uterine artery doppler velocimetry in subjects with
TRANSCRIPT
i
UTERINE ARTERY DOPPLER VELOCIMETRY IN
SUBJECTS WITH PREGNANCY INDUCED
HYPERTENSION IN OAUTHC, ILE-IFE
BY
DR. ABIDOYE Ibukun Anuoluwa (MB; BS IBADAN)
A DISSERTATION SUBMITTED TO THE
FACULTY OF RADIOLOGY, NATIONAL
POSTGRADUATE MEDICAL COLLEGE OF
NIGERIA
IN PARTIAL FULFILLMENT OF AWARD OF
THE FELLOWSHIP (FMCR)
MAY, 2016
ii
DECLARATION
I, Dr Abidoye Ibukun Anuoluwa declare that this dissertation is my original work. It was carried
out in Obafemi Awolowo Teaching Hospitals complex, Ile-Ife, Osun state.
Dr Abidoye Ibukun Anuoluwa
Obafemi Awolowo Teaching Hospitals complex
Ile-Ife
iii
ATTESTATION
We attest that this dissertation represents the original work of Dr Abidoye Ibukun Anuoluwa and was
done during his residency programme at Obafemi Awolowo University Teaching Hospitals Complex,
Ile-Ife, Osun State.
Dr O.O Ayoola (FMCR)
Supervisor
Consultant Radiologist
Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife
Dr. O.M Loto (MSc., FWACS, FMCOG)
Co Supervisor
Consultant Obstetrician and Gynaecologist
Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife
iv
CERTIFICATION
I certify that this dissertation represents the original work of Dr Abidoye Ibukun Anuoluwa and was done
during his residency programme at Obafemi Awolowo University Teaching Hospital, Ile-Ife, Osun state.
Dr (MRS) O.C. Famurewa (FWACS)
Head, Radiology Department
Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife
v
ACKNOWLEDGEMENTS
My gratitude goes to the Almighty God for His Grace.
Special thanks go to my supervisors, Dr O.O Ayoola and Dr O.M Loto
I appreciate, and I am grateful to my Head of Department, Dr (Mrs) O.C Famurewa.
I also want to appreciate my teachers and consultants, Prof V.A Adetiloye, Dr (Mrs) Asaleye and
Dr (Mrs) B.O Ibitoye.
I am also grateful to all my colleagues and other staff of the Department of Radiology and the
Department of Ophthalmology of Obafemi Awolowo University Teaching Hospitals Complex,
Ile-Ife, for all their encouragements.
vi
DEDICATION
I dedicate this work to God, who has graciously had mercy on me.
To my precious Jewel, Olawumi Abidoye and to our wonderful children, Rereloluwa,
Iyanuoluwa and Ifeoluwa, God bless you.
vii
TABLE OF CONTENTS
Title Page i
Declaration ii
Attestation iii
Certification iv
Acknowledgement v
Dedication vi
Table of contents vii
List of Figures viii
List of Tables ix
Summary 1
Introduction 2
Anatomy of the uterus and vascular supply
-Gross Anatomy 5
-Sonographic Anatomy 10
Justification 16
Aims and Objectives 17
Literature Review 18
Subjects and Methods 26
Ethical Considerations 31
Results 32
Discussion 60
viii
Limitations 67
Conclusion 68
Recommendation 69
References 70
Appendix i 79
Appendix ii 80
Appendix iii 81
Appendix iv 82
ix
LIST OF FIGURES
Figure 1: A coronal schematic diagram of the uterus
Figure 2: A sagittal schematic diagram of the uterus
Figure 3: A schematic diagram showing the uterine artery
Figure 4: A schematic diagram showing the branches of the uterine artery within the uterus
Figure 5: A longitudinal section of B-mode sonogram of the pelvis showing the uterus
Figure 6: A colour Doppler image showing uterine artery as it crosses over the iliac artery
Figure 7: A triplex sonogram image showing the uterine artery Doppler waveform in a normal
pregnancy
Figure 8: A bar chart showing number of past episodes of PIH in the PIH group
Figure 9: A pie chart showing distribution of degree of proteinuria in PIH subjects
Figure 10: A Triplex sonogram of the uterine artery in one of the PIH group showing the
presence of prediastolic notching
Figure 11: A Triplex sonogram of the uterine artery in one of the PC group showing normal
spectral pattern
x
LIST OF TABLES
Table 1: A table showing subjects’ demographic characteristics across the 3 groups
Table 2: A table showing the clinical parameters of the subjects across the 3 groups
Table 3: A table showing the scheffe post-hoc analyses for differences in demographic and BP
parameters
Table 4: A table showing parity and EGA of pregnant subjects
Table 5: A table showing uterine artery Doppler parameters across the 3 groups
Table 6: A table showing Scheffe Post-hoc analyses for differences in Doppler parameters
between groups
Table 7: A table showing comparison between both uterine arteries RI in the 3 study groups
Table 8: A table showing comparison between both uterine arteries prediastolic notching in the 3
study groups
Table 9: A table showing mean RI values of the PIH group based on their percentile of EFW
Table 10: A table showing a Chi Square analysis between RIs (using 0.66 as cut-off) of PIH and
PC groups with their percentile of EFW
Table 11: A table showing Chi Square analysis of the RIs (using 0.66 as cut-off) between PC and
PIH groups
Table 12: A table showing the relationship between IUGR and prediastolic notching of the
Uterine artery in the PIH group
Table 13: A table showing comparison of RIs based on the presence of prediastolic notching in
PIH group
Table 14: A table showing the relationship between proteinuria and presence of prediastolic
notching in the PIH group
Table 15: A table showing predictability of IUGR in the PIH group
1
SUMMARY
Background: Pregnancy–induced hypertension (PIH) is a major cause of maternal and perinatal
morbidity and mortality which can be complicated by fetal intrauterine growth restriction
(IUGR). Uterine artery Doppler ultrasound has been found to be of use in evaluating the effect of
this condition on the foetus.
Subjects and Method: This study included 80 pregnant subjects with a history of diagnosed PIH
before the commencement of treatment in the index pregnancy. Also, 80 Pregnant Control (PC)
with normal blood pressure and 80 Non-Pregnant Control (NPC) were recruited to constitute the
control groups. Uterine artery Doppler scan was performed using a 3-5MHz curvilinear probe on
DC-7 Mindray ultrasound machine. Data analysis was done using the Statistical Package for
Social Sciences (SPSS) software version 20 and relevant descriptive and inferential statistics
were presented appropriately.
Results: The mean RI for the PIH group was 0.61 ± 0.14; PC group was 0.50 ± 0.08 while that
of NPC group was 0.75 ± 0.09. For the PIH group, RI > 0.66 had a sensitivity of 50.0%,
specificity of 69.1% and Positive Predictive Value of 22.2% for predicting IUGR. The odds
ratio equals 2.2 with a 95% CI of 0.6-7.8. The presence of prediastolic notching had a sensitivity
of 100.0%, specificity of 96.0% and Positive Predictive Value of 80.0% for predicting IUGR.
The odds ratio equals 22.7 with a 95% CI of 7.5 - 68.5.
Conclusion: Uterine artery Doppler ultrasound is very valuable in predicting foetuses at risk of
IUGR in subjects with established PIH. The presence of prediastolic notching was found to have
100% sensitivity in predicting foetuses at risk of IUGR in the PIH subjects.
Keywords: PIH, uterine artery, Doppler ultrasound scan, IUGR.
2
INTRODUCTION
Pregnancy–induced hypertension (PIH) is a major cause of maternal and perinatal
morbidity and mortality in developing countries including Nigeria.1-4 The present (as at 2013)
maternal mortality ratio in Nigeria is 560 per 100,000 live births.5 Eclampsia, which is a
consequence of PIH is a major contributor to maternal and perinatal mortality worldwide.6 It is
much more common in developing countries like Nigeria where presentation is usually late and
resources are scarce.6 PIH is felt to be the result of abnormal placenta formation involving
abnormal trophoblast invasion of spiral arteries and thus leads to an increase in vascular
resistance in the uteroplacental circulation.7 Subsequently, the increase in vascular resistances
leads to decreased blood flow to the uterus and the foetus which ultimately leads to intrauterine
growth restriction (IUGR), if there is no intervention. With the emergence of increased use of
Doppler technology in evaluating the haemodynamics of the body, the effect of this condition on
the foetus can thus be predicted and/or monitored. Hence the need for this study cannot be
overemphasized.
Hypertension in pregnancy is said to occur when the systolic Blood pressure is greater
than 140mmHg and diastolic Blood pressure is greater than 90mmHg taken on at least 2
occasions, 6 hours apart. PIH encompasses gestational hypertension (hypertension without
proteinuria); Pre-eclampsia which is said to occur when a pregnant woman develops
hypertension with proteinuria and edema; and Eclampsia which encompasses pre-eclampsia with
convulsion in pregnant women.8 In Nigeria, it is estimated that 5-10% of pregnancies are
complicated by hypertensive disorders in pregnancy and it results in more admissions in the
antenatal period than any other disorder.9 Proteinuria is defined as the urinary excretion of
3
≥ 0.3 g protein in a 24-hour specimen. This will usually correlate with ≥ 30 mg/dL (≥ 1+ reading
on dipstick) in a random urine determination with no evidence of urinary tract infection.10
PIH is more common at both ends of reproductive age, and it is influenced by parity,
race/ socioeconomic status, previous history of PIH and family history.11 The major neonatal
complication of PIH is low birth weight.12 Low birth weight foetus can either be growth
restricted or constitutionally small. The diagnosis of intrauterine growth restriction(IUGR) by
antenatal ultrasound remains a challenge for obstetrics care providers.12 In clinical practice, it is
difficult to differentiate between constitutionally small but normally grown and pathological
growth-restricted foetuses using antenatal ultrasound.12 Evaluation of placenta function by
umbilical artery Doppler is a clinical standard to distinguish between small for gestational age
(SGA) and IUGR.13 The uterine artery had been shown to have a better sensitivity and
specificity as compared to the umbilical artery.14 This is the sole aim of this study, evaluating the
Doppler parameters (using the uterine artery of the mother) of low birth weight foetus either
SGA or IUGR as established by their estimated fetal weight on ultrasound scanning.
