Beyond the placental bed: Placental and systemic determinants of the uterine artery Doppler waveform
Introduction
Since the early 1980s, uterine artery blood flow in pregnancy and its determinants have been of great interest to scientists studying the placental bed, to clinicians screening for conditions associated with abnormal placentation and to those involved in caring for women and with pre-eclampsia and their often growth restricted babies. Doppler ultrasound is widely used to assess the uterine artery Doppler waveform as high impedance or abnormal waveforms in the first, and particularly, second trimesters are related to adverse pregnancy outcome [1]. The adaptation of the uterine spiral arteries is classically believed to be related to the success of placentation [2]. However, it is increasingly evident that factors external to placenta and the placental bed are also important determinants of the uterine artery waveform Table 1.
In this review, we discuss the development and refining of ultrasound techniques to assess the uterine artery blood flow. We explore how uterine artery impedance is related to adverse pregnancy outcome and its association with placentation. Finally we consider the extra-placental factors that are emerging as additional determinants of the uterine artery waveform.
Section snippets
Development of techniques for ultrasound assessment
The use of Doppler ultrasound for assessment of the uteroplacental circulation was first reported in 1983 [3]. Prior to this, uterine artery blood flow could only be measured through invasive techniques or those using radio-dilution. However, it was the arcuate vessels in the uterine wall, rather than the uterine arteries, and blood flow, rather than impedance, was measured. Through the use of a linear array ultrasound and a combination of continuous wave and pulsed Doppler, a normogram of
Use of uterine artery Doppler in screening
That abnormal uteroplacental waveforms may be an early predictor of preeclampsia became apparent with the first studies relating Doppler findings to outcome [8]. It was postulated that women with abnormal waveforms in the second trimester could benefit from increased surveillance. With the recognition that both deficient placentation and abnormal uterine or spiral artery Doppler waveforms were associated with adverse obstetric outcomes, and that these were possibly linked, the role of uterine
Models of resistance and flow
With an increased understanding that pathological processes within the uteroplacental bed affected the uterine artery waveform, computer and bio-engineering models were developed to examine the effects of various factors. Electrical analogue modelling indicated that the early diastolic notch was most likely due to wave reflection and the persistence of this into the late second trimester is indicative of abnormally high placental bed resistance [17]. Further, computer modelling has demonstrated
Associations of uterine artery Doppler with histopathology of the placenta
The mechanisms of trophoblast invasion of the spiral arteries and the defects in spiral artery remodelling in relation to pregnancy complications has been comprehensively reviewed [21], [22]. However, though the uterine artery Doppler waveform has proved predictive for adverse outcomes related to utero-placental insufficiency, is the underlying pathological processes associated with these Doppler abnormalities understood?
Brosens' seminal work in 1967 [23] reported that the spiral arteries
Arterial stiffness and endothelial function
In 1985, Trudinger et al. [5] stated that “flow velocity is influenced by the ejection systolic pulse, arterial wall compliance, blood stream inertia and downstream peripheral resistance.” Whilst clinico-pathological findings of the placenta and placental bed correlate with the uterine artery Doppler waveform due to their major contributions to downstream peripheral resistance, other influences have been largely overlooked. The uterine artery waveform in pregnancy is also a reflection of
Maternal heart rate
Heart rate of the women affects uterine artery PI, showing a significant negative correlation [54]. This may appear intuitive, as the slower the heart rate, the longer an individual uterine systolic/diastolic cycle will be, allowing the end diastolic component to tend towards the baseline - in other words a higher PI. Although this effect is recognised, it is not adjusted for in clinical practice nor has it been in screening studies. Adjustment for heart rate can however improve both positive
Hormonal
Variations in impedance of the uterine arteries through the menstrual cycle [7], [56], [57], [58] and even diurnally [59] are described. Uterine artery impedance falls during the luteal phase of the menstrual cycle, particularly in the vessel ipsilateral to the corpus luteum. These reductions in impedance to the secretory endometrium at a time when implantation may occur is strongly correlated with increased plasma levels of progesterone and oestrodiol [7].
