Effect of low-dose aspirin treatment on vascular resistance in the uterine, uteroplacental, renal and umbilical arteries — A prospective longitudinal study on a high risk population

EUROPEAN JOURNAL

OF

U~VI~SOUND E L S E V I E R European Journal of Ultrasound 5 (1997) 17-30

Clinical paper

Effect of low-dose aspirin treatment on vascular resistance in the uterine, uteroplacental, renal and umbilical arteries - a

prospective longitudinal study on a high risk population with persistent notch in the uterine arteries

Peter Zimmerrnann a,*, Vuokko Eiri6% Juhani Koskinen% Kyr6 Niemi b, Ralf Nyman b, Erkki Kujansuu c, Tapio Ranta ~

aDepartment of Obstetrics and Gynecology, Pdijdt-Hiime Central Hospital, Lahti, Finland bDepartment of Pediatrics, Piiijdt-Hdrne Central Hospital, Lahti, Finland

~Department of Obstetrics and Gynecology, University Hospital, Tampere, Finland

Received 2 April 1996; revised 15 November 1996; accepted 18 November 1996

Abstract

Objective: The study focuses on the changes of Doppler flow velocity waveforms in the uterine, uteroplacental, maternal intrarenal and umbilical artery in a selected population at high risk for pre-eclampsia or IUGR with original abnormal Doppler of the uterine arteries, defined as persistent bilateral notches at 22-24 weeks of gestation, who were randomised treated with low-dose aspirin compared to no treatment and low risk controls, longitudinally during pregnancy and 6 months postpartum. Methods: High risk and control patients were collected from a population attending routine ultrasound for confirmation of gestational age. One-hundred-and-seventy-eight high risk patients and 29 normal controls had duplex pulsed wave Doppler ultrasound at 22-24 weeks of gestation. Twenty-eight high risk patients showed bilateral notches in the main uterine arteries. Of those 26 were randomised treated with 50 mg aspirin or had no treatment. Additional Doppler ultrasound examinations were performed twice during pregnancy at 28-32 and 33-40 weeks and once 6 months postpartum. Main outcome criteria were incidence of pregnancy induced hypertension (PIH) and intrauterine growth retardation (IUGR). Results: The notches in the uterine arteries in the high risk group were constant throughout pregnancy in both the aspirin and untreated group in 88.5% (23/26) of the cases. The majority of resistance indices (RI) in the main uterine and uteroplacental arteries of the high risk population ranged above the mean line registered in low risk pregnancies, whereas no differences could be seen in the renal and umbilical artery. Aspirin had no effect on the Doppler waveform in any of the examined vessels except the

* Corresponding author. Vellamontie 4, FIN-15870 Hollola, Finland. Tel.: + 358 40 5109242; fax: + 358 3 7803905.

0929-8266/97/$17.00 © 1997 Elsevier Science Ireland Ltd. All rights reserved. PH S0929-8266(96)00203-0

18 P. Z immermann el al. / European Journal ~[' Ultrasound 5 (1997) 17 30

uteroplacental arteries. At 22 24 weeks of gestation the highest RI were found in high risk patients who developed PIH or IUGR later during pregnancy compared to high risk patients without disease or normal controls. Six months postpartum no differences in vascular resistance were seen any more between the different groups and the RI was still lower than reported for non pregnant women. Aspirin treatment could not prevent PIH or IUGR, but was safe for the foetus. However, in the aspirin group there was one uterine haemorrhage at 36 weeks of gestation and one placental abruption at emergency caesarean section for threatening asphyxia at 38 weeks. Persistent bilateral notches in high risk patients selected a group with 35% incidence of PIH and 12% incidence of IUGR. Conclusions: Low-dose aspirin treatment does not affect the resistance index in the uterine, umbilical or renal circulation. Significant notches in the uterine arteries at 22 24 weeks gestation persist usually throughout pregnancy. The phenomenon is related to higher resistance indices but does not prevent 'physiological' adaptation of vascular resistance in the uterine artery during pregnancy or postpartum. Combining high risk selection and uterine Doppler at 22 24 weeks of gestation may be useful to find a group with high incidences of PIH or IUGR. However, starting low-dose aspirin treatment based on the pathological Doppler, is possibly too late tbr prevention of the disease. © 1997 Elsevier Science Ireland Ltd.

