Ultrasound Obstet Gynecol 2010; 35: 688694 Published online 4 March 2010 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.

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Effect of antihypertensive therapy with -methyldopa on uterine artery Doppler in pregnancies with hypertensive disorders
A. KHALIL*, K. HARRINGTON, S. MUTTUKRISHNA* and E. JAUNIAUX*
*Academic Department of Obstetrics and Gynaecology, UCL Institute for Womens Health, University College London and The Homerton University Hospital NHS Trust, Queen Mary and Westeld College, University of London, London, UK

K E Y W O R D S: alpha methyldopa; antihypertensive; pre-eclampsia; pregnancy; uterine artery Doppler

ABSTRACT
Objectives Antihypertensive drugs lower blood pressure by direct vascular effects or central vasodilatory mechanisms. Their effect on uterine artery Doppler resistance indices in hypertensive disorders of pregnancy is uncertain. This study aimed to evaluate the impact of antihypertensive therapy with -methyldopa on maternal uterine artery Doppler pulsatility index (PI) and resistance index (RI) in women presenting with hypertensive disorders of pregnancy. Methods This was a cross-sectional study of 51 women with pre-eclampsia, 29 with gestational hypertension and 80 matched normotensive controls. Uterine artery PI and RI were measured at recruitment (between 24 and 40 weeks gestation) and, in the hypertensive groups, 2448 h after starting -methyldopa. Differences between mild and severe, and between early- and late-onset pre-eclampsia were compared using the MannWhitney test. The Wilcoxon rank sum test was used to compare measurements before and after treatment. Results Prior to treatment, uterine artery PI and RI were signicantly higher in women with pre-eclampsia compared with those with gestational hypertension and controls (P < 0.0001). The median uterine artery PI multiple of the median (MoM) was signicantly higher (P < 0.0001) in early-onset than in late-onset pre-eclampsia (1.83 (range, 0.883.65) vs. 1.19 (range, 0.911.72)) and in severe compared with mild disease (2.26 (range, 2.023.65) vs. 1.29 (range, 0.882.9)). Uterine artery PI- and RI-MoMs in both pre-eclampsia and gestational hypertension, before and after 34 weeks gestation, were not affected by -methyldopa treatment.

Conclusions Antihypertensive therapy using -methyldopa in women presenting with hypertensive disorders of pregnancy has no signicant effect on uterine artery resistance to blood ow, suggesting that it does not impair uteroplacental circulation in these cases. Copyright 2010 ISUOG. Published by John Wiley & Sons, Ltd.

INTRODUCTION
Pre-eclampsia affects up to 6% of all pregnancies and remains one of the leading causes of maternal mortality and morbidity1 4 . Women who develop pre-eclampsia are also at increased long-term risk of cardiovascular disease and stroke5,6 . There is a general consensus that pre-eclampsia originates from inadequate trophoblastic invasion of the maternal spiral arteries in early pregnancy7 10 . As a result, the spiral arteries fail to convert fully into high-ow, lowresistance vessels capable of meeting the increased demand for blood ow by the placenta11 14 . In non-pregnant women, uterine artery resistance, as measured by pulsatility index (PI) or resistance index (RI), is higher than in pregnant women and the Doppler waveform has an early diastolic notch, indicating the physiological resistance of the uterine artery walls between the systolic and diastolic phases of the cardiac cycle15,16 . In normal pregnancy, as the uterine arteries gradually transform to a high-volume, low-resistance circulation17,18 , this early diastolic notch disappears by 24 weeks gestation19 . Persistence of the diastolic notch and/or raised PI or RI in the uterine arteries as gestation advances indicates increased resistance to blood ow, which is associated with abnormal persistence

Correspondence to: Dr A. Khalil, UCL Institute for Womens Health, 8696 Chenies Mews, London WC1E 6HX, UK (e-mail: asmakhalil79@googlemail.com) Accepted: 12 January 2010

Copyright 2010 ISUOG. Published by John Wiley & Sons, Ltd.

