Early Human Development, 18 (1988) 45-57 Elsevier Scientific Publishers Ireland Ltd. 45 EHD 00907 The uterine artery blood flow velocity pathological pregnancy Leon G.M. Muldersa, Henk W. Jongsmaa, Pieter Peter R. Hein” waveform in F.F. Wijnb, and aDepartment of Obstetrics and Gynaecologv and Winical Vascular Laboratory, St. Radboud Hmpital, Catholic University of Nijmegen, P. 0. Box 9101,650O HB Nijmegen, The Netherlands Accepted for publication 18 Decembrr 1987 Summary Uterine artery blood flow velocity waveforms (FVW) were recorded longitudinally in 41 women with undisturbed pregnancy as well as in 32 women with complicated pregnancy at 4-week intervals from a gestational age of 18 weeks onwards. Of these women, four did not complete the study. In a second group of 76 patients at least one FVW was recorded after admission to the obstetrical department because of com- plicated pregnancy. The Pulsatility-Index (PI) for normal pregnancy was based on the results of the 41 women with undisturbed pregnancy (Mulders et al. (1988) Early Hum. Dev., 17, 55-70). The complete study group (n = 145) was divided in two groups, based on the value of the last measured uterine artery PI before delivery; in the abnormal PI group (PI 3 1.02 before 32 weeks or PI 2 0.91 after 32 weeks, n = 38) hypertension, fetal distress during pregnancy, premature delivery, small for gestational age babies @GA) and lower placental weight were all significantly increased. In each of the groups of patients with either SGA, fetal distress during pregnancy, pre-existing hypertension with proteinuria and pregnancy-induced hypertension with or without proteinuria the mean PI was significantly increased as compared to the results in normal pregnancy. Sensitivity and specificity of the last uterine artery PI for the detection of SGA and/or fetal distress during pregnancy were 48.8% and 82.7%, respectively. The longitudinally studied women (n = 73) were divided in two groups, based on uterine artery PI before 32 weeks of gestation; in the abnormal PI group (PI 21.02, n = 12) pregnancy was more complicated by premature delivery and low birth weight. Sensitivity for the early prediction of path- ological pregnancies (at least one pathological phenomenon as mentioned above) was 30.4%) whereas specificity was 90.0%. 0378-3782/88/$03.50 0 1988 Elsevier Scientific Publishers Ireland Ltd. Published and Printed in Ireland
Transcript
Early Human Development, 18 (1988) 45-57 Elsevier Scientific Publishers Ireland Ltd.
45
EHD 00907
The uterine artery blood flow velocity pathological pregnancy
Leon G.M. Muldersa, Henk W. Jongsmaa, Pieter Peter R. Hein”
waveform in
F.F. Wijnb, and
aDepartment of Obstetrics and Gynaecologv and Winical Vascular Laboratory, St. Radboud Hmpital, Catholic University of Nijmegen, P. 0. Box 9101,650O HB Nijmegen, The Netherlands
Accepted for publication 18 Decembrr 1987
Summary
Uterine artery blood flow velocity waveforms (FVW) were recorded longitudinally in 41 women with undisturbed pregnancy as well as in 32 women with complicated pregnancy at 4-week intervals from a gestational age of 18 weeks onwards. Of these women, four did not complete the study. In a second group of 76 patients at least one FVW was recorded after admission to the obstetrical department because of com- plicated pregnancy. The Pulsatility-Index (PI) for normal pregnancy was based on the results of the 41 women with undisturbed pregnancy (Mulders et al. (1988) Early Hum. Dev., 17, 55-70). The complete study group (n = 145) was divided in two groups, based on the value of the last measured uterine artery PI before delivery; in the abnormal PI group (PI 3 1.02 before 32 weeks or PI 2 0.91 after 32 weeks, n = 38) hypertension, fetal distress during pregnancy, premature delivery, small for gestational age babies @GA) and lower placental weight were all significantly increased. In each of the groups of patients with either SGA, fetal distress during pregnancy, pre-existing hypertension with proteinuria and pregnancy-induced hypertension with or without proteinuria the mean PI was significantly increased as compared to the results in normal pregnancy. Sensitivity and specificity of the last uterine artery PI for the detection of SGA and/or fetal distress during pregnancy were 48.8% and 82.7%, respectively. The longitudinally studied women (n = 73) were divided in two groups, based on uterine artery PI before 32 weeks of gestation; in the abnormal PI group (PI 21.02, n = 12) pregnancy was more complicated by premature delivery and low birth weight. Sensitivity for the early prediction of path- ological pregnancies (at least one pathological phenomenon as mentioned above) was 30.4%) whereas specificity was 90.0%.