Keywords: Doppler ultrasound: Low-dose aspirin treatment: Pregnancy

1. Introduction

Pre-eclampsia is a common cause of foetal growth retardation ( IUGR), morbidity and mor- tality. Although antihypertensive treatment re- duces the maternal morbidity, it does not have influence on the onset of the disease or on the frequency of foetal complications.

Therefore research, on this topic has been con- centrated on the search for early markers of pre- eclampsia and intrauterine growth retardation and the prevention of these complications by low doses of aspirin started at the end of the first or during the second trimester (Uzan et al., 1994).

A number of prospective studies have shown the potential advantage of using low doses of aspirin (50 150 mg/day) as a preventive treatment of intrauterine growth retardation and pre- eclampsia (Beaufils et al., 1985; Wallenburg and Rotmans, 1987; Benigni et al., 1989; Schiff et al., 1989; McParland et al., 1990; Uzan et al., 1991; Hauth et al., 1993; Sibai et al., 1993). However, the selection of the patients who would benefit from a prophylactic aspirin treatment, is still de- bated. So aspirin could reduce the incidence of pre-eclampsia in unselected nulliparous women from 5.6 to 1.7% (Hauth et al., 1993) and from 6.3 to 4.6% (Sibai et al., 1993). However, other studies, like the representative CLASP trial on more than 9000 pregnant women (CLASP, 1994)

and a smaller Finnish trial (Viinikka et al., 1993), could not prove those optimistic results.

Resuming the data of over 15000 pregnant women available so far, a general prophylactic use of low-dose aspirin in unselected pregnancies does not seem to be justified. However, there are patients who are at increased risk of early onset of pre-eclampsia, who might benefit of a low-dose aspirin treatment (Beilin, 1994; Wallenburg, 1995; Ylikorkala, 1995). Aspirin seems to be of little use in multiparae at moderate risk or in a therapeuti- cal sense in cases, where signs of beginning disease are present already (Schiff et al., 1989; Italian study of aspirin in pregnancy, 1993; CLASP, 1994).

Thus, an early marker of pre-eclampsia would be useful for adequate selection for preventive treatment with aspirin. Some authors have suggested that uterine artery Doppler is a very useful risk marker for pre-eclampsia and I U G R (Ar- duini et al., 1987; McParland et al., 1990; Davies et al., 1992; Bower et al., 1993), whereas umbilical artery Doppler seems to be less useful (Atkinson et al., 1994).

The present study focuses on the question, whether low-dose aspirin treatment has any influence on the Doppler waveforms in different maternal and the umbilical arteries in a selected high risk population with original abnormal Doppler of the uterine arteries.

P. Zimmermann et al. / European Journal of Ultrasound 5 (1997) 17-30

Table 1 Criteria for inclusion into high risk group and numbers of patients allocated to treatment and control goups

19

Parity Inclusion criteria Number of patients

Aspirin (n = 13) Untreated (n = 13)

Nulliparous Chronical hypertension l l Familar risk of pre-eclampsia (mother or sister) 2 2

Multiparous Chronical hypertension 3 4 History of pre-eclampsia 5 3 History of IUGR 2 1 History of intrauterine death 0 2

There are results of at least two trials indicating that low-dose aspirin (60 mg), applied from 24 weeks gestation until delivery does not affect Doppler index values in the umbilical artery, foetal renal artery or descending aorta (Owen et al., 1993; Veille et al., 1993). However, less data are reported about possible effects of low-dose aspirin on the Doppler waveform in the maternal uterine, renal and uteroplacental circulation.

Although most studies on maternal renal circulation in pre-eclampsia did not find any changes in renal flow velocities (Levine et al., 1992; Thaler et al., 1992; Liberati et al., 1994), one report describes a correlation between pre-eclampsia and elevated Doppler indices in the renal artery (Sohn und Fendel, 1988). Another study showed a relationship between abnormal flow in the uterine artery and elevated resistance index in the renal artery (Thaler et al., 1992). For those reasons the maternal renal artery was included in the study design.

