Human Reproduction Update 1997, Vol. 3, No. 5 pp.
467–503  European Society for Human Reproduction and Embryology
Doppler ultrasound investigation of uterine and
ovarian blood flow in infertility and early
pregnancy
Richard P.Dickey1
Fertility Institute of New Orleans, New Orleans, LA and Division of Reproductive Endocrinology, Department Obstetrics and
Gynecology, Louisiana State University School of Medicine, New Orleans, LA, USA
TABLE OF CONTENTS
Introduction
Basis of Doppler ultrasound
Methods of analysis
Velocity waveform analysis
Uterine blood flow
Ovarian blood flow
Uterine blood flow in the first
16 weeks of normal pregnancy
Uterine blood flow in abnormal pregnancy
New areas of investigation
Conclusions
References
This review describes the current use of Doppler
ultrasound to examine blood flow in the uterus and
ovaries in infertile patients and during early pregnancy.
The basics of Doppler ultrasound and the different
methods of measuring blood flow are discussed from the
viewpoint of the clinician who may be unfamiliar with
Doppler physics and terminology. Normal values in the
menstrual cycle and the relationship of uterine and
ovarian blood flow to infertility and to implantation
following in-vitro fertilization are presented. Normal
values for uterine blood flow in the first 16 weeks of
pregnancy and the effect of sex steroids and ovulation
induction on their values are described. The possible
relationship of defective uterine blood flow to recurrent
abortion is examined. New areas of investigation, such as
the effect of standing on blood flow, and the effect of
drugs are explored. The findings of this review indicate
that Doppler blood flow studies may provide significant
information about possible causes of some disorders of
1Correspondence should be sent to: Fertility Institute of New Orleans, 6020 Bullard Avenue, New Orleans, LA 70128, USA. Telephone: (504) 246–8971;
fax: (504) 246–9778
infertility and early pregnancy and methods of treatment
for the same.
467
Key words: abortion (miscarriage)/Doppler
468
ultrasound/pregnancy first trimester/uterine blood flow
470
470
477 Introduction
484 Doppler ultrasound analysis has been used in gynaecology
primarily to determine blood flow in ovarian tumours with
486 neoplastic characteristics, and in obstetrics to examine the
493 relationship of blood flow in the uterine and umbilical
494 artery to adverse fetal outcome. These topics have been the
498 subject of numerous reports and are extensively covered in
499 a number of excellent text books. The relationship of
uterine blood flow to ovulation and implantation and to
normal development in early pregnancy has been less
extensively studied. Because these events represent a
continuum from preovulation to development of the
placental circulation, they are subject to many of the same
physiological and hormonal influences. The present paper
begins with a review of Doppler ultrasound techniques
from the viewpoint of the clinician unfamiliar with
principles of Doppler physics, and compares methods of
describing blood flow results.
The seminal article on use of Doppler ultrasound in
infertility was that of Goswamy and Steptoe (1988). Those
authors were the first to suggest that abnormal uterine
artery blood flow might be associated with infertility, and
to develop a classification of uterine artery blood flow
waveforms. They related specific abnormal waveforms
with repeated failure of implantation in in-vitro
fertilization (IVF) patients and successfully improved
uterine circulation and implantation by use of therapeutic
doses of oestrogen (Goswamy et al., 1988). Subsequently,
other authors have confirmed a relationship of uterine and
468 R.P.Dickey
ovarian blood flow to unexplained infertility (Kurjak et al.,
1991; Steer et al., 1994) and to successful implantation
following IVF (Sterzik et al., 1989; Steer et al., 1992;
Favre et al., 1993; Balakier and Stronell, 1994; Coulam
et al., 1994; Serafini et al., 1994; Tekay et al., 1995a;
Cacciatore et al., 1996; Zaidi et al., 1996a,c).
This review continues with an examination of uterine
blood flow in normal and abnormal early pregnancy,
because by understanding uterine blood flow requirements
of early pregnancy, we may eventually be able to learn
more about the causes of early pregnancy loss and
abnormal placental development associated with
complications of late pregnancy. This section begins with a
review of the development of the placental circulation.
Also considered is the relationship of sex steroids
(Jauniaux et al., 1992a, 1994; Dickey and Hower, 1996)
and ovulation induction (Dickey and Hower, 1995c) to
uterine blood flow in pregnancy. Lastly, two new areas are
reviewed: the effect of standing on uterine blood flow and
the effect of drugs on uterine blood flow.
Basis of Doppler ultrasound
Doppler ultrasound is based on the Doppler principle,
named after Christian Andreas Doppler (died 1853), that
sound and light waves change in frequency or wavelength
when either the source or the receiver is moving.
Doppler-shifted echoes are generated when vessel walls or
blood are in motion. These waveforms are familiar as
sounds of heart motion on fetal ultrasound and of pulsatile
flow of blood through vessels. The frequency of sound
waves is expressed in Hertz, named after Heinvich Rudolf
Hertz (died 1894). One Hertz (Hz) is one sound wave cycle
or pulse occurring in 1 s. Pulse repetition frequency is
usually given in kilohertz (kHz); 1000 Hz/s are equal to 1
kHz and 1 × 106 Hz/s are equal to 1 megahertz (MHz).
Sound with a frequency ≥20 000 Hz is called ultrasound,
because it is beyond the frequency range of human hearing.
Ultrasound transducers operate on the principle of
piezoelectricity, by which certain materials produce a
voltage when deformed by applied pressure and produce a
pressure when voltage is applied. Various formulations of
lead zirconate titante (PZT) are commonly used in
transducers. Source transducers operating in a continuous
mode are driven by an alternating voltage and produce an
alternating pressure that propagates as a sound wave. The
frequency of sound, called resonance frequency, is equal to
the frequency of the driving voltage. For each pulse of
ultrasound, a series of echoes are returned as the ultrasound
pulse is reflected off objects at a greater or lesser distance.
These echoes are received by the transducer and converted
into electrical energy, which is processed electronically
and displayed as a series of dots in a single scan line on the
display. Additional pulses travelling along the same path
result in the same scan line being displayed, but if the
starting point for each subsequent pulse is different while
the direction of the path is unchanged, a cross-sectional
image builds up. The rectangular display that results is
called a linear scan. If each pulse originates from the same
starting point but the direction of the path is slightly
different from the previous point, the result is a pie-shaped
sector scan. The terms ‘B scan’ and ‘grey scale’ are often
used to describe linear and sector scans, because the
strength of each returning echo is represented by its
brightness on the display (‘B’ for brightness and ‘grey’
because the resulting image is grey). These B or grey scale
images are refreshed with current data at a rate of 30
frames/s.
Colour flow Doppler instruments provide two-
dimensional, colour-coded Doppler information
superimposed on the real time anatomical display. In
Doppler ultrasound, the change in frequency of the
returning echoes, with respect to the emitted frequency,
results in the so-called Doppler shift. Doppler shifts are
usually in the range of 100 Hz to 11 kHz. The Doppler shift
is dependent on the speed of blood flow (blood circulates at
a speed of 10–100 cm/s), the angle between the source of
sound (the transducer), the direction of the blood vessel
being measured and the operating frequency of the
Doppler. Higher operating frequencies, greater flow
speeds and smaller Doppler angles produce larger Doppler
shifts. At the operating frequency of 5 MHz typically found
in vaginal transducers, blood flowing through the uterine
artery at a velocity of 50 cm/s produces a Doppler shift of
6.5 kHz at an angle of 0°, 5.6 kHz at 30° and 4.6 kHz at 60°.
Blood flowing through spiral arteries or in ovarian stroma
at 10 cm/s produces Doppler shifts of 0.65 kHz at an angle
of 0°, 0.56 kHz at 30° and 0.32 kHz at 60° (Kremkau,
1990).
Continuous wave Doppler utilizes separate voltage
generators and receivers to create a picture of the Doppler
shifts in the area being scanned similar to the grey scale,
except that moving objects, e.g. blood flow, appear as red
or blue against a black background. Slow movements, such
as bowel peristalsis and vessel walls are scanned out by
‘wall’ (also called ‘wall thump’) filters which reject
selected ultrasound frequencies, usually between 50 and
3200 Hz. Continuous wave systems provide motion and
flow information without depth information or selection
capability.
Pulsed-Doppler systems have the ability to select the
depth from which Doppler information is received, thus
 Doppler ultrasound study of uterine and ovarian blood flow
allowing analysis of blood flow within a single vessel. To do
this, the vessel to be studied is first located with continuous
wave ultrasound. Next, a gate is placed over the vessel which
passes only signals that are returned within a defined time.
For example, a gate that passes echoes averaging 13–15 µs
after pulse generation is listening at a depth range of
10.0–11.6 mm. The width of the gate (also called the volume
box) is adjusted to the diameter of the vessel. The returning
Doppler frequency shift echoes are converted electronically
by a mathematical technique called fast Fourier
transformation and displayed as the Doppler shift versus
time waveform. The Doppler waveform represents changes
in the velocity of blood flow during the cardiac cycle. Flow
conditions at the site of measurement are indicated by the
width of the velocity spectrum, with spectral broadening
indicative of disturbed and turbulent flow. Flow condition
downstream, particularly distal flow impedance, is indicated
by the relationship between peak systolic and end diastolic
flow speeds. Continuous forward blood flow is possible
because of vessel wall elasticity, also called the windkessel
effect. When pulse pressure forces fluid into a compliant
vessel, it expands and increases the volume within it. Later,
when the pressure is reduced, it contracts, producing
extended flow later in the cycle. In the aorta and large vessels
with valves, and also in small vessels with little distal
impedance, the windkessel effect produces continuous
forward blood flow. In the iliac arteries with no valves,
reversal of flow occurs in early diastole (triphasic flow) as
pulse pressure decreases and distended vessels contract. In
the ascending uterine artery, early diastolic flow is usually
absent or reversed in non-pregnant patients during menses
and the early proliferative phase of the cycle. Absence of
flow at any time during diastole on the day of human
chorionic gonadotrophin (HCG) administration in IVF
cycles is associated with failure of implantation. In
pregnancy, absence of early diastolic flow or a sharp
decrease in early diastolic flow, also called a protodiastolic
notch, is usually due to increased impedance in distal vessels,
and is associated with poor pregnancy outcome if it persists.
Lack of diastolic flow that occurs only at the end of diastole
may be due to low pulse pressure or to a prolonged interval
between heart beats, and is considered less important than
absence of early diastolic flow.
There is an upper limit to the Doppler shift that can be
detected by pulse instruments. If the Doppler shift
frequency exceeds one half the pulse repetition frequency,
a phenomenon called aliasing occurs, in which the peak of
the velocity waveform appears below the base line.
Aliasing is the most common artefact encountered in
Doppler ultrasound. Aliasing can be eliminated by
increasing pulse repetition frequency, by increasing the
469
Doppler angle, which decreases the Doppler shift for a
given flow, or by baseline shifting. As frequency is
increased, imaging depth decreases and ambiguity occurs
because of attenuation, and because the next pulse is
emitted before all the echoes from the previous pulse have
been returned. Attenuation is the decrease in amplitude and
intensity which occurs due to absorption (conversion to
heat), reflection and scattering as sound travels through
tissue. For soft tissue, attenuation in decibels (dB) is ~0.5
dB of attenuation per cm for each MHz of frequency. Pulse
repetition frequencies are usually in the range 5–20 kHz. At
a pulse repetition frequency of 5 kHz, ambiguity occurs at a
depth beyond 15 cm, and aliasing occurs with Doppler shift
above 2.5 kHz. At a pulse repetition frequency of 20 kHz,
ambiguity occurs at a depth beyond 4 cm and aliasing
occurs with Doppler shifts above 10.0 kHz.
Increasing the Doppler angle to eliminate aliasing
increases the chance of error in detecting flow velocity.
Flow velocity and flow volume can only be determined
accurately if the angle of insonation is accurate.
Measurement of the angle of insonation is usually done by
the operator orienting a line on the anatomic display, so that
it is parallel to the direction of blood flow. The resulting
angle between the transducer and vessel may be included in
the mathematical calculation of velocity by the ultrasound
computer program. A 5° error by the operator in placing the
directional line causes error in measurement of velocity of
<2.0% when the real angle is <10%. This increases to 5.4%
if the real angle is 30°, and to 12% when the angle is 60°.
Accurate determination of velocity is not necessary when
ratios of systolic to diastolic velocity are used to interpret
blood flow, but these ratios themselves become inaccurate
when blood flow is not continuous through the cardiac cycle.
It is important, therefore, to keep the angle of insonation as
small as possible, consistent with determination of
continuous waveforms. Moving the baseline is successful in
eliminating aliasing only if there are no legitimate Doppler
shifts in the region of aliasing.
The width of the Doppler ultrasound volume box,
compared to the width of the vessel wall, may also affect
velocity estimation. In small vessels, the average velocity
may be only one half the velocity at the centre of the
stream, because of turbulence caused by friction from the
vessel wall. Volume box widths which are too small in
relation to vessel size and which are aimed at the centre of
the stream may result in overestimation of velocity. The
ascending uterine artery diameter width ranges from 0.2 to
0.5 cm in non-pregnant patients and becomes much larger
in pregnant patients. Spiral arteries are closer to 1–2 mm in
diameter. Volume box widths that are available usually
start at 1 mm and increase to 10 mm in 1 mm increments.
470 R.P.Dickey

Table I. Waveform classification

Original Revised Description Present

classificationa classificationb classification
Type C Type C Diastolic component continuous with previous Type C
systolic component and present throughout
the cardiac cycle
Type B Type D-I Diastolic component continuous with the Type B
previous systolic component but not present
at the end of the cardiac cycle
Type A Type D-II Diastolic component present at the end of the Type A
cardiac cycle, but not continuous with the
systolic component
None Type D-III Diastolic component present, but neither Type D
continuous with the systolic component nor
present at the end of the cardiac cycle
Type 0 Type D-IV No diastolic component present Type 0
None Type N No systolic or diastolic component present Type N

aReprinted with permission from Goswamy and Steptoe (1988).

bFrom Dickey et al. (1994).