ORIGINAL PAPER

Methyldopa and uteroplacental Doppler of vasoreactive musculature in the wall of the terminal branches of the uteroplacental circulation20 . The most commonly used antihypertensive drug in the UK for the management of women with hypertensive disorders in pregnancy is -methyldopa. There is a theoretical concern that, particularly in women presenting with pre-eclampsia, antihypertensive drugs might adversely affect uteroplacental perfusion by reducing maternal peripheral blood pressure when there is already increased uterine artery resistance21,22 . Previous studies investigating the effect of -methyldopa on uterine artery Doppler indices in women with hypertensive disorders of pregnancy included small numbers and yielded conicting results23 26 . The aim of this study was to evaluate further the impact of antihypertensive therapy with -methyldopa on maternal uterine artery Doppler blood ow indices in hypertensive disorders of pregnancy.
Study population (n = 160)

689

Participants with hypertensive disorders (n = 80)

Matched controls (n = 80)

Pre-eclampsia (n = 51)

Gestational hypertension (n = 29)

Early-onset disease (< 34 weeks gestation) (n = 28)

Late-onset disease ( 34 weeks gestation) (n = 23)

Early-onset disease (< 34 weeks gestation) (n = 13)

Late-onset disease ( 34 weeks gestation) (n = 16)

Figure 1 Flow diagram of women recruited to the study.

METHODS Subjects and study design

This was a prospective study of women with a singleton pregnancy presenting with hypertensive disorders in the second or third trimester. All the women were recruited at the Homerton University Hospital, London, over an 18-month period during which there were approximately 6000 deliveries. Demographic and clinical data including age, body mass index (BMI), parity, blood pressure and gestational age at recruitment were recorded. Gestational age was established on the basis of menstrual dates and/or ultrasonographic examination prior to 14 weeks gestation. All women were followed up until after delivery, and fetal and maternal outcomes were obtained from the womens medical and laborward records. Written consent was obtained from each woman after she had received full written information about the research project. This study was approved by the Camden & Islington Community Local Research Ethics Committee. Exclusion criteria included multiple pregnancy, a history of hypertension, diabetes, renal disease or immune disorders or women who, prior to pregnancy, were taking medication that could affect blood pressure. The study groups included 51 women presenting with pre-eclampsia, 29 with gestational hypertension and 80 controls (Figure 1). Blood pressure was measured in duplicate using a standard mercury sphygmomanometer and the average of the two readings taken. All readings were taken by the same operator (A. K.) with the subject in the sitting position. Korotkoff sounds 1 and 5 were used to dene systolic and diastolic blood pressure, respectively. Mean blood pressure was calculated as diastolic blood pressure + 1/3 pulse pressure. Pre-eclampsia was dened according to the guidelines of the International Society for the Study of Hypertension in Pregnancy27 . Diagnosis required two recordings of diastolic blood pressure of 90 mmHg at least 4 h apart, or one recording of

diastolic blood pressure 120 mmHg, in a previously normotensive woman, and urine protein excretion of 300 mg in 24 h, or two readings of ++ or more on dipstick analysis of a midstream or catheter specimen of urine, if no 24-h collection was available. Severe pre-eclampsia was dened as severe hypertension (diastolic blood pressure 110 mmHg) and mild proteinuria (a 24-h urine sample that contained 0.3 g but < 3.5 g protein), or mild hypertension (diastolic blood pressure 90 mmHg but < 110 mmHg and systolic blood pressure < 160 mmHg) and severe proteinuria (a 24-h urine sample that contained 3.5 g protein or a urine specimen 3+ protein by dipstick measurement). Patients with an abnormal liver function test (aspartate aminotransferase > 70 IU/L) and thrombocytopenia (platelet count < 100 000/ cm3 ) were also classied as having severe pre-eclampsia. Gestational hypertension was dened as a diastolic blood pressure 90 mmHg on at least two consecutive occasions, 4 h apart, in the second half of pregnancy, without proteinuria, in a previously normotensive woman27 . Fetal growth restriction was dened as birth weight less than the 5th centile for gestational age. The control group comprised 80 normotensive women matched for gestational age (4 days), maternal age (3 years) and parity (none or one to two deliveries). All the women in the control group had uncomplicated pregnancies. They had no history of cardiovascular disease, hypertension, proteinuria or fetal growth restriction, and were not taking any medication that could affect blood pressure. In accordance with local protocols, co-existing fetal growth restriction did not inuence the decision to start antihypertensive therapy. In women on antihypertensive treatment, the target blood pressure was 130140/9095 mmHg.