0378-3782/88/$03.50 0 1988 Elsevier Scientific Publishers Ireland Ltd. Published and Printed in Ireland
Normal fetal growth and oxygenation is dependent on adequate perfusion of the vascular bed of the placenta. Reduced placental perfusion is associated with intra- uterine growth retardation (IUGR) and chronic fetal hypoxia with resulting perina- tal mortality and morbidity. Early detection of the women at risk for developing these pathological phenomena would help the physician to improve fetal outcome.
Alterations in uteroplacental blood flow, especially in case of hypertension or IUGR, have been measured indirectly, using radioisotopes [6,9,11,12,14,16,19]. However, this method is not suitable for clinical use, because of potential hazards for the fetus. The introduction of the Doppler ultrasound principle enabled not only the non-invasive study of the fetal placental circulation [7,15], but it also provided a new method of studying the uteroplacental circulation [2]. The blood flow velocity waveform (FVW) of the uterine artery reflects the vascular bed resistance down- stream of the studied artery and provides qualitative information on uteroplacental blood flow. The same indices as applied to the study of the fetal placental circulation [17], can be used to quantitate the uterine artery FVWs. So far, the literature on Doppler FVW analysis of arcuate and uterine arteries has given evidence for a new non-invasive method in the evaluation and surveillance of pathological pregnancy [3,5,8,21,22].
In a previous study [18] we determined the FVWs of the uterine artery longitudinally in normal pregnancies, as well as their intra- and interobserver reproducibility. The aim of the present study was four-fold: (1) To describe the FVW of those patterns with an elevated Pulsatility-Index (PI). (2) To investigate the relation of the PI of the FVWs and pathological pregnancies (such as pregnancies, complicated by hypertension with or without proteinuria, fetal distress during preg- nancy and small for gestational age babies (SGA)). (3) To evaluate if uterine artery PI could predict these pathological phenomena in an early phase of pregnancy. (4) To estimate the validity of this new method.
Patients and Methods
After approval of the study-protocol by the ethical committee of the hospital and after detailed explanation of the investigation, the study was performed in two main groups of patients; the first group consisted of 73 primi- and multigravid women with singleton pregnancy, attending the antepartum clinic. All pregnancies were accurately dated, based on last menstruation and first trimester crown-rump length measurements. In these women, the waveforms were recorded longitudinally at 4- week intervals from a gestational age of 18 weeks onwards until term. Four women did not complete the study; in these four women na results after 32 weeks of gesta-
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tion were available. Forty-one women had fully undisturbed pregnancy and out- come. Results for normal pregnancies were based on these 41 women and have been published previously [18]. The remaining 32 longitudinally studied women did not have an undisturbed pregnancy as defined previously [ 181. Of these women, 25 were admitted during pregnancy because of hypertension (n = lo), suspected IUGR with (n = 1) or without (n = 5) hypertension, premature labour (n = 4) or bad obstetrical history (n = 5). Fourteen women finally gave birth to a SGA infant (seven of them after they had been admitted).
The second group consisted of 76 patients, admitted to the obstetrical department with suspected IUGR, with (n = 59) or without (n = 17) hypertension. These patients had bedrest at the department at the time of the study. In 56 patients only one recording was performed, 20 patients were studied more than once with a total number of recordings of 53.
