Beyond the placental bed: Placental and systemic determinants of the uterine artery Doppler waveform

Placenta 33 (2012) 893e901

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Beyond the placental bed: Placental and systemic determinants of the uterine artery Doppler waveform T.R. Everett a, C.C. Lees a, b, * a b

Dept of Fetal Medicine, Box 228, Rosie Hospital, Cambridge University Hospitals NHS Trust, Cambridge CB2 2SW, UK Department of Development and Regeneration, Katholieke Universiteit Leuven, Belgium

a r t i c l e i n f o

a b s t r a c t

Article history: Accepted 16 July 2012

The uterine artery Doppler waveform has been extensively investigated, though its widespread clinical use as a predictor of adverse pregnancy outcome remains under debate. The determinants of the waveform have classically been ascribed to transformation of the spiral arteries and the development of a low resistance uteroplacental circulation, failure of which predisposes to pre-eclampsia, fetal growth restriction and other adverse outcomes. It has become increasingly evident that although spiral artery transformation determines in some part the characteristics of the Doppler waveform, factors pertaining to maternal vascular and endothelial function are also important. Ó 2012 Elsevier Ltd. All rights reserved.

Keywords: Uterine artery Doppler Placenta Ultrasound

1. Introduction

2. Development of techniques for ultrasound assessment

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.

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 Doppler frequency shift was developed to analyse the waveform through a cardiac cycle. It was realised that in women with proteinuric hypertension, a deviation of a waveform of >2SD at two separate points on the normogram in a cardiac cycle was associated with the adverse outcomes of fetal hypoxia and lower birth weight [3]. These ‘deviations’ correspond to high peak systolic velocity and an early diastolic notch. Further studies confirmed the original findings and that the failure of normal physiological conversion from a high resistance/ low flow to a low resistance/high flow uteroplacental circulation was more common in women with poorer fetal and neonatal outcomes [4]. Development of normograms of the systolic/diastolic (S/D) ratio [5], resistance index (RI) (otherwise known as Pourcelot or resistive index) and pulsatility index (PI) circumvented the need for adjustment of values for angle of insonation (Fig. 1), as was required for velocity based indices. This provided a method of quantifying the waveform hence avoiding purely subjective examination of the waveform (or frequency index profile) and description of its profile. Although the presence of early diastolic

* Corresponding author. Dept of Fetal Medicine, Box 228, Rosie Hospital, Cambridge University Hospitals NHS Trust, Cambridge CB2 2SW, UK. Tel.: þ44 1223 217972; fax: þ44 1223 216185. E-mail address: [email protected] (C.C. Lees). 0143-4004/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.placenta.2012.07.011

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Table 1 Extra-uterine factors affecting uterine artery Doppler impedance. Factor Hormonal

Pharmacological

Infective Extra-uterine pregnancy

Effect Oestrogen [7] Progesterone [7] PCOS [61,62] Labetalol [83e85] Nifedipine [79e81] Verapamil [82] Hydralazine [79] a-Methyldopa [86] NO donors [72e75] Malaria [90] [88,89]

Y Y [ 4 4a 4 4 Y Yb [ Y

Y ¼ Decrease; [ ¼ Increase; 4 ¼ No change. a Decrease seen in high dose regimen. b Some studies show no change.

notches remain, particularly if bilateral, relevant to adverse outcome, even with normal resistance values [6] (Fig. 2). Uterine arteries are not readily visible on gray-scale B-mode ultrasound, but with the advent of colour Doppler, their precise localisation became feasible [7]. This enabled reliably reproducible measurements by defining the standardised sampling site at which the uterine artery Doppler insonation was performed. Whilst the term ‘resistance’ is commonly used in the context of uterine artery Doppler it is, in fact, impedance that is measured as the combination of forward and reflected blood flow. 3. 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 artery Doppler in relation to its predictive utility for preeclampsia became the subject of extensive investigation. When used alone, Doppler assessment of the uteroplacental circulation, has a poor positive predictive value for complications associated with impaired placentation overall [9,10]. In other words, most women with abnormal uterine artery waveforms have uneventful pregnancies. It is unlikely, however, that a complicated pregnancy would have a completely normal uterine artery waveform. Following this observation, the next phase in understanding uterine artery Doppler was the realisation that, although its sensitivity was poor for all preeclampsia and fetal growth restriction at all gestations, it was more sensitive for early-onset (pre-34 week gestation) disease: the earlier and more severe the condition, the better the sensitivity [1,11]. Refinement of the predictive models to include integration of maternal factors [12] improved the prediction for preeclampsia at all gestations. Over the past decade the use of the uterine artery impedance in combination with soluble maternal biomarkers [13,14] and/or maternal vascular characteristics [15] have provided potentially promising models for the prediction of early-onset preeclampsia. Whilst universal screening for preeclampsia has not yet been adopted in most countries, this may change as newer models are validated, and the increasing weight of evidence for the preventative role of aspirin [16]. Whilst a normal uterine artery Doppler PI and waveform has strong negative predictive value for a placental complication of pregnancy, the positive predictive value is poor. This may, in part, be accounted for by the influence of non-placental factors in maternal cardiovascular adaptation and the appearance of the waveform. Uterine artery waveforms may be influenced by maternal factors, and not merely, as has been customarily assumed to date, abnormal Doppler explained as purely placental in origin.

