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The use of Doppler ultrasound in the study of fetal cardiovascular physiology
Journal of Neuroscience Methods, 34 (1990) 159-167
159
Elsevier NSM 01119
The use of Doppler ultrasound in the study of fetal cardiovascular
physiology Kevin P. Hanretty 1 and Peter C. Rubin 2 I The University Department of Midwifery, The Queen Mother's Hospita~ Glasgow(U.K), and z Department of Therapeutics, University of Nottingham, Nottingham ( U.K ) (Received 19 September 1989) (Accepted 26 September 1989)
Key words: Doppler; Fetal physiology; Pharmacology; Nifedipine; Atenolol Doppler velocimetry of the uteroplacental and umbilical arteries provides an opportunity for the safe, reproducible and repeatable study of these circulations and already has led to an increased knowledge of the pathophysiology of pregnancy induced hypertension and intra-uterine growth retardation. This technique, which has only recently been introduced widely into obstetrics, also permits the study of the cardiovascular effects on the fetus of maternally administered drugs. The use of Doppler for these purposes is illustrated with particular reference to intra-uterine growth retardation and the use of the antihypertensive drugs, atenolol and nifedipine.
Introduction The study of the human fetus has always presented one of the most significant challenges in in-vivo monitoring, both in terms of obtaining a basic understanding of fetal physiology and in determining fetal wellbeing. This difficulty relates to the relative inaccessibility of the fetus and the placenta. The concept of 'placental wellbeing' does not normally merit attention but the interaotion of the uteroplacental and fetoplacental circulations is critically important in determining the successful outcome of pregnancy. Until the advent of Doppler velodmetry in obstetrics the dynamic study of these circulations h a d been impossible and the bulk of data concerning fetal haemodynamics has until now been obtained from invasive studies in pregnancies undergoing termination by hysterotomy (Assail et al., 1960) or inferred from patho-
logical examination after delivery. The uteroplacental circulation has hitherto only been studied using radioisotope clearance rates (Brown and Veall, 1953; Kaar et al., 1980) with all of the limitations and dangers for the fetus inherent in this. Furthermore, such investigations by their nature are not suitable for serial assessment of possible circulatory changes. The recognition 6f the limitations of these data is now even more important since there is increasing evidence that in-vivo changes in one circulation will modulate changes in the other. The use of Doppler allows the non-invasive study of fetal cardiovascular physiology and maternal vascular adaptation in both health and disease and permits study of drug effects on the uteroplacental and fetal circulations which have not previously been possible.
I~Oer prineiOe Correspondence: ILP. Hanretty, The Univenity Department of Midwifery, The Queen Mother's Hmpital, Glasgow (33 8SH, U.K.
Most people are familiar with the Doppler principle which states that the frequency of a sound signal perceived by an observer increases
0165-0270/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
160
Fig. 1. A normal low resistance flow velocity waveform from the umbilical artery.
Fig. 2. A normal low resistance uteroplacental waveform.
161
Fig. 3. High resistance pattern from the umbilical artery in severe pre-eclampsia.
Fig. 4. High resistance pattern from the uteroplacental arteries in severe pre-eclampsia.
162
proportionally to the velocity of the emmitter as it approaches (or recedes from) the observer. What is not always immediately obvious is that this is also true of sound reflected from a moving object. In obstetrics, and in vascular surgery, use has been made of this effect to study the change in frequency of a signal reflected from red cells in fetal and maternal vessels. This frequency change, or Doppler shift, is proportional to the velocity of the reflecting material and when plotted against time will produce a velocity time waveform. Figures 1 and 2 show normal waveforms obtained in the 3rd trimester of an uncomplicated pregnancy from the umbilical and uteroplacental arteries, respectively. These waveforms are characteristic of the low resistance to flow found in these circulations in uncomplicated pregnancy. In a number of complicated pregnancies, in particular those with severe intra-uterine growth retardation and pre eclampsia, abnormal waveforms may be obtained from both maternal and fetal vessels (Trudinger et al., 1985). Figures 3 and 4 show patterns representing high resistance, with a reduction in the diastolic component of flow from a case of severe pre-eclampsia. A number of indices have been developed to describe waveforms qualitatively: The systolic/diastolic ratio, also known as the A/B ratio (Stuart and Drumm, 1980) and the pulsatility index (Gosling and Ring, 1975) are most commonly used and for both these indices high values represent high vascular resistance whilst low values represent low resistance to flow. Doppler study now permits the invesigation, in utero, of these changes induced by different complications on fetal wellbeing and cardiovascular status.
DopplersludydlbeumbiHcalc5ruWhinpregnancy-hyprh&m
Almost all of the current knowledge regarding fetoplacental blood flow in pregnancies complicated by h-on has been obtained since the introduction of Doppler velocimetry. However, Abitbol et al. (1987) in an in-vitro study of perfused placentas from women with preeclampsia demonstrated reduced umbilical perfu-
sion. This finding supports to some extent the enthusiasm for Doppler in this clinical condition and Ducey et al. (1987) even suggested that the use of Doppler would permit more accurate classification of the hyperttmsive disorders of pregnancy. They noted an increased incidence of high resistance waveforms in patients with preeclampsia compared to women with chronic hypertension. However, Cameron et al. (1988) and Hanretty et al. (1988) have found no correlation between abnormal Dappler indices and absolute levels of hypertension in severe and mild preeclampsia, respectively. Importantly, clinical outcome, in terms of severity of growth retardation, fetal distress and admission to the neonatal intensive care unit did relate to the abnormalities detected by Doppler. The underlying pathology associated with these waveform changes is tmcertain but must represent increased downstream impedance to blood flow. This may be due to obliteration of tertiary stem villus arterioles. This abnormality has been described by Giles et al. (1985) and by McGowan et al. (1987) but the mechanism underlying this is not known. Repeated embolisation of the fetoplacental vessels in the sheep fetus has reproduced those changes seen in the compromised human fetus (Trudi.nger et al., 1987) supporting the concept of a reduction in placental perfusion from the fetus.