The purpose of this study was: (1) to examine longitudinally during pregnancy

the changes of Doppler flow velocity waveforms in the uterine, uteroplacental, maternal renal and umbilical artery in a selected population at high risk for pre-eclampsia or IUGR with original abnormal Doppler of the uterine arteries, defined as persistent bilateral notches at 22-24 weeks of gestation;

(2) to compare these results with a reference population at low risk;

(3) to assess the effect of low-dose aspirin treatment on the Doppler waveforms;

(4) to compare the Doppler results in the maternal uterine and renal arteries during pregnancy and 6 months postpartum.

2. Patients and experimental methods

From March 1994 to October 1995 we studied patients at high risk for hypertensive disorders of pregnancy or IUGR, in a prospectively designed randomised controlled longitudinal trial. High risk patients were recruited from the population of pregnant women, attending routinely performed ultrasound for confirmation of gestational age at 18-19 weeks at the P/iij/it-H/ime Central Hospital, Lahti, Finland. This population is about 2500 pregnant women per year.

The patients were interviewed by one of the sonographers (V.E.) and offered to participate in the study, if they fitted the inclusion criteria which are defined in Table 1.

Volunteers were invited to a Doppler ultrasound investigation at 22-24 weeks. Before that investigation patients gave informed consent and were checked again for fitting the inclusion criteria by the main author (P.Z,) who performed all Doppler investigations. In case of a constant bilateral early diastolic notch in the main uterine arteries the patients were asked to participate in a randomised controlled trial.

A notch was defined as clearly visible, at least by one third lower early diastolic velocities when compared to mid diastole (as shown in Fig. 3c). The notch was defined 'constant', if it was seen during the whole period of measurement in the particular vessel (20-30 s).

Of the 178 high risk patients 28 had bilateral notches in their uterine arteries, in 10 patients a notch was seen only on one side and in three patients the notch was not constant from beat to beat.

20 P. Zimmermann et al. / European Journal o! Ultrasound 5 (1997) 17-30

Of the 28 patients with bilateral notches finally 26 were willing to participate in the study and randomised. Half of the patients were treated with a daily dose of 50 mg aspirin (Disperin '~) and half had no treatment. Treatment was started at the same day of the Doppler investigation and stopped at 38 completed weeks of pregnancy. The age of the mothers was 28.5 _+ 6.4 years (mean ± S.D.) and 27.3 _+6.4 years in the aspirin and untreated high risk group, respectively. In both groups were three nulliparae and ten multiparae.

The low risk group was recruited from the same population attending routine ultrasound for confirmation of gestational age at the very beginning of the study. Mothers who did not fit the inclusion criteria for high risk with otherwise normal singleton pregnancies were almost consecutively asked to volunteer as reference group. Of the 32 patients who gave consent 29 were followed up and had similar Doppler investigations like the study group. The age of the control group was 28 +3 .0 (mean _+ SD.), 17 mothers were nulliparous and 12 multiparous, respectively. Imbal- ance with regard to parity between study and reference group was due to the low incidence of bilateral notching in the nulliparous group, which was not known at the time when the reference population was examined.

Using a duplex pulsed wave Doppler ultrasound scanner (ALOKA SSD-650) with a 3.5- MHz convex transducer, we registered blood velocity waveforms of both main uterine arteries, the uteroplacental arteries in the region of placental implantation, the intrarenal branches of the right maternal renal artery and the umbilical artery. In all Doppler measurements, the mean peak systolic (S) to end-diastolic (D) ratio of 3 5 cardiac cycles was computed by electronic calipers and the RI calculated: RI = (S-D)/S (Pourcelot, 1975). A high pass filter of 100 Hz was used as standard setting. The sample volume was set to 2 -5 mm. Calipers were adjusted manually to the frozen image of the waveform.

The main uterine artery was located at the uterocervical junction close to the cross over point of the uterine and external iliac artery on both sides. When placental implantation was clearly shifted to the left or right site this was defined as

'placental site'; otherwise the site with the lower resistance index was regarded as 'placental site'. The uteroplacental arteries were localised within the myometrium, close to the placental bed, thus corresponding anatomically to the radial-spiral arteries of the uteroplacental circulation.

Reproducibility was tested for the RI in both uterine arteries in ten patients. Here, both sites were examined five times in an alternating manner by the main author. The intraobserver error was calculated as coefficient of variability (COV = S.D. × 100/mean %). The mean COV was 5.7 _+ 3.3% (mean _+ S.D.) and 7.1 _+2.9% at the non-placental and placental site, respectively. Similar values were found previously for the umbilical arteries.