Fig. 1.

Doppler Index

Formula

Systolic/Diastolic (S/D) ratio

Vmax/Vmin

Resistance Index (RI)

(Vmax-Vmin)/Vmax

Pulsatility Index (PI)

(Vmax-Vmin)/Vmean

Vmax ¼ peak systolic velocity; Vmin ¼ minimum diastolic velocity; Vmean ¼ mean velocity through cardiac cycle.

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Fig. 2. Uterine artery waveforms: a) Normal pregnant waveform. b) Abnormal waveform demonstrating increased impedance and early diastolic notch (arrow).

4. 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 that increases in uteroplacental resistance cause an increase in pulsatility index and the appearance of the early diastolic notch in the uterine artery waveform [18]. However, others have suggested that the early diastolic notch is an indicator of an abnormal maternal artery wall, independent of placental obstructive measurements [19]. Importantly, these effects were accentuated by reduction in the radius of the uterine artery but changes in the mean arterial pressure had little effect on the waveform. This may explain the relative lack of change in the uterine artery waveform in hypertension or with antihypertensive medication. When micro-beads were injected to embolise ovine spiral arteries, a positive linear correlation was found between an increase in uterine vascular resistance and uterine artery pulsatility index, thus providing in vivo validation of the models described above, including development of the early diastolic notch [20]. 5. 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 became physiologically changed in pregnancy. In doing so, spiral arteries lose their smooth muscle and elastica, become dilated and, as a result, enable the maternal blood supply to sustain the increasing requirements to the placenta and fetus (Fig. 3). Whilst the precise mechanisms of trophoblast invasion remain to be elucidated, it is evident that there is trophoblast invasion of both the lumen and the adventitia of the spiral arteries. This results in loss of the smooth muscle wall and creation of an intramural trophoblast and fibrinoid layer in its place. This becomes re-endothelialised. It is widely, though not universally [24], believed that there are two waves of trophoblast invasion [25], initially involving only the superficial myometrium, but progressing into the deep myometrium from 14 weeks gestation. Brosens et al. [26] then demonstrated that in the myometrial placental beds of women with preeclampsia these physiological