The underlying pathology of the reduced maternal perfusion of the placenta in pregnancyinduced hypertension is well d ocumented (Khong et al., 1986). Reduced maternal blood flow has been demonstrated using radioisotopes in hypertensive pregnancies (Lrmell et al., 1982) and there is now a large body of evidence to show that the normal physiological invasion of trophoblast into maternal spiral arteries converting them from high to low. resistance vessels does not occur in some hypertensive pregnancies. Initial studies using Doppler methods suggested that study of the uteroplacental arteries may identify this vascular
163
abnormality even before a clinically detectable problem is identified (Campbell et al., 1986). However, although in very severe pre-eclampsia abnormal waveforms are found, and attributed to widespread vascular pathology, the focal nature of less severe forms of the disease have made the use of Doppler less reliable than had been hoped. Nevertheless Doppler has proved of value in the investigation of drug effects. This will be discussed later. For prediction of disease severity the study of more proximal vessels such as the uterine arteries themselves and the use of colour-mapped Doppler appear promising (Campbell et al., 1988) but awaits further study.
Doppler study of the umbilical circulation in intrauterine growth retardation Re-distribution of blood flow within the fetus is a likely feature of 'placental insufficiency' and occurs in the absence of maternal hypertension although the mechanism may be similar to that invoked for abnormal Doppler waveforms in preeclampsia. Erskine and Ritchie (1985) demonstrated abnormal Doppler wavcforms in the umbilical artery of a small series of severely growthretarded fetuses and since then a number of authors (Fleischer et al., 1985; Trudinger et al., 1985; Reuwer et al., 1987) have demonstrated abnormal waveforms in the severely growth-retarded fetus. Furthermore, from their work it seemed that it would be possible to use Doppler to distinguish between babies actually growth-retarded in utero and those which are merely genetically small and not compromised. Larger studies have produced confusing data regarding the clinical value of umbilical artery Doppler velocirnetry. Berkowitz et al. (1988) found a sensitivity of only 45% when using the technique to identify fetuses destined to weigh less than the 10th centile for gestation at birth. Contrasting with this, Gaziano et al. (1988) found a sensitivity of 79% in such cases. Both of these studies investigated cases known to be at high risk for intra-uterine growth retardation and larger series investigating the value of umbilical Doppler in screening unselected populations have proven disappointing. This may
in part be attributed to the difficulty in distinguishing fetuses who are truly growth-retarded insofar as they do not reach their growth potential but who are not small-for-dates. The ability to identify such fetuses would be a major advance but there are methodological difficulties to be overcome before widespread application of Doppler in this field and the issue of whether waveforms from small-for-dates fetuses are different from uncomplicated pregnancies has still not been determined from controlled studies. We have performed such a study, comparing umbilical artery Doppler indices in 32 pregnancies matched for maternal and gestational age and found that the pulsatility index was significantly higher than controls (Table I) although only 3 of the growth retarded fetuses had results which would be considered abnormal. This evidence supports a redistribution of blood flow within growth-retarded fetuses and this appears to benefit the brain as part of a 'brain sparing' effect. Corroborating evidence is provided by the work of Wladimirrof et al. (1986) who studied waveforms from the internal carotid in a series of severely growth-retarded fetuses and showed an inverse relationship between the pulsatility index in the fetal internal carotid artery and the umbilical artery, i.e. high vascular resistance in the peripheral circulation is associated with a compensatory
TABLE I DOPPLER INDICES IN A COMPARISON OF 32 SMALLFOR-DATES (SFD) FETUSES AND MATCHED CONTROLS
Maternal age (yr) Gestation at time of study Gestation at delivery Birth w~ight
Umbilical artery PI RI Uteroplacental artery PI RI
SFD
Controls
Significance
24.7 (5.5)
24.8 (5.7)
NS
36.5 (3.0)
36.8 (2.6)
NS
38.6 (1.8) 39.2 (1.1) P=O.11 2.42 (0.39) 3.35 (0.35) P < 0.00001
1.04 (0.27) 0.88 (0.16) P < 0.02 0.62 (0.96)
0.56 (0.78) P < 0.02
0.52 (0.16) 0.38 (0.15)
0.61 (0.30) NS 0.39 ( 0 . 1 3 ) N S
PI, pulsatility index; RI, resistance index.
164
reduction in resistance to cerebral blood flow. The pathology of fetal growth retardation on the maternal side is similar in some cases to that of hypertensive pregnancy and the same limitations apply to the use of Doppler as apply to preeclampsia.