The Doppler results were not available to the clinicians and therefore did not influence treatment. Pathological pregnancy was defined by the presence of at least one of the following phenomena, which were also analysed separately: (1) SGA, defined as the child’s birth weight less than the 10th weight centile for the Dutch population, corrected for parity, sex and gestational age [lo]. (2) Fetal distress dur- ing pregnancy as diagnosed by the consultant obstetrician, based on late decelera- tions on the cardiotocogram, sometimes in combination with a low biophysical profile score [ 131. These pregnancies were always terminated by a primary Cesarean Section. (3) Hypertension during pregnancy without proteinuria, defined as a diastolic blood pressure higher than or equal to 90 mmHg (Riva Rocci), measured on at least two separate occasions. Pre-existing hypertension (PEH) and pregnancy- induced hypertension (PIH) were evaluated separately. (4) Hypertension during pregnancy as defined above together with proteinuria of more than 150 mg albumen in 24 h urine.
The bidirectional Continuous Wave (CW) Doppler equipment used to obtain and analyse the uterine artery FVWs has been described previously [ 17,181. The FVW was quantitated by use of the PI. In pathological pregnancies it is well possible, that downstream resistance on one side is completely different from the other, due to varying lesions in the spiral arteries, supplying the placental bed [I]. For the group of patients with a pathological pregnancy in this study we found no significant dif- ference in average PI between left and right uterine artery. Therefore, we chose to take the average value of the patient’s left and right uterine artery PI as test result. As in our report on FVW analysis in normal pregnancies [18] we used the same methodology in calculating and analysing the PI for the individual patient.
Relation of uterine artery PI andpathologicalpregnancy
The complete study group was divided in a normal and abnormal PI group, based on last uterine artery PI; abnormal uterine blood flow was defined as a PI equal to or above the mean + 1.64 SD. of the normal population, approximately corre- sponding with the 95th percentile. This resulted in a PI & 1.02 before 32 weeks of gestation and 2 0.91 after 32 weeks respectively [18]. Characteristics of pregnancy,
TABLE I
Characteristics of the study group (pregnancy, delivery and outcome), related to last uterine artery PI. Abnormal PI was defined as higher than or equal to the mean + 1.64 SD. of the normal population (< 32 weeks: 3 1.02, a32 weeks: M.91).
Normal PI Abnormal PI (?I = 107) (n = 38)
P-value
Age 6-d Parity (olo para 0)
28.9 (+ 4.9) 28.3 (+ 5.0) n.s 51.4 52.6 n.s.
Uterine artery PI Maternal heart rate @pm) Interval last PI/delivery (days)
Apgar 1 (W < 7) 15.0 13.2 n.s. Umbilical artery pH 7.22 ( f 0.07) 7.22 ( f 0.09) n.s.
‘Including three cases with proteinuria (one in the normal PI group, two in the abnormal PI group).
delivery and outcome (as given in Table I) of both PI groups were compared. Fur- thermore, the last test result of the four different groups with pathological phenom- ena (as defined above) were evaluated by plotting distribution columns of the PIs and calculation of mean ( +- S.D.). These results were compared with the results of normal pregnancies as reported previously [ 181.
Early prediction of pathological pregnancy
The longitudinally studied women were also divided in a normal and abnormal PI group, but now based on uterine artery PI before 32 weeks of gestation; abnormal uterine blood flow was defined as above. Again characteristics of pregnancy, deliv- ery and outcome (as given in Table III) of both PI groups were compared. Because
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of small numbers, we did not perform the analysis in hypertension subgroups as was done for the last uterine artery PI. Furthermore, we calculated the mean of the PIs (-+ SD.) before 32 weeks of gestation of the longitudinally studied pregnancies resulting in SGA after 32 weeks of gestation. Also these results were compared with the results of normal pregnancies [ 181. The significance of the differences was deter- mined with a t-test for two independent samples of a Fisher’s exact test at a level of 0.05.
Validity of uterine artery F V W analysis
The validity of last uterine artery PI in predicting SGA and/or fetal distress during pregnancy was estimated by calculation of sensitivity and specificity. We chose for the cut-off point as defined above. In order to assess the validity as an early screening test for pathological pregnancies, the number of pregnancies with at least one of the four pathological phenomena in the normal and abnormal PI group (based on the PI before 32 weeks of gestation) were evaluated. Again, validity was estimated by calculation of sensitivity and specificity. Furthermore, the Receiver Operating Characteristic (ROC curve) [17] of these early PI results was plotted in order to compare our results in terms of sensitivity and specificity with those, reported by Campbell et al. [4].