Because of the difficulty identifying exactly the same branch of the uteroplacental arteries in re- peated measurements, no reproducibility test was performed in those vessels.

The branches of the right maternal renal artery was examined with the woman in the left lateral decubitus position. The right kidney was imaged with the real-time scanner in a longitudinal plane using a translumbar or lateral approach. During a short period of apnoea the renal sinus was visu- alised with real-time ultrasound and the Doppler sample adjusted distally to the sinus along the border of medullar pyramids until the typical low-resistance waveform was obtained from one of the interlobar branches of the renal artery, as described in the literature (Gudmundsson and Mar~al, 1991; Levine et al., 1992) and shown in Fig. 3b. To avoid unnecessary prolongation of the Doppler investigation only the right kidney was examined (right side for convenience). Doppler flow parameters have been found similar in both kidneys (Levine et al., 1992; Thaler et al., 1992).

Measurements in the umbilical artery were per- lbrmed as previously described (Zimmermann et al., 1991).

Postpartum measurements of the uterine arteries were performed using a 5 MHz transvaginal probe. To compare our results with previous reports in the literature, here additionally to the RI also the pulsatility index PI ( P I = (S-D)/mean) was calculated.

P. Zimmermann et al. / European Journal o f Ultrasound 5 (1997) 17-30 21

After the initial Doppler examination at 22-24 weeks of gestation Doppler ultrasound was performed twice during pregnancy at 28-32 and 33-40 weeks and once postpartum. Postpartum investigations were done 24_+ 6 (mean_+ S.D.) weeks after delivery in the study group and 26 _+ 2 weeks in the normal control population.

The incidence of hypertensive disorders of pregnancy (PIH) and foetal growth retardation (IUGR) were recorded as main outcome mea- sures.

Pre-eclampsia was defined as blood pressure of 145/85 mmHg or higher on two or more measurements and proteinuria on dipstick testing of a midstream urine specimen on two or more occa- sions more than 24 h apart, occurring for the first time in the second half of pregnancy. Pregnancy induced hypertension was defined, if the onset was in the second half of pregnancy and chronical hypertension, if the disease was present already in the first trimester. Hypertensive disorders were defined 'severe', if blood pressure exceeded 160/ 100 mmHg.

Foetal growth retardation was defined as birthweight below the 10th centile for normal Finnish population (Ylfi-Outinen, 1984).

To investigate a possible effect of aspirin treatment on maternal blood loss in the study group, hemoglobin was sampled before and after delivery. To exclude possible harmful bleeding in the newborn due to the aspirin treatment, cerebral ultrasound was performed at the third day of life by two of the authors (R.N. and K.N.).

The study was approved by the P/iij/it H/ime Central Hospital's Ethical Committee and informed written consent was obtained from each patient.

Data were analysed statistically using multiple regression analysis to test the effects of high risk/ notching, aspirin treatment and gestational age on the Doppler waveforms. R1 indices of the umbilical and renal arteries were normally distributed. Data of the uterine and uteroplacental circulation demanded logarithmic transformation to fit a normal distribution.

The Sign-test for paired observations was used to compare the resistance indices of the uterine and renal arteries at 22 24 weeks gestation and

postpartum in the study population. The Mann- Whitney U-test for independent observations was performed to compare the postpartum results of the study group with normal references.

The analyses were done with the statistical package Statistica/w TM.

Two-sided P-values are reported for all signifi- cance test; P-values less than 0.05 are considered statistically significant.

3. Results

During pregnancy 95 Doppler waveforms were registered in both uterine arteries and the right maternal renal artery and 94 in the umbilical artery. Due to posterior placental implantation and lack of maternal co-operation the uteroplacental arteries were not always accessible. Thus, only 85 Doppler measurements were available here for the analysis. A total of 113 Doppler measurements were performed in the reference group. Fig. l a - e show plots of single measurements in the different arteries.

Surprisingly, also four patients of our reference population showed a bilateral notch and another four patients a notch at the 'non-placental' site at the initial Doppler investigation at 22 24 weeks. However, none of these notches persisted beyond 30 weeks of gestation and none of the patients developed PIH or IUGR.