In women with polycystic ovary
Nitric oxide
Nitric oxide (NO), generated in the endothelium by the endothelial nitric oxide synthase (eNOS), is essential for proper endothelial function and regulation of vascular tone [63] (Fig. 4). eNOS activity is increased in the uterine arteries in normal pregnancy [64] and nitric oxide plays a key role in systemic vasodilation in normal pregnancy [65]. These effects are mediated predominantly through activation of soluble guanylate cyclase (sGC) by NO and the subsequent conversion of guanosine
Antihypertensive agents and uterine artery Doppler
Antihypertensive agents commonly used to treat hypertensive disorders of pregnancy have largely shown no effect on the uterine artery PI. These include the calcium-channel blockers nifedipine [79], [80], [81] and verapamil [82], hydralazine [79] and labetalol (a mixed alpha/beta antagonist) [83], [84], [85]. Alpha-methyldopa showed a significant decrease in uterine artery impedance in a single study in preeclampsia [86]. Nifedipine is occasionally used for tocolysis at much higher doses than is
Extra-uterine pregnancy
Normal (i.e. low impedance) uterine artery Doppler waveforms have been recorded in extra-uterine pregnancies [88], [89]. This might at first sight appear to be bizarre as there is no intrauterine placental bed to cause downstream resistance. Whilst these case reports do not provide a mechanism for this phenomenon, they do provide one of the clearest indications that factors external to placental resistance may also be responsible for the pregnant uterine artery waveform.
Malaria
One study has investigated the effect of the malaria causing parasite, Plasmodium falciparum, on the uterine artery Doppler waveform [90]. The uterine artery Doppler waveforms were twice as likely to be abnormal in women with malaria parasites detected on blood film and women with abnormal waveforms were likely to delivery prematurely with lower birth weight babies. Acute P. falciparum infection appears to be the cause of increased resistance in the uteroplacental vasculature, although this may
Postpartum
Following delivery, uterine artery impedance and waveforms have been studied for up to 3 months [91]. There is considerable inter-individual variation in the post-partum changes with some studies showing a steady increase in impedance from the first day post-partum to normal values at 4–6 weeks post-partum [92], [93] and others showing uterine artery impedance remaining low until 4 weeks post-partum [94], [95]. Similarly, where an early diastolic notch was present in pregnancy it may reappear
Conclusion
It is evident that the uterine artery waveform in normal pregnancy is a composite of downstream resistance (the placental circulation) and maternal arterial function. That a normal uterine waveform in pregnancy reflects successful trophoblastic invasion and conversion of the spiral arteries is true, but this does not reflect the whole truth. Conversely, that abnormal uterine artery waveforms represent raised placental bed resistance is true – but this also does not represent the complete
References (98)
- et al.
Individualized risk assessment for adverse pregnancy outcome by uterine artery Doppler at 23 weeks
Obstetrics Gynecol
(2001) - et al.
New Doppler technique for assessing uteroplacental blood flow
Lancet
(1983) - et al.
Flow velocity waveforms in the maternal uteroplacental and fetal umbilical placental circulations
Am J Obstet Gynecol
(1985) - et al.
The antenatal assessment of utero-placental and feto-placental blood flow using Doppler ultrasound
Ultrasound Med Biol
(1985) - et al.
Early Doppler ultrasound screening in prediction of hypertensive disorders of pregnancy
The Lancet
(1990) - et al.
One-stage screening for pregnancy complications by color Doppler assessment of the uterine arteries at 23 weeks' gestation
Obstetrics Gynecol
(2000) - et al.
An integrated model for the prediction of preeclampsia using maternal factors and uterine artery Doppler velocimetry in unselected low-risk women
Am J Obstetrics Gynecol
(2005) - et al.
A transmission line modelling approach to the interpretation of uterine Doppler waveforms
Ultrasound Med Biol
(1988) - et al.
Effect of placental resistance, arterial diameter, and blood pressure on the uterine arterial velocity waveform: a computer modeling approach
Ultrasound Med Biol
(1989) - et al.
The uterine spiral arteries in human pregnancy: facts and controversies
Placenta
(2006)
The “Great Obstetrical Syndromes” are associated with disorders of deep placentation
Am J Obstetrics Gynecol
Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy
Placenta
Acute atherosis. A histopathological hallmark of immune aggression?