Results
Abnormal FVWpattern
A typically abnormal FVW of the uterine artery is shown in Fig. la. In most waveforms with an elevated PI, a more oscillating flow signal is seen with the appearance of a notch in early diastole. However, in a minority of the waveforms with an elevated PI no notch is observed as shown in the example of Fig. lb.
Relation of uterine artery PIandpathologicalpregnancy
Characteristics of the complete study group, related to last uterine artery PI, are summarized in Table I. Age and parity of both PI groups were comparable. In the abnormal PI group maternal heart rate (MHR) was lower and interval between the last measurement and delivery was shorter. The occurrence of various pathological phenomena of pregnancy and delivery was significantly increased in the patients with an abnormal uterine artery PI. In the abnormal PI group also the children’s birth weight was lower, while the Apgar score after 1 min and the pH of the umbili- cal artery did not differ between both groups.
Table II presents mean PI (-+ S.D.) of the pregnancies with a particular patho- logical phenomenon, analysed separately before and after 32 weeks of gestation. The mean PI was significantly increased as compared to the results in normal pregnan- cies [18] for all pathological groups with exception of the group PEH without pro- teinuria. Figure 2 provides distribution columns of these PIs within the four groups.
Fig. 1A: a typically abnormal waveform of the uterine artery with an elevated PI (PI = 1.50); note the more oscillating flow pattern with the appearance of a notch in early diastole. B: an example of an abnor- mal waveform of the uterine artery with an elevated PI (PI = 1.47), in which no notch is observed.
Early prediction of pathological pregnancy
Characteristics of pregnancy, delivery and outcome of the longitudinally studied women, related to uterine artery PI before 32 weeks of pregnancy, are summarized in Table III. The abnormal PI group consisted of 12 women. Of these 12 women, nine had also an abnormal last uterine artery PI. The occurrence of premature deliv- ery was increased and birth weight was significantly decreased in the abnormal PI group. However, birth weight below the 10th percentile did not differ between both
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TABLE II
Mean PI (SD) of the last test result before delivery of the different pathological pregnancies. n number of patients with the particular pathological phenomenon.
e <32wks 2 32 wks < 32wks Z 32 wks < 32wks (fl=4) (n=32) , (n=5) (II=101 (ll=l)
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I . . _ .
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.
:
;
: -
:
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&
i
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: .
.
:
.
.
SGA(<P,o) Fetal distress during pregnancy
T With proteinuria *Without proteinuria
.
.
0
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.
.
2 32 wks <32wks (Il=lO)
< (n=2)
. 0
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>, 32wks (rl.LS)
PEH PIH
Fig. 2. Distribution columns of the PIs within four groups of pathological phenomena. The horizontal lines represent the cut-off points (< 32 weeks: 21.02, a32 weeks: 30.91). For explanation of PEH and PIH see text. Columns 1 and 2: 0, patient with or without proteinuria. Columns 3 and 4: 0, patient with proteimuia; 0, patient without proteinuria.
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TABLE III
Characteristics of the study group (pregnancy, delivery and outcome), related to uterine artery PI before 32 weeks of gestation.
Normal PI Abnormal PI (< 1.02) (21.02) (n = 61) (II = 12)
Validity of last uterine artery PI in predicting SGA and/or fetal distress during pregnancy (FD), Cut-off point < 32 weeks PI 2 1.02 and 2 32 weeks PI 3 0.91.
SGA and/or FD + SGA/FD - Totals
Abnormal PI 20 18 38 Normal PI 21 86 107
Totals 41 104 145
Sensitivity: 48.8%; specificity: 82.7%.
PI groups. Table IV presents mean PI ( r S.D.) before and after 32 weeks of gesta- tion of those pregnancies, resulting in SGA after 32 weeks of gestation. Of the 32 SGA pregnancies, eleven were studied longitudinally, so results before 32 weeks were available. The mean PI for the SGA pregnancies was significantly increased as compared to the results in normal pregnancies for the last measurement (see also Table II), but also for the early PI measurements.