Uterine artery Doppler measurements

Uterine artery Doppler indices were measured in the hypertensive and control groups at the time of

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Khalil et al. three groups. The MannWhitney test was used to compare the markers levels between mild and severe, and between early-onset and late-onset pre-eclampsia. The Wilcoxon signed-rank test was used to compare the measurements before and after antihypertensive therapy. Data were analyzed using SPSS (SPSS version 15, 2007, SPSS Inc., Chicago, IL, USA) and GraphPad Prism 5.0 for Windows (InStata, GraphPad Software Inc., San Diego, CA, USA). Results were considered statistically signicant at P < 0.05. All P-values were two-tailed.

recruitment. In women who received -methyldopa therapy, Doppler measurements were taken at the same time as blood pressure recordings immediately before and 2448 h after therapy was initiated. The uterine artery was identied by a combination of real-time and color Doppler techniques (iU22 Ultrasound System, Philips Medical Systems, Bothell, WA, USA). Blood velocity waveforms were recorded by the pulsed Doppler method (3.5-MHz curved probe; 120-Hz high-pass lter). Both uterine arteries were studied, and the mean PI and mean RI calculated. The transducer was placed over the iliac fossa and the course of the uterine artery followed from the lateral pelvic wall across the external iliac artery using color Doppler. Pulsed Doppler was then applied 1 cm medial to the crossover point. The angle of insonation used was less than 30 . Five consecutive ow velocity waveforms of good quality were recorded, and the PI and RI derived. Examination was performed with the woman in a semi-recumbent position. A single operator (A. K.) performed all examinations, eliminating interobserver variability. The intraobserver coefcients of variation for PI and RI were 2.7 and 2.9%, respectively. The peak systolic velocity in all the measurements was more than 60 cm/s.

RESULTS
Figure 1 presents a ow diagram of the women recruited to our study, while the baseline characteristics and clinical features of the different study groups are shown in Table 1, which also shows the time interval between the two measurements in the hypertensive women. The diastolic blood pressure of all women with preeclampsia or gestational hypertension was higher than 95 mmHg. They received oral antihypertensive therapy in the form of -methyldopa 7501500 mg/day for clinical indications according to local clinical protocols. There were signicant falls in both systolic and diastolic blood pressure (mean SD) in women with preeclampsia (systolic 26.7 20.6, P < 0.001; diastolic 16.9 10.7, P < 0.001) and gestational hypertension (systolic 13.7 24.9, P = 0.023; diastolic 12.3 12.2, P < 0.001). The maternal heart rate decreased from 81.0 8.6 to 77.1 7 in women with pre-eclampsia (P < 0.001) and from 82.7 9 to 79.2 8 in those with gestational hypertension (P < 0.001). In the group of women presenting with pre-eclampsia (n = 51), 16 (31.4%) had associated fetal growth restriction and 8 (15.7%) had severe pre-eclampsia. All the severe preeclampsia cases were in the early-onset subgroup. There was no signicant association between either mean PI or mean RI and maternal age, BMI, parity or ethnicity, so we did not adjust for these parameters.

Statistical analysis
We calculated that we would need 24 women in each antihypertensive group to have 80% power to detect a difference of at least 60% of the standard deviation of the difference in mean PI at the 5% level. The DAgostino and Pearson Omnibus test was used to assess normality of continuous data. The data were not normally distributed. Mean PI and mean RI values were converted into gestational week specic multiples of the median (MoM) levels among the controls. Data were analyzed in two gestational age intervals: < 34 weeks (early-onset disease) and 34 weeks (late-onset disease). The KruskalWallis test with Dunns post hoc test was carried out to study the differences among the

Table 1 Baseline characteristics of the study groups according to gestational age at recruitment GA at recruitment < 34 + 0 weeks Characteristic Controls (n = 41) PE (n = 28) GH (n = 13)
P

GA at recruitment 34 + 0 weeks Controls (n = 39) PE (n = 23) GH (n = 16)

P

Age (years)* 31 4 30 5 32 4 27 4 30 4 27 4 Body mass index (kg/m2 )* Nulliparous 25 (61.0) 20 (71.4) 7 (53.8) Current smoker 1 (2.4) 0 (0) 0 (0) Caucasian 20 (48.8) 13 (46.4) 7 (53.8) 30 1.3 30 0.4 30.4 0.8 GA at recruitment (weeks)* 39.7 2.3 33 1.7 36.7 2.9 GA at delivery (weeks)* 3398 529 1685 204 2725 198 Birth weight (g)* 85 12 126.6 12 125.1 12 Mean blood pressure (mmHg) 32 4 34 3 Interval between measurements (h)