changes were not universal and that “normal” spiral arteries without the expected pregnancy related changes were present. In some spiral arteries, the physiological changes may be present in the decidual segments only, leaving the myometrial segments undisturbed [27]. The adaptive failure of the spiral arteries to pregnancy is a distinctive feature in preeclampsia. However, it is also evident in pregnancies complicated by non-proteinuric gestational hypertension [28], chronic hypertension [29] and IUGR without evidence of preeclampsia or hypertension [30]. The second common placental bed abnormality found in preeclampsia is acute atherosis of maternal vessels, with vascular necrosis, and foam cell and perivascular leucocyte infiltration as characteristic features [31]. However, whilst providing clear evidence of an acute vascular pathological process, these findings do not translate into an adverse clinical outcome [2], probably due redundancy within the placental bed allowing sufficient blood flow being maintained through unaffected vessels. Lack of trophoblast invasion is the commonest single feature noted when abnormal uterine artery flow is evident. However non placental bed lesions such as villous infarction, villous hypovascularity, terminal villous fibrosis, increased syncytiotrophoblast knotting, cytotrophoblast proliferation and abruptio placentae have also been reported in association with poor trophoblast invasion [32e34]. Though changes in the placental bed might be expected to primarily affect uterine artery Doppler waveform, as the fetoplacental unit is reliant on uterine artery perfusion, a secondary effect on the umbilical artery Doppler waveform might also be expected. An association between Doppler indices and histopathological changes in the placenta or placental bed was initially investigated in the relation to the changes in the umbilical artery Doppler waveform [35]. Whilst the number of tertiary stem villi did not vary between those with normal and abnormal umbilical artery Doppler waveforms, a reduced small arterial vessel count, probably suggesting an obliterative process, was observed in placentas that had exhibited higher resistance. Similarly lack of depth of trophoblast invasion was also found to be related to increased resistance in the umbilical artery [36,37]. Through the assessment of the umbilical artery, pathology in the placenta could, for the first time, be inferred by Doppler. Whilst not universal, the absence of the normal physiological changes of the spiral arteries in pregnancy and acute atherosis are more common in women with high uterine artery impedance [38]. A greater frequency of placental ischaemic lesions is associated with babies that exhibit intra-uterine growth restriction [39]. Impaired trophoblast migration into the spiral arteries is associated with abnormal uterine artery Doppler waveforms [40] and raised uterine artery S/D ratio is highly predictive (92.3%) of the absence of trophoblast migration. However, the converse does not hold true: uterine artery impedance is normal in just over half of the women who demonstrate impaired trophoblast migration [40]. When placentas of babies with intra-uterine growth restriction

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Fig. 3. Successful trophoblast invasion and remodelling of the spiral artery in normal pregnancy. Lack of trophoblast invasion and spiral artery remodelling is seen in preeclampsia. From Maynard et al., 2008 [93] with permission.

were examined, those exhibiting extensive hypoxic damage (in greater than 30% of terminal villi) or haemorrhagic changes were six times more common in cases in which uterine artery Doppler velocimetry was abnormal [41]. These changes were not associated with maternal hypertension or proteinuria. A gradient exists in the severity of uteroplacental vascular pathology and the degree to which this is reflected by the uterine artery Doppler impedance or clinical correlation [42]. Again, abnormal uterine artery PI was more common in women whose placental bed biopsies show absent or incomplete physiological adaptation. Complete physiological adaptation was also absent in one third of biopsies from women with normal uterine artery Doppler and normal pregnancy outcome. Likewise, one third of women with abnormal uterine artery Doppler and either IUGR or preeclampsia did not have pathological changes on examination of the placental bed biopsy. This mirrors the findings of a similar study in women with preeclampsia [43] that reported absence of trophoblast migration in placental bed biopsies was not commonly seen in women with abnormal uterine artery Doppler impedance. It may be concluded that abnormal Doppler waveforms cannot solely be explained by abnormal uteroplacental vessel histopathology [42].

The studies discussed report placental or placental bed histology from pregnancies in the third trimester and with ultrasound assessment of the uterine arteries performed within two weeks prior to delivery. However, the failure of trophoblast invasion occurs in the late first and early second trimester. First trimester trophoblast in high uterine artery Doppler impedance already shows less endovascular invasion than in those in whom adaptation to a low-impedance flow had occurred [44]. However, in both groups endovascular trophoblast invasion was noted in fewer than half the vessels. This reflects an ongoing process of placentation which continues into the second trimester as is evident from both histopathological and Doppler studies and may be relevant in determining the most appropriate timing of the uterine artery Doppler screening [11]. There is therefore a more pronounced relationship between increased uterine artery Doppler impedance and placental bed lesions than with placental lesions [45,46] but the strongest relationship is seen when combinations of both are present. Conversely, it is also possible for uterine Doppler velocimetry to be abnormal where a placenta does not exhibit pathological vascular lesions [41]. As might be expected, placental, rather than placental

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bed, abnormalities have a stronger association with abnormal umbilical artery Doppler.

change the women from being classified as “low-risk” of complications to “high-risk” or vice-versa.