In contrast to the low risk population, the notches in the uterine arteries were constant throughout pregnancy in both the aspirin and untreated group in 88.5% (23/26) of the cases. The majority of RI in the main uterine (Fig. la, Fig. lb) and uteroplacental arteries (Fig. lc) of the high risk population ranged above the mean line registered in normal pregnancies, whereas no differences could be seen in the renal (Fig. ld) and umbilical artery (Fig. le).

Multiple regression analysis revealed decreasing vascular resistance with increasing gestation in all examined blood vessels except the maternal renal artery (Table 2). This relationship was independent of aspirin treatment in all except the uteroplacental arteries. In these arteries resistance indices were quite similar in the high risk group

P. Zimmrrmunr~ rt al. )/ European Journal of’ l~l~rasound 5 (1997) I7 30 22

P. Zimmermann et al. / European Journal o[' Ultrasound 5 (1997) 17 30 23

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Fig. I. Plots of single measurements of the resistance index in the different arteries during pregnancy• (a) uterine artery (pl.site), (b) uterine artery (non-pl. site), (c) uteroplacental arteries, (d) maternal renal artery, (e) umbilical artery. Large dots represent measurements in selected high risk patients with persistent notch during pregnancy. Overlayed are reference measurements from the normal population shown as small dots (-).Filled circles (O) are results from patients treated with aspirin compared to untreated controls represented by open circles (©). Continuous lines represent regression line of means with 95% confidence interval of the means and the 95% prediction ellipse of the normal population ( ), respectively. Dotted lines ( ...... ) show regression lines of high risk patiens treated with aspirin, interrupted lines (.-.-.-) of untreated high risk patients, respectively.

and normal controls at 2 2 - 2 4 weeks of gestation. Later they were significantly higher in the group treated with low-dose aspirin (betaa~piri .=- 0.220, P = 0.0105), whereas differences almost disappeared after 36 weeks of gestation.

The results of multiple regression analysis (Table 2) show that in the main uterine arteries gestational age had the most marked effect on the Doppler waveform (betagest.tio.), followed by high risk selection and persisting notch (betahigh risk),

24 P. Zimmermwm el al. European Journal o! Ultrasound 5 (1997) 17 30

whereas aspirin treatment had no significant effect (beta~plrm).

In the uteroplacental arteries the effect of high risk selection and persistent notch was most prominent, followed by the effect of aspirin treatment and gestational age.

In the renal artery vascular resistance was not related at all to gestational age, high risk selection or aspirin treatment.

In the umbilical artery a correlation was exclu- sively found with gestational age. Almost all resistance indices measured in the high risk group were within the 95% confidence interval for normal controls. Aspirin had no effect on the Doppler waveform either.

Comparison of vascular resistance in the maternal uterine and renal arteries during pregnancy and postpartum showed in the high risk group significant increases of the R | in the uterine arteries from 0.55 (median) at 22 24 weeks of pregnancy to 0.81 6 months postpartum on the 'placental ' site and from 0.70 to 0.82 on the 'non-placental ' site, respectively (Sign-test: P - 0.0001 and 0.0247). Postpartum, the RI indices in the high risk group were still slightly higher when compared to the normal controls, where a median of 0.77 and 0.80 was found on the 'placental ' and 'non-placental ' site, respectively. The differences, however, were not significant (Mann-Whitney U- test: P = 0.116 and P = 0.200, respectively).

The pulsatility indices (PI) in the uterine arteries of the high risk group postpartum were 1.87 _+ 0.64 (mean _+ S.D.) and 1.95 _+ 0.57 |'or 'placental ' and 'non-placental ' site and were higher when compared to normal controls with 1.56 ± 0.44 and 1.74_+ 0.42, respectively. However, as found for the RI, differences were not statistically significant, when medians were compared. PI medians in the high risk group were 1.77 and 1.98 for 'placental ' and 'non-placental ' site, respectively, compared to 1.55 and 1.65 in normal controls (Mann-Whitney U-test: P = 0.078 and 0.129, respectively). Non-parametric statistics were used because data were not normally distributed.