Visual and mathematical analyses of pulse waveforms
using velocity ratios and measurement of flow volume,
obtained by multiplying average velocity by vessel
cross-sectional area, are the tools used to determine blood
flow status of vessels. Analysis of waveforms in larger
vessels can be used to determine blood flow in smaller
distal vessels, even when the distal (downstream) vessels
are too small to be visualized individually, as in the case of
spiral arterioles in the myometrium or stroma of the ovary.
Methods of analysis
Doppler blood flow may be analysed in three ways by: (i)
waveform, (ii) resistance indices and (iii) flow volume or
velocity. There are situations in which each of these
methods of analysis is best and should be used, and
situations in which each is unreliable. Flow volume
analysis is the closest to true blood flow, but the most
difficult to perform, because it is dependent on the angle of
insonation, accurate measurement of vessel diameter, the
tortuosity of the vessel and the analytical power of the
instrumentation. Flow volume analysis can only be used
for larger vessels, such as the ascending uterine arteries, but
may sometimes be used for ovarian arteries and umbilical
vessels. Resistance indices measure downstream impe-
dance to blood flow and are independent of the angle of
insonation, but are only indirect estimates of flow volume.
They are most useful for estimating blood flow in vessels
distal to the point of examination. Despite claims to the
contrary, resistance indices may be highly inaccurate when
blood flow in the vessel being measured is not continuous
throughout the cardiac cycle. Waveform analysis provides
the most accurate estimate of blood flow in conditions
when blood flow is not continuous throughout the cardiac
cycle, as occurs in the uterine and, sometimes spiral,
arteries in the proliferative phase of the cycle.
Non-continuous flow may persist into the luteal phase and
early weeks of pregnancy. Waveform analysis utilizes
descriptive terms, but because it is not subject to computer
analysis, it is too often omitted in clinical publications of
studies of infertility and early pregnancy.
Velocity waveform analysis
Velocity waveform analysis of the umbilical and uterine
arteries is the gold standard for evaluating normal and
abnormal blood flow in the second and third trimesters
(Fleischer et al., 1986; Harrington et al., 1991, 1996; North
et al., 1994). A deflection or ‘notch’ in late systolic or early
diastolic flow is characteristic of normal uterine artery
blood flow waveforms until the end of the second trimester.
Persistence of an early diastolic notch into the 24th
post-menstrual week, especially if it occurs in both uterine
arteries, is associated with maternal hypertension and
intrauterine growth retardation (IUGR; Harrington et al.,
1996). Absence or reversal of early diastolic flow in the
umbilical artery is associated with IUGR in 84% of
pregnancies in cumulative series and perinatal mortality in
36% of pregnancies (Farin et al., 1995).
Goswamy and Steptoe (1988) developed a highly
valuable classification of flow velocity waveforms for use
in non-pregnant patients (Table I). In their classification,
the term type C was used for waveforms in which diastolic
flow was continuous with systolic flow and present through
the cardiac cycle (Figure 1). Type A was used to designate
waveforms in which the diastolic component was present in
 Doppler ultrasound study of uterine and ovarian blood flow
Figure 1. Waveform type C. Uterine flow velocity waveform show-
ing high systolic flow and diastolic wave extending to the next car-
diac cycle. This indicates good uterine perfusion. Reprinted with
permission from Goswamy and Steptoe (1988).
Figure 2. Waveform type A. Uterine flow velocity waveform show-
ing high systolic flow and absence of early diastolic flow. This indi-
cates poor uterine perfusion. Reprinted with permission from Go-
swamy and Steptoe (1988).
mid diastole, but was absent in early diastole, and might or
might not be present in later diastole (Figure 2). They
considered this to indicate poor perfusion and to be the result
of distal impedance to blood flow. Type B waveforms were
those in which the diastolic component was continuous with
the preceding systolic component, but did not extend to the
systolic component in the next cardiac cycle (Figure 3). They
considered this type of waveform to indicate low impedance
and adequate perfusion. Type 0 waveforms were those in
which no diastolic component was present at any time and
471
Figure 3. Waveform type B. Uterine flow velocity waveform show-
ing diastolic wave continuous with systole, but not extending to the
next cardiac cycle. This indicates good uterine perfusion. Reprinted
with permission from Goswamy and Steptoe (1988).
indicated high distal impedance and low perfusion (Figure
4). Dickey et al. (1994) revised this classification by
substituting the terms D-I, D-II and D-IV (D for
discontinuous) for waveforms B, A and 0 respectively, and
by adding two additional types: D-III for the combination of
type A and type B when flow was present in mid diastole, but
absent in both early and late diastole, and type N, when blood
flow was undetectable in both systole and diastole. This
proved too cumbersome and, as a result, they subsequently
used Goswamy and Steptoe’s original classification with two
additions: type D to represent the combination of type A and
type B, i.e. absence of both early and end diastolic flow, with
some flow in between, and type N for undetectable blood
flow in systole, as well as in diastole. In Goswamy and
Steptoe’s original (1988) classification, type D would still
have been classified as type A.
Goswamy and Steptoe (1988) developed their waveform
classification because they believed that resistance indices,
such as the pulsatility index of Gosling et al. (1971) and the
resistance index of Plainiol et al. (1972), inaccurately
estimated uterine artery blood flow when diastolic flow was
absent during any part of the cardiac cycle. They
subsequently proved the validity of their classification
system when they demonstrated that total absence of
diastolic flow (type 0) and absence of early diastolic flow
(type A and type D) waveforms were associated with
repeated failure of implantation in IVF patients, whereas
continuous flow (type C) and absence of flow only at the end
of diastole (type B) were associated with normal
implantation rates (Goswamy et al., 1988). In this author’s
472 R.P.Dickey
Figure 4. Waveform type O. Uterine flow velocity waveform show-
ing absence of any diastolic flow. This indicates very high imped-
ance. Reprinted with permission from Goswamy and Steptoe
(1988).
experience, undetectable blood flow in both systole and
diastole (type N) in spiral arteries is no more serious than
type A or D, because it is often due to lack of sensitivity of
the instrumentation.
Waveforms are unequalled for detection of downstream
impedance. They should be used instead of resistance
indices, flow volume or velocity estimations whenever
blood flow is not continuous throughout the cardiac cycle.
Resistance indices
Resistance indices are preferred for measurement of small
and tortuous vessels, because they are based on the ratio of
peak systolic flow to some measure of diastolic flow and
thus, are independent of the angle of insonance (Figure 5).
However, the angle of insonance is of little significance if
blood flow is not continuous, because the true ratio cannot be
known. Resistance indices are necessary when waveforms
are continuous to define the magnitude of downstream
resistance.
Resistance indices were developed for use in
cardiovascular disease and were specifically intended to
detect stenosis of distal (downstream) vessels. As such, they
may not be entirely applicable to evaluation of infertility and
early pregnancy. The principle reason for using indices is that
they cancel out errors caused by the Doppler angle, machine
gain, and hypo- or hypertension. They are, however, affected
by the heart rate (Maulik, 1993).
Figure 5. Common resistance indices: (S) peak systolic velocity, (D)
end diastolic velocity, (A) time averaged maximum velocity. RI = re-
sistance index, (S – D)/S;, PI = pulsatility index, S – D/A; S/D ratio,
S/D. TAMV = time averaged maximum velocity.
Fourier pulsatility index (PIF)
This index is considered most accurate for detecting
downstream resistance, but is too complicated to be
calculated automatically by present day software packages.
It is expressed by:
PIF = N = 1[Vn2/Vo2]
where Vo is the mean forward velocity of the waveform, N
is the harmonic number from 1 to infinity, and Vn is the
harmonic of the velocity waveform (Powis and Schwartz,
1991).
Peak to peak pulsatility index (PPI)
This index is used in cardiovascular disease for
measurement of high resistance vascular beds where flow
is reversed in early diastole (triphasic flow), and is rarely
calculated in obstetric or infertility studies. The PPI
measures the total distance from the top to the bottom of the
systolic peak and divides this by the mean velocity over the
cardiac cycle. It is expressed by:
PPI = S/velocitym
where S is the peak systolic velocity and velocitym is the time
averaged maximum velocity over the cardiac cycle. Results
are closely similar to the Fourier pulsatility index. The PPI
normally increases as increasingly distal vessels are
examined (Baker et al., 1986). The presence of long-term
occlusive disease proximal to the site of measurement
decreases the index as a result of distal vasculative dilation to
compensate for the proximal stenosis.
 Doppler ultrasound study of uterine and ovarian blood flow
Resistance index (RI)
This index, also known as Pourcelot’s ratio (Pourcelot,
1974), examines the difference between the peak systolic
and end diastolic velocity and is expressed by:
RI = (S – D)/S
where S is the peak systolic velocity and D is the minimum
or end diastolic velocity. The RI is suitable for low
resistance vascular beds with continuous flow throughout
diastole. If the end diastole value (D) goes to zero, the ratio
converges to 1.
Pulsatility index (PI)
This index, also known as the mean pulsatility index to
distinguish it from the peak to peak pulsatility index, is
expressed by:
PI = (S – D)/velocitym
where S is the peak systolic velocity, D is the end diastolic
velocity and velocitym is the time averaged maximum
velocity over the cardiac cycle (Gosling et al., 1971).
Velocitym is calculated from the average of three or four
cardiac cycles. No correction for heart rate is required
(Gosling et al., 1991). Because it does not go to 1.0 if early
or end diastolic flow goes to 0, the PI is often used for
vessels where flow is absent during all or part of diastole. In
a comment made 20 years after first describing the PI,
Gosling stated, ‘When blood flow sonograms are studied
just proximal to a vascular bed of low impedance, it is
likely that small changes in something itself already small
will make little difference to the waveform shape, which
will mostly be affected by changes in pressure drop across
the vascular bed and not the impedance per se (Gosling
et al., 1991). The PI is not as accurate as RI because of the
variability inherent in measurement of mean velocity with
present day software programs. Trudinger (1991) states,
‘In determining the PI, it is most unlikely that the true mean
velocity can be calculated entirely accurately.’
Systolic/diastolic ratio (S/D)
The systolic/diastolic ratio is the simplest of all indices and
is expressed by S/D, where S is the peak systolic frequency
and D is the end diastolic frequency. It is less frequently
used, now that the PI and RI can be readily calculated by
built-in software programs. Errors in the S/D ratio increase
as diastolic velocity becomes small. Spencer et al. (1991),
using an in-vitro flow model, found that when flow was
reduced in a stepwise fashion, PI and RI increased in linear
fashion, whereas the S/D ratio increased exponentially.
473
Other ratios
Goswamy and Steptoe (1988) modified the S/D ratio and
RI by substituting the peak diastolic frequency for the end
diastolic frequency, but these modified ratios have not been
used by others. The (A – B)/A ratio tests for the presence of
the late systolic inflection in the carotid artery waveform.
In this ratio, A is the peak systolic velocity and B is the
lowest velocity at the inflection in late systole. Designed
specifically for use in the common carotid artery, it has not,
as yet, been used for the uterine, spiral, or umbilical
arteries, but could conceivably be used for vessels, such as
the uterine artery prior to the 20th week of gestation, where
an early systolic notch is present.
Blood flow volume and velocity
By far the most direct way to describe blood flow is to
report blood flow volume or average velocity. Either flow
volume or average velocity plus a resistance index or
waveform (when diastolic flow is not continuous) are
necessary to analyse uterine blood flow satisfactorily. Flow
volume and mean velocity describe the actual volume or
velocity of blood utilized by an organ, while resistance
indices and waveforms indicate the state of smaller vessels
downstream from the vessel being analysed.
Flow volume
Flow volume is the only true measurement of blood flow. It
is expressed by:
Vol = Vel × A
where Vol = flow volume (ml/min), Vel = time averaged
mean velocity throughout the cardiac cycle and A =
cross-sectional area of the vessel, derived from the diameter
(A = π × r2). Note: Time averaged mean velocity as used here
is not the same as time averaged maximum velocity
sometimes reported independently, and used in calculating
PI and RI. Blood flow volume through vessels of ≥2 mm can
be measured by Doppler ultrasound. Velocity should be
calculated from the average of three or four cardiac cycle
waveforms. Diameter should be calculated from the mean of
at least four measurements of vessel diameter made from
frozen two-dimensional grey-scale images. Flow volume
measurements are dependent on the operator’s accuracy in
aligning the angle of insonation and in measuring diameter,
plus the instrument’s ability to calculate the average velocity.
It is difficult to measure accurately in tortuous vessels.
Time averaged maximum velocity (TAMV)
Time averaged maximum velocity (TAMV) is frequently
used when analysing blood flow through small vessels with
no collateral circulation, such as the umbilical and ovarian
474 R.P.Dickey
arteries, when diameter is not or cannot be measured. It is
determined by measuring the average maximum velocity
over a minimum of three cardiac cycles. In many cases,
TAMV mirrors flow volume; however, velocity is
dependent on the angle of isonation and, at points of vessel
narrowing, increases to compensate for decrease in vessel
diameter. Therefore, TAMV may give a false impression of
blood flow in vessels narrowed by disease or stretching.
Other measurements of velocity
Maximum peak systolic velocity (MPSV), or simply peak
systolic velocity (PSV) and minimum diastolic velocity
(MDV), are sometimes reported. These expressions of
velocity are highly unreliable, since they are dependent on
the angle of insonation, display a high degree of variability
on repeat examination (Tekay and Jouppila, 1996), and
cannot describe blood flow over the entire cardiac cycle.
Common abbreviations used for blood flow measurements
are shown in Table II.
Table II. Common abbreviations used when reporting blood
flow measurement
PI Pulsatility index
RI Resistance index, Pourcelot’s index
S/D ratio Systolic/diastolic ratio
Vmax Velocity maximum (same as PSV and MPSV)
MDV Minimum diastolic velocity
PPI Peak to peak pulsatility index
PSV Peak systolic velocity (same as MPSV and Vmax)
MPSV Maximum peak systolic velocity (same as PSV and Vmax)
TAMV Time averaged maximum velocity (same as TAMX and TAPV)
TAMX Time averaged maximum velocity (same as TAMV and TAPV)
TAPV Time averaged peak velocity (same as TAMV and TAMX)
Sources of error in measurement
All blood flow measurements, whether they are of the
uterus and ovary or the aorta and carotid artery, are subject
to many potential sources of error. Certainly, the most
important source in the uterus and ovary is the operator’s
judgement in selecting the vessel to be examined and the
particular part of the vessel on which to focus the Doppler.
Selection of the particular waveform or waveforms to
analyse, out of the many available, is an equally important
operator decision. It must be decided whether to select ones
with the highest peak systolic or diastolic velocity, least
velocity, or an ‘average example’. Doppler blood flow
studies of the uterus and umbilical circulation have been
published which use each of these choices. Doppler
ultrasound operators may cause errors in PI and RI if they
mistake brief gaps in diastolic flow as absence in diastolic
flow. Analysis of flow volume or resistance indices in a
single uterine artery, instead of both arteries, can lead to a
false interpretation of uterine blood flow because of the
considerable cross circulation in the uterus. Analysis of the
relationship between uterine artery flow volume or RI and
spiral artery waveforms or RI show that spiral artery blood
flow is not affected by a marked decrease of flow in a single
uterine artery, but is affected by lesser decreases in flow in
both uterine arteries (Dickey et al., 1994). The reader must
determine from the ‘Methods’ section of a paper which
methods have been used to select vessels, in order to
interpret the results and the relationship of the author’s
findings to other studies.
The angle of insonation is of greatest concern when
measuring velocity and volume. The importance of angle of
insonation is obviated for resistance indices which do not
incorporate velocity in their calculations (e.g. RI, but not PI).
For angles <20°, the maximum error in calculating velocity
and volume caused by a 5% error in estimating the angle of
insonation is ≤1.5% and is entirely obviated when angle
adjustment is incorporated in the analytical software.
Another potential source of error in determining flow
volume is measurement of vessel diameter, both because the
diameter changes during cardiac pulsation and because any
errors in measurement are magnified when squared.
However, the normal distensibility of arteries in adults is
<5% for a 40 mm Hg pulse pressure (Gosling et al., 1991).
Errors due to measurement become less important as vessel
diameter increases. For example, a 1 mm error in measuring
a 20 mm artery diameter results in ±10% error in flow
volume, but if the diameter is 50 mm, a 1 mm error causes
only a ±4% error. At least four separate measurements of
diameter taken from sequential cardiac cycles must be made.
The actual difference found in vessel diameter when
repetitive measurements of diameter were made by the same
observer was ±3%, and when measurements were made by
different observers was ±5.6% (Dickey et al., 1994).
The relative importance of different sources of variability
on blood flow volume measurement is illustrated in Table III,
where interoperator variability was determined in 10
subjects using the paired t-test, as described by Bewley et al.
(1993). After determining that waveforms were continuous
in all vessels, the right and left ascending uterine arteries
were examined in 10 non-pregnant volunteers during the
mid-luteal phase by one of two experienced ultrasono-
graphers and immediately afterward by the second operator,
with the order reversed in half of the patients. Mean velocity
was measured with the transducer held in the position which
resulted in the highest PSV, and the average of three cardiac
cycles was determined by 64 point algorithm. The angle of
insonation was corrected by software. The least correlation
between operators was found for flow volume (r = 0.88),
 Doppler ultrasound study of uterine and ovarian blood flow
followed by mean velocity (r = 0.90), with much less
variability found for vessel diameter (r = 0.94). The best
correlation between operators was for RI (r = 0.97). Other
comparisons of intra-observer variability have yielded
similar results (Pearce et al., 1988; Bewley et al., 1993).
Tekay and Jouppila (1996) assessed intra-observer
variability for three sources of variation (beat to beat,
between frame, and temporal variability) in measurements
of PI and MPSV in uterine arteries and PI, RI and MPSV of
intra-ovarian arteries in 10 normally cycling women with
transvaginal Doppler ultrasound using a 6 MHz transducer.
The intraclass correlation coefficients of temporal variability
for uterine artery PI and MPSV were 0.99 and 0.88
respectively. In contrast, correlation coefficients for
intra-ovarian PI, RI and MPSV were 0.78–0.86, 0.76–0.89
and 0.63–0.68. They concluded that intra-ovarian velocity
measurements were too inconsistent to be reliable.
An important source of error for measurements of flow
volume, TAMV and PI is the instrument’s ability to
determine average velocity. It is impossible to measure
actual velocity of all Doppler signals over even a single
cardiac cycle with present technology. The number of
discrete velocity points or columns which each instrument
actually analyses varies from approximately 60 to 540,
depending on pulse frequency and software. A 60 point
analysis may overestimate or underestimate velocity,
compared to a 120 or 240 point analysis, depending on
where the measurement points fall over the cardiac cycle.
Errors due to infrequent point analyses decrease when
downstream resistance is low and the difference between
systole and diastole is small. The number of points analysed
over a cardiac cycle varies with scroll speed and heart rate. A
faster scroll speed or slower heart rate will result in more
points being analysed per cardiac cycle. For example, when
using the ATL Ultramark 9-HDI Doppler Ultrasound, if the
Table III. Interobserver variability, showing the mean difference between observers 1 and 2, the correlation coefficient (r), stan-
dard error (SE) and standard deviation (SD). Reprinted with permission from Dickey et al. (1994)
Measurement n Mean difference
between 1 & 2
Uterine artery
diameter (cm) 20 0.056
time averaged maximum velocity 20 1.070
flow volume (ml/min) 20 4.500
pulsatility index 20 0.067
resistance index 20 0.004
Spiral artery
pulsatility index 10 0.208
resistance index 10 0.052
475
scroll speed is increased from slow (20 ms/Doppler column)
to fast (5 ms/Doppler column) and the heart rate remains
constant (100 bpm), then the number of columns or points
analysed in one cardiac cycle would increase from 30 to 120.
At a medium scroll speed (10 ms/Doppler column), 60
Doppler columns are analysed per cardiac cycle when the
heart rate is 100 bpm. A decrease in heart rate from 100 to
60 bpm at a medium scroll speed would increase the number
of Doppler columns or points analysed in one cardiac cycle
from 60 to 100. As a consequence, three or more cardiac
cycles should be analysed whenever blood flow volume,
mean velocity, or PI is determined.
Relationship of flow volume and resistance indices
to waveforms
The relationship of uterine artery waveforms to a modifica-
tion of RI and S/D ratio was initially reported by Goswamy
and Steptoe (1988). More recently, the relationship of
ascending uterine artery and spiral artery waveforms to
uterine artery flow volume, PI and RI was investigated by
Dickey et al. (1994) (Table IV). Uterine artery flow volume
was significantly lower and PI was significantly higher when
waveforms were not continuous. Recumbent flow volume in
single (right or left) uterine arteries averaged 40.8 ml/min
when waveforms were continuous, compared to 27.0 ml/min
when only end diastole flow was absent (type B, D-I) and to
19.7–22.0 ml/min when flow was absent in early diastolic
flow (A and D, D-II and D-III). Uterine artery PI was
significantly higher for all non-continuous waveforms,
compared to continuous waveforms, and did not distinguish
waveforms of less clinical significance with absent end
diastolic flow only (type B, D-I) from waveforms of greater
clinical significance (A and D, D-II and D-III). Tekay et al.
(1996b) also reported on the relationship between waveform
type and PI.
r SE of mean SD of mean
difference difference
0.94 0.067 0.300
0.90 2.180 0.470
0.88 2.398 10.721
0.95 0.066 0.296
0.97 0.006 0.027
0.87 0.061 0.193
0.85 0.009 0.028
476 R.P.Dickey

Table IV. Relationship of ascending uterine artery blood flow volume per minute (UA-VOL, ml/min), pulsatility index (PI) and
resistance index (RI) to uterine artery waveforms and spiral artery waveforms while subjects were recumbent and while they
were standing. Values in each column for UA-VOL, UA-PI and UA-RI are mean and SE respectively. Reprinted with permission
from Dickey et al. (1994)

Waveform Recumbent Standing

classification* n UA-VOL UA-PI UA-RI n UA-VOL UA-PI UA-RI
Uterine artery waveforms (n = 148)
C 115 40.8, 2.3 2.47, 0.05 0.86, 0.01 98 37.9, 2.6 2.47, 0.05 0.87, 0.01
D-I (B) 9 27.0, 4.8a 3.47, 0.17b — 0 — — —
D-II (A) 7 19.7, 3.3b 3.59, 0.13b — 31 19.4, 1.9b 3.59, 0.13b —
D-III (D) 17 22.0, 1.6b 3.36, 0.09b — 17 15.2, 2.8b 4.45, 0.41b —
D-IV (0) 0 — — — 2 3.0, 0.90b 9.95, 0.05b —
Spiral artery waveforms (n = 74)
C 59 74.4, 5.8 2.63, 0.08 0.88, 0.01 59 65.4, 6.1 2.67, 0.15 0.87, 0.01
D-I (B) 14 72.8, 11.6 2.90, 0.11 0.92, 0.02 5 80.4, 13.9 2.77, 0.18 0.93, 0.02
D-II (A) 0 — — — 1 45.0, — 3.31, — 0.92, —
D-III (D) 1 46.0, — 2.79, — 0.88, — 3 22.3, 3.0b 4.30, 64.0 1.00, 0.015
D-IV (0) 0 — — — 0 — — —
D-V (N) 0 — — — 6 40.0, 15.8 4.24, 1.18c 0.94, 0.04

*See Table I for waveform classification.

a,b,cSignificance, compared to C (continuous flow) (t-test): aP < 0.05, bP < 0.001, cP < 0.01.

Table V. Relationship between individual ascending uterine artery blood flow volume per minute and uterine artery pulsatility
index and resistance index, and between total uterine artery blood flow volume per minute, average uterine artery pulsatility or
resistance index, and spiral artery pulsatility index and resistance index while subjects were recumbent and while they were
standing for 9–14 min. Reprinted with permission from Dickey et al. (1994)

Recumbent Standing (9–14 min)

r Significance r Significance
Uterine artery blood flow volume per minute
Uterine artery pulsatility index –0.49 P < 0.001 –0.46 P < 0.001
Uterine artery resistance index –0.46 P < 0.001 –0.66 P < 0.001
Spiral artery pulsatility index –0.08 NS –0.28 P = 0.010
Spiral artery resistance index –0.09 NS –0.21 P = 0.042
Uterine artery pulsatility index
Spiral artery pulsatility index 0.24 P = 0.019 0.31 P = 0.005
Spiral artery resistance index 0.26 P = 0.013 0.30 P = 0.006
Uterine artery resistance index
Spiral artery pulsatility index 0.24 P = 0.017 0.54 P < 0.001
Spiral artery resistance index 0.33 P = 0.002 0.54 P < 0.001

r = Pearson’s correlation coefficient; NS = not significant.

Absence of end diastolic flow in spiral artery waveforms
(type V, D-I) was not associated with changes in total (right
plus left) uterine artery flow volume or change in uterine
artery PI or RI, compared to continuous flow (C). However,
absence of early diastolic flow (A and D, D-II and III) and
absence of any visible flow (N) in spiral arteries were
associated with notably lower total uterine artery flow
volume and higher uterine artery mean PI. Non-continuous
spiral artery waveforms were not seen in any subjects, unless
flow volume was notably decreased in both uterine arteries.
Relationship of flow volume to resistance indices
Relationships of uterine and spiral artery RI to uterine
artery flow volume are shown in Table V (reprinted from
Dickey et al., 1994). Only cases in which blood flow was
continuous were analysed. Slightly less than 50% of
uterine artery PI and RI was related to flow volume. This
should not be surprising, since PI and RI are significantly
influenced by downstream resistance. Spiral artery PI and
RI were unrelated to the uterine artery blood flow volume
 Doppler ultrasound study of uterine and ovarian blood flow 477

in the recumbent position and only marginally related to

flow volume when standing. Spiral artery PI and RI were
weakly related to uterine artery PI and RI while recumbent,
but were strongly related to uterine artery RI (r = 0.54;
P < 0.001) while standing.
In in-vitro Doppler ultrasound studies in which water
was driven through rubber tubing by a Harvard pulsatile
pump, measured flow volume was closely related to
Doppler flow volume (r = 0.991), lowest systolic velocity
(r = 0.987), peak systolic velocity (r = 0.972), PI
(r = –0.940) and RI (r = –0.940). However, this study
differed significantly from clinical assessment of blood
flow, because the angle of insonation was fixed and could
be entered into the calculation (Miles et al., 1987). Figure 6. Uterine artery waveform type, S/D (systolic/diastolic) ra-
tio and resistance index (RI) in a multiparous subject during the
menstrual cycle. Reprinted with permission from Goswamy and
Safety
Steptoe (1988). For abbreviations, see Table I.
The effects of Doppler ultrasound on embryonic and fetal
development are not known with certainty. Bioeffects of
Doppler ultrasound are related to the spatial peak time average
intensity (ISPTA) and duration of exposure. The American
Institute of Ultrasound in Medicine (1993) has recommended
that Doppler ultrasound during early pregnancy be limited to
500 s (8.3 min) at an ISPTA <94 mW/cm2.

Uterine blood flow

Uterine blood flow in the normal cycle
Studies of uterine blood flow during the normal cycle are
listed in Table VI. Ultrasound measurements of uterine
artery and ovarian artery blood flow were initially
described by Taylor et al. (1985) using Duplex ultrasound
with an abdominal transducer. Goswamy and Steptoe
(1988) improved on previous methods by using an offset
abdominal Doppler transducer to plot uterine artery
waveforms and their own modification of RI and S/D ratios
in the mid-proliferative to pre-menstrual phase of the
menstrual cycle. They found waveforms were continuous
in most multiparous patients throughout the cycle, except
for a few days immediately after ovulation and during
menstruation (Figure 6), but were only continuous in
nulliparous patients immediately before ovulation (Figure
7). In multiparas, RI fell with the rise in oestrogen
concentrations during the early follicular phase, then rose
along with a post-ovulatory fall in oestrogen
concentrations. A second decrease in RI occurred along
with rising oestrogen and progesterone concentrations
during the mid-luteal phase of the cycle. In nulliparas, RI
was markedly different, especially on days 14 and 21. This
difference may have been due to the fact that waveforms
were not continuous in nulliparas on most days, or due to
Figure 7. Uterine artery waveform type, S/D (systolic/diastolic) ra-
tio and resistance index (RI) in a nulliparous subject during the
menstrual cycle. Reprinted with permission from Goswamy and
Steptoe (1988). For abbreviations, see Table I.
real differences in vascular development and blood flow
following completion of a full-term pregnancy. Two
important principles may be derived from this seminal
study: (i) normal uterine blood flow values must be
obtained from patients with known fertility and ability to
carry to term, and (ii) normal values can only be obtained
from studies in which flow is continuous throughout the
cardiac cycle. Although Goswamy and Steptoe (1988)
established the pattern for blood flow in normal cycles and
the relationship of blood flow to hormone concentrations,
their modified RI and S/D values cannot be easily
translated to standard values. Also, results with trans-
vaginal ultrasound could be different from those obtained
with abdominal ultrasound.
478 R.P.Dickey

Steer et al. (1995a) found that uterine artery PI and S/D
ratio values differed significantly between abdominal
ultrasound and vaginal ultrasound during the normal cycle.
Mean PI values during the mid-luteal phase in non-pregnant
patients for a 3 MHz abdominal transducer, a 5 MHz
abdominal transducer with full bladder and a 5 MHz vaginal
transducer were respectively 4.08, 3.24 and 1.97. Moreover,
intra-observer variability in measurement of PI decreased
from a coefficient of variation of 11.3 and 7.4% respectively
with a 3 MHz and 5 MHz abdominal transducer to 4.1% with
a 5 MHz vaginal transducer. Zaidi et al. (1995c) studied
circadian rhythm in uterine artery blood flow. They found a
nadir in PI and a peak in TAMV at 0600 h, following sleep,
which was unrelated to changes in oestradiol, progesterone,
luteinizing hormone (LH), or follicle stimulating hormone
(FSH). The increased blood flow which they found
following sleep may have been the result of overnight bed
rest, since a similar improvement is seen in pregnant patients
who have been at bed rest continuously for several days
(R.P.Dickey, unpublished data).
Authors other than Goswamy and Steptoe (1988), who
used abdominal ultrasound to measure uterine blood flow,
found no differences in blood flow at different phases of the
cycle (Thompson et al., 1988; Long et al., 1989). Scholtes
et al. (1989), using a 4.25 MHz vaginal transducer, found
little variation in PI in the phases of the cycle and
additionally found no difference in PI on the side of the
dominant follicle or corpus luteum. However, Steer et al.
(1990), using vaginal ultrasound with a 6 MHz transducer,
found marked variation in uterine artery PI during the cycle
in 23 patients, 20 of whom were nulliparous, which was
similar to that reported by Goswamy and Steptoe (1988)
for multiparous patients. Values for PI in cycle days 1–6,
when diastolic flow was frequently absent, ranged from 2.0
to 5.6, with an average of 3.8. Values were lowest 6 days
before the LH peak (average 2.6) and 9 days after the LH
peak (average 1.9). The highest values occurred at the
mid-cycle plasma oestradiol peak (3.7) and 3 days after the
LH peak (3.9). These authors found no difference in PI on
the side of the dominant follicle. Tan et al. (1996) found the
PI significantly lower (3.05 versus 2.34) and TAMV higher
(16.3 versus 13.2 cm) in the uterine artery on the side of the
dominant follicle during the mid-luteal phase, but no
significant changes in either measurement during the
follicular phase of the cycle. However, the lack of
significance may have been due to studying only seven
patients, all with unproven fertility.