The American College of Obstetrician and Gynecologists defines IUGR as a foetus
whose EFW is below the 10th percentile for gestational age.12 Unfortunately, about 70% of the
foetuses identified by this criterion will be normal or constitutionally small-for-gestational-age
infants that are not at risk for adverse fetal or neonatal outcome.15 IUGR is associated with
stillbirth, neonatal death and perinatal morbidity as well as delayed effects including cerebral
palsy and adult diseases.16,17 Placental conditions are the most frequent etiology of IUGR.18 This
has led to the idea of using Doppler ultrasound to assess the velocity of uterine artery blood flow
as part of routine ultrasound screening.19
4
Schulman et al.20 determined that in the non-pregnant state there is a rapid rise and fall in
uterine artery flow velocity during systole and a “notch” in the descending waveform in early
diastole. This defines the prediastolic notching used in this study which was subjectively done.
Once pregnancy occurs (normal pregnancy), vessels in the placenta develop, resulting in a low
resistance to blood flow with a concomitant increase in the height of the diastolic waveform and
disappearance of the prediastolic notch. Persistence of a prediastolic notch (beyond 24weeks’
gestation) or abnormal flow velocity ratios have been associated with inadequate trophoblast
invasion.21 and increased resistance to flow in PIH subjects.11
According to Lees et al.26, the additional finding that both uterine artery RI and notching
contribute independently to birth weight was a novel one. This finding strongly supports the
hypothesis that these two measurements assess different aspect of vascular response; the RI may
reflect the impedance to blood flow while notching may reflect vessel compliance.26 These two
parameters will also be considered in this study in pregnant women with established PIH whose
foetuses are at risk for IUGR as established by the EFW percentile and compared to apparently
normal pregnant women whose fetuses are normal with the primary aim of predicting foetuses at
risk of IUGR in the PIH subjects.
5
GROSS ANATOMY OF THE UTERUS AND ITS VASCULAR SUPPLY
The uterus is a pear-shaped organ located in the female pelvis between the urinary
bladder anteriorly and the rectum posteriorly (Figs 1 and 2). The average dimensions are
approximately 8 cm long, 5 cm across, and 4 cm thick, with an average volume between 80 and
200 mL.27 The uterus is divided into 3 main parts: the fundus, body, and cervix.
The uterus is a dynamic female reproductive organ that is responsible for several
reproductive functions, including menses, implantation, gestation, labor, and delivery. It is
responsive to the hormonal milieu within the body, which allows adaptation to the different
stages of a woman’s reproductive life. The uterus adjusts to reflect changes in ovarian steroid
production during the menstrual cycle and displays rapid growth and specialized contractile
activity during pregnancy and childbirth. It can also remain in a relatively quiescent state during
the prepubertal and postmenopausal years.27
6
FIGURE 1: A coronal schematic diagram of the uterus.
7
FIGURE 2: A sagittal schematic diagram of the uterus.
8
Blood is provided to the uterus by the ovarian and uterine arteries (Fig 3), the latter of
which arises from the anterior division of the internal iliac artery. The uterine artery occasionally
gives off the vaginal artery (although this is usually a separate branch of the internal iliac
around), which supplies the upper vagina, and the arcuate arteries, which surround the uterus. It
then further branches into the radial arteries, which penetrate the myometrium to provide blood
to all layers, including the endometrium27 (Fig. 4).
Once these vessels reach the endometrial level, they branch into the basal arteries and spiral
arteries, which support the specialized functions of each layer. The basal arteries are not
responsive to hormones; they support the basal endometrial layer, which provides the
proliferative cells for endometrial growth. The spiral arteries supply the functional layer and are
uniquely sensitive to steroid hormones. In ovulatory cycles in which pregnancy does not occur,
menses results following constriction of these terminal arteries, causing endometrial breakdown
with desquamation of the glands and stroma.27
9
FIGURE 3: Schematic diagram showing the uterine artery. courtesy of online source @
teachmeanatomy
FIGURE 4: Schematic diagram showing the branches of uterine artery within the uterus.
courtesy of online source @ teachmeanatomy
10
SONOGRAPHIC ANATOMY OF THE UTERUS AND ITS VASCULAR SUPPLY
The surface of the uterus is smooth and well defined (fig.5). A slightly indented isthmus
separates the body from the cervix. The cervix is fixed in the midline of the pelvis, but the body
is often “flexed” and angled (“verted”) with respect to the cervix. The uterus is most commonly
anteflexed and anteverted, lying on the bladder dome. A retroflexed uterus is bent at the isthmus
with the body folded backwards on the cervix. A retroverted uterus is straight but directed
posteriorly. The body may also be angled toward the right or left pelvic side walls. The
myometrium is medium in echogenicity and granular in echotexture.27 Three layers of
myometrium can often be recognized. The inner junctional myometrium is thin, compressed,
hypovascular, and mildly hypoechoic compared to the thick homogeneous middle layer. The
arcuate vessels, which are often prominent, divide the middle layer from the slightly hypoechoic
outer layer. Calcification of the arcuate arteries occurs in older women and diabetics. The
endometrium varies in thickness and appearance with the degree of stimulation by hormones,
primarily estrogens and progesterones. In the neonate, because of maternal hormones, the
endometrium is brightly echogenic but thin. In the prepubertal child, the endometrium remains
thin and is nearly isoechoic with the myometrium. Following puberty, the endometrial
appearance varies with the menstrual cycle. In the proliferative phase, prior to ovulation, the
endometrium assumes a three-layer appearance as it thickens to 4-8 mm.
The central line, which defines the endometrial cavity, is echogenic.27 The proliferating
functional layer, which will slough with menstruation, is hypoechoic. The outer basal layer,
which remains intact throughout the menstrual cycle, is echogenic and surrounded by the
hypoechoic junctional zone of the myometrium. In the secretory phase, following ovulation, the
11
functional layer continues to thicken and becomes echogenic. The entire double-layer thickness
of the endometrium in the secretory phase is 7-14 mm.27
12
FIGURE5: Longitudinal section of B-mode sonogram of the pelvis showing the uterus. The
myometrium is hypoechoic (green arrow), while the endometrium is echogenic (yellow arrow).
The red arrow points to the cervix while the white arrow points to the anechoic urinary bladder.
13
On B mode scanning, the uterine artery appears as tubular sonolucent structure with
echogenic walls as it crosses over the iliac artery and it fills with colour on colour Doppler
imaging (Fig 6). The placenta, through implantation and development, modifies the uterine
circulation from one of low flow and high resistance to one of high flow and low resistance in
normal pregnancy.28 Pulse-waved Doppler ultrasonography is performed to obtain waveforms
(Fig 7) from which indices are measured. The indices include the systolic(S) to diastolic(D)
velocity ratio, pulsatility index(PI) which is equal to (S–D)/Vm, where Vm is the mean of
maximal velocities throughout the cardiac cycle, resistive index(RI) equals (S–D)/S or
prediastolic notching (characteristic waveform indicating decreased early diastolic flow in the
uterine artery compared with the late diastolic flow). Increase in flow resistance as measured by
PI or RI greater than a chosen value (>1.45 or 0.58,respectively) or the presence of unilateral or
bilateral diastolic notches have been considered abnormal for pregnant uterus.25,29
14
FIGURE 6: A colour Doppler image showing uterine artery (long white arrow) as it crosses
over the iliac artery (short white arrow).
15
FIGURE 7: Triplex sonogram image showing the uterine artery Doppler waveform in a normal
pregnancy.
16
JUSTIFICATION FOR THE STUDY
PIH is a major cause of maternal and perinatal morbidity in developing countries including
Nigeria.1-3 With the advent of increasingly use of Doppler technology in developing countries,
the complication of this disease entity (especially intrauterine growth restriction which is a major
cause of perinatal mortality) can be monitored. As it is a fairly reliable predictor of IUGR, RI
values may be used with other parameters to predict the clinical status of the foetus and possibly
be of assistance in predicting when intervention would be necessary. Evaluation of placenta
function by umbilical artery Doppler is a clinical standard to distinguish between SGA and
IUGR.13
The uterine artery had been shown to have a better sensitivity and specificity as compared to the
umbilical artery.14 Considering severe SGA as the outcome, sensitivity improves if Doppler
velocimetry of the uterine artery is added to the EFW percentile.30 This is the reason why the
uterine artery was chosen in this study.
Doppler velocimetry of the uterine artery is a non-invasive procedure and does not use ionizing
radiation, hence its suitability for pregnant women. It is also affordable and reproducible hence
various researchers can repeat and easily compare the figures.