In the maternal renal arteries resistance indices were similar in high risk patients and normal controls and also similar during pregnancy and postpartum. At 22 24 weeks of pregnancy the RI

was 0.60 _+ 0.04 (mean _+ S.D.) and 0.62 _+ 0.04 in high risks and controls, respectively, compared to 0.61 _+ 0.04 and 0.63 + 0.05 postpartum.

Doppler results of the high risk population were divided into two groups with regard to the incidence of PIH or I U G R and compared to the low risk controls. Fig. 2 a - b show in both uterine

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Fig. 2. Comparison of resistence indices (R[) of the maternal uterine (a: 'placental site', b: 'non-placental' site) and c: renal arteries during pregnancy and 6 months postpartum. Squares show results of the low risk population, triangles high risk patients with normal pregnancies and diamonds high risk patients with PIH or IUGR. Boxes represent medians and 25th/75th centiles, whiskers lst/99th centiles.

P. Zimmermann et al./ European Journal of Ultrasound 5 (1997) 17 30 25

Fig. 3. Doppler flow velocity waveforms in the different arteries at 22 + 1 weeks' gestation. (a) umbilical artery, (b) maternal renal artery, (c) uterine artery (pl. site), (d) uterine arery (non-pl. site). The patient, a 42-year-old G2P1 developed HELPP syndrome at 24 weeks' gestation and delivered at 28 + 5 weeks' a growth retarded fetus of 745 g (APGAR 4/8) by emergency caesarean section.

arteries during pregnancy the highest resistance indices in high risk patients who developed PIH or I U G R , followed by high risk patients without the disease and low risk controls, whereas all differences disappeared postpartum. The measurements in the maternal renal artery showed a uni- form distribution with almost no differences between the different groups at the different occa- sions of investigation (Fig. 2c).

In the study group 35% (9/26) of the patients suffered from some form of PIH and 12% (3/26) of IUGR: Of those five patients developed severe pre-eclampsia. Of the pre-eclamptic patients one mother in the untreated group developed H E L P P syndrome and delivered at 29 weeks a foetus with severe growth retardation. Fig. 3 shows original Doppler registrations of this patient. One patient had moderate pre-eclampsia and three patients

pregnancy induced hypertension without other complications. Additionally to the mother with HELPP syndrome two more patients delivered growth retarded foetuses at term. One foetus died in utero at 24 weeks gestation 2 days after pathological Doppler.

Table 3 reveals the effects of aspirin treatment on pregnancy outcome. Aspirin did not prevent hypertensive disorders or I U G R in our small study group. No differences were seen with regard to gestational age at delivery, birthweight or maternal blood loss. The treatment was safe to the foetus. However, in the aspirin group one patient had moderate vaginal haemorrhage at 36 weeks' gestation, and in the same group one mother with severe pre-eclampsia showed placental abruption at emergency caesarean section for threatening asphyxia at 38 weeks.

26 P. Zimmermann et al. / European Journal o f Ultrasound 5 (1997) 17 30

Table 3 Effects of aspirin treatment on pregnancy outcome

High risk study group

Aspirin (n = 13) Untreated (n = 13)

Low risk control group (n = 29)

Intrauterine death 0 Uterine haemorrhage/placental abruption 2 Pregnancy induced hypertension 2 Pre-eclampsia 4 IUGR ( < 10th percentile) 2 Premature delivery (< 37 weeks gestation) 1 Neonatal intraventricular haemorrhage (cerebral ultra- 0

sound) Difference of maternal pre- and postpartal haemoglobin

(g/I) Gestational age at delivery (weeks) Birthweight (g)

20.0 _+ 9.5

39.2 + 1.6 3199 + 487

11.4 _+ 14.3

38.5 + 3.3 3405 ___ 937

39.4 + 1.6 3425 + 540

Results shown are mean values + S.D.s or numbers, as appropriate.

4. Discussion

Doppler flow velocimetry of the uterine artery has been suggested as a potential risk marker for the development of pre-eclampsia and IUGR (Beaufils et al., 1985; McParland et al., 1990; Bower et al., 1993). Several criteria for definition of a pathological Doppler in the uterine artery have been used in the literature like persistent early-diastolic notch (Fleischer et al., 1986), elevation of the RI > 2 S.D. above the mean of a normal population (RI > 0.58) (Pearce et al., 1988), or elevation of the RI > 95% of the range of a normal population (Bewley et al., 1989) (RI > 0.74vl ...... t~l site and RI > 0.77 . . . . . . p t . . . . tal site)" The persistent notch phenomenon is said to have even higher prognostic value compared to the RI (Bower et al., 1993).