0.6 31 4 30 4 325 0.07 28 3 27 5 29 5 0.6 21 (53.8) 16 (69.6) 9 (56.2) 1 2 (5.1) 1 (4.3) 0 (0) 0.7 23 (59.0) 13 (56.5) 9 (56.2) 0.5 36.6 2.4 36 2.3 36.4 2 < 0.001 39.8 1.6 37.3 2 38.6 2.3 < 0.001 3405 526 2896 689 3174 591 < 0.0001 85 11 121.1 11.1 114.5 6.1 38 6 39 7

0.2 0.2 0.3 1 0.4 0.4 < 0.001 < 0.001 < 0.0001

Data are given as mean SD or n (%). GA, gestational age; GH, gestational hypertension; PE, pre-eclampsia. *Data analyzed by one-way ANOVA with Bonferroni post hoc analysis.

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Before -methyldopa therapy

Before 34 weeks gestation, prior to treatment, the median uterine artery PI-MoM was signicantly higher in women presenting with pre-eclampsia (1.83 (range, 0.883.65)) than in women with gestational hypertension (1.1 (range, 0.541.47)) or in controls (1.05 (range, 0.631.53)) (P < 0.0001) (Figure 2a). There was no signicant difference between women with gestational hypertension and controls (P = 0.86). A similar pattern of results was seen at 34 weeks gestation prior to treatment (Figure 2b). The median PI-MoM in women with pre-eclampsia (1.19 (range, 0.911.72)) was signicantly higher than in women with gestational hypertension (0.92 (range, 0.741.47)) or controls (0.93 (range, 0.691.39)) (P < 0.0001). There was no signicant difference between women with gestational hypertension prior to treatment and controls (P = 0.95). The mean RI-MoM measurements followed a similar pattern (Figure 3). Prior to treatment before 34 weeks gestation, the median RI-MoM was signicantly higher in women with pre-eclampsia (1.58 (range, 1.442.01)) than in women with gestational hypertension (0.94 (range, 0.781.16)) or controls (0.95 (range, 0.721.35)) (P < 0.0001) (Figure 3a). At this gestational age there was no signicant difference between women with gestational hypertension prior to treatment and controls (P = 0.58). After 34 weeks, the median RI-MoM was signicantly higher in women with pre-eclampsia prior to treatment (1.57 (range, 1.381.67)) than in women with gestational hypertension (0.97 (range, 0.871.03)) and in controls (0.99 (range, 0.891.16)) (P < 0.0001) (Figure 3b). At this gestational age there was also no signicant difference between women with gestational hypertension prior to treatment and controls (P = 0.05).
P < 0.0001 P < 0.0001 (a) 4 Mean pulsatility index MoM P = 0.07 P = 0.86

After -methyldopa therapy

In women with pre-eclampsia, there was no signicant difference in the median uterine artery PIMoM before and after treatment, in either gestational age interval: < 34 weeks (1.83 (range, 0.883.65) vs. 1.83 (range, 0.823.61), P = 0.07); 34 weeks (1.19 (range, 0.911.72) vs. 1.2 (range, 0.891.65), P = 0.7). Similarly, in women with gestational hypertension, there was no signicant difference before and after treatment: < 34 weeks (1.1 (range, 0.541.47) vs. 1.11 (range, 0.541.47), P = 0.27); 34 weeks (0.92 (range, 0.741.47) vs. 0.91 (range, 0.741.49), P = 0.39). Antihypertensive treatment with -methyldopa was not associated with any signicant change in the mean RIMoM in women with either pre-eclampsia or gestational hypertension, at any gestation (Figure 3). In women with pre-eclampsia before 34 weeks, the median RI-MoM before and after treatment was 1.58 (range, 1.442.01) and 1.56 (range, 1.41.92) (P = 0.08). The equivalent gures for women with gestational hypertension were 0.94 (range, 0.781.16) and 0.96 (range, 0.81.16) (P = 0.61). After 34 weeks gestation, median RI-MoM in women with pre-eclampsia before and after treatment was 1.57 (range, 1.381.67) and 1.62 (range, 1.291.69) (P = 0.5). The equivalent gures for women with gestational hypertension after 34 weeks were 0.97 (range, 0.871.03) and 0.99 (range, 0.911.01) (P = 0.62).