17
AIM AND OBJECTIVES
Broad :
To ascertain the predictability of uterine artery Doppler ultrasound in determining foetuses at
risk of Intrauterine Growth Restriction in PIH subjects.
Specific:
1. To compare RIs of PIH subjects with normal pregnant and non-pregnant subjects.
2. To determine relationship between RIs of PIH subjects and IUGR as established by EFW
as derived by ultrasound.
3. To determine relationship between uterine artery flow notching and IUGR as established
by EFW as derived by ultrasound.
4. To determine if a relationship exists between uterine artery flow notching and RI value.
Hypothesis
Uterine artery Doppler velocimetry shows increase in resistive index and notching in foetuses at
risk of IUGR in PIH subjects.
18
LITERATURE REVIEW
Hypertensive disorders of pregnancy remain a major cause of maternal morbidity and
mortality, yet we still struggle to understand the etiology, implement effective screening, and
offer prophylactic treatment or prevent its complications.29 PIH is more common at either end of
reproductive age, influenced by parity, race and socioeconomic status, previous history of PIH
and family history.11 PIH was defined as hypertension (blood pressure ≥140/90 mmHg) with or
without proteinuria (≥300 mg/24 hours) emerging after 20 weeks gestation, but resolving up to
12 weeks postpartum.8,31-33 Proteinuria is defined as the urinary excretion of ≥ 0.3 g protein in a
24-hour specimen. This will usually correlate with ≥ 30 mg/dL (≥ 1+ reading on dipstick) in a
random urine determination with no evidence of urinary tract infection.10
Pre-eclampsia is now recognized to be a multi-system disease of the vascular
endothelium, with vasoconstriction, renal vascular damage and abnormal coagulation in the
mother, and varying degrees of intrauterine growth restriction in the foetus.29,34 Pre-eclampsia
and intrauterine growth restriction are characterized by abnormal placenta formation,35,36 which
results in inadequate uteroplacental blood flow. This has led to the idea of using Doppler
ultrasonography to assess the velocity of uterine artery blood flow as part of routine ultrasound
screening.19 Low end-diastolic velocities and prediastolic notching characterize the waveforms of
uterine artery blood flow in women who are not pregnant or are in their first trimester.
Persistence of a prediastolic notch (beyond 24 weeks’ gestation) or abnormal flow velocity ratios
have been associated with inadequate trophoblast invasion.37 Accurate prediction of pre-
eclampsia and intrauterine growth restriction is crucial to allow judicious allocation of resources
for monitoring and preventive treatment to improve maternal and perinatal outcomes.38,39
19
According to Duley et al.39, pre-eclampsia can affect maternal organs, leading to
problems in liver, kidneys and brain, and to abnormalities of the clotting system. As the placenta
also is involved, there are increased risks for the baby. The most common are poor growth due to
inadequate blood supply through the damaged placenta, and the problems of prematurity (related
either to the spontaneous onset of preterm labour or to early delivery to protect the mother or the
foetus). Law et al.12, also noted that the major neonatal complication of PIH is low birth weight.
Low birth weight foetus can either be growth restricted or constitutionally small. The diagnosis
of intrauterine growth restriction(IUGR) by antenatal ultrasound remains a challenge for
obstetrics care providers.12 In clinical practice, it is difficult to differentiate between
constitutionally small but normally grown and pathological growth-restricted foetuses using
antenatal ultrasound.12 This has led to the idea of using Doppler ultrasound to assess the velocity
of uterine artery blood flow as part of routine ultrasound screening.19 Thus, early recognition of
IUGR as evidenced by derailed Doppler velocimetry is needed for timely intervention.
High resistance patterns assessed by Doppler velocimetry of the uterine artery have been
closely correlated with impaired trophoblastic migration assessed by examination of placenta bed
biopsies.40 This can be demonstrated by increased impedance in the uterine arteries as measured by
Doppler ultrasound.41 Assessment of impedance in the uteroplacental circulation has usually
relied upon basic descriptions of the waveform, such as the resistance index (RI), pulsatility
index (PI) and the ratio of peak systolic to end-diastolic blood flow velocities (S/D ratio), both of
which depend upon just two points on the waveform: the peak of systole and the end of
diastole.42
The clinical studies of uterine artery Doppler Screening are contradictory as there have
been differences in the anatomical sites of measurement, the indices used to describe an
20
abnormal waveform, and the outcome measures for which the test is predictive.29,43 Olivier Irion
et al.44 examined both uterine artery at their apparent crossing with the external iliac artery, while
Gomez et al.45 used measurement taken approximately 1cm distal to the crossover with the
external iliac artery.
Campbell et al.46 showed that a cut off of 0.58 for the resistive index at 20weeks of
gestation predicted PIH, IUGR or asphyxia in labor with a sensitivity of 68% and a positive
predictive value of 42%. Zhong et al.25 in a study done at the department of Obstetrics and
Gynaecology, Washington University School of Medicine, St Louis, USA, also noted that
increase in flow resistance as measured by PI or RI greater than a chosen value (>1.45 or 0.58
respectively) or percentile (90th -95th) or the presence of unilateral or bilateral diastolic notches
have been investigated for the prediction of preeclampsia and IUGR47. This is similar to what
Coleman et al.48 found in their study on “Mid-trimester uterine artery Doppler screening as a
predictor of adverse pregnancy outcome in high-risk women”. They noted that RI > 0.58 was
abnormal and RI > 0.70 was associated with small for gestational age foetus with sensitivity and
specificity of 55% and 73% respectively. However, Bewley et al.49 reported a cut-off value of
0.65 while Zimmermann et al.50 used a cut-off of 0.68. Schulman et al.20 reported 0.63 and
Fleischner et al.51 reported 0.62 as their cut-off value. These differences in values were due to the
fact different study populations were investigated and their techniques also differ slightly.
Irion et al.44 found out that uterine artery Doppler velocimetry waveform analysis does
not qualify as a reliable screening test for pre-eclampsia or low birth weight for gestation in low
risk pregnancies but may be useful in selected high risk populations. The performance of the
Doppler measurements taken at 18 pregnancy weeks was poor. For instance, predictive
properties of an peak systolic/early diastolic velocity ratio ≥ 2.5 at 18 weeks were a sensitivity
21
of 0.50, a specificity of 0.57, a positive predictive value of 0.05 and a likelihood ratio for an
abnormal test of 0.88 (95% CI 0.63–1.23) (P = 0.44). Thus, the results of the Doppler
measurements taken at 18 weeks are not further presented. Giordano et al.52 also noted that the
predictive value of Doppler testing in a low risk population of women appears to below, and
currently there are no available interventions to prevent adverse outcomes based on an abnormal
result. Effective interventions to prevent late pregnancy complications (preeclampsia, growth
restrictions) in women considered at low risk with abnormal early pregnancy uterine artery
Doppler studies are needed. Until such time as these are available, routine uterine artery Doppler
screening of women considered at low risk is not recommended. Uterine artery Doppler
screening of high-risk women (e.g, history of chronic hypertension or preeclampsia, prior fetal
growth restriction, or stillbirth) with singleton gestations appears to identify those at substantially
increased risk for adverse pregnancy outcomes.52 This present study focused on patient with PIH
with or without proteinuria. Abnormal testing in these women (i.e high risk) could potentially
lead to increased surveillance (earlier and more frequent assessment of fetal growth and maternal
clinical condition) and interventions that might improve clinical outcomes. However, further
study is needed to determine which high-risk conditions are amenable to such screening, what
testing regimen is optimal for a normal or abnormal test in these women, and what interventions
based on these findings will improve pregnancy outcomes.
Although numerous studies have demonstrated, the value of 20-24week uterine artery
Doppler screening of high risk populations, its role in early pregnancy is still far from defined.22-
24 Also the detection rate of uterine artery screening for preeclampsia or IUGR at any gestation is
better for severe than for mild disease.25 Increased resistance indices in the first trimester are
particularly effective in identifying preterm, rather than term, preeclampsia.53,54 For a 5% false-
22
positive rate, uterine arteries Doppler in the first trimester had detection rates of 50 – 77% for
preterm preeclampsia, compared with 22 – 27% for all types of preeclampsia.55,56 On the other
hand, Martinet al.57 reported that uterine Doppler PI at 11 – 14 weeks had a disappointing
sensitivity of 11.7% for all IUGR, but for IUGR requiring delivery by 32 weeks sensitivity
increased to 27.8%. This disparity may result from the distinction between the pathophysiology
of preterm and term preeclampsia/IUGR or from the different methodologic approaches used in
the different studies.