Validity of uterine artery FVWanalysis
Validity of last uterine artery PI in predicting SGA and/or fetal distress during pregnancy is presented in Table V. In 41 women, pregnancy was complicated by SGA (n = 26), SGA with the development of fetal distress during pregnancy (n = 10) or fetal distress without SGA (n = 5). The sensitivity of the last uterine artery PI in predicting the above mentioned complications was 48.8% (20/41), whereas specificity was 82.7% (86/104).
Validity of uterine artery PI before 32 weeks of gestation in predicting the pregnancies developing at least on pathological phenomenon is presented in Table VI. In terms of an early screening test, sensitivity and specificity of uterine artery PI
TABLE VI
Validity of uterine artery PI before 32 weeks of gestation in predicting the pregnancies with at least one pathological phenomenon. Cut-off point: PI > 1.02.
Fig. 3. The ROC curve of the early PIs of the longitudinally studied women. Changes in cut-off point causes subsequent changes in sensitivity and specificity. The cut-off point of Campbell et al. [4] is plotted in the curve (+).
were 30.4% (7/23) and 90.0% (45/50), respectively. Figure 3 presents the ROC curve of these early PI results with the sensitivity and specificity, as reported by Campbell et al. (68% and 69070, respectively) [4] plotted in it.
Discussion
In this study we evaluated the FVWs of the ascending vasculature of the uterine artery in pathological pregnancies. Also Fleischer et al. [8] studied the FVWs of the uterine artery in pathological pregnancies; however, in most patients the recordings were obtained transvaginally. Furthermore, Campbell et al. [2,3,4] as well as Tru- dinger et al. [21,22] performed their blood flow studies on the subplacental (and/or non-placental) [4] arcuate arteries. In a previous report [ 181, we already discussed the sampling problem and why to record most proximally in course of the uterine vasculature, especially in case of pathological pregnancy. We also concluded that the approach of pattern recognition seemed reliable considering the reproducibility of the waveforms, which experiments were done in both normal as well as pathologi- cal pregnancies. Under pathological conditions the flow signal usually becomes more oscillating with the appearance of a notch in early diastole (Fig. la), indicating an area of elevated resistance downstream the point of measurement. This notch is not consistently present in the abnormal waveform (Fig. lb). In our study group no case of negative (receding) end-diastolic blood flow was observed, not even for the waveforms with the highest PI. Thus in our study group there is no resemblance between the FVW of the uterine artery under pathological conditions and the exter- nal iliac artery, which has always the characteristic high resistance flow pattern with backward flow [20].
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The incidence of several pathological phenomena (PIH with proteinuria, fetal distress during pregnancy, premature delivery, SGA and lower placental weight, see Table I) was significantly increased in the women with an abnormal last PI. The sig- nificantly higher prevalence of PIH with proteinuria in the abnormal PI group seems to indicate that uteroplacental blood flow can be impaired in this group of hypertensive patients. This was confirmed by the results of Table II. Whether this is also true for the patients with PEH with proteinuria, could not be concluded because of too small numbers. Noteworthy is the decreased mean MHR in the path- ological PI group. In a previous report, we found an inverse relationship between MHR and uterine artery PI in most cases [ 181. One could speculate, that the signifi- cantly lower mean MHR in the abnormal PI group could partially be responsible for the higher PIs. However, the absolute difference in mean MHR between both PI groups was so small that most probably this was only of minor importance.
The results of the radioisotope studies in pregnancies complicated by pre- eclampsia and IUGR [11,12,19] indicate reduced uteroplacental blood flow. A plausible morphological explanation for this reduced placental blood supply is the concept of physiological changes (trophoblastic invasion of the spiral arteries) in normal pregnancies, which are less marked and extensive in pathological pregnan- cies with the appearance of narrowing vascular lesions and subsequently ischaemic lesions of the placenta [ 11. Our PVW data (Tables I, III) are in agreement with these morphological observations, assuming that the PI of the ascending vasculature of the uterine artery is merely determined by the resistance in the spiral arteries.