Placenta
Effect of hypoxia on trophoblast in organ culture. A morphologic and autoradiographic study
Am J Obstetrics Gynecol
Relationship between placental histologic features and umbilical cord blood gases in preterm gestations
Am J Obstetrics Gynecol
Acute atherosis in preeclampsia: maternal determinants and fetal outcome in the presence of the lesion
Am J Obstetrics Gynecol
Doppler blood flow in pregnancy
Placenta
A high uterine artery pulsatility index reflects a defective development of placental bed spiral arteries in pregnancies complicated by hypertension and fetal growth retardation
Eur J Obstet Gynecol Reprod Biol
Uterine artery Doppler velocimetry in relation to trophoblast migration into the myometrium of the placental bed
Obstetrics Gynecol
Uterine Doppler velocimetry and placental hypoxic-ischemic lesion in pregnancies with fetal intrauterine growth restriction
Placenta
Uterine artery Doppler flow and uteroplacental vascular pathology in normal pregnancies and pregnancies complicated by pre-eclampsia and small for gestational age fetuses
Placenta
Histomorphology of the placenta and the placental bed of growth restricted fetuses and correlation with the Doppler velocimetries of the uterine and umbilical arteries
Placenta
Altered vascular function in healthy normotensive pregnant women with bilateral uterine artery notches
BJOG: Int J Obstetrics Gynaecol
Raised uterine artery impedance is associated with increased maternal arterial stiffness in the late second trimester
Placenta
Uterine and ovarian flow velocity waveforms in the normal menstrual cycle: a transvaginal Doppler study
Fertil Steril
The role of color Doppler imaging in the diagnosis of polycystic ovary syndrome
Am J Obstetrics Gynecol
Abnormal endothelial cell function of resistance arteries from women with preeclampsia
Am J Obstetrics Gynecol
The role of nitric oxide in the pathogenesis of preeclampsia
Am J Obstetrics Gynecol
Urine but not plasma nitric oxide metabolites are decreased in women with preeclampsia
Am J Obstetrics Gynecol
The effect of isosorbide dinitrate on uterine artery and umbilical artery flow velocity waveforms at mid-pregnancy
Obstet Gynecol
The effects of S-nitrosoglutathione on platelet activation, hypertension, and uterine and fetal Doppler in severe preeclampsia
Obstetrics Gynecol
Changes in fetal and maternal doppler parameters observed during acute severe hypertension treatment with hydralazine or labetalol: a randomized controlled trial
Ultrasound Med Biol
Effect of labetalol infusion on uterine and fetal hemodynamics and fetal cardiac function
Eur J Obstet Gynecol Reprod Biol
Abdominal pregnancy: a perfusion confusion?
Placenta
A longitudinal Doppler ultrasonographic assessment of the alterations in peripheral vascular resistance of uterine arteries and ultrasonographic findings of the involuting uterus during the puerperium
Am J Obstet Gynaecol
Doppler ultrasound of the uteroplacental circulation as a screening test for severe pre-eclampsia with intra-uterine growth retardation
Eur J Obstet Gynaecol
Blood viscosity and uterine artery flow velocity waveforms in pregnancy: a longitudinal study
Placenta
Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants
Br J Obstet Gynaecol
Uteroplacental blood flow velocity-time waveforms in normal and complicated pregnancy
Br J Obstet Gynaecol
Comparison of color Doppler uterine artery indices in a population at high risk for adverse outcome at 24 weeks' gestation
Ultrasound Obstet Gynecol
Transvaginal colour flow imaging of the uterine arteries during the ovarian and menstrual cycles
Hum Reprod
Doppler investigation of uteroplacental blood flow resistance in the second trimester: a screening study for pre-eclampsia and intrauterine growth retardation
BJOG: Int J Obstetrics Gynaecol
Hypertensive disorders in pregnancy: screening by biophysical and biochemical markers at 11–13 weeks
Ultrasound Obstet Gynecol
Evaluation of 7 serum biomarkers and uterine artery Doppler ultrasound for first-trimester prediction of preeclampsia: a systematic review
Obstet Gynecol Surv
First trimester markers for the prediction of pre-eclampsia in women with a priori high risk
Ultrasound Obstet Gynecol
Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis
Obstetrics Gynecol
Uterine flow velocity waveform shape as an indicator of maternal and placental development failure mechanisms: a model-based synthesizing approach
Ultrasound Obstet Gynecol
Micro-bead embolization of uterine spiral arteries and changes in uterine arterial flow velocity waveforms in the pregnant ewe
Ultrasound Obstet Gynecol
The physiological response of the vessels of the placental bed to normal pregnancy
J Pathol Bacteriol
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Understanding the uterine artery Doppler waveform and its relationship to spiral artery remodelling
2021, PlacentaCitation Excerpt :During the luteal phase of the menstrual cycle UtA impedance falls [15–17]. Women with polycystic ovarian syndrome (PCOS), who have chronically raised leutinising hormone (LH) [5], have a higher UtA impedance [37]. Furthermore, the UtA waveform exhibits a diurnal variation with higher PI in the evening, although this is greater than can be accounted for by changes in LH alone [38].
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