There is emerging evidence to suggest that preterm preeclampsia with IUGR may have a
different pathophysiologic pathway as compared to term preeclampsia. Placental pathologic
studies indicate that preeclampsia or IUGR resulting in preterm delivery before 34 weeks has
high rates of thrombotic placental pathologic findings of the villous trees.58 In contrast, term
preeclamptic and/or IUGR demonstrate either normal or minimal pathologic findings.59 Doppler
studies also suggest that preterm preeclampsia/IUGR is associated with defective invasion of the
spiral arteries, whereas the spiral artery defect plays a much smaller role in the cases nearer
term.60 Thus, term preeclampsia/IUGR seems to be associated with normal trophoblast
transformation in the first trimester, and late atherosclerotic changes in spiral arterioles. Such late
changes may be the consequence of increased placental mass, as occurs in diabetic and twin
pregnancies, related to the senescence of the placenta in prolonged pregnancy or as a result of
placental edema and necrosis in fetal hydrops.61,62 This is further supported by the observation
that preterm preeclampsia is often associated with low birth weight, whereas infants of women
with term preeclampsia often have normal or even increased birth weights.63 In addition, uterine
artery Doppler in the first and the second trimesters was shown to have a remarkably higher
23
sensitivity in women with preeclampsia complicated by small-for-gestational-age (SGA) babies
compared with uncomplicated preeclampsia or SGA alone.63
Evaluation of placenta function by umbilical artery Doppler is a clinical standard to
distinguish between SGA and IUGR.13 Lakhkar et al.14 found out that the uterine artery had a
better specificity (90-95%) as compared to the umbilical artery (85-90%)for predicting bad
maternal and perinatal outcome in PIH and SGA babies. Among other indices, he also found out
that PI had a better specificity (90-95%) as compared to the RI and S/D ratios (85-90%). The
diastolic notch had a specificity of 95%.With respect to IUGR, Cnossen et al.21 found that an
increased PI alone or in combination with notching was most valuable for predicting IUGR in
low risk women, whereas an increase in RI was the best predictor of the condition in high- risk
pregnant women. The additional finding that both uterine artery RI and notching contribute
independently to birth weight is a novel one.26 Hollis et al.64 demonstrated a negative correlation
between first-trimester uterine artery resistance assessed by color Doppler ultrasound and birth
weight. Low uterine artery resistance and absence of early diastolic notching are associated with
birth weights above the mean for gestational age. Conversely high uterine artery resistance and
diastolic notching, probably indicating a poorer trophoblastic invasion of the maternal spiral
arteries, are associated with birth weights below the mean for gestation.
Although previous research has shown an association between uterine artery Doppler
and both pre-eclampsia and IUGR, the prediction of the latter is much weaker than that of pre-
eclampsia in low risk population.22,23,44 According to Bower et al.22, by including a prediastolic
notch in the definition of an abnormal flow velocity waveform the prediction of pre-eclampsia is
markedly improved compared to IUGR; the relative risk to a woman with an abnormal waveform
of developing moderate or severe pre-eclampsia is increased 24-fold. Audibert et al.65 also found
24
out that the presence of a uterine notch was associated with a significantly higher risk of both
preeclampsia and IUGR in general pregnant population. In another study66 the sensitivity of the
notch observation in 20-24 week in the uterine Doppler velocimetry for the prediction of PIH
and/or IUGR in the third trimester was 73.68% and the specificity 97.15%. The presence of a
notching late in pregnancy is an indicator of increased uterine vascular resistance and impaired
uterine circulation.67 Bilateral notching is more concerning. Unilateral notching of the uterine
artery on the ipsilateral side of the placenta if the placenta is along one lateral wall (right or left)
carries the same significance as bilateral notching.68 As it is documented that prediastolic
notching is important on the side the placenta is located in cases of lateral placenta.69 The
presence of an early diastolic notch can however be a normal finding in a non-pregnant uterus
and even in a pregnant gravid uterus at least up to 16 weeks.68
This is difficult to explain given that both pathological processes are related to abnormal
placentation. Giovanni Di Lorenzo et al.30 in a study of third trimester abdominal fetal weight
and uterine artery Doppler for the identification of newborns small and large for gestational age
included uterine artery Doppler velocimetry measurements. This was based on the evidence that
an impaired placental flow negatively affects fetal growth. This finding of persistence high
resistance in the third trimester may contribute to the identification of foetuses undergoing
intrauterine growth restriction, among the SGA group.21 Chien et al.70 noted that an abnormal
flow waveform ratio + or – diastolic notch as the measurement parameter used for uterine artery
Doppler flow velocity has a limited predictive value for pre-eclampsia, IUGR and perinatal death
in a study conducted on population at low and high risk of developing pre-eclampsia and its
complications. Zimmermann et al.50 found out that uterine artery Doppler proved to be more
efficient at predicting a complicated pregnancy in patients who were at high risk: a positive
25
medical history alone was associated with a 3-fold greater risk of developing pre-eclampsia
and/or IUGR. In the high-risk group a single pathological Doppler sign accounted for an
additional 3-to 4-fold increased risk, and the combination of all 3 pathological signs, a 7-fold
additional risk for later disease. In this group, pre-eclampsia and/ or IUGR was found in 58.3%,
compared to 8.3% if Doppler results were abnormal. Thaler et al.71 who also found that the
presence of prediastolic notching was associated with a much higher RI value. They studied 140
women with hypertension in pregnancy generally. Twenty-five of the women had prediastolic
notching in their uterine artery waveform, 14 had systolic notch and it was absent in 101 of the
women. Those that had prediastolic notch had a mean RI value of 0.75 ± 0.09 while those
without a notch had a much lower RI value of 0.65 ± 0.10. They also noted that the rate of IUGR
were significantly higher in women with notch than those without a notch.
For clarity, Small-for-gestational age (SGA) fetuses are generally healthy, suffering only
a slight increase in perinatal mortality and morbidity in comparison to normally grown fetuses.72
In contrast, IUGR which is as a consequence of chronic uteroplacental insufficiency, is
associated with abnormal Doppler parameters and a high risk of perinatal mortality and
morbidity coupled.73
26
SUBJECTS AND METHOD
This was a prospective cross-sectional study which was carried out at the Department of
Radiology, Obafemi Awolowo University Teaching Hospital Complex, Ile Ife, Osun state,
Nigeria. The town is situated in the south western zone of Nigeria. The duration of study was
between February 2014 and January 2015.
SUBJECT SELECTION
Three groups of subjects were recruited namely:
1. Pregnant subjects with PIH
2. Apparently healthy Pregnant Control (PC)
3. Apparently healthy Non Pregnant Control (NPC)
All pregnant subjects were recruited from Obstetrics and Gynaecology Department,
OAUTHC, Ile-Ife. Pregnant subjects with a history of diagnosed PIH before treatment in the
index pregnancy and who have met the inclusion and exclusion criteria constituted the PIH
group. The PC group were those with normal blood pressure and had met the inclusion and
exclusion criteria. The NPC group were women who came for scanning in the Department of
Radiology. Both the PC group and NPC groups were matched age for age with the PIH group.
Written informed consent was taken in all the subjects across the groups.
The sample size for the study was determined using the Fisher formula74
27
N= Z ² pq
d²
Where,
N= Sample size
z= Standard deviation =1.96 corresponding to 95% confidence level.
p= Prevalence= 5%= 0.059
q = 1- p= 1-0.05= 0.95
d= degree of accuracy= 0.05
Hence the sample size turned out to be 80 PIH subjects.
The PC and NPC groups were also 80 each after matching them age for age.
INCLUSION CRITERIA
This included all pregnant women recruited from Obstetrics and Gynaecology unit of
OAUTHC, Ile-Ife, with BP of / or greater than 140/90mmHg or when the systolic blood pressure
exceeds 30mmHg, or diastolic blood pressure exceeds 15mmHg above the recorded baseline
blood pressure measurement on two occasions at least 6 hours apart. Patients in the PC group
included subjects with BP of less than 140/90mmHg after screening for the exclusion criteria.
The NPC group were patients that came for routine ultrasound scan in the department whose
LMP was known to ascertain they were not pregnant. Written informed consent was obtained
from all of them to participate in the study.
28
EXCLUSION CRITERIA (FOR PIH AND PC)
The following categories of patients were excluded from the study.
1) Diabetes mellitus.
2) Smokers.
3) Chronic Hypertension.
4) Chronic cardiovascular disorders.
5) Patients on any drug treatment during pregnancy, apart from routine hematinics.
6) Multiple gestations.
7) Chronic renal disease.
8) Foetal congenital anomalies
EXCLUSION CRITERIA FOR NPC
1. Any uterine Pathology
2. Post Menopausal
EQUIPMENTS
1) MINDRAY Real time Ultrasound model DC- 7 with Doppler Ultrasound facility.
Shenzhen Mindray Bio-Medical Electronics Co., LTD. Shenzhen, China. 2012.
2) Transducer probes with frequency of 3.5-5 MHz.
3) Ultrasound acoustic gel, ECO-GEL 200.
4) Blood pressure measuring apparatus.
29
TECHNIQUE
Written informed consent was obtained in all subjects. On presentation, medical histories
were reviewed and the blood pressures of selected patients were rechecked. Laboratory results
were checked to look for the presence of and the degree of proteinuria. Women were defined as
being proteinuric in the presence of greater or equal 0.3g/l of urine (≥ 1+ reading on dipstick).
Information such as presenting complaint, patient age and drug history were retrieved from
ultrasound request card or direct interviewing of the patient. Doppler ultrasound assessments
were performed before the commencement of medication in the PIH group.
Each subject was placed in supine position on the examination couch. After appropriate
exposure, coupling gel was applied over the abdomen and a routine obstetric scan was performed
to establish the EFW using Hadlock formula on Mindray DC-7 and also to rule out any
congenital anomaly in the foetus. The probe was placed on the lower quadrant of the abdomen,
angled medially, and again color Doppler imaging was used to identify both uterine arteries at
the apparent crossover with the external iliac artery. Measurements were taken approximately
1cm distal to the crossover point.45 This point was chosen after a pilot study had been done
because it is more easily reproducible.