The high incidence of bilateral notches (4/29 = 13.8%) in the low risk population at the initial Doppler investigation at 22-24 weeks of gestation was a surprise to us, because it was quite similar to the incidence in the high risk population (28/ 176 = 15.9%). High incidences of notching in un- complicated pregnancies are reported also in the literature. At 20 weeks' gestation notching has been found in 16 (Bower et al., 1993) to 37%

(Steel et al., 1990), dropping to 5 (Bower et al., 1993) and 11% (Steel et al., 1990) at 24 weeks, respectively.

A problem is the exact definition of the notch phenomena. It has been tried to quantify the notch, calculating a ratio between peak systolic and early diastolic blood flow velocities (North et al., 1994). However, notching was not superior to the RI as a screening parameter for pre-eclampsia or IUGR in this study.

An explanation for the high incidences in our low risk population may be the fact that we examined those patients at the very beginning of the study, thus being to some extend too 'critical' defining a significant notch. The fact that all notches in our low risk population had disappeared at the control investigation at 28 30 weeks' may point to some degree of 'experience bias' influencing our results.

On contrast to the notches in the control population, in the high risk group majority of notches (23/26--88.5%) were seen throughout pregnancy, thus can be regarded as significant.

Although Doppler in the uterine arteries of our high risk population was significantly abnormal at 22-24 weeks of gestation in terms of persistent notches, the median RI was 0.55 and 0.70 on the

P. Zimmermann et al. / European Journal of Ultrasound 5 (1997) 17-30 27

placental and non-placental uterine arteries, respectively. Compared to our normal reference population with medians of 0.54 and 0.63 for the two different sites, only the value on the non-placental uterine artery was slightly elevated. But even there the difference was not statistically significant (Mann-Whitney U-test: P = 0.183).

Vascular resistance of both uterine arteries de- creased in a 'physiological' manner with proceeding pregnancy also in this risk group, however on a higher level of baseline. Possibly this increased level is determined at the time of trophoblastic invasion, which takes place at 8 - 18 weeks gestation (Pijnenborg et al., 1980), the time, when according to the recent literature, prophylactic low-dose aspirin probably should be started (Beilin, 1994; Wallenburg, 1995; Ylikorkala, 1995). Once trophoblastic invasion has happened, aspirin obviously does not any more influence the waveform, as our study shows.

The higher level of vascular resistance in the uterine arteries may explain the association with hypertensive disorders of pregnancy and foetal growth retardation, described in the literature (Arduini et al., 1987; McParland et al., 1990; Davies et al., 1992; Bower et al., 1993), and observed also in our study population. On the other hand, the ability of the uterine circulation to increase flow with proceeding gestation in a 'physiological' manner may give an explanation why pathological Doppler does not necessarily correlate with adverse foetal outcome other than IUGR (McParland et al., 1990; Steel et al., 1990; Davies et al., 1992).

Somewhat puzzling are the Doppler results registered in the uteroplacental circulation in our study: almost no differences were found between the high risk group and normal controls at 22- 24 weeks of gestation. Later, RI indices were significantly higher in the high risk group and even significantly higher in the group treated with low-dose aspirin, whereas differences almost disappeared after 36 weeks gestation. We have no other explanation for this observation than it might be due to methodological problems. Firstly, our study population was very small,

thus it may be just an effect by chance, secondly the uteroplacental arteries represent a relative in- homogeneous group of vessels, where reproducibility of Doppler indices without the use of colour Doppler is worse than in the main stem uterine arteries.

In our hands measurement of the RI in the main stem uterine arteries had an intraobserver error of 5.7-7.1% (COV) which is in good agreement with reports in the literature (Bewley et al., 1993).

After delivery vascular resistance in the uterine arteries increased in a 'physiological' manner: no differences could be detected compared to normal references. Although a notch was seen in all patients, diastolic flow did no cease completely at any time of the cardiac cycle. Doppler measurements of the uterine arteries of the non- pregnant uterus usually are reported as pulsatility indices (PI) in the literature. Doppler investigations in our study population 6 months postpartum revealed a pulsatility index of 1.87 + 0.48 (mean_+ S.D.) and 1.95_+ 0.42 for the 'placental' and 'non-placental' site, respectively. According to the literature, the PI increases abruptly after delivery reaching a level of 1.75 +0.56 by the end of the 12th week, which is far below the pulsatility indices of uterine arteries in non-pregnant women (2.53 + 0.98) (Tekay and Jouppila, 1993).