Early-onset versus late-onset disease

We further analyzed women presenting with preeclampsia, comparing early-onset with late-onset disease and severe with mild pre-eclampsia. The median uterine artery PI-MoM was signicantly higher in early-onset compared with late-onset pre-eclampsia (1.83 (range, 0.883.65) vs. 1.19 (range, 0.911.72)) and in women with severe compared with mild disease (2.26 (range,

P < 0.0001 (b) 3 Mean pulsatility index MoM P < 0.0001 P = 0.95

3 P = 0.27 2

P = 0.7

P = 0.39

PE before

PE after

GH before

GH after

Controls

PE before

PE after

GH before

GH after

Controls

Figure 2 Box-and-whisker plots of uterine artery pulsatility index multiples of the median (MoM) before and after antihypertensive therapy in women with pre-eclampsia (PE) or gestational hypertension (GH), and in normotensive controls, stratied according to gestation: (a) at < 34 weeks; (b) at 34 weeks. Boxes show median and interquartile range. Whiskers represent minimum and maximum values.

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P < 0.0001 P < 0.0001 P = 0.08 P = 0.58 P < 0.0001 (b) 2.5 P = 0.61 Mean resistance index MoM P = 0.5 2.0 1.5 1.0 0.5 0.0 P = 0.62 P < 0.0001

Khalil et al.

P = 0.05

(a) 2.5 Mean resistance index MoM 2.0 1.5 1.0 0.5 0.0

PE before

PE after

GH before GH after

Controls

PE before

PE after

GH before GH after

Controls

Figure 3 Box-and-whisker plots of uterine artery resistance index multiples of the median (MoM) before and after antihypertensive therapy in women with pre-eclampsia (PE) or gestational hypertension (GH), and in normotensive controls, stratied according to gestation: (a) at < 34 weeks; (b) at 34 weeks. Boxes show median and interquartile range. Whiskers represent minimum and maximum values.
P < 0.0001 P < 0.0001 (b) 2.2 Mean resistance index MoM 2.0 1.8 1.6 1.4 1.2 P = 0.45 P < 0.001

(a) 4 Mean pulsatility index MoM

Early-onset PE Late-onset PE

Severe PE

Mild PE

Early-onset PE Late-onset PE

Severe PE

Mild PE

Figure 4 Box-and-whisker plots of uterine artery Doppler pulsatility index multiples of the median (MoM) (a) and resistance index MoM (b) in women with early-onset compared with late-onset pre-eclampsia (PE), and severe compared with mild PE. Boxes show median and interquartile range. Whiskers represent the minimum and maximum values.

2.023.65) vs. 1.29 (range, 0.882.9)) (P < 0.0001) (Figure 4a). Median RI-MoM was signicantly higher in women with severe pre-eclampsia than in those with mild pre-eclampsia (1.67 (range, 1.62.01) vs. 1.56 (range, 1.381.78)) (P < 0.001) (Figure 4b), but there was no signicant difference in RI between women with earlyonset and late-onset disease (1.58 (range, 1.442.01) vs. 1.57 (range, 1.381.67)) (P = 0.45).

Pre-eclampsia complicated by fetal growth restriction

In the pre-eclamptic group, we compared the cases who developed fetal growth restriction (n = 16) with those who did not (n = 35). The median uterine artery PI-MoM was signicantly higher in the fetal growth restriction group compared with the non-fetal growth restriction group (2.08 (range, 1.443.65) vs. 1.27 (range,

0.882.18)) (P < 0.0001). In both groups there was no signicant difference in the median uterine artery PI-MoM before and after treatment (fetal growth restriction group: 2.08 (range, 1.443.65) vs. 2.06 (range, 1.393.65) (P = 0.19); non-fetal growth restriction group: 1.27 (range, 0.882.18) vs. 1.25 (range, 0.822.14) (P = 0.05)). A similar pattern was seen in RI measurements. Median RI-MoM was signicantly higher in the fetal growth restriction group than in the non-fetal growth restriction group (1.65 (range, 1.442.01) vs. 1.54 (range, 1.381.67)) (P = 0.001). In both groups there was no signicant difference in the median uterine artery RI-MoM before and after treatment (fetal growth restriction group: 1.65 (range, 1.442.01) vs. 1.62 (range, 1.441.92) (P = 0.06); non-fetal growth restriction group: 1.54 (range, 1.381.67) vs. 1.55 (range, 1.291.76) (P = 0.91)).