6. Arterial stiffness and endothelial function

8. Hormonal

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 vascular tone. Women with preeclampsia are at higher long-term risk of cardiovascular disease [45] and women with “traditional” cardiovascular risk factors prepregnancy are at higher risk of preeclampsia. Women with preeclampsia, particularly of earlyonset, or IUGR have poorer endothelial function for at least two years postpartum [47,48], although whether the long-term risks to cardiovascular health are evident prepregnancy or are due to the effect of preeclampsia on the vasculature is yet to be determined. Further, cardiac function in women with abnormal uterine artery Doppler who suffer from early onset pre-eclampsia is severely impaired up to two years after delivery [49]. The gold-standard non-invasive assessment of endothelial function is flow-mediated dilatation (FMD), with lower FMD values indicating endothelial dysfunction. Women exhibiting bilateral uterine artery notches, in the absence of preeclampsia, showed reduced FMD [50] and lower concentrations of nitric oxide metabolites. When women with preeclampsia were studied, those with bilateral notches had lower FMD than those with normal waveforms, implying endothelial dysfunction. These findings have been replicated in a more recent study [51] which also found higher levels of high sensitivity CRP (hsCRP), a marker of systemic inflammation, in preeclamptic women with abnormal uterine artery waveforms compared to those with normal waveforms. More recently surrogate assessments of endothelial health have been investigated in relation to preeclampsia and arterial stiffness: arterial pulse wave reflection using augmentation index (AIx) and aortic pulse wave velocity (aPWV), a measure of aortic stiffness. Higher aPWV has been demonstrated in women with increased uterine artery impedance [52]. If the same pathological processes that cause increased aortic stiffness also affect the uterine arteries, these stiffer uterine arteries could result in changes to the uterine artery Doppler waveform. AIx is inversely correlated to heart rate and hence requires adjustment for heart rate. This may be standardised to a value of 75 bpm (AIx-75) or to the heart rate within the study population (which in pregnancy is likely to be higher than 75 bpm). Two studies [15,52] have not shown a relationship between AIx-75 and uterine artery PI. However we have shown that when AIx is adjusted to the heart rate of the study population, there is a positive linear correlation between AIx and uterine artery PI in the late second trimester and we confirm the findings of the positive relationship between aPWV and uterine artery PI [53].

Variations in impedance of the uterine arteries through the menstrual cycle [7,56e58] 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 syndrome (PCOS) there is frequently disruption of the normal ovarian cycle. Chronically raised levels of luteinising hormone (LH) result in anovulation and subsequent lack of the luteal phase of the menstrual cycle; this is commonly associated with hyperandrogenism. The direct vasoconstriction and stiffening effects of chronic hyperandrogenism on the vessel wall alongside chronic hyperinsulinaemia are postulated mechanisms of vascular damage. This can be evidenced by premature carotid artery atherosclerosis in women with PCOS [60]. It is unlikely that the uterine arteries fully escape these effects. Women with PCOS have been shown to have higher uterine artery impedance than women with normal menstrual cycles [61,62]. It is unlikely that there is a single factor causing this difference, as positive associations between LH concentrations, haematocrit and haemoglobin and uterine artery impedance have been demonstrated.

7. 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 and negative predictive values [55] and may

9. 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 triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). Decreased concentrations of NO metabolites, nitrate and nitrite are detected in women with preeclampsia [66,67] when compared to normal pregnancies and lower levels of eNOS have been found in women with raised uterine artery impedance [68]. However, the picture remains far from clear as more recently a study has shown whilst there is a moderately strong positive correlation between NO metabolites and uterine artery PI, this is not the case for cGMP and no difference in NO or cGMP was seen between normotensive woman and those with preeclampsia [69]. There is increased eNOS expression in the placentas of women with bilateral uterine artery notches [70]. This may be contrary to what would be expected, though not if an increase in eNOS activity compensates for a vasculature that is less sensitive to NO in preeclampsia than in normal pregnancy. This is consistent with findings that flow-mediated dilation in response to NO is impaired in preeclampsia [71]. In the uterine arteries, this might manifest as increased PI. The maternal vascular effects of preeclampsia are thus believed to be in part due to disruption of the normal nitric oxide pathways resulting in endothelial dysfunction and increased vascular tone. In the uterine arteries, this could be observed as increased impedance. When intravenous glyceryl trinitrate (GTN) is administered to women with high uterine artery Doppler impedance in the late second trimester, impedance falls [72] and the early-diastolic uterine artery notch becomes less evident. Interestingly, the doses used in this study were at concentrations that did not alter maternal blood pressure, heart rate or carotid artery resistance