In all cases, it was ensured that the angle of insonation was less than 600, the pulsed
Doppler gate was placed in the middle of the vessel. Angle correction was then applied and the
signal updated until three similar consecutive waveforms were obtained. The RI, PI and S/D of
the left and right uterine arteries were measured using autotrace (Fig 7). These measurements
were taken 3 times by the same researcher under the supervision of Consultant Radiologist and
their averages were taken to get a more accurate result. The presence or absence of a unilateral or
30
bilateral prediastolic notching was noted. A notch was defined as a persistent short/ sharp
decrease in blood flow velocity in early diastole, below the diastolic peak velocity.
DATA ANALYSIS
The RI, PI, and sonographic parameters of the hypertensive and normotensive pregnant
women were recorded in the patient proforma (Appendix i). These were entered into the
computer spreadsheet using Statistical Package for Social science (SPSS) for windows (SPSS
Inc, USA) version 20. The data were analyzed using appropriate descriptive and inferential
statistical methods and displayed by means of varied statistical presentations. The significance
level was determined at p < 0.05. One-way analysis of variance (ANOVA) was used to compare
means of variables between the three groups. The chi square test was used to evaluate
associations between parity, EGA, Doppler velocimetry parameters, percentile EFW and
presence of proteinuria.
31
ETHICAL CONSIDERATION
An approval for the study was obtained from the Ethical Committee of the Obafemi Awolowo
University Teaching Hospital Complex, Ile –Ife (Appendix iv). Participation in this study was
voluntary after subjects had gone through the subject information sheet (Appendix ii) and asked
questions to clear any doubt they have about the study. Designed informed written consent
(Appendix iii) was obtained from all the study participants. This study was conducted in a way
that subject confidentiality was ensured. This was achieved by identifying study subjects with
designated numbers rather than their names and keep study materials under lock and key.
32
RESULTS
In this prospective cross-sectional study, 80 cases of Pregnancy Induced Hypertension (PIH)
were investigated along with 80 apparently healthy Pregnant Control (PC) and 80 Non-Pregnant
Control (NPC). They were categorized into PIH, PC and NPC groups. All the study groups were
all matched age for age (Table 1). The mean age in years of PIH cases was 31.8 ± 4.7 with a
range of 20 – 40. This was comparable to NPC group with a mean age in years of 31.7 ± 5.5
(range of 20 – 42) and PC group, 31.8 ± 4.7 (range of 20 – 42). There was no statistical
difference in the means across the age group (p=0.991). Most of the cases across the groups were
between the ages of 30 – 34 years while the least number of cases across the groups were noted
to be less than 25 years. Also, most of the cases across groups had tertiary education with the
least number of cases noted to have primary education (Table 1). The PIH group had the highest
number of cases (68%) who had tertiary education.
The mean height in meters(Table 2) for the PIH group was 1.63 ± 0.06, for PC group,
1.60 ± 0.11 while for the NPC group, 1.61 ± 0.09, which were all comparable (p=0.070). The
PIH group had the highest weight, with a mean of 86.0 ±18.1, followed by the PC group with a
mean of 72.8 ±12.7 and lastly the NPC group with a mean of 64.2 ±7.0. There was a statistically
significant difference (p=<0.001) in the mean weight of the PIH group and PC group.
The highest blood pressure was recorded in the PIH group, with a mean systolic blood
pressure (SBP) of 149.8 ± 11.5mmHg while the lowest blood pressure with a mean SBP of 117.6
± 8.8mmHg was found in the PC group (Table 2).The difference in the means of the weight,
SBP, diastolic blood pressure (DBP) and mean arterial pressure (MAP) across the groups were
all statistically significant (p=0.000). However the difference in the means of the SBP between
the NPC and PC was not significant statistically (p=0.057) as shown in Table 3.
33
Table 1: A table showing subjects' demographic characteristics across the 3 groups
Variables NPC PC PIH
χ2 df P
value n = 80 n = 80 n = 80
Age in years
0.991 Mean ± SD* 31.7 ± 5.5 31.8 ± 5.6 31.8 ± 4.7
0.009 2, 237 (Range) (20 - 42) (20 - 42) (20 - 40)
n (%)
<25 9 (11.2) 8 (10.0) 6 (7.5)
8.818 8 0.358
25–29 15 (18.8) 19 (23.8) 14 (17.5)
30 – 34 34 (42.5) 24 (30.0) 35 (43.8)
35 -39 13 (16.2) 24 (30.0) 20 (25.0)
≥ 40 9 (11.2) 5 (6.2) 5 (6.2)
Education, n (%)
Primary 11 (13.8) 10 (12.5) 10 (12.5)
0.849 4 0.932 Secondary 19 (23.8) 16 (20.0) 15 (18.8)
Tertiary 50 (62.5) 54 (67.5) 55 (68.8)
χ2 - chi square test statistic; * oneway ANOVA used to compare means
34
Table 2: A table showing the clinical parameters of the subjects across the 3 groups
F means Oneway ANOVA
Variables NPC PC PIH F Df P
value
Height (m) 1.61 ± 0.09 1.60 ± 0.11 1.63 ± 0.06 2.684 2, 237 0.070
Weight (Kg) - 72.8 ± 12.7 86.0 ± 18.1 4.4631 158 0.000
Blood Pressure
SBP (mmHg) 121.4 ± 9.1 117.6 ± 8.8 149.8 ± 11.5 254.42 2, 237 0.000
DBP (mmHg) 79.8 ± 5.7 68.5 ± 8.3 95.8 ± 8.8 251.18 2, 237 0.000
MAP (mmHg) 93.67 ± 5.8 84.9 ± 6.9 113.8 ± 7.8 371.65 2, 237 0.000
35
Table 3: A table showing Scheffe Post-hoc Analyses for differences in demographic variables
and blood pressures
Variables P values
NPC vs. PC NPC vs. PIH PIH vs. PC
Height (m) 0.657 0.385 0.073
SBP (mmHg) 0.057 0.000 0.000
DBP (mmHg) 0.000 0.000 0.000
MAP (mmHg) 0.000 0.000 0.000
36
Table 4 showed that there was no statistical difference between the EGA and parity of PIH group
and PC group (p=0.053). The highest numbers of subjects which is 29 (36.2%) of PIH group
investigated were between the EGA of 30 – 34 while the highest in the PC group, 27 (33.8%),
were between the EGA of 35 – 39. In the PIH group, 2 (2.5%) of subjects were above 40 weeks
EGA, while none was above 40weeks in the PC group. About 27 (33.8%) of subjects in the PIH
group were para 0, which was the highest, while in the PC group, para 2 was the highest which
were 34 (42.5%) of the subjects.
37
Table 4: A table showing parity and EGA of pregnant subjects
Risk Factor PC PIH χ2 df P value
n=80 n=80
EGA
n (%)
<25 19 (23.8) 7 (8.8)
9.335 4 0.053
25–29 9 (11.2) 15 (18.8)
30 – 34 25 (31.2) 29 (36.2)
35 -39 27 (33.8) 27 (33.8)
≥ 40 0 (0.0) 2 (2.5)
Parity
n (%)
0 10 (12.5) 27 (33.8)
8.818 4 0.015
1 22 (27.5) 21 (26.2)
2 34 (42.5) 26 (32.5)
3 11 (13.8) 4 (5.0)
4 3 (3.8) 2 (2.5)
38
Out of the 80 PIH subjects, 47(58.75%) had no history of past episodes of PIH, while
27(33.75%) had one episode, and 6(7.50%) had two episodes (Fig 8).
For the family history of PIH in the PIH group, a larger number, 73 (91.25%) claimed not to
have any of such history.
Urinalysis done for the PIH subjects (Fig 9) revealed that 56 (70.0%) had no proteinuria, 12
(15%) had 2 pluses and 12(15%) had 3 pluses.
39
Figure 8: A bar chart showing number of past episodes of PIH in the PIH group
No. of past episodes of PIH
47 (58.75%) 6 (7.50%) 27 (33.75%)
40
Figure 9: A pie chart showing distribution of degree of proteinuria in the PIH group
41
Uterine arteries Doppler parameters of NPC, PC and PIH groups
The mean RIs of the right uterine artery from the highest to the lowest across the groups
were (Table 5); NPC group was 0.75 ± 0.09, followed by PIH group which was 0.61 ± 0.14 and
PC group was 0.50 ± 0.08 (p=0.000). The left uterine artery also followed the same pattern; NPC
group was 0.75 ± 0.09, PIH group was 0.62 ± 0.11 and PC group was 0.48 ± 0.10 (p=0.000).
The PI also followed the same trend (Table 5). The NPC group had the highest mean PI
of 1.74 ± 0.40, followed by the PIH group with a mean of 1.39 ± 0.86 and lastly the PC group
with a mean of 0.87 ± 0.22 for the right uterine artery (p=0.000). The same pattern was also
noted in the left uterine artery; NPC group had a mean of 1.74 ± 0.40, PIH group had a mean of
1.36 ± 0.67 and PC group had a mean of 0.81 ± 0.23 (p=0.000).
For the S/D ratio, the NPC group had the highest mean of 5.18 ± 1.62 for the right and
left uterine arteries, followed by the PIH group with mean S/D ratio of 2.98 ± 1.53 and 2.92±
1.11 for the right and left respectively and lastly the PC group with a mean of 2.07 ± 0.33 and
1.99 ± 0.36, right and left respectively (p=0.000).
A Scheffe Post-hoc Analyses for differences in means of the Doppler parameters between groups
showed significant statistical difference (Table 6).