Table VI. Studies of uterine blood flow in the normal cycle

Investigation Wave Flow TAMV, Vmax, PSV, MDV PI RI S/D

form volume TAMX MPSV ratio
Taylor et al. (1985) (A,O) x x
Goswamy and Steptoe (1988) (A,E) x x x
Thompson et al. (1988) (A) x x x x
Long et al. (1989) (A)
Scholtes et al. (1989) (A) x
Steer et al. (1990) (E) x
Kupesic & Kurjak (1993) (O,S) x x x
Sladkevicius et al. (1993) (S) x x
Weiner et al. (1993) (E,O) x
Dickey et al. (1994) (S) x x x x x
Deichert & Buurman (1995) (IA) x x x
Steer et al. (1995a) (A/V) x x
Strigini et al. (1995) (E,O) x
Tekay et al. (1996b) (E) x x
Zaidi et al. (1995c) (C) x x
Tan et al. (1996) (E) x x

A = abdominal ultrasound; A/V = abdominal and vaginal ultrasound; C = circadian rhythm also studied; E = relationship to
oestrogen, progesterone and ovulation induction studied; IA = common, external and internal iliac arteries also measured; O =
ovarian blood flow also measured; S = spiral arteries also measured; STD = standing blood flow also measured. See Table II for
other abbreviations.
 Doppler ultrasound study of uterine and ovarian blood flow 479

Table VII. Studies of uterine blood flow in in-vitro fertilization and infertility

Investigation and Wave Flow TAMV, Vmax, PSV, MDV PI RI S/D

when measured form volume TAMX MPSV ratio
Goswamy and Steptoe x
(1988) (A) IV
Sterzik et al. (1989) (O) II x x
Strohmer et al. (1991) I x
Kurjak et al. (1991) (INF) x
Steer et al. (1992) III x x
Favre et al. (1993) III x
Fujino et al. (1993) (INF) x
Steer et al. (1994) (INF) x
Bassil et al. (1995) I,II,III x
Levi-Setti et al. (1995) I,II x
Tekay et al. (1995a) III x x
Zaidi et al. (1995b) (INF) x x
Cacciatore et al. (1996) III x x
Tekay et al. (1996b) III x x x x
Zaidi et al. (1996c) I x

A = abdominal ultrasound; O = ovarian blood flow also measured; INF = infertility. I = measured on or before day of human
chorionic gonadotrophin administration; II = measured on day of oocyte retrieval; III = measured on day of embryo transfer; IV =
measured in mid-luteal phase. See Table II for other abbreviations.

Deichert and Buurman (1995) examined blood flow in
the common, external and internal iliac arteries every 3
days during the menstrual cycle with a 2.2 MHz Doppler
abdominal transducer in nine ovulatory volunteers. The
mean right and left PI of the internal iliac artery rose
slightly the day before ovulation, and fell significantly the
day after ovulation. No significant cyclic changes in PI and
RI were found in the external and common iliac arteries.
The mean right and left internal iliac artery PI was lower
than those of the external iliac and common iliac arteries.
The mean PI of the external iliac artery was higher than that
of the common iliac artery. Continuous diastolic
waveforms were found only in the internal iliac arteries,
and only following ovulation.
Spiral artery, as well as the uterine artery, PI and TAMV
were measured throughout the cycle with vaginal ultrasound
using a 5 MHz transducer by Sladkevicius et al. (1993).
Continuous diastolic flow in the uterine artery was present in
all examinations. Spiral artery PI was much lower than
uterine artery PI (0.8–1.0 versus 2.4–3.4), but mirrored the
changes in average values for the uterine arteries throughout
the cycle. Values for PI were lowest for the spiral and uterine
artery on days 7 and 12 post-ovulation and highest 2 days
after the LH surge. Velocity was highest for the spiral artery
on days –1, +7 and +12 from the LH peak, and highest in
uterine arteries on day –2. These authors found marked
differences between the dominant and non-dominant ovary
side in mean uterine artery velocity, and to a lesser extent in
PI, in the peri-ovulatory and early luteal phase. Spiral artery
and uterine artery PI and RI were measured during the
peri-ovulatory period in 27 patients with spontaneous cycles
and 51 patients with stimulated cycles by Kupesic and
Kurjak (1993). All had male factor infertility, but parity was
not stated. Results from right and left uterine arteries were
averaged when they found no consistent differences between
the side with the dominant follicle and the contralateral side.
Diastolic flow was absent in both uterine arteries in 15% of
spontaneous cycles. At their nadir the day before ovulation,
the average uterine artery PI and spiral artery PI were 2.22
and 1.13 respectively. No periodical variations in PI were
noted in patients stimulated with clomiphene citrate or
human menopausal gonadotrophin (HMG).
Relationship to oestrogen, progesterone and
ovulation induction
Several researchers have measured serum oestradiol and
progesterone, as well as blood flow during the normal
cycle (Goswamy and Steptoe, 1988; Steer et al., 1990; Tan
et al., 1996). Goswamy and Steptoe (1988) noted that
uterine blood flow increased with rising concentrations of
oestradiol and progesterone and decreased when oestradiol
fell immediately following ovulation. In marked contrast,
Steer et al. (1990) found that maximum uterine artery PI
values, indicating highest impedance to blood flow,
occurred on the day of serum oestradiol peak, then fell by
25% to a mid-cycle nadir 2 days following the urine LH
peak, rose again the next day for 1 day only before falling
480 R.P.Dickey
again to an even lower mid-luteal phase nadir 10 days after
the LH peak, while oestradiol concentrations were still
high and progesterone concentrations were high but
declining. Tan et al. (1996) found that the TAMV of the
dominant uterine artery was correlated with the rise in
progesterone concentrations in the luteal phase (r = 0.52)
and with oestradiol concentrations throughout the cycle
(r = 0.27), but found no relationship between PI and
oestradiol or progesterone at any time in the cycle.
The relationship of uterine and ovarian artery PI to number
of follicles >15 mm diameter and to serum oestradiol and
progesterone concentrations was studied in 11 patients
receiving HMG by Weiner et al. (1993). They found a
consistent decrease in PI from the early follicular to early
luteal phase of the cycle which was negatively correlated
with serum oestradiol concentrations (r = –0.51), but not
with progesterone concentrations (r = –0.25) or follicle
number. However, Kupesic and Kurjak (1993) found no
cyclic change in uterine artery PI in patients who had
received clomiphene citrate or HMG. Tekay et al. (1995b)
found no difference in mean uterine artery PI and MPSV
between patients with ovarian hyperstimulation syndrome
(OHSS) and asymptomatic IVF patients when first measured
8–13 days after oocyte retrieval, but found significantly
lower PI at gestational week 9 in OHSS patients (1.78 ±
0.22), compared to pregnant controls (2.43 ± 0.46). The
difference may have been due to an 80% multiparity rate in
the OHSS group. Strigini et al. (1995) measured uterine
artery and intra-ovarian PI in spontaneous and FSH
stimulated cycles and also following administration of 100
mg progesterone. Uterine artery PI was significantly lower in
FSH cycles than in spontaneous cycles on the day of
oestradiol peak and 5 days later. Progesterone significantly
decreased uterine artery PI further in spontaneous cycles and
FSH cycles, but did not affect intra-ovarian PI.
Thus, the relationship between serum hormone
concentrations and uterine blood flow appears to differ,
depending on which authors are consulted and which blood
vessels were sampled. Uterine artery flow volume was not
measured in any of the studies thus far reported. Spiral
arteries were rarely sampled. It may be that factors produced
in the ovary, other than oestradiol and progesterone, are
responsible for apparent cyclic changes in uterine vessels.
This is discussed below, with regard to pregnancy.
Relationship to IVF outcome
Studies of uterine blood flow in IVF and infertility are
listed in Table VII. The relationship between Doppler
ultrasound and IVF outcome has been reviewed by Tekay
et al. (1996a). A relationship between failure of
implantation and inadequate uterine blood flow was
established by Goswamy et al. (1988). A total of 153
patients with three IVF failures, despite transfer of good
quality embryos, was examined with a 3 MHz offset
Doppler abdominal ultrasound in the mid-luteal phase of
spontaneous cycles. All patients had received oestradiol
valerate, 2 mg daily, continuously from the fifth cycle day
during their last IVF cycle. Abnormal uterine artery
waveforms, in which diastolic flow was absent or not
continuous with preceding systolic flow (type 0, A, or D,
Table I), were present in 43% of the patients with repeated
implantation failure. Patients with abnormal waveforms
were treated with oral oestradiol valerate, 2 mg, and
norgestrel, 0.5 mg, for 21 days from the fifth cycle day for
three cycles; 82% of these patients with abnormal
waveforms responded to this treatment with improvement
in waveforms to continuous diastolic flow or absent end
diastolic flow (type C and B). Patients with three previous
transfer failures who had normal waveforms proceeded
directly to another IVF attempt. All patients with initially
normal waveforms who chose to attempt another IVF cycle
received 2 mg oestradiol valerate from cycle day 5. The
pregnancy rate for patients with initially normal
waveforms who repeated IVF was 31%. The pregnancy
rate for patients with initially abnormal waveforms which
improved after therapy was 43%. Patients with initially
abnormal waveforms who did not improve after therapy
had embryos cryopreserved and later received oestradiol
valerate in incremental doses, up to 6 mg daily, before
embryo thaw and transfer plus i.m. progesterone, 50 mg
daily before and 100 mg daily after transfer, with a resultant
50% pregnancy rate.
This study established a role for Doppler ultrasound in
assessment of patients undergoing IVF and for two
methods of treatment: hormonal therapy before IVF, and
cryopreservation with subsequent hormone therapy and
transfer. It did not determine the parameters of blood flow
compatible with fertility in normal cycles, since blood flow
may have been increased due to the high oestradiol and
progesterone concentrations which occur during ovulation
induction (Robertson et al., 1971; Ghosh et al., 1994;
Dickey and Hower 1995c). Furthermore, findings with
abdominal ultrasound needed to be repeated with
transvaginal ultrasound utilizing at least a 5 MHz
transducer, which could notably improve measurements of
waveforms, velocity, and RI (Steer et al., 1995a).
Strohmer et al. (1991) investigated uterine artery PI in
323 IVF patients on the day of HCG administration using
vaginal Doppler ultrasound with a variable transducer
(2.25–4.45 MHz), but examined only one uterine artery
and were unable to measure continuous flow in many
 Doppler ultrasound study of uterine and ovarian blood flow
patients. They nevertheless found significant differences
between PI in 46 pregnant (2.55 ± 0.78 SD) and 277
non-pregnant (2.84 ± 1.29 SD) cycles. They declined to
suggest a cut-off value above which HCG should not be
administered, nor IVF attempted. From their SD, that value
would be >3.33. Zaidi et al. (1996c) measured uterine
artery PI the day of HCG injection, using vaginal
ultrasound with a 5 MHz transducer, in 139 IVF cycles.
They found no difference in pregnancy rate or implantation
rate for PI values of 1.0–2.0, compared to 2.0–2.9 or ≥3.0.
They also found no significant difference in PI for pregnant
cycles (2.52 ± 0.50), compared to non-pregnant cycles
(2.64 ± 0.80). Furthermore, they found no significant
correlation between serum oestradiol concentrations and
PI.
Sterzik et al. (1989) measured uterine artery and ovarian
artery RI by vaginal ultrasound with a 4.5 MHz transducer
on the day of follicle aspiration in 45 IVF patients. They
used only the uterine and ovarian arteries with the lowest
RI in their analysis. These authors found a difference
between uterine artery RI in 12 patients who conceived
(0.78 ± 0.06 SE) and 43 who did not conceive (0.84 ± 0.05
SE); however, there was considerable overlap. Early
diastolic flow (type A, D, or 0) was absent in seven
patients, none of whom conceived.
Steer et al. (1992) measured mean uterine artery PI (right
and left) on the day of embryo transfer, using vaginal
ultrasound with a 4 MHz transducer, in 82 IVF patients. No
pregnancies occurred when the average PI was ≥3.0. There
were no differences in pregnancy rate, implantation rate, or
multiple pregnancy rate between patients with PI <2.0 and
2.0–3.0. Favre et al. (1993) measured mean right and left
uterine artery PI in 198 IVF patients on the day of embryo
transfer using vaginal ultrasound with a 4.5 MHz transducer.
In patients treated with gonadotrophin-releasing hormone
(GnRH), the PI was significantly lower (2.87) than in
non-GnRH-treated patients. The PI was not significantly
different in conception and non-conception cycles when
GnRH and non-GnRH patients were analysed separately. No
ongoing pregnancies occurred when the PI was >3.55 on the
day of embryo transfer. Cacciatore et al. (1996) measured
uterine artery PI and RI on the day of embryo transfer in 200
patients using a vaginal ultrasound with a 5.0–6.5 MHz
transducer. Mean right and left PI and RI were significantly
lower in pregnant than in non-pregnant patients, but there
was considerable overlap (2.45 ± 0.54 SD, 0.85 ± 0.04 versus
2.66 ± 0.39, 0.87 ± 0.04 respectively). There was no
difference between PI and RI values in pregnancies which
went to term (2.42 ± 0.95, 0.85 ± 0.05 respectively) and those
which aborted (2.45 ± 0.40, 0.85 ± 0.05 respectively). The
pregnancy rate dropped from 41% when the PI was <3.0 to
481
15% when the PI was ≥3.0 and to 10% when the PI was ≥3.5.
The pregnancy rate was 39% when the RI was <0.91,
compared to 13% when the RI was ≥0.92. The best cut-off
values were 3.3 for PI and 0.95 for RI. Absent diastolic
velocity was noted in only six patients, one of whom
conceived but aborted. Tekay et al. (1996b) measured flow
velocity waveform type, PI, MPSV and MDV with a 6 MHz
vaginal transducer on the day of embryo transfer in 25
patients during a GnRH–HMG cycle, and in 32 patients
having frozen embryo transfer in spontaneous cycles. There
were no conceptions when both uterine arteries had flow
velocity waveforms with absent end diastolic flow (type B
and D or D-II and D-III). The mean PI was significantly
lower, and the mean MDV was significantly higher, but
mean MPSV was not different in GnRH-HMG cycles,
compared to spontaneous cycles. There were no differences
in mean PI, MPSV, or MDV between conception and
non-conception cycles among patients with continuous
diastolic flow. However, individual PI values were always
<4.0 in conception cycles.
Bassil et al. (1995) measured mean (right and left) uterine
artery RI with a 6.5 MHz vaginal transducer from the
beginning of HMG administration to the day of embryo
transfer in 152 patients (196 cycles) after GnRH. Only 102
cycles in which three good quality embryos were
transferred and in which endometrial thickness was ≥9 mm
were analysed. A significant increase in RI was seen during
7 days of stimulation, which stabilized for 3 days before
decreasing markedly from day 9 until day 13, when HCG
was given. After HCG administration, the RI increased
significantly until the day of oocyte retrieval, then
decreased slightly until embryo transfer. In cycles which
resulted in pregnancy, RI values were initially lower on
cycle day 2 before starting HMG (0.775 ± 0.003 versus
0.790 ± 0.003), started to decline earlier (cycle day 8 versus
cycle day 10), and were significantly lower on the day of
HCG (0.773 ± 0.003 versus 0.790 ± 0.003), compared to
non-pregnant cycles, but were no different on the day of
oocyte retrieval or embryo transfer. Bassil et al. (1995)
concluded that an RI value >0.79 before starting HMG was
associated with a poor uterine response, and suggested that
an increased dose of HMG might improve blood flow and
uterine receptability.
Levi-Setti et al. (1995) also measured mean (right and left)
uterine artery PI with a 6.5 MHz vaginal transducer, from 5
days before HCG administration until oocyte retrieval, in 87
IVF patients, 17 of whom had multiple cycles of treatment.
Three or more embryos were transferred in all cycles. The
number of patients with continuous waveforms was not
stated. During the first IVF cycle, the PI was significantly
lower from 4 days before HCG through retrieval in patients
482 R.P.Dickey
who conceived. First cycle PI values were also lower in
patients with multiple cycles who conceived after the first
cycle. The greatest difference between pregnant and
non-pregnant cycles was observed on the day after HCG
administration. A PI ≤ 3.0 on the day of HCG administration
was associated with a 42% pregnancy rate, compared to 24%
if the PI was >3.0.
Thus, a consensus of published work indicates that
implantation in IVF cycles is decreased when uterine artery
PI is ≥3.3–3.5 and when the RI is ≥0.95, or when waveforms
show absence of early or end diastolic flow at the time of
HCG administration, oocyte retrieval, or embryo transfer.
Studies of uterine blood flow relationship to IVF outcome
performed thus far strongly suggest that the uterine blood
flow can help to define which patients will become pregnant.
More longitudinal studies like those of Bassil et al. (1995)
and Levi-Setti et al. (1995) are needed. An important
element missing from all previous studies is that they were
performed only while patients were recumbent. Standing
upright may markedly change blood flow in some patients
(see the section on postural changes). Also, the effect of
blood flow on the ovary and on oocyte development must be
considered (see the section on the ovary).
Relationship to infertility
Following the pioneer work of Goswamy et al. (1988),
Kurjak et al. (1991), Fujino et al. (1993) and Steer et al.
(1994) investigated uterine blood flow in women with a
history of infertility who were not undergoing IVF cycle
stimulation.
Kurjak et al. (1991) measured waveforms and RI by
vaginal ultrasound with a 6 MHz transducer in 100 infertile
women. They noted infertility in 11 of 12 women who
lacked end diastolic flow during both the proliferative and
luteal phases of the cycle, but no difference in mean right
and left uterine artery RI between infertile and fertile
women.
Fujino et al. (1993) measured uterine artery PI by
vaginal ultrasound with a 5.0 MHz transducer throughout
the cycle in 60 infertile women. The mean right and left PI
was low in pregnant, compared to non-pregnant cycles,
during the follicular phase (1.67 ± 0.22 SD versus 2.30 ±
0.78 SD) and mid-luteal phase (2.33 ± 0.69 versus 2.50 ±
0.97), but not during the ovulatory phase (1.89 ± 0.41
versus 2.5 ± 0.51). Fujino et al. (1993) did not suggest a
cut-off point. They also did not mention whether
waveforms were continuous during diastole.
Steer et al. (1994) measured mid-luteal phase mean right
and left uterine artery PI by vaginal ultrasound with a 4 MHz
transducer in 161 patients with various infertility diagnoses
and in 23 presumably fertile women with azoospermic
husbands. Supposedly normal patients had an average PI of
1.9 (range 0.8–2.7). Among patients with various causes of
infertility, the values and ranges were: unexplained (n = 35)
2.45 (range 1.0–7.0), tubal damage (n = 92) 2.65 (1.3–8.0),
endometriosis (n = 8) 2.32 (2.1–5.1) and anovulation (n =
22) 3.03 (1.6–7.0). The PI was higher than the normal range
in 50% of patients with endometriosis and anovulation, in
35% with tubal damage and in 23% with unexplained
infertility. Significant numbers of patients with infertility had
absence or reverse of flow during diastole. Right and left
uterine artery PI were similar, except in cases where a
Fallopian tube had been removed. There was no correlation
between PI and age, number of years of infertility, serum
oestradiol, or serum progesterone. The authors concluded
that decreased uterine blood flow may be an important factor
in upwards of 23% of infertility patients. Right and left
uterine artery PSV and RI, as well as perifollicular PSI and
PI, were measured throughout the cycle, with multiple
measurements on the day of expected ovulation in one
patient with luteinized unruptured follicle syndrome (Zaidi
et al., 1995b). No significant difference was found between
uterine arteries at any time during the cycle.
Many questions remain to be answered about the role of
uterine blood flow in infertility, not the least of which is
how much blood flow is enough. None of the studies of
infertility and very few of IVF cycles have measured
velocity, and none have measured flow volume, even
though these might be as important as impedance to flow as
represented by PI and RI. Moreover, according to
Goswamy and Steptoe (1988), the only parameter
measured in these three studies, PI, is unreliable when flow
is absent at any part of diastole, and waveforms must be
reported instead. Finally, the important effect of standing
on blood flow in infertility remains to be addressed
(Dickey et al., 1994).
Relationship to endometrial thickness and pattern
Studies of the relationship of uterine blood flow to
endometrial thickness are listed in Table VIII. The relative
importance of uterine blood flow and endometrial
thickness or pattern as predictors of implantation was
investigated by Coulam et al. (1994) and Serafini et al.
(1994) on the day of HCG injection, by Cacciatore et al.
(1996) and Tekay et al. (1996b) on the day of embryo
transfer in IVF cycles, and by Steer et al. (1995b) in frozen
embryo transfer cycles. Steer et al. (1994) investigated the
relationship of uterine blood flow to endometrial thickness
in non-IVF infertility patients.
 Doppler ultrasound study of uterine and ovarian blood flow 483

Table VIII. Studies of the relationship of uterine blood flow to endometrial thickness and pattern. See Table II for abbreviations

Wave Flow TAMV, Vmax, PSV, MDV PI RI S/D

form volume TAMX MPSV ratio
Coulam et al. (1994) x
Serafini et al. (1994) x x
Steer et al. (1994) x
Steer et al. (1995b) x
Cacciatore et al. (1996) x x
Tekay et al. (1996b) x x x x

Table IX. Studies of ovarian blood flow in normal cycles

Investigation Wave Flow TAMV, Vmax, PSV, MDV PI RI S/D

form volume TAMX MPSV ratio
Taylor et al. (1985) (A) x x
Scholtes et al. (1989) x
Bourne et al. (1991) x x
Collins et al. (1991) x x x
Kurjak et al. (1991) x
Jurkovic et al. (1991) x
Campbell et al. (1993) x x
Kupesic and Kurjak (1993) (E) x x x
Sladkevicius et al. (1993) x
Strigini et al. (1995) (E) x
Tekay et al. (1995) (E,H) x x
Bourne et al. (1996) x x
Tan et al. (1996) x x
Zaidi et al. (1996b) (C) x x

A = abdominal ultrasound; C = circadian rhythm also studied; E = relationship to oestrogen, progesterone, or ovulation induction
also studied; H = hyperstimulation syndrome also studied. See Table II for other abbreviations.