3
2-
Doppler and developmentalpharmacology The use of drugs in pregnancy, antihypertensives in particular, has been contentious since the first reports by Dixon et al. (1963) who suggested that rauwolfia alkaloids reduced maternal perfusion of the placenta. Their studies were performed using radionuclide tests and were uncontrolled. Doppler allows the repeatable non-invasive assessment of both uteroplacental and fetoplacental blood flow. We have used Doppler to study uteroplacental and fetoplacental perfusion in patients receiving atenolol or ulfedipine for pregnancy-induced hypertension. Atenolol has been shown to reduce blood pressure effectively in pregnancy-induced hypertension and may reduce the number of women going on to develop proteinuria (Rubin et al. 1983). Consequently its use is attractive. A recent report (Montan et al. 1987) suggested that atenolol produced an increased resistance to maternal perfusion though their study was uncontrolled. We have studied Doppler indices from the uteroplacental and umbilical arteries in 10 patients receiving 50 or 100 mg of atenolol for pregnancy-induced hypertension. The mean reduction in systolic blood pressure was 24 mm Hg and in diastolic blood pressure was 13 mm Hg after between 6 and 7 days treatment. In this study we used the pulsatility index to evaluate waveforms and Figs. 5 and 6 show the uteroplacental and umbilical artery pulsatility index before and after treatment. There was no change in this waveform index following atenolol. This is reassuring and suggests that redistribution of blood flow within the fetus is unlikely following atenolol therapy. These patients were also compared with untreated cases matched for gestational and maternal age. The median umbilical artery pulsa-
Fig. 5. Uteroplacental pulsatility index before and after treatment.
3"
Fig. 6. Umbilical artery pulsatility index before and after treatment.
157 (18) 99 (9) 78 (12) 143 (7) 1.73 (0.61) 1.20 (0.60)
0
1
142 (9) 85 (5) 81 (18) 145 (11) 1.85 (0.73) 1.24 (0.80)
141 (13) 84 (6) 82 (17) 142 (10) 1.90 (0.57) 1.22 (0.85)
2 143 (9) 84 (7) 79 (16) 143 (9) 1.81 (0.55) 1.41 (1.05)
3
4 148 (14) 85 (7) 79 (16) 140 (10) 1.86 (0.55) 1.35 (1.10)
5 146 (14) 86 (7) 75 (12) 142 (11) 1.87 (0.50) 1.31 (0,88)
6 146 (9) 89 (9) 72 (12) 140 (7) 1.73 (0.49) 1.26 (0.80)
8
154 (19) 153 (13) 91 (11) 90 (10) 73 (15) 70 (16) 141 (9) 13.9 (7) 1.82 (0.48) 1.78 (0.45) 1.22 (0.83) 1.20 (0.84)
7
P ffi 0.022 P < 0.001 P ffi 0.013 P = 0.878 P=0.848 P=0.871
Significance
Figures in parenthesis are standard deviations SBP, systolic blood pressure; DBP, diastolic blood pressure; FHR, fetal heart rate; UMB PI, umbilical artery pulsatility index; UTR PI, uteroplacental pulsatility index.
SBP DBP PULSE FHR UMBPI UTRPI
Time (h)
Time effects were studied by repeated measures analysis of variance. (Reproduced with permission of the Editor, British Medical JournaL)
THE EFFEC]" OF ORAL NIFEDIPINE ON MATERNAL AND FETAL HEART RATE, BLOOD PRESSURE AND DOPPLER INDICES
TABLE II
Ltt
166 tility index of 1.07 in the treated cases was the same as that of the untreated cases. In fulminant pre-eclampsia it m a y be necessary to control blood pressure more rapidly than is o b t a i n e d using beta-blockade. Nifedipine, a calcium channel blocker which has already been used in a limited way as a second-line agent in pre-eclampsia (Constantine et al. 1987) is a particularly attractive agent which can be given orally and rapidly reduces blood pressure but its effects on uteroplacental and fetoplacental blood flow have been incompletely investigated. We have studied 9 w o m e n with severe preeclampsia to determine the acute effects of 20 mg nifedipine on uteroplacental and umbilical artery D o p p l e r waveforms. T h e pulsatility index in these vessels was measured before therapy and hourly after c o m m e n c e m e n t of treatment for 8 h. Despite a rapid and sustained effect on blood pressure there was no change in D o p p l e r indices in either of the circulations studied (Table II). These data contrast with the results of studies of the calcium channel blocker, nicardipine, which was shown to decrease uteroplacental blood flow and produce fetal hypoxia in fetal sheep. Our results are consistent with a recent study by L i n d o w et al. (1988) which showed uteroplacental blood flow to be maintained fgllowing nifedipine when assessed radioisotopically. Serial measurements were not possible with their m e t h o d and our data are reassuring that there is not an adverse effect for a longer period than is possible to study using such methods. Furthermore, since there is a need for an effective antihypertensive agent in the acute situation these studies, only possible using D o p p l e r methods, justify further studies of calcium channel blockers in preeclampsia.
Conclusions The role of D o p p l e r methods in obstetric m a n a g e m e n t remains to be determined in large controlled studies but already this relatively new technique has improved our understanding of the h a e m o d y n a m i c s of conditions such as intra-uterine
growth retardation and of the effects of therapy for pre-eclampsia. This information should lead to better m e t h o d s of fetal assessment and developm e n t of safe drug regimens where such therapy is indicated.