42
Table 5: A table showing uterine artery Doppler parameters across the 3 groups
Variables NPC PC PIH
F df P
value
Right uterine
artery RI 0.76 ± 0.09 0.50 ± 0.08 0.61 ± 0.14 109.51 2, 237 0.000
Left uterine artery
RI 0.75 ± 0.09 0.48 ± 0.10 0.62 ± 0.12 142.87 2, 237 0.000
Right uterine
artery PI 1.74 ± 0.40 0.87 ± 0.22 1.39 ± 0.86 47.71 2, 237 0.000
Left uterine artery
PI 1.74 ± 0.40 0.81 ± 0.23 1.36 ± 0.67 77.52 2, 237 0.000
Right uterine
artery S/D 5.18 ± 1.62 2.07 ± 0.33 2.98 ± 1.53 119.05 2, 237 0.000
Left uterine artery
S/D 5.18 ± 1.62 1.99 ± 0.36 2.92 ± 1.11 159.78 2, 237 0.000
F means Oneway ANOVA
43
Table 6: A table showing Scheffe Post-hoc Analyses for differences in Doppler
parameters between groups
Variables P values
NPC vs. PC NPC vs. PIH PIH vs. PC
Right uterine artery RI 0.000 0.000 0.000
Left uterine artery RI 0.000 0.000 0.000
Right uterine artery PI 0.000 0.000 0.000
Left uterine artery PI 0.000 0.000 0.000
Right uterine artery S/D 0.000 0.000 0.000
Left uterine artery S/D 0.003 0.001 0.001
44
Table 7 showed comparison between right and left uterine arteries RIs in all the study
groups. There was no statistical difference in their means. Therefore for convenience, the right
artery will henceforth be used to represent RI in further analysis. It was further gotten from this
study that the PC group had a mean RI of 0.50 ± 0.08, therefore the 95th percentile RI of this
current study in the normal pregnant control is 0.66 (i.e 95th percentile= mean + 2SD). This puts
the upper limit of RI in this study to be 0.66.
Prediastolic notching was only present in the PIH and NPC group (Table 8). There was
no prediastolic notching recorded in the PC. However, the presence of prediastolic notching was
consistently much higher on the right uterine artery in the PIH and NPC groups (p= 0.000).
Therefore, since the right uterine artery also had more prediastolic notches, for conveniences, it
was also chosen for further analysis. Fig 10 showed the presence of prediastolic notching in one
of the PIH group while Fig 11 showed normal spectral pattern in one of the PC group.
45
Table 7: A table showing comparison between both uterine arteries RIs in the 3 study groups
Uterine Artery RI Mean ± SD t df P
value
NPC Group Right uterine artery RI 0.75 ± 0.09
1.511 79 0.135 Left uterine artery RI 0.75 ± 0.09
PC Group Right uterine artery RI 0.50 ± 0.08
1.856 79 0.067 Left uterine artery RI 0.48 ± 0.10
PIH Group Right uterine artery RI 0.61 ± 0.14
-1.015 79 0.313 Left uterine artery RI 0.62 ± 0.11
46
Table 8: A table showing comparison between both uterine arteries prediastolic notching in the 3
study groups
Study Group
N
Uterine artery side
Prediastolic Notch
χ2
df
P
value Present
N (%)
Absent
N (%)
NPC Group 80 Right uterine artery 14 (17.5) 66 (82.5)
73.117 1 0.000 Left uterine artery 13 (16.2) 67 (83.8)
PC Group 80 Right uterine artery 0 (0.0) 0 (0.0)
- - - Left uterine artery 0 (0.0) 0 (0.0)
PIH Group 80 Right uterine artery 15 (18.8) 65 (81.2)
29.32 1 0.000 Left uterine artery 12 (15.0) 68 (85.0)
47
Fig 10: A Triplex sonogram of the uterine artery in one of the PIH group showing presence of
prediastolic notch (red arrows).
48
Fig 11: A Triplex sonogram of the uterine artery in one of the PC group showing normal spectral
pattern.
49
Relationship between RIs of PIH group and IUGR
Out of the 80 PIH subjects investigated, 12 had their EFW below the 10th percentile and thus
have a high risk of IUGR; the remaining 68 have their EFW above the 10th percentile (Table 9).
Their mean RI was significantly increased for the IUGR group which was 0.69 ± 0.07, compared
to those above the 10th percentile which was 0.59 ± 0.15 (p = 0.025). Further analysis on the PIH
group using the 0.66 cut-off value in RI established in this study, out of the 12 that had IUGR (<
10th percentile), 6 (50%) had the RI above 0.66 while the remaining 6 (50%) had their RI below
0.66 (Table 10). However, out of the 68 of those that had their EFW above the 10th percentile, a
greater percentage (69.1%, n=47), of them had their RI below 0.66 (p=0.197).
In the PC group, out of the 8 that had their EFW below the 10th percentile, none had their RI
above 0.66 (Table 10). However, 3 out of the 72 of that had their EFW above the 10th percentile
had their RI above 0.66 (p= 0.726).
Generally, Table 11 showed that more of the subjects in the PIH group had RI greater than 0.66
which was 27 (33.8%) out of the 80 investigated compared to the PC group which is only 3
(3.8%) out of the 80 subjects investigated (p= 0.000).
50
Table 9: A table showing mean RI values of the PIH group based on their percentile of EFW
Study group Percentile of EFW
(N)
N Mean ± SD t df P
value
Uterine artery RI < 10th percentile 12 0.69 ± 0.07
2.292 78 0.025 > 10th percentile 68 0.59 ± 0.15
51
Table 10: A Table showing Chi Square analysis between RIs (using 0.66 as cut-off) of PIH and
PC groups with Percentile of EFW
*Two cells (50.0%) have expected count less than 5. Thus Fischer exact test was used to test
statistics.
Parameters
Percentile of EFW χ2 Df p-value
< 10th
Percentile
> 10th
Percentile
Uterine
Artery RI in
PIH group
>0.66 N (%) 6 (50.0) 21 (29.9)
1.667 1 0.197 <0.66 N (%) 6 (50.0) 47 (69.1)
Total N (%) 12 (100.0) 68 (100.0)
Uterine
Artery RI*
in PC group
>0.66 N (%) 0 (0.0) 3 (4.2)
0.645* 1 0.726 <0.66 N (%) 8 (100.0) 69 (95.8)
Total N (%) 8 (100.0) 72 (100.0)
52
Table 11: A table showing Chi Square analysis of the RIs (using 0.66 cut -off value) between PC
and PIH groups
Study Groups
χ2 Df P -
value PC
N (%)
PIH
N (%)
Uterine artery RI
categories
<0.66 77 (96.2) 55 (66.2)
23.631 1 0.000 >0.66 3 (3.8) 27 (33.8)
Total 80 (100) 80 (100)
53
Relationship between uterine artery flow notching and IUGR in the PIH group
All of the 12 (100.0%) of the subjects in the PIH group that had their EFW less than 10th
percentile, had prediastolic notching on the right uterine artery waveform (Table 12).While out
of the remaining 68 subjects, only 3 (4.4%) whose EFW was above the 10th percentile had
prediastolic notching on the right uterine artery waveform. The presence of prediastolic notching
in those with suspected IUGR (i.e EFW less than 10th percentile) was statistically significant
(p = 0.000).
54
Table 12: A table showing the relationship between IUGR and prediastolic notching of the
uterine artery in the PIH group
*Two cells (50.0%) have expected count less than 5. Thus Fischer exact test was used to test
statistics.
Parameters
Percentile of EFW χ2 Df p-
value < 10th
Percentile
> 10th
Percentile
Prediastolic
notching
Present N (%) 12 (100.0) 3 (4.0)
56.621* 1 0.000 Absent N (%) 0 (0.0) 65 (96.0)
Total N (%) 12 (100.0) 68 (100.0)
55
Relationship between uterine artery prediastolic notching and RI values in the PIH group
Out of the 80 uterine arteries investigated in the PIH subjects on the right, 15 of them had
prediastolic notching in their waveform. It was found out that they also had higher mean RI of
0.73 ± 0.10 (Table 13) compared to the remaining 65 who do not have prediastolic notch with a
mean RI of 0.58 ± 0.12 (p =0. 000).
Relationship between proteinuria and presence of prediastolic notching in the PIH group
All the 15 (100%) of those that had prediastolic notching on their uterine artery waveform had
proteinuria (p< 0.001). Table 14 showed that 9 (60.0%) of them had two pluses while 6 (40.0%)
of them had three pluses.
56
Table 13: A table showing comparison of RI based on presence of prediastolic notching in the
PIH group
Parameters Presence of pre-
diastolic notch
N Mean ± SD t df P
value
Right uterine artery RI Absent 65 0.58 ± 0.12
-4.084 78 0.000 Present 15 0.73 ± 0.10
Left uterine artery RI
Absent 68 0.61 ± 0.11 -2.726 78 0.008
Present 12 0.70 ± 0.09
57
Table14: A table showing the relationship between proteinuria and presence of prediastolic
notching in the PIH group
Proteinuria Presence of prediastolic notch
χ2 df p
value
Absent N (%) Present N (%)
None 56(86.2) 0(0.0)
32.941 1 <0.001 ++ 3(4.6) 9(60.0)
+++ 6(9.2) 6(40.0)
Total 65(100.0) 15(100.0)
58
Therefore, to ascertain the predictability of uterine artery RI and prediastolic notching in foetuses
at risk of IUGR in the PIH group, the right uterine artery was chosen for this purpose because of
the reasons earlier mentioned. The RI chosen for this purpose was 0.66 which was the upper
limit of normal, i.e the 95th percentile of this study (Table 5). The RI > 0.66 had a sensitivity of
50.0%, specificity of 69.1% and Positive Predictive Value of 22.2% (calculation based on Table
10). The odds ratio equals 2.2 with a 95% CI of 0.6 -7.8 (Table 15). This means that the chance
of developing IUGR is increased by 2.2 folds in subjects with PIH whose RI value is greater than
0.66.