In the first study (Coulam et al., 1994), mean right and left
uterine artery PI and endometrial thickness and pattern were
measured by transvaginal ultrasound with a 5 MHz
transducer on the day of HCG administration in 41 IVF
cycles, on the day of progesterone administration in 20 donor
oocyte cycles, and the day of ovulation in 24 natural cycles
with transfer of cryopreserved embryos. The PI was
significantly lower in conception cycles (2.79) than in
non-conception cycles (3.50), for natural cycles with transfer
of cryopreserved embryos, but no significant differences
were found in IVF or oocyte donor cycles. The 95th centile
of PI in conception cycles was >3.3, similar to that reported
by Strohmer et al. (1991). There was no difference in
average endometrial thickness in conception and
non-conception cycles; however, no pregnancies occurred
when the thickness was <6 mm. Lack of a triple-layered
endometrial pattern was significantly associated with failure
of conception in donor oocyte cycles, but not in other cycles.
Unfortunately, the correlation of PI with endometrial
thickness and pattern was not analysed.
In the second study, both discontinuous flow during
diastolic and triple pattern endometrium were significantly
associated with failure to achieve a term pregnancy, but
uterine artery RI and endometrial thickness were not
(Serafini et al., 1994). Non-continuous diastolic flow (types
A, B, D, and 0) was present on the day of HCG injection in
12% of patients who delivered term pregnancies, in 27%
who had clinical abortions and in 34% who did not become
pregnant. Endometrial pattern was triple in 63% with term
pregnancy, 27% with clinical abortion and 24% who failed to
become pregnant. However, Serafini et al. (1994) measured
blood flow in only one uterine artery and included absent end
diastolic flow (type B) among the abnormal waveforms
(types A, D, 0).
Steer et al. (1994) found a significant correlation between
mean right and left uterine artery PI measured in the
mid-luteal phase and endometrial thickness in normal patients
(r = –0.85), those with unexplained infertility (r = –0.84),
endometriosis (r = –0.90) and anovulation (r = –0.77) and also
a lesser correlation with tubal infertility (r = –0.37).
484 R.P.Dickey
Steer et al. (1995b) subsequently reported that uterine
artery PI was significantly lower on the day of starting
progesterone before frozen embryo transfer in 19 patients
who became pregnant, compared to 57 who did not
conceive; however, there was significant overlap: 2.85
(range 1.4–3.6) versus 4.15 (range 2.1–6.8). There was a
significant correlation between PI and a 24-kDa protein (r =
–0.58), oestradiol receptor (r = –0.71) and endometrial
histological dating (r = 0.43), but not endometrial thickness,
on the same day in a trial cycle consisting of GnRH and
oestrogen preceding the cycle of transfer. Cacciatore et al.
(1996) found a significant correlation between mean right
and left uterine artery PI and both oestradiol (r = 0.37) and
progesterone (r = –0.32), but not endometrial thickness on
the day of embryo transfer. None of these authors speculated
about methods of treatment to increase uterine blood flow.
Ovarian blood flow
Studies of ovarian blood flow in normal cycles are listed in
Table IX. Ovarian blood flow has been studied extensively
in recent years, in the hope that knowledge of normal and
abnormal blood flow would provide an explanation for
some cases of infertility and for failure of ovarian response
to gonadotrophic stimulation. The majority of studies have
come from a single laboratory: Kings College, London
(Bourne et al., 1991, 1996; Collins et al., 1991; Jurkovic et
al., 1991; Campbell et al., 1993; Zaidi et al., 1995a,b,
1996a,b; Tan et al., 1996).
Taylor et al. (1985), in a classic study, measured ovarian
artery blood flow by Doppler ultrasound, using an
abdominal transducer, and by an invasive technique
employing a 10 MHz directional continuous wave flow
meter applied directly to the ovarian, iliac, and uterine
arteries. They demonstrated that ovarian and uterine
arteries, waveforms and PI were identical for both
techniques, and that the PI was lower on the side with the
dominant follicle. They also performed longitudinal
studies during the menstrual cycle which demonstrated that
increased blood flow on the side of the dominant follicle
occurred by day 5, before the dominant follicle could be
distinguished by ultrasound, and continued into early
pregnancy. Continuous diastolic flow was present on the
side of the dominant follicle and corpus luteum, whereas
no diastolic flow could be found on the side of the
quiescent ovary. They proposed that Doppler ultrasound
could be used to study luteal phase defect.
Subsequently, Scholtes et al. (1989), using vaginal
ultrasound with a 4.25 MHz transducer, were able to detect
continuous diastolic flow in 74% of ovarian arteries. They
confirmed a significantly lower PI in the ovarian artery on
the side of the ovary bearing the dominant follicle, from
cycle day 13 preceding ovulation through day 21, but
found no difference on cycle day 7. Sladkevicius et al.
(1993) observed similar changes in the dominant follicles’
peak velocity and PI, with less changes in the ovarian hilum
and stroma during the preovulatory period. Increased
blood flow on the side of the dominant follicle was also
demonstrated by decreased RI (Kurjak et al., 1991),
decreased PI (Weiner et al., 1993) and increased PSV (Tan
et al., 1996). Bourne et al. (1996) noted that PSV of corpus
luteum vessels rose following ovulation and was correlated
with serum progesterone (r = 0.77). In studies of corpus
luteum blood flow during the first trimester of pregnancy,
the peak velocity and TAMV did not change, and the PI
was decreased in some reports (Valentin et al., 1996) but
not in others (Jurkovic et al., 1992).
Bourne et al. (1991) first measured intra-ovarian blood
flow changes during the hours preceding and immediately
following ovulation in a single patient. Collins et al. (1991)
and Campbell et al. (1993) subsequently measured
intrafollicular flow in the peri-ovulatory period in larger
numbers of normal women. They observed a marked
increase in PSV in the presence of a relatively constant PI,
beginning 12 h after the LH surge or 29 h before follicular
rupture, with a peak velocity immediately following
ovulation.
Unlike uterine artery blood flow (Zaidi et al., 1995c), no
significant circadian rhythm was found in ovarian
follicular or stromal PI or PSV (Zaidi et al., 1996b). Tekay
and Jouppila (1996) found that, while intra-observer
reproducibility of transvaginal Doppler measurement of
intra-ovarian artery PI and RI was satisfactory, repeated
measurements of PSV showed too much variability to be
reliable.
Relationship to oestrogen, progesterone and
ovulation induction
In patients stimulated with HMG, the PI of the ovarian
vessels supplying the dominant follicle and corpus luteum
was positively correlated with the number of follicles ≥15
mm and with serum oestradiol concentrations, but not with
serum progesterone in one study whose authors suggested
that oestradiol increased stromal blood flow, but not corpus
luteum blood flow (Weiner et al., 1993). However, in
another study, no difference was seen in ovarian PI or RI in
HMG stimulated cycles, compared to spontaneous cycles,
but a relationship was seen between follicular response and
stromal PSV in HMG-stimulated patients (Kupesic and
Kurjak, 1993). Strigini et al. (1995) measured intra-
ovarian and uterine artery PI on the day of oestradiol peak
and 5 and 10 days later in spontaneous cycles and in
 Doppler ultrasound study of uterine and ovarian blood flow
FSH-stimulated cycles. Intra-ovarian PI was significantly
lower in FSH-stimulated cycles than in spontaneous cycles
on the day of oestradiol peak, but did not show any
significant change after ovulation. Moreover, during the
luteal phase, the PI of intra-ovarian arteries was not
significantly different in FSH-treated cycles than in
spontaneous cycles, whereas uterine artery PI was lower in
FSH cycles. Administration of 100 mg progesterone i.m.
during the luteal phase significantly suppressed uterine
artery PI further, but did not affect intra-ovarian artery PI.
A strong negative correlation (r = –0.80) was noted
between serum progesterone and intra-ovarian vessel RI
during the mid-luteal phase of the cycle by Glock and
Brumsted (1995). Tekay et al. (1995b) could find no
difference in intra-ovarian arterial PI or MPSV between
OHSS patients and asymptomatic IVF patients 8–13 days
after oocyte retrieval.
Relationship to IVF outcome
Studies of ovarian blood flow in IVF and infertility are
listed in Table X. Barber et al. (1988), using transvaginal
ultrasound to measure blood flow to the corpus luteum
after embryo transfer, found that no pregnancies occurred
when the RI was >0.5 on day 3 after embryo transfer.
Weiner et al. (1993) reported that failure of the stromal PI
to fall during HMG stimulation was associated with less
than three follicles at retrieval. In the same study, the
ovarian artery PI remained low in the late luteal phase in
patients who became pregnant. The relationship of ovarian
stromal blood flow on the second or third cycle day to
follicular development in response to HMG was studied in
105 IVF patients by Zaidi et al. (1996a). They defined poor
response as fewer than six follicles aspirated at retrieval.
PSV was, but PI was not, related to subsequent follicular
response, suggesting to Zaidi et al. (1996a) that peak
velocity could be used to screen for poor responders prior
to initiating HMG. The mean peak velocity prior to HMG
was 10.2 cm/s in the good response groups and 5.2 cm/s in
poor responders. Only 10 patients met the criteria for poor
response, and two of these were cancelled because of
detection of only a single follicle. The pregnancy rate in the
eight who went to retrieval, despite poor response, was no
different than in the 95 normal responders. Oyesanya et al.
(1996) noted that recovery of oocytes at IVF retrieval was
related to the presence of a detectable velocity waveform,
but not to the size of follicles. However, they did not
indicate the size of the follicles that they measured. Their
recovery rate was low; only 17% of patients had oocytes
recovered from 75% of follicles, and the correlation
485
between the number of follicles with pulsatility and
number of oocytes recovered was modest (r = 0.47).
Nargund et al. (1996) attempted to establish a relationship
between Doppler ultrasound indices of follicular quality and
oocyte or embryo quality. They measured PI and PSV in 126
follicles from 27 patients immediately before aspiration. The
absence of follicular blood flow was highly correlated with
failure to retrieve an oocyte. PSV was significantly higher in
follicles associated with a good-quality preimplantation
embryo, compared with follicles which yielded oocytes that
did not fertilize or produced inferior embryos (19.7 ± 10.8
versus 9.9 ± 5.3 cm/s). When PSV was ≥10 cm/s, there was a
70% chance of producing a good-quality embryo, compared
to a 14% chance if PSV was ≤10 cm/s. There was no
corresponding relationship to PI. There were only six clinical
pregnancies, so that they were unable to associate blood flow
with whether or not pregnancy ended in abortion. Nargund et
al. suggested that use of Doppler ultrasound might help to
determine which embryos to transfer.
Thus, investigations of ovarian and follicular blood flow
have so far failed to realize the hope that they would yield
information that could be used to predict or alter the
outcome of IVF. Because oxygen availability may affect
meiotic division during the peri-ovulatory period, blood
flow studies may yet reveal significant information about
the quality or even the genetic makeup of human embryos.
Ovarian blood flow in polycystic ovarian syndrome
and luteal insufficiency
PSV, TAMV and PI of ovarian stroma were measured on
cycle day 2 or 3 in 25 patients with polycystic ovarian
syndrome (PCOS) (Zaidi et al., 1995a). Mean PSV and
TAMV were significantly higher in patients with PCO
without elevated LH or anovulation (16.9 and 10.5
respectively) and PCO with elevated LH or anovulation
(16.9 and 10.9), than in patients with normal ovaries (8.7 and
5.4). There was no difference in PI. Zaidi et al. (1995a)
speculated that the increased stromal blood flow may explain
the excessive response seen in PCO patients during HMG
stimulation. Aleem and Predanic (1996) studied 40 PCO
patients throughout the cycle. Blood flow in the stroma was
visualized in 88% of PCO versus 50% of normal ovaries
from cycle day 3 to 8 and in all ovaries after ovulation when a
corpus luteum was present. Significantly lower PI and RI
were seen in PCO patients on days 3–8, compared to normal
ovaries. Values for PI and RI in normal ovaries on days
15–22 equalled those seen in PCO patients on days 3–8. PSV
was not significantly different between PCO and normal
patients on days 3–8, but was markedly higher in normal
patients on days 15–22. Vascular impedance was not
influenced by ovarian volume or the number of follicles. No
486 R.P.Dickey

correlation was found between serum oestradiol,
progesterone, or testosterone and RI, but a positive
correlation was present between LH and PSV. Additionally,
there was a trend towards lower PI and RI with higher LH.
Aleem and Predanic (1996) speculated that LH acts to
increase blood flow by stimulating prostaglandin synthesis.
Intra-ovarian RI, PSV and TAMV were measured by
vaginal ultrasound with a 5 MHz transducer five times
during the cycle in patients with presumptive luteal phase
defect by Glock and Brumsted (1995). Women with luteal
phase defect by histological dating were found to have
higher RI and lower TAMV during the late proliferative to
mid-luteal phase, but no difference in PSV, compared to
women with in-phase endometrium.
Perifollicular blood flow, as well as uterine artery blood
flow, was measured throughout the cycle, with multiple
measurements near the time of expected ovulation, in one
patient with a luteinized unruptured follicle (Zaidi et al.,
1995b). PSV was low before and after the LH surge,
compared to the dominant follicle in normal cycles,
suggesting to Zaidi et al. (1995b) that the primary defect
was deficient follicular development during the
proliferative phase.
Uterine blood flow in the first 16 weeks of
normal pregnancy
Development of placental circulation
Doppler ultrasound has greatly enhanced understanding of
uteroplacental circulation. The ascending uterine arteries
give rise to approximately eight arcuate arteries that run in
parallel to the surface of the uterus and form anastomoses
with the contralateral ascending uterine arteries. The
arcuate arteries, in turn, give rise to centripedal radial
arteries, which penetrate the middle third of the
myometrium and, in turn, give rise to ~200 spiral arteries.
After implantation, trophoblastic cells spread out from the
ends of anchoring villi penetrating the lumina of the
intradecidual portion of the spiral arteries, replacing the
musculoelastic architecture, thereby converting the spiral
arteries into low resistance uteroplacental arteries.
Recent anatomical and ultrasonographic studies suggest
that infiltration of the decidua down to the superficial
myometrium by columns of extravillous trophoblastic
cells and the transformation of spiral arteries is not
completed until mid-gestation in normal pregnancies.
Before the 10th week of gestation, the trophoblastic shell is
continuous and forms plugs inside the lumens of spiral
arteries, allowing only filtered plasma to penetrate the
placenta. During the 10th week, these plugs begin to break
up, so that limited circulation of maternal blood around
villi begins. This process is not completed, and full
maternal circulation within the whole intervillous chamber
is not established until the 12th week in normal pregnancy
(Hustin and Schaaps, 1987; Hustin et al., 1988, 1995;
Jauniaux et al., 1991a,b, 1992b; Jaffe and Woods, 1993).
Recently, Jauniaux (1996) reported that limited areas of
intervillous blood flow can sometimes be detected before
the 10th week in normal pregnancy. Merce et al. (1996),
however, using Doppler ultrasound, found intervillous
blood flow from 6 weeks onward, in accord with classical
embryological studies which reported the establishment of
intervillous blood flow around day 14 or 15 of embryonic
life (Wilken, 1958).

Table X. Studies of ovarian blood flow in in-vitro fertilization and infertility

Investigation Wave Flow TAMV, Vmax, PSV, MDV PI RI S/D

form volume TAMX MPSV ratio
Barber et al. (1988) x
Kurjak et al. (1991) x x
Weiner et al. (1993) (E) x
Glock & Brumsted (1995) x x x x
(INF,LI,N,E)
Zaidi et al. (1995a) (INF,PCO) x x x
Zaidi et al. (1995b) (INF,LI) x x
Aleem & Predanic (1996) x x x
(E,N,PCO)
Nargund et al. (1996) x x
Oyesanya et al. (1996) x x x
Zaidi et al. (1996a) x x

E = relationship to oestrogen, progesterone and ovulation induction also studied; INF = infertility LI = luteal insufficiency; N = normal
cycle also studied; PCO = polycystic ovaries. See Table II for other abbreviations.
 Doppler ultrasound study of uterine and ovarian blood flow 487

Table XI. Studies of uterine blood flow in normal early pregnancy

Investigation Wave Flow TAMV, Vmax, PSV, MDV PI RI S/D

form volume TAMX MPSV ratio
Deutinger et al. (1988) x x
Stabile et al. (1990) (S) x
Thaler et al. (1990) x
Jaffe and Warsof (1991) (S) x
Jauniaux et al. (1991b) x x
Jurkovic et al. (1991) (S) x x
Jauniaux et al. (1992a) (E,O,S) x x
Jauniaux et al. (1992b) x
Jaffe and Woods (1993) (S) x
Kurjak et al. (1993 (S) x
Jauniaux et al. (1994b) (E) x x x
Van Zalen-Sprock et al. (1994) (S) x
Dickey and Hower (1995a) (S) x x x x
Dickey and Hower (1995b) (C,E,S) x x x x
Dickey and Hower (1995c) (E,S) x x x x
Tekay et al. (1996b) x
Coppens et al. (1996) (S) x
Dickey and Hower (1996) x x x x
Guanes et al. (1996) x x
Merce et al. (1996) (S) x x x
Valentin et al. (1996) (O,S) x x x

C = relationship to crown–rump length and chorionic sac diameter also studied; E = relationship to oestrogen, progesterone and ovulation
induction also studied; O = ovarian blood flow also measured; S = spiral artery also measured. See Table II for other abbreviations.