References Abitbol, M.M., LaGamma, E.F., Demeter, E. and Cipollina, C.M. (1987) Umbilical flow in the normal and pre-eclamptic placenta. Acta Obstet. Gynecol. Scand., 66: 689-694. Assali, N.S., Rauramo, L. and Peitonen, T. (1960) Measurement of uterine blood flow and uterine metabolism. Am. J. Obstet. Gynecol., 79: 86-98. Berkowitz, G., Chitkara, U., Rosenberg, J., Cog,swell, C., Walker, B., Lahman, E.A., Mehalek, K.E. and Berkowitz, R.L. (1988) Sonographic estimation of fetal weight and Doppler analysis of umbilical velocimetry in the prediction of intra-uterine growth retardation: a prospective study. Am. J. Obstet. Gynecol., 158: 1149-1153. Brown, J.C.M. and Veall, N. (1953) The maternal placental blood flow in normotensive and hypertensive women. J. Obstet, Gynaecol. Brit. Emp., 60: 141-147. Cameron, A.D., Nicholson, S.F., Nimrod, C.A., Harder, J.R. and Davies, D.M. (1988) Doppler waveforms in the fetal aorta and umbilical artery in patients with hypertension in pregnancy. Am. J. Obstet. Gyneool., 158: 339-345. Constantine, G., Beevers, D.G., Reynolds, A.L. and Luesley, D.M. (1987) Nifedipine as a second line antihypertensive drug in pregnancy. Br. J. Obstet. Gynaecol., 94: 1136-1142. Dixon, H.G., Browne, J.C.M. and Davey, D.A. (1963) Choriodecidual and myometrial blood flow. Lancet, ii: 369-373. Ducey, J., Schulman, H., Farmakides, G., Rochelson, B., Bracero, L., Fleischer, A., Guzman, E., Winter, D. and Penny, B. (1987) A classification of hypertension in pregnancy based on Doppler veloeimetry. Am. J. Obstet. Gynecol., 157: 680-685. Erskine, R.L.A. and Ritchie, J.W.K. (1985) Umbilical artery blood flow characteristics in normal and growth-retarded fetuses. Br. J. Obstet. Gynaecol., 92: 605-610. Fleischer, A., Rochelson, B., Farmakides, G. and Bracero, L. (1985) Umbilical velocity waveforms in intrauterine growth retardation. Am. J. Obstet. Gynecol., 151: 502-505. Gaziano, E., Knox, E., Wager, G.P., Bendel, R.P., Boyce, D.J. and Olson, J. (1988) The predictability of the small-for-gestational-age infant by real time ultrasound derived meaurements combined with pulsed Doppler umbilical artery velocimetry. Am. J. Obstet. Gynecol., 158: 14311439. Giles, W.B., Trudinger, B.J. and Baird, P.J. (1985) Fetal umbilical artery flow velocity waveforms and placental resistance: pathological correlation. Br. J. Obstet. Gynaecol., 92: 31-38.
167 Gosling, R.G. and King, D.H. (1975) Ultrasound angiology in Marcus, A.W. and Adamson, L. (Eds.) Arteries and Veins, Churchill Livingstone. Edinburgh, pp.61-98. Haxtretty, K.P., Whittle, M.J. and Rubin, P.C. (1988) Fetoplacental and uteroplacental flow velocity waveforms in mild pregnancy-induced hypertension. In C.T. Jones (Ed.), Fetal and Neonatal Development (Research in Per[natal Medicine, Vol. VII), Perinatology Press, New York, pp. 536-538. Kaar, K., Jouppila, P., Kuikka, J., Luotola, J., Toivanen, J. and Rekonen, A. (1980) InterviUous blood flow in normal and complicated pregnancy measured by means of an intravenous Xe 133 method. Acta Obstet. Crynecol. Scand., 59: 7-10. Khong, T.Y., DeWolf, F., Robertson, W.B. and Brosens, I. (1986) Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br. J. Obstet. Gynaecol., 93: 1049-1059. Lindow, S.W., Davies, D.A., Davey, D.A. and Smith, J.A. (1988) The effect of sublingual nifedipine on uteroplacental blood flow in hypertensive pregnancy. Br. J. Obstet. Gynaecol., 95: 1276-1281. Lunell, N.O., Nylund, L., Lewander, R. and Sarby, B. (1982) Uteroplacental blood flow in pre-eclampsia. Measucements with Indium 113 and a computer linked gamma camera. Clin. Exp. Hypertens., BI: 105-117. McCowan, L.M., Mullen, B.M. and Ritchie, K. (1987) Umbilical artery flow velocity waveforms and the placental vascular bed. Am. J. Obstet. Gynecol., 157: 900-902.
Montan, S., Liedholm, H., Lingman, G., Marsal, K., SjSberg, N. and Solum, T. (1987) Fetal and uteroplacental haemodynamics during short term atenolol treatment of hypertension in pregnancy. Br. J. Obstet. Gynaecol., 94: 312-317. Reuwer, P.J.H.M., Sijmons, E.A., Rietman G.W., Van Tiel, M.W.M. and Bruinse H.W. (1987) Intrauterine growth retardation: prediction of perinatal distress by Doppler ultrasound. Lancet ii: 415-418. Rubin, P.C., Butters, L., Clark, D.M., Reynolds, B., Sumner. D.J., Steedman, D., Low, R.A.L. and Reid, J.L. (1983) Placebo controlled trial of atenolol in treatment of pregnancy associated hypertension. Lancet, i: 431-434. Stuart, B., Drumm, J., FitzGerald, D.E. and Duignan, N.M. (1980) Fetal blood velocity waveforms in normal pregnancy. Br. J. Obstet. Gynaecol., 87: 780-785. Trudinger, B.J., Giles, W.B. and Cook C.M. (1985) Flow velocity waveforms in maternal uteroplacental and umbilical placental circulations. Am. J. Obstet. Gynecol., 152: 155-160. Trudinger, B.J., Stevens, D., Cormelly, A., Hales, J.R.S., Alexander, G., Bradley, L., Fawcett, A. and Thompson, R.S. (1987) Umbilical artery flow velocity waveforms and placental resistance: the effects of embolisation of the umbilical circulation. Am. J. Obstet. Gynecol., 157: 14431448. Wladimiroff, J.W., Tonge, H.M. and Stewart, P.A. (1986) Doppler ultrasound assessment of cerebral blood flow in the human fetus. Br. J. Obstet. Gynaecol., 93: 471-475.