The prediastolic notching had a sensitivity of 100.0%, specificity of 96.0% and Positive
Predictive Value of 80.0% in those with established PIH (calculation based on Table 12) in
predicting foetuses at risk of IUGR. The odds ratio equals 22.7 with a 95% CI of 7.5 - 68.5
(Table 15). This means that the chance of developing IUGR is increased by 22.7 folds in subjects
with established PIH with the presence of prediastolic notching in their uterine artery waveform.
59
Table 15: A table showing predictability of IUGR in the PIH group
Sensitivity
(%)
Specificity
(%)
PPV (%) NPV (%) Odd ratio 95% CI
RI >0.66 50.0 69.1 22.2 88.7 2.2 0.6-7.8
Prediastolic
Notching
100.0 96.0 80.0 100.0 22.7 7.5-68.5
60
DISCUSSION
Pregnancy-induced hypertension (PIH) is one of the leading causes of maternal morbidity
and mortality in developing countries including Nigeria.1,2,4 Pre-eclampsia and IUGR are felt to
be the result of abnormal placenta formation involving abnormal trophoblast invasion of spiral
arteries and subsequently leads to a increase in vascular resistance in the uteroplacental
circulation.7,36 This eventually leads to a decrease in blood flow to the uterus and the foetus. This
has led to the idea of using Doppler ultrasound to assess the velocity of uterine artery blood flow
as part of routine ultrasound screening.19 Thus, early recognition of IUGR as evidenced by
derailed Doppler velocimetry is needed for timely intervention. IUGR is associated with
stillbirth, neonatal death and perinatal morbidity as well as delayed effects including cerebral
palsy and adult diseases.16,17
This study sets out to predict IUGR in PIH subjects using the RI and prediastolic
notching. The prediastolic notching (using the right uterine artery), had a sensitivity of 100.0%,
specificity of 96.0% and Positive Predictive Value of 80.0% in predicting IUGR in the PIH
subjects. The odds ratio equals 22.7 with a 95% CI of 7.5 - 68.5 (Table 11). This means that the
chance of developing IUGR is increased by 22.7 folds in subjects with established PIH with the
presence of prediastolic notching in their uterine artery waveform. In this study, the 100.0%
sensitivity of the prediastolic notch probably reflects that, PIH had caused some form of vascular
comprise (reflected in the form of prediastolic notch) to the foetus before IUGR sets in. Audibert
et al.65 also found out that the presence of a uterine notch was associated with a significantly
higher risk of both preeclampsia and IUGR in general pregnant population. In another study66 the
sensitivity of the notch observation in 20-24 week in the uterine Doppler velocimetry for the
prediction of PIH and/or IUGR in the third trimester was 73.68% and the specificity
61
97.15%.These were all comparable to what was found in this study and also the high risk in this
study was coned down to only subjects with established PIH, having excluded other causes of
IUGR. Among the various uterine waveform parameters, the prediastolic notch had been found
to have the highest sensitivity and specificity.14 The presence of a prediastolic notch late in
pregnancy is an indicator of increased uterine vascular resistance and impaired uterine
circulation.67 Bilateral notching is more concerning. Unilateral notching of the uterine artery on
the ipsilateral side of the placenta if the placenta is along one lateral wall (right or left) carries the
same significance as bilateral notching.68 Although, there was a significant difference in the
number of prediastolic notches on the right and left uterine artery, the right uterine artery was
used in this study partly for uniformity and because it had the higher sensitivity.
The presence of a prediastolic notch can however be a normal finding in a non-pregnant
uterus and even in a pregnant gravid uterus at least up to 16 weeks.68 According to some
researchers23,28,51, they also discovered that the use of the prediastolic notch as the definition of
abnormality have improved the reliability and predictive value of uterine Doppler studies in
pregnancy as per pre-eclampsia and IUGR. Thaler et al.71 also noted in their study on systolic or
diastolic notch in uterine artery blood flow velocity waveforms in hypertensive pregnant patients,
that the presence of a prediastolic notch in uterine artery flow velocity waveforms is a better
predictor of poor pregnancy outcome than is the RI alone. The presence of prediastolic notching
signals that the uteroplacental circulation is greatly impaired, and carries the worst prognosis for
the foetus.71
The mean RI of the right uterine artery (Table 5) of the PIH group in this study was 0.61 ±
0.14.This was noted to be higher than the PC group which was 0.50 ± 0.08, but lower than the
NPC group which was 0.75 ± 0.09 (p = 0.000). This is in keeping with what various researchers
62
had found out.7,28,36 The placenta, through implantation and development, modifies the uterine
circulation from one of low flow and high resistance to one of high flow and low resistance in
normal pregnancy.28 The primary defect that predisposes pregnancies to uteroplacental
complications appear to be partial or complete failure of trophoblastic invasion,7 although the
reason for this failure is still not clear,28 this is what happens in PIH subjects.36 The uterine artery
waveform in a non-pregnant uterus demonstrates notching at the beginning of diastole with low
flow at the end of diastole because of high resistance to blood flow, thus usually have a high RI.
This agrees with what was found in this study, with the NPC group having the highest mean RI
of 0.75 ± 0.09 compared to the other groups (see Table 5). Once pregnancy occurs vessels in the
placenta develop, resulting in a low resistance to blood flow with a concomitant increase in the
height of the diastolic waveform resulting in more blood flow to the gravid uterus.28 This is
reflected in the low RI value seen in normal pregnant subjects. This study also corroborates this
fact. The PC group had the lowest mean RI value of 0.50 ± 0.08 in keeping with low resistant
flow in normal pregnancy. This does not however happen in subjects with established PIH
because of the abnormal trophoblastic invasion as mentioned earlier, and thus may explain the
growth restriction the foetus might be subjected to. Persistence of a diastolic notch (beyond
24weeks’ gestation) or abnormal flow velocity ratios have been associated with inadequate
trophoblastic invasion in the PIH subjects.21 This is reflected in the high RI values seen in PIH
subjects compared to normal pregnant subjects as shown in this study (PIH mean RI = 0.61 ±
0.14 vs PC mean RI = 0.50 ± 0.08) and various other studies done.7,28
The PC group in this study had the lowest RI with a mean value of 0.50 ± 0.08, which
conforms to the general knowledge of decrease RI in normal pregnancy. The 95th percentile in
the PC group in this current study is mean + 2SD which was equal to 0.66. This formed the basis
63
of the 0.66 cut-off of RI value used in this study. We found out that RI > 0.66 had a sensitivity of
50.0%, specificity of 69.1% and Positive Predictive Value of 22.2% in predicting fetuses at risk
of IUGR. The odds ratio equals 2.2 with a 95% CI of 0.6 -7.8 (Table 15). This means that the
chance of developing IUGR is increased by 2.2 folds in subjects with PIH whose RI value is
greater than 0.66.
This is similar to the work of Zimmermann et al 50. During a 20-month period they
studied 175 pregnant women at high risk for hypertensive disorders of pregnancy or intrauterine
growth retardation, and 172 patients at low risk, in a prospectively designed cross-sectional trial.
They found out that persistent notches in the main stem uterine arteries and elevated resistance
indices of > 0.68 in the uterine arteries and > 0.38 in the uteroplacental arteries were defined as
abnormal waveforms. However, Zhong et al.25 noted that increase in flow resistance as measured
by PI or RI greater than a chosen value (>1.45 or 0.58 respectively) or percentile (90th -95th ) or
the presence of unilateral or bilateral diastolic notches have been investigated for the prediction
of preeclampsia. This was similar to Campbell et al.46 who showed that a cutoff of 0.58 for the
RI at 20 weeks of gestation predicted PIH, IUGR or asphyxia in labour with a sensitivity of 68%
and a positive predictive value of 42%. The difference in the cut-off RI value could be explained
partly because all the studies quoted where done in different population and also because of
technical differences.