In complicated early pregnancies, trophoblastic invasion
of both the decidua and the lumen in spiral arteries is
reduced, the trophoblastic shell is thinner, and circulation
within the placenta may be seen earlier than in normal
pregnancy (Khong et al., 1987; Hustin et al., 1988). The
presence of numerous echo-poor areas with flow in the first
trimester may be an indication of subsequent pregnancy
complications, according to Jaffe et al. (1995) and Jauniaux
(1996).
Independent evidence in support of the onset of
intervillous circulation at between 10 and 12 weeks is the
notable decrease in uterine artery PI and RI at this time
(Jauniaux et al., 1992b; Jaffe and Woods, 1993; Kurjak et al.,
1993; Dickey and Hower, 1995a; Guanes et al., 1996), and
the corresponding increase in uterine artery velocity and
volume at the same time (Dickey and Hower, 1995a).
Additionally, the diastolic notch in spiral arteries disappears
between at between 10 and 13 weeks (Coppens et al., 1996).
The development of the fetal placental circulation is
discordant with changes from the maternal side. At the end
of the sixth menstrual week, the villous vasculature is
connected with the embryonic heart and umbilical
circulation begins (Benirschke and Kauffmann, 1990). The
umbilical circulation may be detected by Doppler from 7
weeks of gestation as systolic flow (Den Ouden et al., 1990;
Jauniaux et al., 1991a,b). End diastolic flow is usually absent
from umbilical arteries until the 12th week of gestation and
does not become detectable in all pregnancies until 15 weeks
(Den Ouden et al., 1990; Arduini and Rizzo, 1991). The
appearance of end diastolic flow is accompanied by a sharp
decrease in umbilical artery PI.
Uterine blood flow during early normal pregnancy
Studies of uterine blood flow in normal early pregnancy are
listed in Table XI. Normal embryonic and fetal growth and
development depend on adequate perfusion of the
intervillous space through the maternal spiral arterioles
(Clapp et al., 1982; Campbell et al., 1983). Although the
first 16 gestational (post-menstrual) weeks are the most
critical period in human development, uterine artery blood
flow volume before week 16 has been measured in only
two studies (Thaler et al., 1990; Dickey and Hower,
1995a). Thaler et al. (1990) reported that blood flow
volume and vessel diameter increased at a constant rate
between the mid-luteal phase of the cycle and 36–39
weeks. However, they measured only the left uterine artery,
performed measurements only twice during the first 16
weeks, at 6–8 weeks and at 14–16 weeks, and used mid-
luteal phase measurements from non-pregnant patients as a
488 R.P.Dickey

Figure 8. Uterine artery; total (right plus left) flow volume (A), mean cross-sectional area (B), mean time averaged maximum velocity (C), heart
rate (D), mean resistance index (E), and spiral artery resistance index (F). Mean (SE) filled symbols, smoothed curve open symbols. Reprinted
with permission from Dickey and Hower (1995a).

starting point. A linear increase in uterine artery MPSV
between weeks 4 and 5 and weeks 13 through 16 was
reported by Jauniaux et al. (1992a) and Tekay et al.
(1995a). However, Jauniaux et al. (1992b) reported
elsewhere that peak uterine artery velocity doubled
between weeks 13 and 14. Valentin et al. (1996) found that
TAMV and PSV, measured from the fifth to the 11th
gestational week, increased exponentially in both the
dominant and non-dominant uterine artery, and in the
subchorionic (spiral) arteries, in contrast to PI, which
decreased linearly in both vessels.
Dickey and Hower (1995a) measured uterine blood flow
with transvaginal Doppler ultrasound at 1–3 week intervals
in 44 patients with primary or secondary infertility during
 Doppler ultrasound study of uterine and ovarian blood flow
the first 16 weeks of pregnancy. They found that total (right
plus left) uterine artery flow volume increased very
gradually, an average of 16 ml/min per week from 77
ml/min at post-menstrual week 5 to 159 ml/min at
post-menstrual week 10, and then more rapidly to reach
665 ml/min at week 16 (Figure 8A). Uterine artery
cross-sectional area increased linearly through the first 16
weeks (Figure 8B), while TAMV remained level or
increased slowly until week 8, then rapidly until week 16,
with a tendency to plateau from week 12 to 15 (Figure 8C).
Studies of indices of resistance begun before the eighth
week are rare because of the infrequency with which
patients are referred for scanning in early pregnancy.
Linear decreases in uterine artery PI and RI in early
pregnancy between weeks 4–6 and weeks 16–32 have been
reported by several authors (Deutinger et al., 1988;
Jauniaux et al., 1991a,b; Jurkovic et al., 1991; Van
Zalen-Sprock et al., 1994; Coppens et al., 1996; Valentin et
al., 1996), but others (Jauniaux et al., 1992b; Jaffe and
Woods, 1993; Kurjak et al., 1993; Guanes et al., 1996)
have reported no change in PI and RI until week 8–12 (the
onset of intervillous circulation), with a rapid decrease
thereafter. Dickey and Hower (1995a) found that uterine
artery RI (Figure 8E) and PI (not shown) were the
reciprocal of velocity, and decreased slowly from week 5 to
week 10, then rapidly from week 10 to week 16.
A linear decrease in spiral artery indices of resistance
between post-menstrual weeks 4–6 and weeks 15–16 has
been consistently reported by all authors [Stabile et al.,
1990; Jurkovic et al., 1991; Jaffe and Warsof, 1991;
Jauniaux et al., 1992b; Jaffe and Woods, 1993; Kurjak
et al., 1993; VanZalen-Sprock et al., 1994; Dickey and
Hower, 1995a (Figure 8F); Coppens et al., 1996; Merce
et al., 1996; Valentin et al., 1996].
Analysis of covariance performed before and after week
10, the putative onset of intravillous flow, by Dickey and
Hower (1995a), revealed that cross-sectional area of the
uterine artery was the most important factor in determining
uterine artery flow volume before week 10, while TAMV
was the most important factor after week 10 (Table XII).
Uterine artery PI and RI were related more closely to
velocity than to flow volume for all weeks. Spiral artery PI
and RI were positively related to flow volume, that is spiral
artery impedance decreased and flow increased when
uterine artery flow volume decreased before week 10, but
not from week 10 to 16. This may be due to the ability of
myometrial vessels, but not placental vessels, to respond to
decreased uterine artery volume by vasodilatation
(Kauppila et al., 1980).
The total flow volume from both uterine arteries,
measured during the fifth to sixth gestational weeks by
489
Dickey and Hower (1995a) (Figure 8) was equal to that
reported by Thaler et al. (1990) for a single artery of
non-pregnant patients during the mid-luteal phase. By the
16th week, however, total flow volume in Figure 8 was
twice that reported by Thaler et al. (1990) for a single artery
during the 31st to the 33rd weeks, but was similar to the 500
ml/min reported by Maini et al. (1985) for the same weeks
of gestation using an invasive radioisotope method.
The most obvious explanation for the marked decrease
in uterine artery RI and PI and consequent increase in
velocity, which began at 8 weeks, is the onset of
intervillous circulation. The linear decrease in spiral artery
RI and PI from week 4 or 5 is consistent with the finding of
Jaffe and Woods (1993) that trophoblastic invasion of the
spiral artery musculo-elastic architecture begins soon after
implantation.
According to Duvekot et al. (1993), a decrease in
systemic vascular tone, lowering both afterload and
preload, begins early in pregnancy between post-menstrual
weeks 5 and 8 (Duvekot et al., 1993; Duvekot and Peeters,
1994). Cardiac output increases in response to an increase
in heart rate in early pregnancy. Later, increases in the
stroke volume are more important as ventricular filling
status normalizes. According to Duvekot and Peeters
(1994), 60% of all of the systemic and cardiac changes
have occurred by mid-pregnancy. In the study by Dickey
and Hower (1995a), however, uterine artery flow volume
showed no relationship to maternal heart rate and, after the
10th week, 80% of the difference in uterine artery flow
volume between patients could be explained by velocity
and vessel size alone.
In a review of recent developments in understanding
uteroplacental circulation in early pregnancy, Jauniaux
(1996) stated, ‘Longitudinal evaluation of placental blood
flow is the only possible approach for future study of in
vivo early pregnancy.’ He could have added that studies
should be started in the fourth week of gestation, should be
carried out weekly, should include either flow volume or
TAMV in addition to indices of resistance, and should
include only pregnancies delivered of normal babies at
term.
A longitudinal study of uterine artery and spiral artery
blood flow in patients with normal outcome is underway in
the our clinic, with results reported as centiles. Preliminary
results indicate that normal flow volumes for the 10th and
50th centiles are approximately 30 ml/min and 100 ml/min
respectively from the mid-luteal phase of the cycle through
the fifth post-menstrual week, rise slowly until the 10th or
12th post-menstrual week, and then increase rapidly
thereafter until the end of study at week 16.
490 R.P.Dickey

Table XII. Analysis by covariance of the relative effects of uterine blood flow variables to
uterine artery blood flow volume, with gestational age, pulse rate, other uterine blood flow
variables, and subject as covariants. Data are expressed as F-values. Reprinted with per-
mission from Dickey et al. (1995a)

Flow volume
Week 5–9 Week 10–16
F Significance F Significance
Velocity 9.54 <0.001 9.77 <0.001
Cross-sectional area 11.89 <0.001 5.58 <0.001
Uterine artery RI 1.35 NS 1.32 NS
Spiral artery RI 2.00 0.038 1.27 NS
Gestational age 0.80 NS 2.77 NS
Pulse rate 0.90 NS 1.16 NS

RI = resistance index; NS = not significant.

Table XIII. Analysis of covariance of the relative effects of serum oestradiol or progesterone on uterine blood flow variables in
early pregnancy with gestational age, subject, and oestrogen or progesterone as covariants. Data are expressed as F-values.
Signs are derived from multiple linear regression. Reprinted with permission from Dickey and Hower (1996)

Uterine artery Spiral artery

Flow Average Average Pulsatility Resistance Pulsatility Resistance
volume velocity diameter index index index index
Weeks 5–16 (n = 118)
Oestradiol –1.70a 0.87 –1.94a –1.88a –2.49b 1.24 1.12
Progesterone 1.89a 2.05a 1.24 –0.96 –1.22 0.77 0.89
Weeks 5–9 (n = 48)
Oestradiol 0.36 1.71 –1.03 –1.53 –1.07 0.40 0.30
Progesterone 2.23a 1.30 1.10 0.55 0.44 0.73 0.92
Weeks 10–16 (n = 72)
Oestradiol –1.40 0.60 –1.89a –1.23 –1.72 1.24 1.37
Progesterone 1.05 1.41 0.99 –1.23 –0.96 0.49 0.65

a,bSignificance: aP < 0.05, bP < 0.01.

Effect of oestrogen and progesterone
Oestradiol administered to postmenopausal women causes
decreased resistance in the systemic circulation (Magness
and Rosenfeld, 1989; Magness et al., 1993; Penotti et al.,
1993), and causes dilation of the uterine arteries in sheep
(Anderson et al., 1977) and women (de Ziegler et al., 1991;
Hillard et al., 1992). Progesterone opposes the effect of
oestradiol in some studies (Hillard et al., 1992; Marsh
et al., 1994), but not in others (de Ziegler et al., 1991).
These observations suggest that rising oestrogen and
progesterone concentrations might be the cause of
increased uterine blood flow in early pregnancy. However,
such findings may not be transferable to pregnancy, where
the uterine vasculature may already be responding
maximally to oestrogen and progesterone as a prerequisite
for implantation (Sterzik et al., 1989; Steer et al., 1992).
Indeed, Anderson et al. (1977), using chronically
implanted electromagnetic flow probes around the left
middle uterine artery, determined that oestradiol secretion
was not responsible for the increase in uterine blood flow in
ovine pregnancies. Oestrogen-induced vasodilatation of
uterine and systemic blood vessels is now believed to be
mediated through nitric oxide (Kharitonov et al., 1994;
Ramsey et al., 1995; Cicinelli et al., 1996) and is
antagonized by nitric oxide synthesis inhibitors (Van Buren
et al., 1992).
Two Doppler ultrasound studies appear to support the
premise that oestradiol and progesterone are responsible
for increased uterine blood flow during the first 16 weeks
of pregnancy, because both hormones were found to be
negatively related to uterine artery RI (Jauniaux et al.,
1992a, 1994a). However, in the same studies, no associ-
ation was found between oestradiol or progesterone and
uterine artery PI or peak velocity, although both are
 Doppler ultrasound study of uterine and ovarian blood flow
ordinarily closely associated with RI. Also, uterine artery
blood flow volume, a more direct indication of uterine
perfusion, was not measured. Multiple linear regression
analysis, which was performed for the entire period of
weeks 5 through 16 in these studies, may have missed
important changes in uterine blood flow that occur after the
beginning of intervillous circulation during the 10th week
of gestation. Dickey and Hower (1996) analysed the
relationship between uterine blood flow and serum
oestradiol and progesterone, first for weeks 5 through 16
inclusive, and then separately before and after 10 weeks.
They used analysis of covariance to adjust for gestational
age, effect of sex steroids not in the primary analysis, and
repeat analysis of the same subjects (Bland and Altman,
1995). When studies with non-continuous uterine artery
waveforms were excluded from analysis, both PI and RI
were negatively related to oestradiol for weeks 5–16 (Table
XIII). Uterine artery flow volume and diameter were also
negatively related to oestradiol for weeks 5–16, despite the
decrease in downstream resistance represented by the
negative relationships of oestradiol to PI and RI.
Progesterone concentrations were positively related to
both total flow volume and average velocity for weeks
5–16. When ultrasound examinations with non-continuous
waveforms were included in the analysis, uterine artery RI
was negatively related to oestradiol, but uterine artery PI
was unrelated to oestradiol for weeks 5–16 (data not
shown), as previously reported by Jauniaux et al. (1994b).
When relationships were reanalysed separately before and
after week 10, oestradiol concentrations were negatively
related to diameter, but not to flow volume, PI, or RI for
weeks 10–16. Progesterone was positively related to flow
volume during weeks 5–9 and was unrelated to volume or
velocity during weeks 10–16. Thus, during the first 10
weeks of pregnancy, the net effect of progesterone was to
increase uterine blood flow, while the effect of oestradiol
was nil, a decrease in uterine artery diameter being
cancelled by a decrease in distal vessel impedance. After
the 10th week, the effect of progesterone was negligible,
while oestradiol had an adverse effect on uterine artery
diameter and flow volume.
The paradoxical finding that oestradiol is associated with
both decreased uterine artery blood flow volume and
decreased downstream resistance can be explained if
oestradiol affects uterine blood flow by two different
mechanisms, one acting on the uterine arteries and the other
acting on smaller vessels. Vasodilatation mediated through
nitric oxide is now a well-known effect of oestrogen
(Kharitonov et al., 1994; Ramsey et al., 1995; Cicinelli et al.,
1996). The negative association between oestradiol and
uterine artery diameter found in spontaneous cycles could be
491
explained by the finding that oestrogens can potentiate
α-adrenergic vasoconstriction in response to prostaglandins
(Colucci et al., 1982; Miller and Vanhoutte, 1990). On the
other hand, apparent relationships between oestradiol or
progesterone and increased uterine blood flow during early
pregnancy may be due to nothing more than colinearity.
Duvekot et al. (1993), in a study of cardiovascular, renal and
endocrine changes throughout pregnancy, concluded that
cardiovascular changes in pregnancy were not the result of
increased oestradiol, progesterone, or plasma renin
concentrations. Anderson et al. (1977) also concluded that
oestrogen was not responsible for the increase in uterine
blood flow volume in ovine pregnancy.
The premise that oestradiol and progesterone have a direct
effect on uterine blood flow during pregnancy is supported
by the findings that receptors for these hormones are present
in the muscle cells of non-pregnant uterine arteries
(Perrot-Applanat et al., 1988), that oestradiol may have a
direct, smooth muscle relaxing effect, mediated by a
calcium-channelled blockage mechanism (Jiang et al.,
1991), and that oestradiol may potentiate vasodilatation, via
endothelial-derived relaxin factor and endothelial-
independent vasodilators (Gilligan et al., 1994; Kharitonov
et al., 1994; Ramsey et al., 1995; Cicinelli et al., 1996).
Irrespective of the relationship to uterine blood flow,
oestrogen apparently has no role in the maintenance of
early pregnancy, since oestradiol replacement without
progesterone replacement is unable to prevent abortion in
patients lutectomized in early pregnancy (Csapo et al.,
1973) or in ovariectomized primates (Ghosh et al., 1994).
The relationship between uterine blood flow, hormone
concentrations and embryo development during the first 16
weeks of pregnancy is difficult to assess and to analyse, due
to the rapid changes which occur, problems of colinearity,
and the onset of intervillous circulation. Studies on uterine
artery blood flow and steroid measurements summarized
in Table VI were performed in patients with a history of
infertility or previous pregnancy loss and, therefore, results
of similar studies in an entirely normal population may be
different.
Effect of ovulation induction drugs
Ovulation induction with HMG and clomiphene citrate
results in marked increases in oestradiol and progesterone
which continue into early pregnancy (Robertson et al., 1971;
Dickey et al., 1991, 1992a, 1993c; Ghosh et al., 1994).
Uterine blood flow was previously measured during
ovulation induction with HMG (Weiner et al., 1993) and at
the time of embryo transfer (Sterzik et al., 1989; Steer et al.,
1992), but such studies were not continued into pregnancy.
492 R.P.Dickey
Figure 9. Mean (SE) serum oestradiol-17β (A) and progesterone (B) after treatment with human menopausal gonadotrophin (HMG, ◊) or clomi-
phene citrate (CC, s), or spontaneous ovulation (×). Reprinted with permission from Dickey and Hower (1995c).
Dickey and Hower (1995c) studied the effects of HMG
or clomiphene citrate on uterine artery and spiral artery
blood flow and their relationship to oestradiol and proges-
terone concentrations in patients who conceived singleton
pregnancies after treatment for primary or secondary infer-
tility. During the first 8 post-menstrual weeks, serum oes-
tradiol and progesterone concentrations were increased by
300% in patients who had received HMG and 60–100% in
patients who had received clomiphene citrate, compared to
spontaneous ovulation (Figure 9A and B). Despite these
considerable changes, uterine artery blood flow volume
increased by only 33% following HMG and by 20% fol-
lowing clomiphene citrate, compared to spontaneous
ovulation (Figure 10A). Uterine artery diameter was in-
creased by 15% for both HMG and clomiphene citrate
groups (Figure 10B). Time averaged maximum velocity
increased by 37% in patients who received HMG (Figure
10C). Uterine artery RI decreased by 3–5% only in patients
who received HMG (Figure 10D). When analysed by mul-
tiple linear regression analysis and analysis of covariance,
oestradiol concentrations were negatively related to uterine
artery diameter, but only for spontaneously pregnant pa-
tients, and were unrelated to flow volume and TAMV or RI
for any group. Progesterone concentrations were positively
related to TAMV in spontaneous pregnancy, but not in
clomiphene citrate- or HMG-induced pregnancy. These
findings strongly suggest that there is no direct relationship
between either oestradiol or progesterone and uterine ar-
tery blood flow during early pregnancy, and that the rela-
tionships observed by ourselves (Dickey and Hower, 1996)
and others (Jauniaux et al., 1992a, 1994a) were the result of
colinearity or due to other factors.
Relationship to chorionic sac and crown–rump
length
Dickey and Hower (1995b) examined the relationship be-
tween recumbent uterine blood flow and average chorionic
sac diameter (CSD) and crown–rump length (CRL) during
the first 16 gestational weeks in normal singleton preg-
nancies to determine whether differences in blood flow
could explain some of the variability that occurs in normal
human embryos in early pregnancy (Nishimura et al.,
1968; Rossavik et al., 1988; Dickey and Gasser, 1993;
Guirgus et al., 1993). During gestational weeks 5 through
12, CSD increased 12-fold and CRL increased 13-fold,
while mean total (right plus left) uterine artery blood flow
increased only ~3-fold. After adjustment for the effect of
gestational age and oestradiol, by multiple regression
analysis, CSD was negatively related to spiral artery PI and
RI, but not to uterine artery blood flow volume PI or RI.
CRL was positively related to uterine artery blood flow
volume and negatively related to uterine artery PI and RI.
The findings of a relationship between uterine artery resis-
tance indices and CRL suggest that there may also be an
association between uterine blood flow and embryonic
growth and well-being during the first trimester. In late preg-
nancy, increased uterine artery resistance and impaired uter-
ine blood flow are associated with intrauterine growth
retardation (Fleischer et al., 1986; Jacobson et al., 1990; Kay
et al., 1991; North et al., 1994). Thus, a lag in CSD or CRL
found using grey scale ultrasound in the first trimester may
be an indication that additional studies of uterine blood flow
need to be performed and, if abnormal, that efforts should be
directed towards improving blood flow.
 Doppler ultrasound study of uterine and ovarian blood flow 493

Figure 10. Mean (SE) uterine artery total (right plus left) flow volume (A), mean diameter (B), mean time averaged maximum velocity (C) and
mean resistance index (D), following treatment with human menopausal gonadotrophin (HMG, ◊) or clomiphene citrate (CC, s), or spontaneous
ovulation (×). Reprinted with permission from Dickey and Hower (1995c).

Uterine blood flow in abnormal pregnancy
Increased impedance of uterine and umbilical artery blood
flow, presenting as elevated RI and PI ratios and persistence
of the early diastolic notch into the third trimester is asso-
ciated with intrauterine growth retardation (IUGR), prema-
ture delivery, maternal hypertension and in severe cases, fetal
death (Gerretsen et al., 1981; Trudinger et al., 1985;
Fleischer et al., 1986; Jacobson et al., 1990; Harrington et
al., 1991; Meekins et al., 1994; Murakoshi et al., 1996). The
first 12 weeks of gestation are the period of most rapid
embryonic development (O’Rahilly and Muller, 1987). Im-
pairment of subplacental blood flow at this time by vasoac-
tive drugs has been shown to result in birth defects
(Danielsson et al., 1989) and may be the mechanism by
which diabetes results in birth defects associated with a lag in
embryo growth (Pedersen and Moldsted-Pedersen, 1981).
Jaffe et al. (1995) noted that 50% of complicated preg-
nancies demonstrated abnormal first trimester Doppler
characteristics. They later followed up 32 patients who had
spiral artery RI above 2 SD and blood flow in the intervillous
space before 12 weeks. They found that when the
intraplacental RI was greater than the umbilical RI between
22 and 25 weeks, 80% of pregnancies had an abnormal
outcome (Jaffe and Woods, 1996). Chianchianco et al.
(1991) found an association with abnormal uteroplacental
blood flow, pregnancy related hypertension and a history of
recurrent abortion. However, most uterine blood flow
studies have failed to show significant differences in
resistance indices between pregnancies with normal
outcomes and pregnancies which subsequently ended in
abortion (Alfirevic and Kurjak, 1990; Arduini et al., 1991;
Jaffe and Warsof, 1992). Jauniaux et al. (1994b) found that
mean uterine artery PI was elevated in missed abortions,
but that mean uterine artery RI and spiral artery PI and RI
were within normal limits. Pathological examination of the
missed abortion specimens in their study showed a
fragmented or absent trophoblastic shell in 53%, reduced
or absent trophoblastic infiltration in 43%, and absent or
reduced physiological changes in spiral arteries in 63% of
cases. Other histological studies of spontaneous abortion
494 R.P.Dickey
have also demonstrated defective transformation of the
spiral arteries and a reduced trophoblastic infiltration of the
decidua (Khong et al., 1987; Hustin et al., 1990). None of
the studies of the relationship of uterine blood flow to
abortion have reported the karyotype of the aborti. As a
result, given the high degree of variability in individual
values in these studies, it is impossible to know whether
abnormal blood flow was responsible for abortion of a
karyotypically normal embryo, was the result of
inadequate trophoblastic invasion of a karyotypically
abnormal embryo, or was the end result of embryo demise
irrespective of whether the karyotype was normal or not.
In an ongoing study in our clinic, in which recumbent and
standing uterine artery flow volume and uterine and spiral
artery PI and RI are recorded at the time of the first positive
quantitative pregnancy test and at each subsequent visit,
patients are encouraged to undergo a dilatation and curettage
procedure to obtain tissue for karyotype diagnosis whenever
a diagnosis of inevitable abortion is made by ultrasound.
Recumbent blood flow volume prior to loss of viability was
below the 50th centile in 8/10 subsequent pregnancy losses
with normal karyotype (46XX = 5, 46XY = 5), in 5/5
biochemical pregnancies, and in 1/3 with an abnormal
karyotype. A 50% decrease in blood flow volume during
standing occurred in 5/10 losses with normal karyotype
(46XY = 4, 46XX = 1) and 1/3 with an abnormal karyotype.
Uterine RI was ≥0.80 in 6/10 pregnancy losses with normal
karyotypes, 4/5 biochemical pregnancies, and 1/3 with
abnormal karyotypes. Uterine artery PI was ≥2.50 in 3/10
with normal karyotypes (all 46XY), in 3/5 biochemical
pregnancies, and in 0/3 with abnormal karyotypes. Spiral
artery RI was ≥0.80 in 7/10 with normal karyotypes, 5/5
biochemical pregnancies, and 2/3 with abnormal karyotypes.
In preliminary studies of uterine blood flow in the small
sac syndrome, where the difference between mean
gestational sac diameter and embryo crown–rump length is
<5 mm before gestational day 65 (Bromely et al., 1988;
Nazari et al., 1991) and most embryos are karyotypically
normal (Dickey et al., 1992c), small gestational sac size was
associated with higher than normal spiral artery PI and RI
(R.P.Dickey, unpublished observations). Administration of
oral micronized progesterone or i.m. progestin was followed
by significant decreases in spiral artery PI and RI and by
significant increases in gestational sac diameter (R.P.Dickey,
unpublished observations).
New areas of investigation
Postural studies
A consistent limitation of Doppler ultrasound studies of
uterine blood flow is that measurements have been obtained
only in the recumbent position. Blood flow measurements
while standing may be equally or more important
physiologically, and may differ significantly from recumbent
measurements. Standing causes a change in position and/or
downward movement of the uterus, which may result in
acute angulation or stretching of the uterine arteries,
especially in patients with poor uterine support. As a
consequence, arterial diameter may be decreased, and if
uncompensated for by increased pulse rate or decreased
downstream resistance, can result in a decrease in blood flow
volume.
Dickey et al. (1994) measured blood flow by Doppler
ultrasound during the mid-luteal phase in 74 non-pregnant
patients, first while recumbent and then twice while
standing: once immediately, and again after 9–14 min of
standing, without removal of the vaginal probe. Blood
pressure and pulse rate were recorded during each
measurement period (Table XIV). Total right plus left uterine
artery blood flow volume fell progressively while standing
in 70% of patients by an average 11% after 3–8 min and by
an average 34% after 9–14 min (Figure 11). Decreases in
blood flow volume while standing were accompanied by
significant decreases in mean uterine artery diameter and
significant increases in mean uterine artery PI, with no
change in uterine artery RI nor in spiral artery PI and RI. In
subjects with unchanged or increased blood flow volume
while standing, there was no change in mean diameter, but
mean uterine artery PI and RI were decreased. Pulse rate and
mean blood pressure were increased equally in patients both
with decreased and with increased flow volume.
Decreases in blood flow volume at 3–8 min and at 9–14
min of standing could be entirely accounted for by decreases
in cross-sectional area, which averaged 22% at 3–8 min and
34% at 9–14 min. Increased flow volume while standing was
due to both an increase in pulse rate, which resulted in
increased end diastolic flow, and to a decrease in
downstream vessel impedance.
Waveforms became worse in 16% of individual uterine
arteries (right or left) while standing (Table IV). Uterine
artery waveforms with absent end diastolic flow only while
recumbent (B or D-I) became continuous in seven of nine
cases while standing, due to increased pulse rate, and
degraded to absence of early diastolic flow (A or D, D-II or
D-III) in two cases (22%). Twelve percent of patients
demonstrated either absent early diastolic flow (A or D, D-II
or D-III) or no visible flow (N) for the first time while
standing. Poor uterine support was associated with increased
uterine artery PI (r = 0.33) while standing, but not while
recumbent. A history of previous spontaneous abortion was
associated with decreased uterine blood flow and increased
 Doppler ultrasound study of uterine and ovarian blood flow 495