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much higher doses than is used for treatment of hypertension and at these doses has been shown decrease uterine artery PI [87]. 11. 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. 12. 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 be reversible with clearance of the parasitaemia. This provides an example of placental pathology e presumed vasoconstriction secondary to release of pro-inflammatory cytokines and local vascular damage e unrelated to the adaptation of the spiral arteries causing abnormal uterine artery waveforms. 13. Postpartum

Fig. 4. Nitric oxide schematic pathway. ADMA ¼ Asymmetric dimethylarginine; eNOS ¼ endothelial nitric oxide synthase; NO ¼ nitric oxide; sGC ¼ soluble guanylate cyclase; GTP ¼ guanosine triphosphate; cGMP ¼ cyclic guanosine monophosphate; sEng ¼ soluble endoglin; sFlt ¼ fms-like tyrosine kinase-1; VEGF ¼ vascular endothelial growth factor.

indicating that the effects of endothelial dysfunction at this stage may be limited to the uterine arteries or placental bed. Similar results were reported by other studies using a variety of nitric oxide donor preparations at different gestations in women without preeclampsia [73e75]. The effects of NO donors on the waveforms in women with clinically evident preeclampsia have been less consistent with some studies [76e78] reporting a reduction and others showing no change in the uterine artery impedance [79e81]. 10. 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 [79e81] and verapamil [82], hydralazine [79] and labetalol (a mixed alpha/beta antagonist) [83e85]. Alpha-methyldopa showed a significant decrease in uterine artery impedance in a single study in preeclampsia [86]. Nifedipine is occasionally used for tocolysis at

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 4e6 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 as early as 2 days post-partum [91] or remain absent at 5 weeks post-partum [95]. However, whilst there is considerable variation, it is clear that the normal non-pregnant uterine waveform takes several weeks to return to normal following removal of the placenta. This again suggests that there are other factors, probably hormonal affecting the responsiveness of the endothelium, as well as trophoblast that affect the uterine artery impedance. 14. 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 e but this also does not represent the complete picture. This assertion may be unexpected to clinicians working in the field, but is not to those that have developed computer software based and mechanical models to describe the uteroplacental circulation. The uterine artery Doppler waveform can be normal in cases where pathology is evident and may be abnormal in the absence of placental and placental bed pathology. The considerable redundancy within the uteroplacental circulation would

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account for the former finding. With a normal placenta and placental bed, the consequences of the HagenePoiseuille law   plasma viscosity , particularly in relation to vessel Resistancef vessel radius4 radius, plays an important role in determining the uterine artery Doppler waveform. Although extra-placental factors were recognised early in the history of the uterine Doppler [5] and their effects modelled, they have since been largely overlooked. Whilst the changes in plasma viscosity in pregnancy have been shown to only have a minor and insignificant influence on uterine artery impedance [96,97] they has an effect in the non-pregnant state. By the nature of the HagenePoiseuille equation, changes of the radius will have a far greater effect on the resistance. The normal adaptation to pregnancy noted in the case reports of extra-uterine pregnancy [88,89] would suggest profound vasodilatation is responsible for modifying the uterine artery waveform. Although the mechanism for this remains unclear, vascular hormonal effects in combination with upregulation of eNOS and NO signalling are plausible. With the realisation that poorer cardiovascular health is evident in later life in women who have had a “placental disease” of pregnancy, it is suggested that these women may in fact have poorer cardiovascular health pre-pregnancy or a phenotype the prevents adequate response to pregnancy [45]. Abnormal vascular function, which may involve derangement of eNOS and NO signalling, lack of response to the increased shear stress during pregnancy [98] or preexisting alterations of the vessel wall architecture, may consequently lead to decreased compliance and prevent sufficient vasodilatation, resulting in increased resistance in the uterine arteries. On the basis of the evidence presented, it is perhaps time to challenge the view prevalent throughout the last three decades that raised uterine artery impedance is solely a result of spiral artery maladaptation and that poor pregnancy outcome is caused through uteroplacental insufficiency alone. An alternative e or complementary e view is that the uterine artery waveform is also a reflection of maternal vascular and endothelial function. Impaired maternal vascular adaptation may both determine the uterine artery waveform and per se lead to adverse obstetric outcome. The two hypotheses are not mutually exclusive, but the precise relationship between spiral artery adaptation and maternal vascular function and the timing of these changes remains to be elucidated.

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