Furthermore, a low diastolic flow and high indices (RI and PI) characterized the
pregnancies with abnormal outcomes.14,64 The PI in the PIH group in this study was notably
higher than the PC group. The PIH group had a mean PI of 1.39 ± 0.86 compared to the PC
group with a mean PI of 0.87 ± 0.22 (P= 0.000). The RI had been discussed earlier. This is
similar to what some researchers found, that increase in flow resistance as measured by PI or RI
64
greater than a chosen value (>1.45 or 0.58,respectively) or the presence of unilateral or bilateral
diastolic notches have been considered abnormal for pregnant uterus.25,29,47
It was noted in this study that subjects with established PIH, that had their EFW below
10th percentile (qualified as IUGR), had a higher mean RI value compared to those whose EFW
was above the 10th percentile. Those below the 10th percentile had a mean RI of 0.69 ± 0.07
while those above the 10th percentile had a mean RI of 0.59 ± 0.15. This is similar to what
Coleman et al.48 found in their study on “Mid-trimester uterine artery Doppler screening as a
predictor of adverse pregnancy outcome in high-risk women”. They noted that RI > 0.58 was
abnormal and RI > 0.70 was associated with small for gestational age foetus with sensitivity and
specificity of 55% and 73% respectively. However, this study had categorized all EFW below
the 10th percentile in the PIH group as suspected IUGR. For clarity, Small-for-gestational age
(SGA) fetuses are generally healthy, suffering only a slight increase in perinatal mortality and
morbidity in comparison to normally grown fetuses.72 This study also noted the SGA fetuses in
the PC group to have normal Doppler parameters (Tables 8 and 10). In contrast, IUGR in the
PIH group, which is as a consequence of chronic uteroplacental insufficiency, is associated with
abnormal Doppler parameters and a high risk of perinatal mortality and morbidity coupled.72,73
Figueras et al.13 reported that serial fundal height measurement plotted on customized charts is a
useful screening tool for IUGR, however, fetal biometry and Doppler flow are the mainstay for
investigation and diagnosis of IUGR. In normal pregnancies, the flow velocity waveforms
showed a good diastolic flow and fall in indices as pregnancy progressed. Hollis et al.64 found
that low uterine artery resistance and absence of prediastolic notching are associated with birth
weights above the mean for gestational age. This was corroborated in this study, where those
foetuses above the 10th percentile in the PC group had no prediastolic notching (Table 8), while
65
only 3 (4.2%) of the 72 that had their EFW above the 10th percentile in the PC group had their RI
above 0.66. Whereas in the PIH group, 3 (4.0%) of the 68 that had their EFW above the 10th
percentile had prediastolic notching (see Table 12) and 21 (29.9%) of them had their RI above
0.66 (see Table 10). This is because patients with PIH generally have high RI as mentioned
earlier.
A comparison between the mean RIs of those that had prediastolic notching in their
uterine waveform with those without prediastolic notching in the PIH group in this study showed
a much higher RI in the former (p=0.000). Those with prediastolic notching had a mean RI of
0.73 ± 0.12 compared to those without, with a mean RI of 0.58 ± 0.12 (Table 14). This was in
agreement with Thaler et al.71 who also found that the presence of prediastolic notching was
associated with a much higher RI value. They studied 140 women with hypertension in
pregnancy generally. Twenty-five of the women had prediastolic notching in their uterine artery
waveform, 14 had systolic notch and it was absent in 101 of the women. Those that had
prediastolic notch had a mean RI value of 0.75 ± 0.09 while those without a notch had a much
lower RI value of 0.65 ± 0.10. They also noted that the rate of IUGR were significantly higher in
women with notch than those without a notch. Controversy exists concerning the predictive
value of uterine artery Doppler in adverse outcome of PIH.24,44
However, using the 0.66 cut-off in RI established in this study, out of the 12 that had
IUGR (< 10th percentile), 50% had the RI above 0.66 (Table 10). This may imply that high RI is
a fairly good indicator whether the foetus is at risk of IUGR or not. This is in agreement with the
work of Thaler et al.71 who found that the presence of a notch in uterine artery flow velocity
waveforms is a better predictor of poor pregnancy outcome than is the RI alone. However, it is
note worthy that subjects with PIH whether they have IUGR or not will most of the time have
66
high RI compared to normal pregnant women. The inclusion of uterine artery Doppler
velocimetry is based on the evidence that impaired placenta flow negatively affects fetal
growth.21 The finding of a persistent high resistance in the third trimester may contribute to the
identification of foetuses undergoing IUGR, among the small for gestational age group.53
The additional finding that both uterine artery RI and notching contribute independently to
birth weight is a novel one.26 This finding strongly supports the hypothesis that these two
measurements assess different aspects of vascular response; the RI may reflect the impedance to
blood flow while notching may reflect vessel compliance.26
67
LIMITATIONS
The presence of prediastolic notching on the right and left uterine artery was not correlated with
the location of lateral placentas viz-a-viz right lateral and left lateral placental respectively. As it
is documented that prediastolic notching is important on the side the placenta is located in cases
of lateral placenta.69 Also, unilateral notching of the uterine artery on the ipsilateral side of the
placenta if the placenta is along one lateral wall (right or left) carries the same significance as
bilateral notching in predicting pregnancy outcome.68 Inaccuracies of fetal weight estimation on
ultrasound might affect the placing of foetuses in their appropriate weight group. This is not a
prospective study, therefore IUGR can only be suspected. The confirmation of IUGR will require
monitoring the growth pattern of the foetuses overtime. Ultrasound is user dependent hence there
may be minor variations in the values obtained. Also part of the limitations in this study is that
there was no objective way of assessing whether the subjects had PIH previously as some did not
have proper documentation. So, the subjects were interviewed and whatever they said was taken.
68
CONCLUSION
Uterine artery Doppler ultrasound is very valuable in predicting foetuses at risk of IUGR in
subjects with established PIH. Abnormal uterine artery velocimetry and/or abnormal waveforms
were found in all the PIH subjects. The presence of prediastolic notching was found to have
100% sensitivity in predicting foetuses at risk of IUGR in the PIH subjects. Also, the PC group
that had their foetuses below the 10th percentile of their EFW had normal velocimetry and
waveform probably signifying that they may be constitutionally small, apart from 3 (4.2%) out of
the 72 that had RI> 0.66.
69
RECOMMENDATION
Uterine artery Doppler velocimetry should be a routine investigation in patients with PIH in
order to aid the identification of foetuses at risk of IUGR. This will facilitate timely and
appropriate management which will in turn reduce morbidity and mortality associated with
IUGR in such patients.
70
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PROFORMA
PATIENTS BIODATA
NAME_______________________________________________________
AGE_________________ HOSP. NO ________________
PHONE NO ________________
LMP ______________________ PARITY GA __________ weeks
B.P_______ WGT ______ HT _______
PREVIOUS EPISODES OF PIH: YES/NO
IF YES, STATE NUMBER OF EPISODES: __________
FETAL BIOMETRY
BPD __________cm
HC __________ cm
AC __________cm
FL ___________ cm
ULTRASOUND GA ______________ weeks
First trimester CRL, if available ___________ cm
ESTIMATED FETAL WEIGHT ___________ kg
MEASUREMENTS RIGHT UTERINE
ARTERY
LEFT UTERINE ARTERY
RESISTIVE INDEX(RI)
PULSATILITY INDEX(PI)
S/D
PRESENCE OF
PREDIASTOLIC NOTCH
Appendix I
80
UTERINE ARTERY DOPPLER VELOCIMETRY IN SUBJECTS WITH PREGNANCY
INDUCED HYPERTENSION IN OAUTHC, ILE-IFE.
SUBJECT INFORMATION SHEET
Investigator: ABIDOYE IBUKUN ANUOLUWA. Telephone No: 08032426494
E-mail:[email protected]
Institution: ObafemiAwolowo University Teaching Hospitals Complex, Ile-Ife.
Department: Radiology
TITLE OF PROJECT:UTERINE ARTERY DOPPLER VELOCIMETRY IN SUBJECTS
WITH PREGNANCY INDUCED HYPERTENSION IN OAUTHC, ILE-IFE.
INTRODUCTION: From a random selection process you have been chosen as one of the
participants in a research study. This document is designed to provide you with the necessary
information about this study and obtain your consent to participate.
PURPOSE: To ascertain the predictability of uterine artery Doppler ultrasound in determining
foetuses at risk of Intrauterine Growth Restriction in Pregnancy Induced Hypertension subjects
so as to help to institute early appropriate treatment.
PROCEDURES: You will be interviewed and questions will be asked about your demographic
characteristics and medical history. I will ask you a number of questions to solicit this
information and the entire interview should last not longer than two minutes. I will have to re-
check your blood pressure again. Afterwards I would do a routine ultrasound scan of your baby
and will further go ahead to scan your uterine arteries all of which will not take more than 5-7
minutes.
BENEFITS: If you agree to this study, it will enable you to know if your baby is growing well
or not. This will enable your doctors to manage you properly.
RISKS: There are no physical risks involved. You will not be required to answer any questions
that you may find embarrassing.
COMPENSATION: There will be no compensation for participating in the study.
CONFIDENTIALITY: All information gathered in this study will be kept confidential.
RESPONDENTS’ RIGHTS: Selected participants have a right to decline participation in the
study or withdraw at any time.
CONFLICT OF INTEREST: To the best of my knowledge, there is none.
FOR THE RECORDS: Nil
Appendix II
81
UTERINE ARTERY DOPPLER VELOCIMETRY IN SUBJECTS WITH PREGNANCY
INDUCED HYPERTENSION IN OAUTHC, ILE-IFE.
Subject’s Agreement/Consent Form:
I have read the information provided in the subject information sheet, or it has been read to me.
I have had the opportunity to ask questions about it and any question I have asked have been
answered to my satisfaction. I consent voluntarily to participate in this study and understand that
Doppler ultrasound scan of my uterine arteries will be done. I have the right to withdraw from
the study at any time.
I agree to participate in the study.
YES NO
-------------------------------------------------------------------------------------
Signature/Thumb print of Research Respondent. Date:
_____________________________________________________________________
Printed name of research/Subject’s legal guardian.
_____________________________________________________________________
Signature/Thumb print of Person Obtaining Consent Date:
_____________________________________________________________________
Printed name of person obtaining consent.
Appendix III
82
Appendix IV