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DISCUSSION
Our data indicate that antihypertensive therapy using -methyldopa in women with hypertensive disorders of pregnancy has no signicant effects, either adverse or benecial, on maternal uterine artery Doppler indices of resistance, in spite of a reduction in maternal systemic blood pressure. We found that -methyldopa did not have an effect on uterine artery RI or PI in either preeclampsia or gestational hypertension, either before or after 34 weeks gestation. Similar results were found in women with severe pre-eclampsia and those with fetal growth restriction who presented with the highest values of uterine resistance to blood ow. Our data conrm the ndings of previous studies indicating that, before antihypertensive therapy, uterine artery PI and RI are increased in women with pre-eclampsia but not in women with gestational hypertension, compared to normotensive controls23,28 32 . The impairment of uteroplacental perfusion found in pre-eclampsia can explain the less favorable fetal and neonatal outcomes observed in these cases compared with pregnancies complicated by gestational hypertension33 35 . Frusca et al.36 have shown that abnormal uterine artery Doppler waveforms are common in women with pre-eclampsia compared with women with gestational hypertension but that in both groups, the presence of abnormal uterine Doppler parameters is related to poorer pregnancy outcome. Andersch et al.37 have also shown that maternal and fetal complications are more common in hypertensive women with proteinuria than in hypertensive women without proteinuria. In their study, even the non-proteinuric hypertensive women had a higher rate of maternal complications than normotensive controls (13 vs. 4%), conrming that non-proteinuric hypertension is a pathological condition. We found that, independent of gestational age, methyldopa therapy had no signicant effect on uterine artery Doppler resistance to blood ow in 51 cases of pre-eclampsia and 29 cases of gestational hypertension. Four smaller studies that previously examined the effect of -methyldopa on uterine artery Doppler indices in women with hypertensive disorders of pregnancy yielded conicting results23 26 . The rst study by Montan et al.24 included 20 women presenting with pre-eclampsia in the third trimester. They were given 750 mg of -methyldopa daily for a week and no signicant effect was found on uterine artery PI. In the second study by the same authors, isradipine and -methyldopa were used, and no effect on the uterine artery PI was observed25 . In contrast, the study by Rey26 comparing 25 women with pre-eclampsia (14 on treatment, 11 untreated), 43 women with chronic hypertension (14 on treatment, 29 untreated) and 22 normotensive controls, treated with -methyldopa 750 mg daily for a week, found a decrease in uterine artery PI in treated women in both hypertensive groups. Similarly, Gunen c et al.23 compared 24 women with preeclampsia treated with 1 g of -methyldopa per day for a week, with 20 normotensive pregnant controls. They found that the uterine artery PI, RI and systolic/diastolic ratio were lower after antihypertensive therapy.

It is possible that the lack of effect of -methyldopa therapy on uterine artery resistance in our study was due to the relatively short duration of treatment before repeat measurements. When we analyzed separately those women who had repeat measurements after 24 or 48 h, we found no signicant correlation between effect on resistance and time interval between the rst dose of -methyldopa and Doppler examination. However, we cannot exclude the possibility that more prolonged therapy with -methyldopa might have affected uterine artery PI, as in some of the studies mentioned above. A recent systematic review has shown that antihypertensive drug therapy in cases presenting with mild to moderate hypertension during pregnancy has no benecial effect on the risk of fetal demise (relative risk 0.73; 95% CI, 0.501.08), small for gestational age babies (relative risk 1.04; 95% CI, 0.841.27) or on any other adverse fetal outcome38 . Overall, the main benet of antihypertensive treatment in these women is an improvement in maternal outcomes, in particular a halving of the risk of developing severe hypertension (relative risk 0.50; 95% CI, 0.410.61). We have previously shown in the same population of women that -methyldopa therapy is associated with a fall in maternal serum and placental levels of soluble fms-like tyrosine kinase 1, soluble endoglin39 , inhibin A, activin A40 and in arterial stiffness as measured by pulse-wave analysis41 , in women presenting with pre-eclampsia. In the current study the absence of any signicant fall in uterine artery resistance to blood ow suggests that resistance in the uterine arteries is inuenced more by the resistance in the downstream spiral arteries than by systemic vascular conditions. These ndings also indicate that antihypertensive therapy using methyldopa is unlikely to lead to further fetal compromise, even in the presence of pre-existing increased uterine artery resistance in those with pre-eclampsia combined with fetal growth restriction.

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Ultrasound Obstet Gynecol 2010; 35: 688694.