159
Elsevier NSM 01119
The use of Doppler ultrasound in the study of fetal cardiovascular
physiology Kevin P. Hanretty 1 and Peter C. Rubin 2 I The University Department of Midwifery, The Queen Mother's Hospita~ Glasgow(U.K), and z Department of Therapeutics, University of Nottingham, Nottingham ( U.K ) (Received 19 September 1989) (Accepted 26 September 1989)
Key words: Doppler; Fetal physiology; Pharmacology; Nifedipine; Atenolol Doppler velocimetry of the uteroplacental and umbilical arteries provides an opportunity for the safe, reproducible and repeatable study of these circulations and already has led to an increased knowledge of the pathophysiology of pregnancy induced hypertension and intra-uterine growth retardation. This technique, which has only recently been introduced widely into obstetrics, also permits the study of the cardiovascular effects on the fetus of maternally administered drugs. The use of Doppler for these purposes is illustrated with particular reference to intra-uterine growth retardation and the use of the antihypertensive drugs, atenolol and nifedipine.
Introduction The study of the human fetus has always presented one of the most significant challenges in in-vivo monitoring, both in terms of obtaining a basic understanding of fetal physiology and in determining fetal wellbeing. This difficulty relates to the relative inaccessibility of the fetus and the placenta. The concept of 'placental wellbeing' does not normally merit attention but the interaotion of the uteroplacental and fetoplacental circulations is critically important in determining the successful outcome of pregnancy. Until the advent of Doppler velodmetry in obstetrics the dynamic study of these circulations h a d been impossible and the bulk of data concerning fetal haemodynamics has until now been obtained from invasive studies in pregnancies undergoing termination by hysterotomy (Assail et al., 1960) or inferred from patho-
logical examination after delivery. The uteroplacental circulation has hitherto only been studied using radioisotope clearance rates (Brown and Veall, 1953; Kaar et al., 1980) with all of the limitations and dangers for the fetus inherent in this. Furthermore, such investigations by their nature are not suitable for serial assessment of possible circulatory changes. The recognition 6f the limitations of these data is now even more important since there is increasing evidence that in-vivo changes in one circulation will modulate changes in the other. The use of Doppler allows the non-invasive study of fetal cardiovascular physiology and maternal vascular adaptation in both health and disease and permits study of drug effects on the uteroplacental and fetal circulations which have not previously been possible.
I~Oer prineiOe Correspondence: ILP. Hanretty, The Univenity Department of Midwifery, The Queen Mother's Hmpital, Glasgow (33 8SH, U.K.
Most people are familiar with the Doppler principle which states that the frequency of a sound signal perceived by an observer increases
0165-0270/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
160
Fig. 1. A normal low resistance flow velocity waveform from the umbilical artery.
Fig. 2. A normal low resistance uteroplacental waveform.
161
Fig. 3. High resistance pattern from the umbilical artery in severe pre-eclampsia.
Fig. 4. High resistance pattern from the uteroplacental arteries in severe pre-eclampsia.
162
proportionally to the velocity of the emmitter as it approaches (or recedes from) the observer. What is not always immediately obvious is that this is also true of sound reflected from a moving object. In obstetrics, and in vascular surgery, use has been made of this effect to study the change in frequency of a signal reflected from red cells in fetal and maternal vessels. This frequency change, or Doppler shift, is proportional to the velocity of the reflecting material and when plotted against time will produce a velocity time waveform. Figures 1 and 2 show normal waveforms obtained in the 3rd trimester of an uncomplicated pregnancy from the umbilical and uteroplacental arteries, respectively. These waveforms are characteristic of the low resistance to flow found in these circulations in uncomplicated pregnancy. In a number of complicated pregnancies, in particular those with severe intra-uterine growth retardation and pre eclampsia, abnormal waveforms may be obtained from both maternal and fetal vessels (Trudinger et al., 1985). Figures 3 and 4 show patterns representing high resistance, with a reduction in the diastolic component of flow from a case of severe pre-eclampsia. A number of indices have been developed to describe waveforms qualitatively: The systolic/diastolic ratio, also known as the A/B ratio (Stuart and Drumm, 1980) and the pulsatility index (Gosling and Ring, 1975) are most commonly used and for both these indices high values represent high vascular resistance whilst low values represent low resistance to flow. Doppler study now permits the invesigation, in utero, of these changes induced by different complications on fetal wellbeing and cardiovascular status.
DopplersludydlbeumbiHcalc5ruWhinpregnancy-hyprh&m
Almost all of the current knowledge regarding fetoplacental blood flow in pregnancies complicated by h-on has been obtained since the introduction of Doppler velocimetry. However, Abitbol et al. (1987) in an in-vitro study of perfused placentas from women with preeclampsia demonstrated reduced umbilical perfu-
sion. This finding supports to some extent the enthusiasm for Doppler in this clinical condition and Ducey et al. (1987) even suggested that the use of Doppler would permit more accurate classification of the hyperttmsive disorders of pregnancy. They noted an increased incidence of high resistance waveforms in patients with preeclampsia compared to women with chronic hypertension. However, Cameron et al. (1988) and Hanretty et al. (1988) have found no correlation between abnormal Dappler indices and absolute levels of hypertension in severe and mild preeclampsia, respectively. Importantly, clinical outcome, in terms of severity of growth retardation, fetal distress and admission to the neonatal intensive care unit did relate to the abnormalities detected by Doppler. The underlying pathology associated with these waveform changes is tmcertain but must represent increased downstream impedance to blood flow. This may be due to obliteration of tertiary stem villus arterioles. This abnormality has been described by Giles et al. (1985) and by McGowan et al. (1987) but the mechanism underlying this is not known. Repeated embolisation of the fetoplacental vessels in the sheep fetus has reproduced those changes seen in the compromised human fetus (Trudi.nger et al., 1987) supporting the concept of a reduction in placental perfusion from the fetus.