The analysis of the SGA pregnancies, which were studied longitudinally revealed that already early in pregnancy there was evidence for impaired circulation, which might result in a diminished growth (potential) (Table IV). In the analysis of all lon- gitudinally studied women (Table III), SGA was doubled in the abnormal PI group, but this difference was not statistically significant. Premature delivery and absolute birth weight were the only phenomena, which were significantly increased in the abnormal PI group. So, in terms of an early screening test for the detection of path- ological pregnancies our results were disappointing. This was supported by the cal- culation of sensitivity and specificity for the prediction of pathological pregnancies; when demanding a high specificity, sensitivity was only 30.4% (Table VI). Nine of the 12 women with an abnormal PI before 32 weeks of gestation had also an abnor- mal last PI before delivery; this is in agreement with the before mentioned impaired trophoblastic invasion of the spiral arteries with the occurrence of possible pathology later in pregnancy. However we think, that the small number of women with an abnormal PI before 32 weeks does not justify definite conclusions about the value of uterine artery PI as an early screening test for pathological pregnancies.
The validity of uterine artery PI to detect SGA and/or fetal distress during pregnancy was also disappointing when based on the last PI before delivery (Table V). When analysing the sensitivity of the last PI measurement for the detection of SGA and fetal distress during pregnancy separately, sensitivity for SGA was similar (18/36 = 50%) (Pig. 2, first column), while sensitivity for fetal distress was higher (11/15 = 73.3%) (Pig. 2, second column). However, this difference was not statisti- cally significant (x’- test: P = 0.2). Only one out of two fetuses is predicted correctly
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to be growth retarded (sensitivity of 50070). These results resemble our previous results on validity of umbilical artery FVW analysis to predict SGA (sensitivity of 53.3%) [17]. In our opinion, the many causes of SGA as discussed earlier [17] could be responsible for the low sensitivity of both umbilical artery as well as uterine artery PI in the prediction of SGA.
Fleischer et al. [8] demonstrated similar results in a normal and abnormal waveform group, using the S/D ratio as waveform index. Their results were based on one single measurement in the third trimester or a mean value of serial measurements. When we compare both studies and estimate our validity of uterine artery PI in the way Fleischer did (the ability to predict optimal outcome i.e. delivery at 37 weeks of gestation or beyond and/or birth weight > 2500 g), our sensitivity was 57.9% (22/38) with a specificity of 86.9% (93/107). Their reported specificity (9OOro) was comparable with our value, while their sensitivity (81%) is higher than our value; however, this difference was not significant (x2 test: P = 0.09).
Campbell et al. [4] studied the arcuate arteries at 16 to 18 weeks of gestation to determine if pathological pregnancy could be predicted. They concluded that their results seemed to represent an improvement over existing predictive techniques. When we analysed our results of the women with an uterine artery PI before 32 weeks of gestation (n = 71, Table III) in a similar way, there seemed to be large dif- ferences. They reported a specificity of 69% which was lower than our value of 90.0%, while their sensitivity (68%) was higher than ours (30.4%). How- ever, by plotting their results in the ROC curve of our results (Fig. 3), it can be clearly seen that the results are in fact similar and can be explained by the different cut-off points. Although their cut-off Resistance-Index (RI) was based on the mean f 2 S.D. of the normal population, specificity of the results in their study group was only 69% instead of the expected 95%. Apparently, the patients with a normal waveform in their study group were different from the women with a normal wave- form in the reference group [2], on which the cut-off RI was based.
From this study, we conclude that there is a good relationship between (last) uterine artery PI and pathological pregnancies. However, sensitivity and specificity (48.8% and 82.7% respectively) for the detection of SGA and/or fetal distress dur- ing pregnancy was disappointing. Furthermore, evidence was found for the early prediction of premature delivery and SGA. Sensitivity for the early prediction of pathological pregnancies was low (30.4%) when demanding a high specificity (90.0%). More extensive studies in an aselect population have to be performed before one can consider the method to be applicable in clinical practice as an early screening test.
Acknowledgements
The authors wish to thank Mrs. Anne Veldhorst for the dedicated assistance in recording the FVWs and Jan G. Nijhuis for critical reading of the manuscript.
References
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