Figure 11. Effect of standing (percentage change), mean (SE) on (A) ascending uterine artery [flow volume (UA-VOL, unbroken line), pulsatility
index (dashed line), resistance index (dotted line)] and (B) spiral artery [pulsatility index (dashed line), resistance index (dotted line)] in all subjects
(a), subjects with increased UA-VOL, (b), and subjects with decreased UA-VOL (c). Reprinted with permission from Dickey et al. (1994).

uterine artery PI or RI while recumbent, but not while
standing.
Spiral artery PI initially rose in all subjects upon standing
and then decreased at 9–14 min in subjects with increased
uterine artery flow volume, but remained elevated in subjects
with decreased flow volume (Figure 11). This suggested that
these two groups respond differently to the challenge of
changing from a recumbent to a standing position. Spiral
artery flow which had indicated absence of end diastolic
flow (B or D-I) while recumbent converted to continuous
flow in 13 of 14 cases and degraded to A or D-II in one case
while standing (Table IV). Spiral artery PI and RI were
related to uterine artery blood flow volume while standing,
but not while recumbent, and were more strongly related to
uterine artery PI and RI while standing than while recumbent
(Table V).
Possible explanations for the initial rise in spiral artery PI
in all subjects, followed by a fall only in those with
unchanged or increased uterine artery flow volume, include
individual differences in endothelium-dependent relaxing
factor (Meyer et al., 1993), prostaglandins (Greiss, 1972), or
adrenergic innervation (Ford et al., 1984). Alternatively, a
fall in uterine artery blood flow may be the normal response
to standing, and the increase in blood flow may be aberrant.
This possibility is suggested by the finding that average
recumbent uterine blood flow volume was initially lower in
subjects who experienced a rise in flow volume while
standing (Table XIV).
496 R.P.Dickey

Table XIV. Effect of standing on ascending uterine artery (UA) and spiral artery (SA) blood flow volume per minute (VOL), diame-
ter (DIA), pulsatility index (PI) and resistance index (RI). Values are mean ± SE. Modified and reprinted with permission from
Dickey et al. (1994)

Recumbent Standing (3–8 min) Standing (9–14 min)

Value Value % Change Value % Change
Subjects with increased or unchange UA-VOL (n = 22)
UA-VOL (ml) 61.6 ± 6.6 80. ± 10.9 126.2 ± 6.6b 90.0 ± 12.8 142.8 ± 9.1c
UA-DIA (mm) 2.78 ± 0.06 2.70 ± 0.05 97.6 ± 2.0 2.76 ± 0.05 100.0 ± 2.5
UA-PI 2.76 ± 0.14 2.50 ± 0.11 89.8 ± 3.4b 2.40 ± 0.13 86.6 ± 2.5c
UA-RI 0.90 ± 0.02 0.86 ± 0.02 96.3 ± 1.6a 0.85 ± 0.02 94.8 ± 1.4c
SA-PI 2.10 ± 0.10 2.07 ± 0.11 102.5 ± 6.7 0.95 ± 0.08 96.4 ± 5.8
SA-RI 0.84 ± 0.02 0.80 ± 0.02 96.2 ± 2.8 0.81 ± 0.02 97.4 ± 4.3
Pulse rate 72.4 ± 2.4 89.4 ± 4.2 124.2 ± 4.6c 91.1 ± 5.0 126.4 ± 6.0c
Mean BP 89.4 ± 1.9 92.8 ± 2.1 104.2 ± 2.4 94.3 ± 1.8 105.2 ± 1.6+
Subjects with decreased UA-VOL (n = 52)
UA-VOL (ml) 78.9 ± 6.6 57.6 ± 4.5 78.5 ± 4.3c 50.5 ± 4.4 65.8 ± 2.8c
UA-DIA (mm) 2.88 ± 0.05 2.69 ± 0.05 94.1 ± 1.5c 2.65 ± 0.04 92.8 ± 1.5c
UA-PI 2.65 ± 0.08 2.73 ± 0.11 103.5 ± 2.9 3.08 ± 0.22 115.2 ± 6.7a
UA-RI 0.89 ± 0.01 0.90 ± 0.01 101.5 ± 1.1 0.90 ± 0.06 102.0 ± 1.2
SA-PI 1.95 ± 0.08 2.05 ± 0.09 108.2 ± 4.8 2.06 ± 0.09 109.0 ± 5.2
SA-RI 0.83 ± 0.02 0.82 ± 0.02 99.6 ± 2.4 0.81 ± 0.02 98.4 ± 2.4c
Pulse rate 75.4 ± 1.5 91.1 ± 2.2 122.3 ± 2.7c 94.0 ± 2.6 125.0 ± 3.6c
Mean BP 91.4 ± 1.0 93.5 ± 1.3 102.7 ± 1.4 96.1 ± 1.6 105.3 ± 1.6b

BP = blood pressure.
a,b,cPaired t-test, standing versus recumbent, 3–8 min versus 9–14 min: aP < 0.05, bP < 0.01, cP < 0.001.