The underlying pathology of the reduced maternal perfusion of the placenta in pregnancyinduced hypertension is well d ocumented (Khong et al., 1986). Reduced maternal blood flow has been demonstrated using radioisotopes in hypertensive pregnancies (Lrmell et al., 1982) and there is now a large body of evidence to show that the normal physiological invasion of trophoblast into maternal spiral arteries converting them from high to low. resistance vessels does not occur in some hypertensive pregnancies. Initial studies using Doppler methods suggested that study of the uteroplacental arteries may identify this vascular
163
abnormality even before a clinically detectable problem is identified (Campbell et al., 1986). However, although in very severe pre-eclampsia abnormal waveforms are found, and attributed to widespread vascular pathology, the focal nature of less severe forms of the disease have made the use of Doppler less reliable than had been hoped. Nevertheless Doppler has proved of value in the investigation of drug effects. This will be discussed later. For prediction of disease severity the study of more proximal vessels such as the uterine arteries themselves and the use of colour-mapped Doppler appear promising (Campbell et al., 1988) but awaits further study.
Doppler study of the umbilical circulation in intrauterine growth retardation Re-distribution of blood flow within the fetus is a likely feature of 'placental insufficiency' and occurs in the absence of maternal hypertension although the mechanism may be similar to that invoked for abnormal Doppler waveforms in preeclampsia. Erskine and Ritchie (1985) demonstrated abnormal Doppler wavcforms in the umbilical artery of a small series of severely growthretarded fetuses and since then a number of authors (Fleischer et al., 1985; Trudinger et al., 1985; Reuwer et al., 1987) have demonstrated abnormal waveforms in the severely growth-retarded fetus. Furthermore, from their work it seemed that it would be possible to use Doppler to distinguish between babies actually growth-retarded in utero and those which are merely genetically small and not compromised. Larger studies have produced confusing data regarding the clinical value of umbilical artery Doppler velocirnetry. Berkowitz et al. (1988) found a sensitivity of only 45% when using the technique to identify fetuses destined to weigh less than the 10th centile for gestation at birth. Contrasting with this, Gaziano et al. (1988) found a sensitivity of 79% in such cases. Both of these studies investigated cases known to be at high risk for intra-uterine growth retardation and larger series investigating the value of umbilical Doppler in screening unselected populations have proven disappointing. This may
in part be attributed to the difficulty in distinguishing fetuses who are truly growth-retarded insofar as they do not reach their growth potential but who are not small-for-dates. The ability to identify such fetuses would be a major advance but there are methodological difficulties to be overcome before widespread application of Doppler in this field and the issue of whether waveforms from small-for-dates fetuses are different from uncomplicated pregnancies has still not been determined from controlled studies. We have performed such a study, comparing umbilical artery Doppler indices in 32 pregnancies matched for maternal and gestational age and found that the pulsatility index was significantly higher than controls (Table I) although only 3 of the growth retarded fetuses had results which would be considered abnormal. This evidence supports a redistribution of blood flow within growth-retarded fetuses and this appears to benefit the brain as part of a 'brain sparing' effect. Corroborating evidence is provided by the work of Wladimirrof et al. (1986) who studied waveforms from the internal carotid in a series of severely growth-retarded fetuses and showed an inverse relationship between the pulsatility index in the fetal internal carotid artery and the umbilical artery, i.e. high vascular resistance in the peripheral circulation is associated with a compensatory
TABLE I DOPPLER INDICES IN A COMPARISON OF 32 SMALLFOR-DATES (SFD) FETUSES AND MATCHED CONTROLS
Maternal age (yr) Gestation at time of study Gestation at delivery Birth w~ight
Umbilical artery PI RI Uteroplacental artery PI RI
SFD
Controls
Significance
24.7 (5.5)
24.8 (5.7)
NS
36.5 (3.0)
36.8 (2.6)
NS
38.6 (1.8) 39.2 (1.1) P=O.11 2.42 (0.39) 3.35 (0.35) P < 0.00001
1.04 (0.27) 0.88 (0.16) P < 0.02 0.62 (0.96)
0.56 (0.78) P < 0.02
0.52 (0.16) 0.38 (0.15)
0.61 (0.30) NS 0.39 ( 0 . 1 3 ) N S
PI, pulsatility index; RI, resistance index.
164
reduction in resistance to cerebral blood flow. The pathology of fetal growth retardation on the maternal side is similar in some cases to that of hypertensive pregnancy and the same limitations apply to the use of Doppler as apply to preeclampsia.
