. This finding was not observed in the 20–24week gestation group (Table 2). Comparison of the Doppler-derived parameters in the second trimester time period between the two groups showed no significant difference (Table 2). Comparison of the Doppler-derived characteristics from the MCA in the early third trimester showed a significant prolongation in the % EST in the group of patients destined to develop pre-eclampsia (45.2 ± 4.2 vs. 42.3 ± 4.1; P < 0.01).

DISCUSSION Transcranial Doppler (TCD) has been used to identify changes in MCA and blood flow dynamics in preeclamptic patients5 – 8 . Previous studies conducted in preeclamptic patients have shown significant increases in systolic velocity, diastolic velocity and mean velocity in patients who are pre-eclamptic and eclamptic9,10 . Previous attempts to use these standard Doppler parameter changes occurring in the MCA to predict preeclampsia have yielded conflicting results. We previously identified no significant difference in MCA blood flow parameters in patients who develop pre-eclampsia Table 1 Maternal and neonatal characteristics Characteristic

Normotensive Pre-eclamptic

n 40 27.0 ± 1 Maternal age (years, mean ± SD) Primigravida incidence (%) 70 Gestational age at delivery 39 ± 1 (weeks, mean ± SD) 3450 ± 200 Birth weight (g, mean ± SD) Smoking incidence (%) 21.5 60 ± 11 Pre-pregnancy weight (kg) Height (cm) 163 ± 6

20 27.4 ± 2



79 35 ± 2

NS < 0.0001

2670 ± 165

< 0.0001

28.5 63 ± 13 162 ± 7


NS, not significant. Table 2 Maternal middle cerebral artery waveform parameters Parameter




Second trimester MAP (mmHg) PI Mean CBFV (cm/s) EST (ms) % EST

77.6 ± 6.4 1.05 ± 1.9 66.46 ± 1.2 27.5 ± 2.6 40.1 ± 3.9

79 ± 6.6 1.92 ± 0.21 69.25 ± 14.7 27.1 ± 2.7 41.5 ± 4.4


Third trimester MAP (mmHg) PI Mean CBFV (cm/s) EST (ms) % EST

77.3 ± 7.5 1.04 ± 0.19 66.62 ± 15 27.2 ± 3.7 42.3 ± 4.1

87.44 ± 7.7 1.03 ± 0.19 67.13 ± 13.5 26.3 ± 3.1 45.2 ± 4.2

0.0001 NS NS NS 0.01

CBFV, cerebral blood flow velocity; EST, early systolic time; % EST, percentage early systolic time; MAP, mean arterial blood pressure; NS, not significant; PI, pulsatility index.

Ultrasound Obstet Gynecol 2004; 23: 254–256.

Williams and Moutquin


compared to patients who remained normotensive1 . However, Riskin-Mashiah et al. in a nested, controlled study done between 19 and 28 gestational weeks identified that MCA PI and resistance index were lower in 10 normotensive women who developed preeclampsia compared with 20 pregnant women who remained normotensive (0.73 and 0.50 vs. 0.83 and 0.54; P < 0.05)11 . We therefore chose to assess other non-traditional Doppler parameters. The profile of the TCD ultrasound waveform depends on many factors including cardiac function and vascular compliance in addition to resistance in the distal arterial bed. Cerebrovascular autoregulation functions to maintain steady cerebral blood flow. If the resistance is increased in the distal cerebral vascular bed an increase will occur in the duration and/or the percentage time spent in systole in order to maintain normal cerebral blood flow. The waveform characteristics of systolic time and percentage systolic time that we assessed have not been applied to the MCA but similar parameters based on systolic function have been applied to other organ systems2,3,12 . Previously, systolic acceleration time was used in the renal artery as a measure of downstream resistance with increased systolic acceleration time occurring as downstream resistance increased in the in vitro model2 . When there was a greater than 50% reduction in the diameter of the renal artery there was a significant increase in systolic acceleration time. We hoped by utilizing different Doppler parameters that more sensitively reflect downstream resistance that we would be able to identify early changes in the second trimester in the middle cerebral circulation and use these to predict the development of pre-eclampsia. Our study identified that these changes in the MCA are present only in the third trimester. The observed variation in EST and % EST suggest downstream resistance changes in the maternal middle cerebral vascular bed as early as 28 weeks. The non-significant variation at around 20–24 weeks suggests that vascular resistance, already increased in most vascular beds by the mid-second trimester (16–20 weeks), is not yet installed in the cerebral vascular bed. This may be an unknown protective effect

Copyright  2004 ISUOG. Published by John Wiley & Sons, Ltd.

on the cerebral circulation or the changes are not yet sufficiently significant to be detected in the sitting position. Changes in the MCA waveform parameters in the second trimester necessary to predict pre-eclampsia may occur only after provocative testing (i.e. hand grip, CO2 reactivity)11 .

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