Studies of the effect of standing in pregnant patients are
now underway in our clinic. Pregnant patients are allowed to
stand for no more than 5–6 min while repeating blood flow
measurements. Early results indicate that 70% of pregnant
patients experience a decrease in blood flow volume while
standing during the fourth and fifth gestational weeks, the
same proportion as for non-pregnant patients.
Approximately 4% of pregnant patients experience a fall in
uterine blood flow of ≥50% while standing during the first
10 weeks of gestation. Both the percentage of patients who
experience a decrease in blood flow while standing and the
extent of the decrease appear to decline as pregnancy
progresses. This may be an important adaptation to the need
for increased blood flow and oxygenation. The reasons for
this adaptation may be entirely mechanical, due to
enlargement of the uterus and its vessels and to changes in its
position within the pelvis, or may be due to maturation or
adaptation of humeral or neurological factors or a
combination of these. Vasodilation has been shown to occur
in response to reduced uterine perfusion during the second
and third trimesters of normal pregnancy, presumably due to
release of endogenous nitrous oxide in the vascular
epithelium (Cameron et al., 1993; Ramsey et al., 1994).
Improvement in the response to decreased uterine artery
blood flow volume caused by postural changes may be a
necessary physiological adaptation, because the placental
vessels are unable to increase perfusion by vasodilation
(Kauppila et al., 1980).
Although previous ultrasound studies of systemic
(Duvekot et al., 1993) and uterine (Thaler et al., 1990;
Jurkovic et al., 1991; Jauniaux et al., 1992b; Jaffe and
Woods, 1993) blood flow in early pregnancy have failed to
consider the effect of posture, assessment of the effect of
posture on cardiac and uterine blood flow is not new.
Lindhard (1913) reported a decrease in cardiac output in men
upon changing from the recumbent to the standing position.
In 1956, Morris et al., using the 24NA clearance method,
found increased uterine blood flow during bed rest,
compared with exercise during pregnancy. Suonio et al.
(1976) noted a 23% decrease in placental blood flow in late
pregnancy when moving from the left lateral recumbent to a
standing position. Dickey et al. (1966) reported an 80%
decrease in urinary oestriol excretion when changing from a
recumbent to a standing position during the third trimester,
which they attributed to a change in placental perfusion.
Schiff et al. (1991) studied the use of Doppler ultrasound of
uterine arteries to increase the sensitivity of the rollover test
of Gant et al. (1974) to predict patients at increased risk of
 Doppler ultrasound study of uterine and ovarian blood flow
pregnancy-induced hypertension. Indeed, this new evidence
of the effect of standing on uterine blood flow may explain
why bed rest has been traditionally considered to be
beneficial in preventing recurrent or threatened abortion
(Hertig and Livingstone, 1944).
Standing studies are not without difficulty. Transvaginal
scanning of both ascending uterine arteries and of
myometrial spiral arteries while the subjects are standing is
not possible in very obese subjects, in subjects with very
large ovaries due to hyperstimulation, and when the uterus
is greatly enlarged by fibroids. Some subjects became faint
while standing, especially in early pregnancy.
Measurement of flow volume requires more time than
measurement of uterine and spiral artery indices, so that
acute changes may be missed. More precise assessment of
time-related uterine blood flow changes after standing,
with instrumentation which allows instantaneous and
measurement of minute blood flow volume, PI and RI, is
needed. However, the findings of standing studies to date
indicate that, when possible, measurements of uterine
blood flow should be performed both with patients
standing and recumbent.
Non-steroidal drugs
At the present time, not enough is known about the effect of
drugs, other than oestrogen and progesterone, on human
uterine and ovarian blood flow in infertility and early
pregnancy. This situation should change because of the
ease with which blood flow may be measured with vaginal
Doppler ultrasound under physiological conditions.
Investigation of drug effects on uterine blood flow in
infertility and early pregnancy can be ranked in order of
significance as (i) studies performed during late pregnancy,
(ii) studies of non-pregnant reproductive age women, (iii)
inferences from animal studies during pregnancy, (iv)
inferences from human investigations of the effects of
drugs on the systemic circulation and (v) anecdotal reports.
The largest number of reports concern late pregnancy, and
are concerned with three types of drugs: nitrous oxide,
aspirin and vasodilators. It is now known that arterial
circulation is continuously dilated by nitric oxide released
from arterial and arteriole endothelium (Vallance and Collier,
1994). The role of nitric oxide in late pregnancy, its
relationship to pre-eclampsia, and its role as a widespread
biological mediator have been reviewed recently (Vallance
and Collier, 1994; Morris et al., 1996a). Endothelial-derived
relaxing factor, discovered by Furchgott and Zawadski
(1980), was proven to be nitric oxide by two groups acting
independently (Ignarro et al., 1987; Palmer et al., 1987).
Nitric oxide has been shown to mediate oestrogen-induced
497
vasodilation (Van Buren et al., 1992). Endothelial-derived
nitric oxide may be a key regulator of placental blood flow
during pregnancy (Moncada et al., 1991; Chang et al., 1992;
Myatt et al., 1992; Hull et al., 1994). Circulating
concentrations of nitrite, an oxidative metabolite of nitric
oxide, are reduced in patients with pre-eclampsia (Seligman
et al., 1994). In non-pregnant women of reproductive age,
circulating concentrations of nitric oxide metabolites are
higher in the proliferative phase of the menstrual cycle than
in the luteal phase and they peak at mid cycle (Cicinelli et al.,
1996). In patients undergoing IVF, nitrite and nitrate
(NO3/NO2) concentrations in follicles ≥4 mm diameter are
related to ovarian artery PI (Anteby et al., 1996).
In animals, nitric oxide synthesis activity in maternal
tissue begins to increase early in pregnancy (Weiner et al.,
1994). Prolonged blockage of nitric oxide synthesis
produces a pre-eclampsia-like syndrome in rats (Molnar
et al., 1994). Inhibition of nitric oxide synthesis results in
growth retardation and limb defects in rats (Diket et al.,
1994).
Glycerol trinitrate (GTN) is a nitric oxide donor which
preferentially dilates veins and other vessels that have low
basal output of nitric oxide. Ramsey et al. (1994) have
shown that administration of intravenous GTN to pregnant
patients with abnormally elevated uterine artery RI (> 0.6)
and bilateral notching resulted in lowering of RI and PI
with no change in TAMV and no associated changes in
heart rate, systemic blood pressure, or resistance indices in
the umbilical or maternal carotid artery. During GTN
infusion, 50% of uterine artery waveforms with
discontinuous early diastole flow (A, D or D-II, D-III) were
converted to continuous flow. Changes due to GTN were
greater than those caused by prostacyclin in the same study.
The use of organic nitrates as active vasodilators in
clinical medicine dates back to 1847. Therapeutically
administered organic nitrates became the drugs of choice
when nitrates were indicated. Tolerance is one of the main
problems of nitrate use. After 12–14 h of continuous
administration, almost complete tolerance occurs. The
drug must be discontinued for 12 h before the vasodilator
effect is again observed within the coronary arteries.
Tolerance to the vasodilator effect in the uterine arteries is
not as yet known.
Low-dose aspirin (ASA) began to be investigated as a
means of preventing pre-eclampsia in the mid 1980s
because of its antiplatelet activity and because it decreased
the synthesis of thromboxane A2 (Beaufils et al., 1985;
Benigni et al., 1989; Uzan et al., 1994). The effect of ASA
on uterine blood flow in patients with pre-eclampsia was
investigated by McParland et al. (1990) and Bower et al.
(1996). A large multicentre collaborative study of ASA in
498 R.P.Dickey
pregnancy (CLASP, 1994) reached the conclusion that
there was no significant reduction in the incidence of
pre-eclampsia, intrauterine growth retardation, stillbirth,
or neonatal death. However, some centres with expertise in
Doppler ultrasound diagnosis of pre-eclampsia reached the
opposite conclusion. Bower et al. (1996), who participated
in the CLASP study, found that ASA reduced the incidence
of pre-eclampsia and severe eclampsia by ~50%. They
suggested that ASA should be started earlier than 24 weeks
to achieve maximum results. In a study of nulliparous
patients who had abnormal waveforms, there was no
overall difference in total adverse outcomes between 84
patients who were untreated and 102 who were started on
100 mg ASA daily beginning at 18 weeks. Although the
incidence of pre-eclampsia was 4% in the treatment group
versus 11% in the placebo group, this was offset by a higher
incidence of birth weight in the <10th centile (27 versus
22%) and antepartum haemorrhage (4 versus 2%) in the
treatment group (Morris et al., 1996b).
In a study of hormone replacement for frozen embryo
replacement, patients with impaired uterine perfusion were
given ASA, 150 or 300 mg, once daily starting from day
13. The cancellation rate was lower (33 versus 48%) and
the pregnancy rate was higher (25 versus 15%) in patients
receiving 300 mg, compared to 150 mg per day. In a second
phase, patients cancelled initially received ASA from the
first day of hormonal replacement, with the result that 83%
underwent replacement and 47% of these became pregnant
(Wada et al., 1994).
None of the studies examined the effect of ASA on the
spiral arteries. In a preliminary study from our clinic,
Doppler ultrasound screening was performed during the
mid-luteal phase prior to IVF cycles. Patients with
abnormal waveforms and elevated RI and PI were given
300 mg ASA orally. Waveforms became continuous and RI
and PI were notably reduced in 80% of patients 1–2 h after
ASA administration.
Animal studies conducted with electromagnetic flow
probes in the 1970s demonstrated that ovine myometrial
vasculature responded to very small doses of the
α-adrenergic drugs epinephrine and norepinephrine by
vasoconstriction, was resistant to α-adrenergic blockade,
and responded to β-adrenergic stimulation with vasodi-
lation (Greiss, 1972). The same studies found that ovine
placental vascularization was less sensitive to α-adrenergic
stimulation and more sensitive to α blockade than uterine
vasculature. They also established that the response of
myometrial vasculature did not change, even in late
pregnancy, indicating that myometrial vasculative
response to sympathetic neurohormone stimulation was
unaltered by the high concentrations of sex steroids that
occur in pregnancy.
The β-adrenergic agents fenoterol and isoxsuprine are
commonly used in pregnancy as uterine relaxants. Their
effect on myometrial and intervillous blood flow was
studied with intravenous 133Xe before the availability of
Doppler ultrasound (Kauppila et al., 1978). Fenoterol, but
not isoxsuprine, significantly increased myometrial blood
flow. Neither drug increased intervillous blood flow.
Doppler ultrasound studies of the vasodilators nifedipine
(Lindow et al., 1988) and atenolol (Montane et al., 1987)
have shown that these drugs do not increase uterine blood
flow significantly. Vasoconstrictive drugs have been
shown to cause birth defects in animals by causing
vasoconstriction of uterine vessels, but vasodilating drugs
may also cause birth defects (Danielsson et al., 1989). The
latter are believed to act by a decrease in uteroplacental
blood flow caused by excessive hypotension.
In studies of other drugs, no significant changes were
found in uterine or umbilical artery blood flow following
maternal betamethasone administration (Cohlen et al.,
1996) or following methyldopa (Montan et al., 1993).
During the oxytocin challenge tests, fetal heart rate
decelerations were associated with rapid and exaggerated
increases in uterine and umbilical artery PI during uterine
contractions, but returned to resting levels during uterine
relaxation (Olofsson et al., 1996). Growth hormone and
insulin-like growth factor were shown to increase ovarian
vascularization by Ryan and Mackis (1987).
Among anecdotal reports is that of Bonilla-Musoles
et al. (1995), who reported that 100 mg of Paracetainol, an
anti-inflammatory agent, caused immediate disappearance
of ovarian vascular flow, and that 600 mg per day Elorgan,
a xanthine-type vasodilator, caused increased uterine
artery blood flow in 60% of patients.
Conclusions
Doppler ultrasound measurement of uterine blood flow
holds the promise of being as helpful for investigation of
infertility and early pregnancy loss as Doppler analysis of
uterine and umbilical blood flow has been in the second
and third trimesters of pregnancy. This promise has not yet
been fulfilled, in part due to the difficulty of interpreting
blood flow measurements performed during the menstrual
cycle and early pregnancy when diastolic blood flow is
often not continuous in uterine and spiral arteries. Lack of
fulfilment is also due, in part, to the fact that most studies
have measured only downstream impedance, which is
critical in the second and third trimesters, but may not be as
 Doppler ultrasound study of uterine and ovarian blood flow
important in infertility and early pregnancy, and to the fact
that studies have been performed only in the recumbent
position. Despite these limitations, the majority of studies
agree that implantation cannot occur when the mean (right
and left) uterine artery PI is ≥3.0–4.0 or diastolic flow is not
continuous in at least one artery on the days of HCG
administration, oocyte retrieval, or embryo transfer in IVF
and donor embryo cycles.
Investigation of ovarian blood flow has also proven
disappointing, not allowing the predetermination of which
follicles will produce oocytes capable of fertilization and
implantation, but it may soon help our understanding of
luteal insufficiency and the cause of poor oocyte quality in
polycystic ovaries. Even more intriguing is the possibility
that ovarian blood flow studies may link intrafollicular
hypoxia to errors of nondysjunction during meiosis.
Early pregnancy, insofar as uterine blood flow is
concerned, can be divided into two periods, i.e. before and
after the onset of maternal intervillous circulation, which
begins, according to the most recent authorities, between
the 10th and 12th gestational weeks. Notable changes
occur during the 10th to 12th weeks in uterine artery RI, PI,
mean velocity and flow volume. The 10th week coincides
with the end of embryological development, according to
classical embryology studies. Uterine blood flow during
the earlier period is most like that in the mid to late
follicular phase of non-pregnant fertile women, while
uterine blood flow in the later period is more like that of the
second or third trimester of pregnancy. It is interesting to
speculate that deficient uterine blood flow in the earlier
period may lead to infertility and abortion, just as deficient
blood flow in the later period can lead to intrauterine
growth retardation in the baby and to hypertension in the
mother.
Additional Doppler investigations into physiological
and pharmacological methods to improve uterine blood
flow in infertility and early pregnancy are clearly needed.
Present pharmacological methods are limited to ASA,
which has its own inherent side-effects, and to nitric oxide
donors, whose length of use is severely limited by rapid
development of tolerance. Doppler ultrasound may
establish a scientific basis for use of physiological
methods, such as bed rest and progesterone, in preventing
abortion.
Doppler ultrasound measurement of uterine and ovarian
blood flow is a relatively new technique. Its role in clinical
medicine has still to be established for infertility and early
pregnancy. As more investigations are performed, as
clinicians become familiar with its use, and as
instrumentation is improved, it may yet prove to be an
499
indispensable tool for clinical investigation of disorders of
oocyte development, implantation and early pregnancy.
References
Aleem, F.A. and Predanic, M. (1996) Transvaginal color Doppler
determination of the ovarian and uterine blood flow characteristics in
polycystic ovary disease. Fertil. Steril., 65, 510–516.
Alfirevic, Z. and Kurjak, A. (1990) Transvaginal color Doppler ultrasound in
normal and abnormal early pregnancy. J. Perinatal Med., 18, 173–180.
American Institute of Ultrasound in Medicine (1993) Bioeffects and Safety of
Diagnostic Ultrasound. AIUM, Laurel, MD, p. 96.
Anderson, S., Hacksaw, B., Still, G. and Greiss, F. (1977) Uterine blood flow
and its distribution after chronic estrogen and progesterone
administration. Am. J. Obstet. Gynecol., 127, 138–142.
Anteby, E.Y., Hurwitz, A., Korach, O. et al. (1996) Human follicular nitric
oxide pathway: relationship to follicular size, estradiol concentrations,
and ovarian blood flow. Hum. Reprod., 11, 1947–1951.
Arduini, D. and Rizzo, G. (1991) Umbilical artery velocity waveforms in
early pregnancy: a transvaginal color Doppler study. J. Clin.
Ultrasound, 12, 335–339.
Arduini, D., Rizzo, G. and Romanini, C. (1991) Doppler ultrasonography in
early pregnancy does not predict adverse outcome. Ultrasound Obstet.
Gynecol., 1, 180–185.
Baker, A.R., Evans, D.H., Prytherch, D.R. et al. (1986) Some failings of the
pulsatility index and damping factor. Ultrasound Med. Biol., 12,
878–881.
Balakier, H. and Stronell, R.D. (1994) Color Doppler assessment of
folliculogenesis in in vitro fertilization patients. Fertil. Steril., 62,
1211–1216.
Barber, R.J., McSweeney, M.B., Gill, R.W. et al. (1988) Transvaginal pulsed
Doppler ultrasound assessment of blood flow to the corpus luteum in
IVF patients following embryo transfer. Br. J. Obstet. Gynaecol., 95,
1226–1230.
Bassil, S., Magritte, J.P., Roth, J. et al. (1995) Uterine vascularity during
stimulation and its correlation with implantation in in vitro fertilization.
Hum. Reprod., 10, 1497–1501.
Beaufils, M., Uzan, S., Donsimoni, R. and Colau, J.C. (1985) Prevention of
preeclampsia by early antiplatelet therapy. Lancet, i, 840–842.
Benigni, A., Gregorini, G., Frusca, T. et al. (1989) Effect of low dose aspirin
on fetal and maternal generation of thromboxane by platelets in women
at risk for pregnancy-induced hypertension. N. Engl. J. Med., 321,
357–362.
Benirschke, K. and Kauffmann, P. (1990) Pathology of the Human Placenta,
3rd edn. Springer Verlag, New York.
Bewley, S., Chang, T.C. and Campbell, S. (1993) Uteroplacental resistance
index: analysis of intra- and interobserver variability. Ultrasound
Obstet. Gynecol., 3, 417–421.
Bland, J.M. and Altman, D.G. (1995) Calculating correlation coefficients
with repeated observations: Part I: Correlations with subjects. Br. Med.
J., 310, 446.
Bonilla-Musoles, F., Ballester, M.J., Raga, R. et al. (1995) Transvaginal
color Doppler sonography from folliculogensis to implantation: normal
and abnormal evolution. Assist. Reprod. Rev., 5, 158–169.
Bourne, T.H., Jurkovic, D., Waterstone, J. et al. (1991) Intrafollicular blood
flow during human ovulation. Ultrasound Obstet. Gynecol., 1, 53–59.
Bourne, T.H., Hagstrom, H.G., Hahlin, M. et al. (1996) Ultrasound studies of
vascular and morphological changes in the human corpus luteum during
the menstrual cycle. Fertil. Steril., 65, 753–758.
Bower, S.J., Harrington, K.F., Schuchter, K. et al. (1996) Prediction of
preeclampsia by abnormal uterine Doppler ultrasound and modification
by aspirin. Br. J. Obstet. Gynaecol., 103, 625–629.
Bromely, B., Harlow, B.L., Laboda, L.A. and Benecerraf, B.R. (1988) Small
sac size in the first trimester: a predictor of poor fetal outcome.
Radiology, 71, 81–83.
Cacciatore, B., Simberg, N., Fusaro, P. and Titinen, A. (1996) Transvaginal
Doppler study of uterine artery blood flow in in vitro
fertilization–embryo transfer cycles. Fertil. Steril., 66, 130–134.
500 R.P.Dickey
Cameron, J.T., Van Pependorp, C.L., Palmer, R.M.J. et al. (1993)
Relationship between nitric oxide synthesis and increase in systolic
blood pressure in women with hypertension in pregnancy. Hypertension
Pregnancy, 12, 85–92.
Campbell, S., Griffin, D.R., Pearce, J.M. et al. (1983) New Doppler
technique for assessing uteroplacental blood flow. Lancet, 1, 675–677.
Campbell, S., Bourne, T.H., Waterstone, J. et al. (1993) Transvaginal color
blood flow imaging of the periovulatory follicle. Fertil. Steril., 60,
433–438.
Chang, J.K., Roman, C. and Heymann, M.A. (1992) Effect of
endothelium-derived relaxing factor inhibition on the umbilical–
placental circulation in fetal limbs in utero. Am. J. Obstet. Gynecol.,
166, 727–734.
Chianchiano, N., Rossi, C., Bertolino, G. et al. (1991) Uteroplacental blood
flow in pregnant women with hypertension and recurrent spontaneous
abortion. Acta Eur. Fertil., 22, 151–152.
Cicinelli, E., Ignarro, L.J., Lograno, M. et al. (1996) Circulating levels of
nitric oxide in fertility women in relation to the menstrual cycle. Fertil.
Steril., 66, 1036–1038.
Clapp, J.F., McLaughlin, M.K., Larrow, R. et al. (1982) The uterine
hemodynamic response to repetitive unilateral vascular embolization in
the pregnant ewe. Am. J. Obstet. Gynecol., 144, 309–318.
CLASP (Collaborative Low Dose Aspirin Study in Pregnancy)
Collaborative Group (1994) A randomized trial of low-dose aspirin for
the prevention and treatment of preeclampsia among 9364 pregnant
women. Lancet, 343, 619–629.
Cohlen, B.J., Stigter, R.H., Derks, J.B. et al. (1996) Absence of significant
hemodynamic changes in the fetus following maternal betamethasone
administration. Ultrasound Obstet. Gynecol., 7, 252–255.
Collins, W., Jurkovic, D., Bourne, T. et al. (1991) Ovarian morphology,
endocrine function, and intra-follicular blood flow during the
periovulatory period. Hum. Reprod., 6, 319–324.
Colucci, W.S., Gimbrone, M.A., McLaughlin, M.K. et al. (1982) Increased
vascular catecholamine sensitivity and a-adrenergic receptor affinity in
female and estrogen-treated male rats. Circ. Res., 50, 805–811.
Coppens, M., Loquet, P., Kollen, M. et al. (1996) Longitudinal evaluation of
uteroplacental and umbilical blood flow changes in normal early
pregnancy. Ultrasound Obstet. Gynecol., 7, 114–121.
Coulam, C.B., Bustillo, M., Soenksen, D.M. and Britten, S.T. (1994)
Ultrasonographic predictors of implantation after assisted reproduction.
Fertil. Steril., 62, 1004–1010.
Csapo, A.I., Pulkkinen, M.O. and Kaihola, H.L. (1973) The effect of
estradiol replacement therapy on early pregnant lutectomized patients.
Am. J. Obstet. Gynecol., 117, 987–990.
Danielsson, B.R., Reiland, S., Rundqvist, E. and Danielson, M. (1989)
Digital defects induced by vasodilating agents: relationship to reduction
in uteroplacental blood flow. Teratology, 40, 351–358.
Deichert, U. and Buurman, C. (1995) Transabdominal Doppler sonographic
measurements of blood flow differences in the main pelvic arteries
during physiological spontaneous ovarian cycles. Hum. Reprod., 10,
1531–1536.
Den Ouden, M., Cohen-Overbeck, T.E. and Waldimiroff, J.W. (1990)
Uterine and fetal umbilical artery flow velocity waveforms in normal
first trimester pregnancies. Br. J. Obstet. Gynaecol., 97, 716–719.
Deutinger, J., Rudelstorfer, R. and Bernaschek, G. (1988)
Vaginosonographic velocimetry of both main uterine arteries by visual
vessel recognition and pulsed Doppler method during pregnancy. Am. J.
Obstet. Gynecol., 159, 1072–1076.
Deutinger, J., Reinthaller, A. and Bernaschek, G. (1989) Transvaginal pulsed
Doppler measures of blood flow velocity in the ovarian arteries during
cycle stimulation and after follicle puncture. Fertil. Steril., 51, 466–470.
de Ziegler, D., Bessis, R. and Frydman, R. (1991) Vascular resistance of
uterine arteries: physiological effects of estradiol and progesterone.
Fertil. Steril., 55, 775–779.
Dickey, R.P. and Gasser, R.F. (1993) Ultrasound evidence for variability in
the size and development of normal human embryos before the tenth
postinsemination week after assisted reproductive technologies. Hum.
Reprod., 8, 331–337.
Dickey, R.P. and Hower, J.F. (1995a) Ultrasonographic features of uterine
blood flow during the first sixteen weeks of pregnancy. Hum Reprod,
10, 2448–2452.
Dickey, R.P. and Hower, J.F. (1995b) Relationship of uterine blood flow to
chorionic sac and embryo growth rates. Hum. Reprod., 10, 2676–2679.
Dickey, R.P. and Hower, J.F. (1995c) Effect of ovulation induction on uterine
blood flow and oestradiol and progesterone concentrations in early
pregnancy. Hum. Reprod., 10, 2875–2879.
Dickey, R.P. and Hower, J.F. (1996) Relationship of estradiol and
progesterone levels to uterine blood flow during early pregnancy. Early
Preg. Biol. Med., 2, 113–120.
Dickey, R.P., Carter, W.T., Besch, P.K. and Vorys, N. (1966) Relationship of
posture to estrogen excretion. Am. J. Obstet. Gynecol., 96, 127–130.
Dickey, R.P., Olar, T.T., Taylor, S.N. et al. (1991) Relationship of follicle
number, serum estradiol, and other factors to birth rate and multiparity in
human menopausal gonadotropin-induced intrauterine insemination
cycles. Fertil. Steril., 56, 89–92.
Dickey, R.P., Olar, T.T., Taylor, S.N. et al. (1992a) Relationship of follicle
number and other factors to fecundability and multiple pregnancy in
clomiphene citrate induced intrauterine insemination cycles. Fertil.
Steril., 57, 613–619.
Dickey, R.P., Olar, T.T., Curole, D.N. et al. (1992b) Endometrial pattern and
thickness associated with pregnancy outcome after assisted
reproduction technologies. Hum. Reprod., 7, 418–421.
Dickey, R.P., Olar, T.T., Taylor, S.N. et al. (1992c) Relationship of small
gestational sac-crown rump difference to abortion and abortus
karyotypes. Obstet. Gynecol., 79, 554–557.
Dickey, R.P., Olar, T.T., Taylor, S.N. et al. (1993a) Relationship of
biochemical pregnancy to preovulatory endometrial thickness and
pattern in patients undergoing ovulation induction. Hum. Reprod., 8,
327–330.
Dickey, R.P., Olar, T.T., Taylor, S.N. et al. (1993b) Relationship of
endometrial thickness and pattern to fecundity in ovulation induction
cycles: effect of clomiphene citrate alone and with human menopausal
gonadotropin. Fertil. Steril., 59, 756–760.
Dickey, R.P., Olar, T.T., Taylor, S.N. et al. (1993c) Sequential clomiphene
citrate and human menopausal gonadotropin for ovulation induction:
comparison to clomiphene citrate alone and human menopausal
gonadotropin alone. Hum. Reprod., 8, 56–59.
Dickey, R.P., Hower, J.F., Matulich, E.M. and Brown, G.T. (1994) Effect of
standing on non-pregnant uterine blood flow. Ultrasound Obstet.