3
2-
Doppler and developmentalpharmacology The use of drugs in pregnancy, antihypertensives in particular, has been contentious since the first reports by Dixon et al. (1963) who suggested that rauwolfia alkaloids reduced maternal perfusion of the placenta. Their studies were performed using radionuclide tests and were uncontrolled. Doppler allows the repeatable non-invasive assessment of both uteroplacental and fetoplacental blood flow. We have used Doppler to study uteroplacental and fetoplacental perfusion in patients receiving atenolol or ulfedipine for pregnancy-induced hypertension. Atenolol has been shown to reduce blood pressure effectively in pregnancy-induced hypertension and may reduce the number of women going on to develop proteinuria (Rubin et al. 1983). Consequently its use is attractive. A recent report (Montan et al. 1987) suggested that atenolol produced an increased resistance to maternal perfusion though their study was uncontrolled. We have studied Doppler indices from the uteroplacental and umbilical arteries in 10 patients receiving 50 or 100 mg of atenolol for pregnancy-induced hypertension. The mean reduction in systolic blood pressure was 24 mm Hg and in diastolic blood pressure was 13 mm Hg after between 6 and 7 days treatment. In this study we used the pulsatility index to evaluate waveforms and Figs. 5 and 6 show the uteroplacental and umbilical artery pulsatility index before and after treatment. There was no change in this waveform index following atenolol. This is reassuring and suggests that redistribution of blood flow within the fetus is unlikely following atenolol therapy. These patients were also compared with untreated cases matched for gestational and maternal age. The median umbilical artery pulsa-
Fig. 5. Uteroplacental pulsatility index before and after treatment.
3"
Fig. 6. Umbilical artery pulsatility index before and after treatment.
157 (18) 99 (9) 78 (12) 143 (7) 1.73 (0.61) 1.20 (0.60)
0
1
142 (9) 85 (5) 81 (18) 145 (11) 1.85 (0.73) 1.24 (0.80)
141 (13) 84 (6) 82 (17) 142 (10) 1.90 (0.57) 1.22 (0.85)
2 143 (9) 84 (7) 79 (16) 143 (9) 1.81 (0.55) 1.41 (1.05)
3
4 148 (14) 85 (7) 79 (16) 140 (10) 1.86 (0.55) 1.35 (1.10)
5 146 (14) 86 (7) 75 (12) 142 (11) 1.87 (0.50) 1.31 (0,88)
6 146 (9) 89 (9) 72 (12) 140 (7) 1.73 (0.49) 1.26 (0.80)
8
154 (19) 153 (13) 91 (11) 90 (10) 73 (15) 70 (16) 141 (9) 13.9 (7) 1.82 (0.48) 1.78 (0.45) 1.22 (0.83) 1.20 (0.84)
7
P ffi 0.022 P < 0.001 P ffi 0.013 P = 0.878 P=0.848 P=0.871
Significance
Figures in parenthesis are standard deviations SBP, systolic blood pressure; DBP, diastolic blood pressure; FHR, fetal heart rate; UMB PI, umbilical artery pulsatility index; UTR PI, uteroplacental pulsatility index.
SBP DBP PULSE FHR UMBPI UTRPI
Time (h)
Time effects were studied by repeated measures analysis of variance. (Reproduced with permission of the Editor, British Medical JournaL)
THE EFFEC]" OF ORAL NIFEDIPINE ON MATERNAL AND FETAL HEART RATE, BLOOD PRESSURE AND DOPPLER INDICES
TABLE II
Ltt
166 tility index of 1.07 in the treated cases was the same as that of the untreated cases. In fulminant pre-eclampsia it m a y be necessary to control blood pressure more rapidly than is o b t a i n e d using beta-blockade. Nifedipine, a calcium channel blocker which has already been used in a limited way as a second-line agent in pre-eclampsia (Constantine et al. 1987) is a particularly attractive agent which can be given orally and rapidly reduces blood pressure but its effects on uteroplacental and fetoplacental blood flow have been incompletely investigated. We have studied 9 w o m e n with severe preeclampsia to determine the acute effects of 20 mg nifedipine on uteroplacental and umbilical artery D o p p l e r waveforms. T h e pulsatility index in these vessels was measured before therapy and hourly after c o m m e n c e m e n t of treatment for 8 h. Despite a rapid and sustained effect on blood pressure there was no change in D o p p l e r indices in either of the circulations studied (Table II). These data contrast with the results of studies of the calcium channel blocker, nicardipine, which was shown to decrease uteroplacental blood flow and produce fetal hypoxia in fetal sheep. Our results are consistent with a recent study by L i n d o w et al. (1988) which showed uteroplacental blood flow to be maintained fgllowing nifedipine when assessed radioisotopically. Serial measurements were not possible with their m e t h o d and our data are reassuring that there is not an adverse effect for a longer period than is possible to study using such methods. Furthermore, since there is a need for an effective antihypertensive agent in the acute situation these studies, only possible using D o p p l e r methods, justify further studies of calcium channel blockers in preeclampsia.
Conclusions The role of D o p p l e r methods in obstetric m a n a g e m e n t remains to be determined in large controlled studies but already this relatively new technique has improved our understanding of the h a e m o d y n a m i c s of conditions such as intra-uterine
growth retardation and of the effects of therapy for pre-eclampsia. This information should lead to better m e t h o d s of fetal assessment and developm e n t of safe drug regimens where such therapy is indicated.