Thus, vascular resistance 6 months postpartum was still lower than reported for non-pregnant women and confirm the observation cited in (Tekay and Jouppila, 1993) that 'some of the haemodynamic changes associated with pregnancy have not completely regressed 24 weeks after delivery' (Robson et al., 1987).

It is interesting that this finding was independent of whether the patient had suffered from severe pre-eclampsia or had gone through a normal pregnancy. For instance, our patient with HELPP syndrome during pregnancy showed 14 weeks postpartum lower vascular resistance in the 'non-placental' artery (PI--2.44) compared to the 27th week of pregnancy when the disease was getting worse (PI = 2.53).

In contrast to the changes in vascular resistance in the uterine and uteroplacental circulation, the resistance index in the maternal renal

28 P. Zimmermann et al. / European Journal o/ Ultrasound 5 (1997) 17-30

artery was not affected either by gestational age or aspirin treatment and was found to be the same in high risk patients with pathological uterine Doppler and the normal reference population.

We found a RI of 0.60 _+ 0.04 and 0.61 + 0.04 (mean + S.D.) during pregnancy and postpartum, respectively, which is in close agreement to reports of the literature (Gudmundsson and Margfil, 1991; Levine et al., 1992; Thaler et al., 1992), who describe mean RI values of 0.6 and no relationship to gestational age or presence of hypertensive disease. Thus, maternal renal artery vascular resistance obviously is quite independent of pregnancy and also independent of the degree of hypertensive disease. Also, the normal RI in the renal artery of our patient with HELPP syndrome points into this direction.

The majority of resistance indices in the umbilical artery of the high risk patients were found within the reference range of the normal population and aspirin had no effect on the Doppler waveform either. This result support recent reports in the literature, where application of low- dose aspirin from 24 weeks gestation until delivery did not significantly affect umbilical artery Doppler values (Owen et al., 1993).

The number of patients in this study is too small to comment, really, on the clinical useful- ness and safety of low-dose aspirin treatment. However, our results are in agreement with the large studies on this topic (Sibai et al., 1993; CLASP, 1994). In our small study group aspirin was safe for the foetus, but we had one uterine haemorrhage and one abruptio placentae.

The number of patients is also too small to calculate the predictive value of Doppler investigation of the uterine artery with regard to PIH and IUGR. A larger cross-sectional study is in preparation to examine this topic. In this study, pathological uterine Doppler at 22--24 weeks of gestation in a high risk group selected a population of patients who develop hypertensive disorders of pregnancy or foetal growth retardation in almost 50%.

However, starting low-dose aspirin treatment at that time, was possibly too late for prevention of pre-eclampsia and I U G R in our small study population.

5. Conclusions

Low-dose aspirin treatment does not affect the resistance index in the uterine, :umbilical or renal circulation.

Significant notches in the uterine arteries at 22-24 weeks gestation persist usually throughout pregnancy. The phenomenon is related to higher resistance indices but does not prevent 'physiological' adaptation of vascular resistance in the uterine artery during pregnancy or postpartum.

Pathological uterine Doppler in a high risk group selects a population with almost 50% incidence of hypertensive disorders of pregnancy or foetal growth retardation, but starting low-dose aspirin prophylaxis at 22-24 weeks gestation is possibly too late for prevention of those disorders.

Acknowledgements

The study was supported by a grant of the Finnish Society for Ultrasound in Medicine and Biology. The authors are grateful to Pentti Joup- pila, Assistant Professor Oulu, and Pertti Kirki- nen, Assistant Professor Kuopio for their advice. Mrs. Seija Kiuru and the staff of the P~ij/it H/ime Central Hospital antenatal and delivery department are acknowledged for their enthusiastic help in collecting the data.

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Effect of low-dose aspirin treatment on vascular resistance in the uterine, uteroplacental, renal and umbilical arteries — A prospective longitudinal study on a high risk population