Gynecol., 4, 480–487.
Diket, A.L., Pierce, M.R., Munshi, U.K. et al. (1994) Nitric oxide inhibition
causes intrauterine growth retardation and hind-limb disruptions in rats.
Am. J. Obstet. Gynecol., 171, 1243–1250.
Duvekot, J.J. and Peeters, L.L.H. (1994) Maternal cardiovascular
hemodynamic adaptation to pregnancy. Obstet. Gynecol. Surv. (Suppl.),
49, 1–14.
Duvekot, J.J., Cheriex, E.C., Piters, F.A.A. et al. (1993) Early pregnancy
changes in hemodynamics and volume homeostasis are consecutive
adjustments triggered by a primary fall in systemic vascular tone. Am. J.
Obstet. Gynecol., 169, 1382–1392.
Farin, D., Kelly, N., Ryan, G. et al. (1995) In Copel, J.F. and Reed, K.L. (eds),
Doppler Ultrasound in Obstetrics and Gynecology, Chapter 20. Raven
Press, New York, pp. 187–197.
Favre, R., Bettahar, K., Grange, G. et al. (1993) Predictive value of
transvaginal uterine Doppler assessment in an in vitro fertilization
program. Ultrasound Obstet. Gynecol., 3, 350–353.
Fleischer, A., Schulman, H., Farmakides, G. et al. (1986) Uterine artery
Doppler velocimetry in pregnant women with hypertension. Am. J.
Obstet. Gynecol., 154, 806–813.
Ford, S.P., Reynolds, L.P. and Farley, D.B. (1984) Interaction of ovarian
steroids and periarterial alpha-1-adrenergic receptors in altering uterine
blood flow during the estrous cycle of gilts. Am. J. Obstet. Gynecol.,
150, 480–484.
Fujino, Y., Ito, F., Matuoka, I. et al. (1993) Pulsatility index of uterine artery
in pregnancy and non-pregnant women. Hum. Reprod., 8, 1126–1128.
Furchgott, R.F. and Zawadski, J.V. (1980) The obligatory role of endothelial
cells in the relaxation of arterial smooth muscle by acetylcholine.
Nature, 288, 373–376.
Gant, N.F., Chand, S. and Worley, R.T. (1974) A clinical test useful for
predicting the development of acute hypertension in pregnancy. Am. J.
Obstet. Gynecol., 120, 1–7.
 Doppler ultrasound study of uterine and ovarian blood flow
Gerretsen, G., Huisjes, H.J. and Elema, J.D. (1981) Morphological changes
of the spiral arteries in the placental bed in relation to preeclampsia and
fetal growth retardation. Br. J. Obstet. Gynaecol., 88, 876–881.
Ghosh, D., De, P. and Sengupta, J. (1994) Luteal phase ovarian oestrogen is
not essential for implantation and maintenance of pregnancy from
surrogate embryo transfer in the rhesus monkey. Hum. Reprod., 9,
629–637.
Gilligan, D.M., Badar, D.M., Panza, J.A. et al. (1994) Acute effects of
estrogen in postmenopausal women. Circulation, 90, 786–791.
Glock, J.L. and Brumsted, J.R. (1995) Color flow pulsed Doppler ultrasound
in diagnosing luteal phase defect. Fertil. Steril., 64, 500–504.
Gosling, R.G., Dunbar, G., King, D.H. et al. (1971) The quantitative analysis
of occlusive peripheral arterial disease by a non-intrusive ultrasonic
technique. Angiology, 22, 52–55.
Gosling, R.G., Lo, P.T.S. and Taylor, M.G. (1991) Interpretation of
pulsatility index in feeder arteries to low impedance vascular beds.
Ultrasound Obstet. Gynecol., 1, 175–179.
Goswamy, R.K. and Steptoe, R.P. (1988) Doppler ultrasound studies of the
uterine artery in spontaneous ovarian cycles. Hum. Reprod., 3, 721–726.
Goswamy, R.K., Williams, G. and Steptoe, P.C. (1988) Decreased uterine
perfusion—a cause of infertility. Hum. Reprod., 3, 955–959.
Greiss, F.C. (1972) Differential reactivity of the myoendometrial and
placental vasculatures: adrenergic responses. Am. J. Obstet. Gynecol.,
112, 20–30.
Guanes, P.P., Remohi, J., Gallardo, E. et al. (1996) Age does not affect
uterine resistance to vascular flow in patients undergoing oocyte
donation. Fertil. Steril., 66, 265–270.
Guirgis, R.R., Alshawaf, T., Dave, R. and Craft, I.L. (1993) Transvaginal
crown–rump measurements of 224 successful pregnancies which
resulted from gamete intrafallopian transfer or in vitro fertilization.
Hum. Reprod., 8, 1933–1937.
Harrington, K.F., Campbell, S., Bewley, S. and Brower, S. (1991) Doppler
velocimetry studies of the uterine artery in the early prediction of
preeclampsia and intrauterine growth retardation. Eur. J. Obstet.
Gynaecol., Reprod. Biol., 42, S14–S20.
Harrington, K., Cooper, D., Lees, C. et al. (1996) Doppler ultrasound of the
uterine artery: the importance of bilateral notching in the prediction of
preeclampsia, placental abruption, or delivery of a small for gestational
age baby. Ultrasound Obstet. Gynecol., 7, 182–188.
Hertig, A.T. and Livingstone, R.G. (1944) Spontaneous, threatened, and
habitual abortion: their pathogenesis and treatment. N. Engl. J. Med.,
230, 797–806.
Hillard, T.C., Bourne, T.H., Whitehead, M.I. et al. (1992) Differential effects
of transdermal estradiol and sequential progestins of impedance to flow
within the uterine arteries of postmenopausal women. Fertil. Steril., 58,
959–963.
Hull, A.D., White, C.R. and Pearce, W.J. (1994) Endothelium-derived
relaxing factor and cyclic GMP-dependent vasorelaxation in human
chorionic plate arteries. Placenta, 15, 365–375.
Hustin, J. (1995) Vascular physiology and pathophysiology of early
pregnancy. In Vourne, T., Jauniaux, E. and Jurkovic, D. (eds),
Transvaginal Colour Doppler, Springer-Verlag, Heidelberg, pp. 47–56.
Hustin, J. and Schaaps, J.P. (1987) Echographic and anatomic studies of the
maternotrophoblastic border during the first trimester of pregnancy. Am.
J. Obstet. Gynecol., 157, 162–168.
Hustin, J., Schaaps, J.P. and Lambotte, R. (1988) Anatomical studies of the
utero-placental vascularization in the first trimester of pregnancy.
Trophoblast. Res., 3, 49–60.
Hustin, J., Jauniaux, E. and Schaaps, J.P. (1990) Histological study of the
materno-embryonic interface in spontaneous abortion. Placenta, 11,
477–486.
Ignarro, L.J., Buga, G.M., Wood, K.S. et al. (1987) Endothelium-derived
relaxing factor produced and released from artery and vein is nitric
oxide. Proc. Natl. Acad. Sci. USA, 84, 9265–9269.
Jacobson, S.L., Imhof, R., Manning, N. et al. (1990) The value of Doppler
assessment of the uteroplacental circulation in predicting preeclampsia
or intrauterine growth retardation. Am. J. Obstet. Gynecol., 162,
110–114.
Jaffe, R. and Warsof, S.L. (1991) Transvaginal color Doppler imaging in the
assessment of uteroplacental blood flow in the normal first trimester
pregnancy. Am. J. Obstet. Gynecol., 164, 781–785.
501
Jaffe, R. and Warsof, S.L. (1992) Color Doppler imaging in the assessment
of the uteroplacental blood flow in abnormal first trimester intrauterine
pregnancies: an attempt to define etiologic mechanisms. J. Ultrasound
Med., 11, 41–44.
Jaffe, R. and Woods, J.R. (1993) Color Doppler imaging and in vivo
assessment of the anatomy and physiology of the early uteroplacental
circulation. Fertil. Steril., 60, 293–297.
Jaffe, R. and Woods, J.R. (1996) Doppler velocimetry of intraplacental fetal
vessels in the second trimester: improving the prediction of pregnancy
complications in high-risk patients. Ultrasound Obstet. Gynecol., n,
262–266.
Jaffe, R., Dorgan, A. and Abramowicz, J.S. (1995) Color Doppler imaging of
the uteroplacental circulation in the first trimester: value in predicting
pregnancy failure or complication. Am. J. Roentgenol., 164,
1255–1258.
Jauniaux, E. (1996) Intervillous circulation in the first trimester: the phantom
of the color Doppler obstetric opera. Ultrasound Obstet. Gynecol., 8,
71–76.
Jauniaux, E., Burton, G.J., Moscoso, G.J. and Hustin, J. (1991a)
Development of the early human placenta: a morphometric study.
Placenta, 12, 269–276.
Jauniaux, E., Jurkovic, D. and Campbell, S. (1991b) In vivo investigations of
anatomy and the physiology of early human placental circulation.
Ultrasound Obstet. Gynecol., 1, 435–445.
Jauniaux, E., Jurkovic, D., Delogne-Desnock, J. and Meuris, S. (1992a)
Influence of human chorionic gonadotropin, oestradiol and
progesterone on uteroplacental and corpus luteum blood flow in normal
early pregnancy. Hum. Reprod., 7, 1467–1473.
Jauniaux, E., Jurkovic, D., Campbell, S. and Hustin, J. (1992b) Doppler
ultrasonographic features of the developing placental circulation:
correlation with anatomic findings. Am. J. Obstet. Gynecol., 166,
585–587.
Jauniaux, E., Johnson, M.R., Jurkovic, D. et al. (1994a) The role of relaxin in
the development of the uteroplacental circulation in early pregnancy.
Obstet. Gynecol., 84, 338–342.
Jauniaux, E., Zaidi, J., Jurkovic, D. et al. (1994b) Comparison of color
Doppler features and pathological findings in complicated early
pregnancy. Hum. Reprod., 12, 2432–2437.
Jiang, C., Sarrel, P.M., Lindsay, D.C. et al. (1991) Endothelium-independent
relaxation of rabbit coronary artery by 17β oestradiol in vitro. Br. J.
Pharmacol., 104, 1033–1037.
Jurkovic, D., Jauniaux, E., Kurjak, A. et al. (1991) Transvaginal color
Doppler assessment of the uteroplacental circulation in early pregnancy.
Obstet. Gynecol., 77, 365–369.
Kauppila, A., Kuikka, J. and Tuimala, R. (1978) Effect of fenoterol and
isoxsuprine on myometrial and intervillous blood flow during late
pregnancy. Obstet. Gynecol., 52, 558–562.
Kauppila, A., Koskinem, M., Puolakka, J. et al. (1980) Decreased
intervillous and unchanged myometrial blood flow in supine
recumbancy. Obstet. Gynecol., 55, 203–205.
Kay, H.H., Carroll, B.B., Dahmus, M. and Killam, A.P. (1991) Sonographic
measurements with umbilical and uterine artery Doppler analysis in
suspected intrauterine growth retardation. J. Reprod. Med., 36, 65–68.
Kharitonov, S.A., Logan-Sinclair, R.B., Busset, C.M. and Shinebourne, E.A.
(1994) Peal expiratory nitric oxide difference in men and women:
relation to the menstrual cycle. Br. Heart J., 72, 243–245.
Khong, T.Y., Liddell, H.S. and Robertson, W.B. (1987) Defective
haemochorioal placentation as a cause of miscarriage. A preliminary
study. Br. J. Obstet. Gynaecol., 94, 649–655.
Kremkau, W. (1990) Doppler Ultrasound: Principles and Instruments. W.B.
Saunders, Philadelphia, London.
Kupesic, S. and Kurjak, A. (1993) Uterine and ovarian perfusion during the
periovulatory period assessed by transvaginal color Doppler. Fertil.
Steril., 60, 439–443.
Kurjak, A., Kupesic-Urek, S., Schulman, H. and Zalud, I. (1991)
Transvaginal color flow Doppler in the assessment of ovarian and
uterine blood flow in infertile women. Fertil. Steril., 56, 870–873.
Kurjak, A., Crvenkovic, G., Salihagic, A. et al. (1993) The assessment of
normal early pregnancy by transvaginal color Doppler ultrasonography.
J. Clin. Ultrasound, 21, 3–8.
502 R.P.Dickey
Levi-Setti, P.E., Rognoni, G., Bozzo, M. et al. (1995) Color Doppler
velocimetry of uterine arteries in pregnant and nonpregnant patients
during multiovulation induction for IVF. J. Assist. Reprod. Genet., 12,
413–417.
Lindhard, J. (1913) Arch. Physiol., 30, 395–397. Cited in Vorys, N., Ullery, J.
and Hanusek, G. (1961) The cardiac output changes in various positions
in pregnancy. Am. J. Obstet. Gynecol., 82, 1312–1321.
Lindow, S.W., Davies, N., 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.
Long, M.G., Boultbee, J.E., Hanson, M.E. and Begent, R.H.J. (1989)
Doppler time velocity waveform studies of the uterine artery and uterus.
Br. J. Obstet. Gynaecol., 96, 588–593.
Magness, R.R. and Rosenfeld, C.R. (1989) Local and systemic
estradiol-17β: effects on uterine and systemic vasodilation. Am. J.
Physiol., 256, 536–542.
Magness, R.R., Parker, C.R. and Rosenfeld, C.R. (1993) Systemic and
uterine responses to chronic infusion of estradiol-17β. Am. J. Physiol.,
265, E690–E698.
Maini, C.L., Galli, G., Bellati, U. et al. (1985) Non-invasive radioisotopic
evaluation of placental blood flow. Obstet. Gynecol. Invest., 19,
196–206.
Marsh, M.S., Bourne, T.H., Whitehead, M.I. et al. (1994) The temporal
effect of progesterone on uterine artery pulsatility index in
postmenopausal women receiving sequential hormone replacement
therapy. Fertil. Steril., 62, 771–774.
Maulik, D. (1993) Hemodynamic interpretation of the arterial Doppler
waveform. Ultrasound Obstet. Gynecol., 3, 219–227.
McParland, P., Pearce, J.M. and Chamberlain, G.V.P. (1990) Doppler
ultrasound and aspirin in recognition and prevention of pregnancy
induced hypertension. Lancet, 335, 1552–1555.
Meekins, J.W., Pijnenborg, R., Hanssens, M. et al. (1994) A study of
placental bed spiral arteries and trophoblast invasion in normal and
severe preeclamptic pregnancies. Br. J. Obstet. Gynecol., 101, 669–674.
Merce, L., Barco, M.J. and Bau, S. (1996) Color Doppler sonographic
assessment of placental circulation in the first trimester of normal
pregnancy. J. Ultrasound Med., 15, 135–142.
Meyer, M.C., Brayden, J.E. and McLaughlin, M. (1993) Characteristics of
vascular smooth muscle in the maternal resistance circulation during
pregnancy in the rat. Am. J. Obstet. Gynecol., 169, 1510–1516.
Miles, R.D., Menke, J.A., Bashiru, M. and Colliver, J.A. (1987)
Relationships of five Doppler measures with flow in an in vitro model
and clinical findings in newborn infants. J. Ultrasound Med., 6,
597–599.
Miller, V.M. and Vanhoutte, P.M. (1990) 17β-Estradiol augments
endothelium-dependent contractions to arachidonic acid in rabbit aorta.
Am. J. Physiol., 258, 1502–1507.
Molnar, M., Suto, T., Toth, T. and Hertelendy, F. (1994) Prolonged blockade
of nitric oxide synthesis in gravid rats produces sustained hypertension,
proteinuria, thrombocytopenia, and intrauterine growth retardation. Am.
J. Obstet. Gynecol., 170, 1458–1466.
Moncada, S., Palmer, R.M.J. and Higgs, E.A. (1991) Nitric oxide:
physiology, pathophysiology and pharmacology. Pharmacol. Rev., 43,
109–142.
Montan, S., Liedholm, H., Lingman, G. et al. (1987) Fetal and uteroplacental
haemodynamics during short term atenolol treatment of hypertension in
pregnancy. Br. J. Obstet. Gynaecol., 94, 312–317.
Montan, S., Anandakumar, C., Arulkumaran, S. et al. (1993) Effects of
methyldopa on uteroplacental and fetal hemodynamics in pregnancy
induced hypertension. Am. J. Obstet. Gynecol., 168, 152–156.
Morris, N., Osborn, S.B., Wright, H.P. and Hart, A. (1956) Effective uterine
blood flow during exercise in normal and preeclamptic pregnancies.
Lancet, ii, 481–484.
Morris, N.H., Eaton, B.M. and Dekker, G. (1996a) Nitric oxide, the
endothelium, pregnancy, and preeclampsia. Br. J. Obstet. Gynaecol.,
103, 4–15.
Morris, J.M., Fay, R.A., Ellwood, D.A. et al. (1996b) A randomized
controlled trial of aspirin in patients with abnormal uterine artery blood
flow. Obstet. Gynecol., 87, 74–78.
Murakoshi, T., Sekizuka, N., Takakuwa, H. et al. (1996) Uterine and spiral
artery flow velocity waveforms in pregnancy-induced hypertension
and/or intrauterine growth retardation. Ultrasound Obstet. Gynecol., 7,
122–128.
Myatt, L., Brewer, A.S., Langdon, G. and Brockman, D. (1992) Attenuation
of the vasoconstrictor effects of the thromboxane and endothelin by
nitric oxide in the human fetal placental circulation. Am. J. Obstet.
Gynecol., 166, 224–230.
Nargund, G., Bourne, T., Doyle, P. et al. (1996) Associations between
ultrasound indices of follicular blood flow, oocyte recovery, and
preimplantation embryo quality. Hum. Reprod., 11, 109–113.
Nazari, A., Check, J.H., Epstein, R.H. et al. (1991) Relationship of small for
dates sac size to crown-rump length and spontaneous abortion in
patients with a known date of ovulation. Obstet. Gynecol., 78, 369–373.
Nishimura, H., Takano, K., Tanimura, T. and Yasuda, M. (1968) Normal and
abnormal development of human embryos: first report of the analysis of
1,213 intact embryos. Teratology, 1, 281–290.
North, R.A., Ferrier, C., Long, D. et al. (1994) Uterine artery Doppler flow
velocity waveforms in the second trimester for the prediction of
preeclampsia and fetal growth retardation. Obstet. Gynecol., 83,
378–386.
Olofsson, P., Thuring-Jonsson, A. and Marsal, K. (1996) Uterine and
umbilical circulation during the oxytocin challenge test. Ultrasound
Obstet. Gynecol., 7, 247–251.
O’Rahilly, R. and Muller, F. (eds) (1987) Developmental Stages in Human
Embryos. Meriden-Stienhour Press, Merident, CT.
Oyesanya, O.A., Parsons, J.H., Collins, W.P. and Campbell, S. (1996)
Prediction of oocyte recovery rate by transvaginal ultrasonography and
color Doppler imaging before human chorionic gonadotropin
administration in in vitro fertilization cycles. Fertil. Steril., 65, 806–809.
Palmer, R.M.J., Ferrige, A.G. and Moncada, S. (1987) Nitric oxide released
accounts for the biological activity of endothelium-derived relaxing
factor. Nature, 327, 524–526.
Pearce, J.M., Campbell, S., Cohen-Overbeek, T. et al. (1988) References
ranges and sources of variation for indices of pulsed Doppler flow
velocity waveforms from the uteroplacental and fetal circulation. Br. J.
Obstet. Gynaecol., 95, 248–256.
Pedersen, J.F. and Molsted-Pedersen, L. (1981) Early fetal growth delay
detected by ultrasound marks increased risk of congenital malformation
in diabetic pregnancy. Br. Med. J., 283, 269–271.
Penotti, M., Memcioni, T., Gabrielli, L. et al. (1993) Blood flow variations in
internal carotid and middle cerebral arteries induced by postmenopausal
hormone replacement therapy. Am. J. Obstet. Gynecol., 169,
1226–1232.
Perrot-Applanat, M., Groyer-Picard, M.T., Garcia, E. et al. (1988)
Immunocytochemical demonstration of estrogen and progesterone
receptors in muscle cells of uterine arteries in rabbits and humans.
Endocrinology, 123, 1511–1519.
Planiol, T., Pourcelot, L. and Pottier, J.M. (1972) Etude de la circulation
carotidienne par les methodes ultrasongigues de la thermographie. Rev.
Neurol., 126, 127–141.
Pourcelot, L. (1974) Applications clinique de pexamen Doppler
transcutance. In Pourcelot, L. (ed.), Belocimetric Ultrasonore Doppler.
INSERM, Paris, p. 213.
Powis, R.L. and Schwartz, R.A. (1991) Practical Doppler Ultrasound for
the Clinician, Williams and Wilkins, Baltimore, MD, p. 187.
Ramsay, B., De Belder, A., Campbell, S. et al. (1994) A nitric oxide donor
improves uterine artery diastolic blood flow in normal early pregnancy
and in women at high risk of preeclampsia. Eur. J. Clin. Invest., 24,
76–78.
Ramsay, B., Johnson, M.R., Leone, A.M. and Steer, P.J. (1995) The effect of
exogenous oestrogen on nitric oxide production in women: a placebo
controlled crossover study. Br. J. Obstet. Gynaecol., 102, 417–319.
Robertson, D.M., Mester, J. and Kellie, A.E. (1971) The measurement of
oestradiol and progesterone in plasma from normal, infertile, and
clomiphene treated women. Acta Endocrinol., 68, 523–533.
Rossavik, I.K., Torjusen, G.O. and Gibbons, W.E. (1988) Conceptual age
and ultrasound measurements of gestational sac and crown-rump length
in in vitro fertilization pregnancies. Fertil. Steril., 49, 1012–1017.
Ryan, K.J. and Mackis, A. (1987) Significance of angiogenic and growth
factors in ovarian follicle development. Adv. Exp. Med. Biol., 219,
203–209.
 Doppler ultrasound study of uterine and ovarian blood flow
Schiff, E., Tamarkin, M., Ben-Baruch, G. et al. (1991) Prediction of
pregnancy-induced hypertension by a combination of rollover test and
Doppler flow velocity measurement. J. Perinatal Med., 19, 245–250.
Scholtes, M.C.W., Wladimiroff, J.W., van Rijen, H.J.M. and Hop, W.C.J.
(1989) Uterine and ovarian flow velocity waveforms in the normal
menstrual cycle: a transvaginal study. Fertil. Steril., 52, 981–985.
Seligman, S.P., Buyon, J.P., Clancy, R.M. et al. (1994) The role of nitric
oxide in the pathogenesis of preeclampsia. Am. J. Obstet. Gynecol., 171,
944–948.
Serafini, P., Batzofin, J., Nelson, J. and Olive, D. (1994) Sonographic uterine
predictors of pregnancy in women undergoing ovulation induction for
assisted reproductive treatments. Fertil. Steril., 62, 815–822.
Sladkevicius, P., Valentin, L. and Marsal, K. (1993) Blood flow velocity in
the uterine and ovarian arteries during the normal menstrual cycle.
Ultrasound Obstet. Gynecol., 3, 199–208.
Spencer, J.A.D., Giussani, D.A., Moore, P.D. and Hanson, M.A. (1991) In
vitro validation of Doppler indices using blood and water. J. Ultrasound
Med., 10, 305–308.
Stabile, I., Grudzinskas, J. and Campbell, S. (1990). Doppler
ultrasonographic evaluation of abnormal pregnancies in the first
trimester. J. Clin. Ultrasound, 18, 497–501.
Steer, C.V., Campbell, S., Pampiglione, J. et al. (1990) Transvaginal colour
flow imaging of the uterine arteries during the ovarian and menstrual
cycles. Hum. Reprod., 5, 391–395.
Steer, C.V., Campbell, S., Tan, S.L. et al. (1992) The use of transvaginal
color flow imaging after in vitro fertilization to identify optimum uterine
conditions before embryo transfer. Fertil. Steril. 57, 372–376.
Steer, C.V., Tan, S.L., Mason, B.A. and Campbell, S. (1994) Midluteal phase
vaginal color Doppler assessment of uterine artery impedance in a
subfertile population. Fertil. Steril., 61, 53–58.
Steer, C.V., Williams, J., Zaidi, J. et al. (1995a) Intraobserver, interobserver,
interultrasound transducer and intercycle variation in colour Doppler
assessment of uterine artery impedance. Hum. Reprod., 10, 479–481.
Steer, C.V., Tan, S.L., Dillon, D. et al. (1995b) Vaginal color Doppler
assessment of uterine artery impedance correlates with
immunohistochemical markers of endometrial receptivity required for
the implantation of an embryo. Fertil. Steril., 63, 101–108.
Sterzik, K., Hutter, W., Grab, D. et al. (1989) Doppler sonographic findings
and their correlation with implantation in an in vitro fertilization
program. Fertil. Steril., 52, 825–828.
Striginc, F., Scida, P., Parri, C. et al. (1995) Modifications in uterine and
intraovarian artery impedance in cycles of treatment with exogenous
gonadotropins: effects of luteal phase support. Fertil. Steril., 64, 76–80.
Strohmer, H., Herczeg, C., Plockinger, B. et al. (1991) Prognostic appraisal
of success and failure in an in vitro fertilization program by transvaginal
Doppler ultrasound at the time of ovulation induction. Ultrasound
Obstet. Gynecol., 1, 272–274.
Suonio, S., Simpanen, A.L., Olkkonen, H. and Haring, P. (1976) Effect of the
left lateral recumbent position compared with the supine and upright
positions on placental blood flow in normal late pregnancy. Ann. Clin.
Res., 8, 22–26.
Tan, S.L., Zaidi, J., Campbell, S. et al. (1996) Blood flow changes in the
ovarian and uterine arteries during the normal menstrual cycle. Am. J.
Obstet. Gynecol., 175, 625–631.
Taylor, K.J.M., Burns, P.N., Wells, P.N.T. et al. (1985) Ultrasound Doppler
flow studies of the ovarian and uterine arteries. Br. J. Obstet. Gynecol.,
92, 240–246.
Tekay, A. and Jouppila, P. (1996) Intraobserver reproducibility of
transvaginal Doppler measurements in uterine and intraovarian arteries
in regularly menstruating women. Ultrasound Obstet. Gynecol., 7,
129–134.
Tekay, A., Martikainen, H. and Jouppila, P. (1995a) Blood flow changes in
uterine and ovarian vasculature, and predictive value of transvaginal
pulsed colour Doppler ultrasonography in an in-vitro fertilization
programme. Hum. Reprod., 10, 688–693.
Tekay, A., Martikainen, H. and Jouppila, P. (1995b) Doppler parameters of
the ovarian and uterine blood circulation in ovarian hyperstimulation
syndrome. Ultrasound Obstet. Gynecol., 6, 50–53.
503
Tekay, A., Martikainen, H. and Jouppila, P. (1996a) The clinical value of
Doppler ultrasound. Hum. Reprod., 11, 1589–1593.
Tekay, A., Martikainen, H. and Jouppila, P. (1996b) Comparison of uterine
blood flow characteristics between spontaneous and stimulated cycles
before embryo transfer. Hum. Reprod., 11, 364–368.
Thaler, I., Manor, D., Itskovitz, J. et al. (1990) Changes in uterine blood flow
during human pregnancy. Am. J. Obstet. Gynecol., 162, 121–125.
Thompson, R.S., Trudinger, B.J. and Cook, C.M. (1988) Doppler ultrasound
waveform indices: A/B ratio, pulsatility index, and Pourcelot ratio. Br. J.
Obstet. Gynaecol., 95, 581–588.
Trudinger, B.J. (1991) Obstetric Doppler applications. In Fleischer, A.C.,
Romero, R., Manning, F.A. et al. (eds), The Principles and Practice of
Ultrasonography, Chapter 12. Appleton and Lange, CT, pp. 173–192.
Trudinger, B.J., Giles, W.B., Cook, C.M. et al. (1985) Fetal umbilical artery
flow waveform and placental resistance: clinical significance. Br. J.
Obstet. Gynaecol., 92, 23–30.
Usan M, Haddad B, Breart G, Uzan, n. (1994) Uteroplacental Doppler and
aspirin therapy in the prediction and prevention of pregnancy
complications. Ultrasound Obstet. Gynecol., 4, 342–349.
Valentin, L., Sladkevicius, P., Laurini, R. et al. (1996) Uteroplacental and
luteal circulation in normal first trimester pregnancies: Doppler
ultrasonographic and morphologic study. Am. J. Obstet. Gynecol., 174,
768–775.
Vallance, P. and Collier, J. (1994) Biology and clinical relevance of nitric
oxide. Br. Med. J., 309, 453–457.
Van Buren, G.A., Yang, D. and Clark, K.E. (1992) Estrogen-induced uterine
vasodilatation is antagonized by L-nitroarginine methyl ester, an
inhibitor of nitric oxide synthesis. Am. J. Obstet. Gynecol., 167,
828–833.
Van Zalen-Sprock, M.M., Van Vugt, J.M.G., Colenbrander, G.J. and Van
Geijin, H.P. (1994) First trimester uteroplacental and fetal blood flow
velocity waveforms in normally developing fetuses: a longitudinal
study. Ultrasound Obstet. Gynecol., 4, 284–288.
Wada, I., Hsu, C.C., Williams, G. et al. (1994) The benefits of low-dose
aspirin therapy in women with poor uterine perfusion. Abstract of the
2nd International Meeting of the British Fertility Society, Glasgow, pp.
35 and 61.
Weiner, Z., Thaler, I., Levron, J. et al. (1993) Assessment of ovarian and
uterine blood flow by transvaginal color Doppler in ovarian-stimulated
women: correlation with the number of follicles and steroid hormone
levels. Fertil. Steril., 59, 743–749.
Weiner, C.P., Knowles, R.G. and Moncada, S. (1994) Induction of nitric
oxide synthases early in pregnancy. Am. J. Obstet. Gynecol., 171,
838–843.
Wilken, P. (1958) “Morphogenese”. In Snoeck, J. (ed.), Le Placenta
Humain. Masson, Paris, p. 23.
Zaidi, J., Campbell, S., Pittrof, R. et al. (1995a) Ovarian stromal blood flow
in women with polycystic ovaries—a possible new marker for
diagnosis. Hum. Reprod., 10, 1992–1996.
Zaidi, J., Jurkovic, D., Campbell, S. et al. (1995b) Luteinized unruptured
follicles: morphology, endocrine function and blood flow changes
during the menstrual cycle. Hum. Reprod., 10, 44–49.
Zaidi, J., Jurkovic, D., Campbell, S. et al. (1995c) Description of circadian
rhythm in uterine artery blood flow during the periovulatory period.
Hum. Reprod., 10, 1642–1646.
Zaidi, J., Barber, J., Kyei-Mensah, A. et al. (1996a) Relationship of ovarian
stromal blood flow at the baseline ultrasound scan to subsequent
follicular response in an in vitro fertilization program. Obstet. Gynecol.,
88, 779–784.
Zaidi, J., Collins, W., Campbell, S. et al. (1996b) Blood flow changes in the
intraovarian arteries during the periovulatory period: relationship to the
time of day. Ultrasound Obstet. Gynecol., 7, 135–140.
Zaidi, J., Pittrof, R., Shaker, A. et al. (1996c) Assessment of uterine artery
blood flow on the day of human chorionic gonadotropin administration
by transvaginal color Doppler ultrasound in an in vitro fertilization
program. Fertil. Steril., 65, 377–381.
Received on December 30, 1996; accepted on August 18, 1997