References Abitbol, M.M., LaGamma, E.F., Demeter, E. and Cipollina, C.M. (1987) Umbilical flow in the normal and pre-eclamptic placenta. Acta Obstet. Gynecol. Scand., 66: 689-694. Assali, N.S., Rauramo, L. and Peitonen, T. (1960) Measurement of uterine blood flow and uterine metabolism. Am. J. Obstet. Gynecol., 79: 86-98. Berkowitz, G., Chitkara, U., Rosenberg, J., Cog,swell, C., Walker, B., Lahman, E.A., Mehalek, K.E. and Berkowitz, R.L. (1988) Sonographic estimation of fetal weight and Doppler analysis of umbilical velocimetry in the prediction of intra-uterine growth retardation: a prospective study. Am. J. Obstet. Gynecol., 158: 1149-1153. Brown, J.C.M. and Veall, N. (1953) The maternal placental blood flow in normotensive and hypertensive women. J. Obstet, Gynaecol. Brit. Emp., 60: 141-147. Cameron, A.D., Nicholson, S.F., Nimrod, C.A., Harder, J.R. and Davies, D.M. (1988) Doppler waveforms in the fetal aorta and umbilical artery in patients with hypertension in pregnancy. Am. J. Obstet. Gyneool., 158: 339-345. Constantine, G., Beevers, D.G., Reynolds, A.L. and Luesley, D.M. (1987) Nifedipine as a second line antihypertensive drug in pregnancy. Br. J. Obstet. Gynaecol., 94: 1136-1142. Dixon, H.G., Browne, J.C.M. and Davey, D.A. (1963) Choriodecidual and myometrial blood flow. Lancet, ii: 369-373. Ducey, J., Schulman, H., Farmakides, G., Rochelson, B., Bracero, L., Fleischer, A., Guzman, E., Winter, D. and Penny, B. (1987) A classification of hypertension in pregnancy based on Doppler veloeimetry. Am. J. Obstet. Gynecol., 157: 680-685. Erskine, R.L.A. and Ritchie, J.W.K. (1985) Umbilical artery blood flow characteristics in normal and growth-retarded fetuses. Br. J. Obstet. Gynaecol., 92: 605-610. Fleischer, A., Rochelson, B., Farmakides, G. and Bracero, L. (1985) Umbilical velocity waveforms in intrauterine growth retardation. Am. J. Obstet. Gynecol., 151: 502-505. Gaziano, E., Knox, E., Wager, G.P., Bendel, R.P., Boyce, D.J. and Olson, J. (1988) The predictability of the small-for-gestational-age infant by real time ultrasound derived meaurements combined with pulsed Doppler umbilical artery velocimetry. Am. J. Obstet. Gynecol., 158: 14311439. Giles, W.B., Trudinger, B.J. and Baird, P.J. (1985) Fetal umbilical artery flow velocity waveforms and placental resistance: pathological correlation. Br. J. Obstet. Gynaecol., 92: 31-38.
167 Gosling, R.G. and King, D.H. (1975) Ultrasound angiology in Marcus, A.W. and Adamson, L. (Eds.) Arteries and Veins, Churchill Livingstone. Edinburgh, pp.61-98. Haxtretty, K.P., Whittle, M.J. and Rubin, P.C. (1988) Fetoplacental and uteroplacental flow velocity waveforms in mild pregnancy-induced hypertension. In C.T. Jones (Ed.), Fetal and Neonatal Development (Research in Per[natal Medicine, Vol. VII), Perinatology Press, New York, pp. 536-538. Kaar, K., Jouppila, P., Kuikka, J., Luotola, J., Toivanen, J. and Rekonen, A. (1980) InterviUous blood flow in normal and complicated pregnancy measured by means of an intravenous Xe 133 method. Acta Obstet. Crynecol. Scand., 59: 7-10. Khong, T.Y., DeWolf, F., Robertson, W.B. and Brosens, I. (1986) Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br. J. Obstet. Gynaecol., 93: 1049-1059. Lindow, S.W., Davies, D.A., Davey, D.A. and Smith, J.A. (1988) The effect of sublingual nifedipine on uteroplacental blood flow in hypertensive pregnancy. Br. J. Obstet. Gynaecol., 95: 1276-1281. Lunell, N.O., Nylund, L., Lewander, R. and Sarby, B. (1982) Uteroplacental blood flow in pre-eclampsia. Measucements with Indium 113 and a computer linked gamma camera. Clin. Exp. Hypertens., BI: 105-117. McCowan, L.M., Mullen, B.M. and Ritchie, K. (1987) Umbilical artery flow velocity waveforms and the placental vascular bed. Am. J. Obstet. Gynecol., 157: 900-902.
Montan, S., Liedholm, H., Lingman, G., Marsal, K., SjSberg, N. and Solum, T. (1987) Fetal and uteroplacental haemodynamics during short term atenolol treatment of hypertension in pregnancy. Br. J. Obstet. Gynaecol., 94: 312-317. Reuwer, P.J.H.M., Sijmons, E.A., Rietman G.W., Van Tiel, M.W.M. and Bruinse H.W. (1987) Intrauterine growth retardation: prediction of perinatal distress by Doppler ultrasound. Lancet ii: 415-418. Rubin, P.C., Butters, L., Clark, D.M., Reynolds, B., Sumner. D.J., Steedman, D., Low, R.A.L. and Reid, J.L. (1983) Placebo controlled trial of atenolol in treatment of pregnancy associated hypertension. Lancet, i: 431-434. Stuart, B., Drumm, J., FitzGerald, D.E. and Duignan, N.M. (1980) Fetal blood velocity waveforms in normal pregnancy. Br. J. Obstet. Gynaecol., 87: 780-785. Trudinger, B.J., Giles, W.B. and Cook C.M. (1985) Flow velocity waveforms in maternal uteroplacental and umbilical placental circulations. Am. J. Obstet. Gynecol., 152: 155-160. Trudinger, B.J., Stevens, D., Cormelly, A., Hales, J.R.S., Alexander, G., Bradley, L., Fawcett, A. and Thompson, R.S. (1987) Umbilical artery flow velocity waveforms and placental resistance: the effects of embolisation of the umbilical circulation. Am. J. Obstet. Gynecol., 157: 14431448. Wladimiroff, J.W., Tonge, H.M. and Stewart, P.A. (1986) Doppler ultrasound assessment of cerebral blood flow in the human fetus. Br. J. Obstet. Gynaecol., 93: 471-475.