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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79

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:ibukunabidoye@yahoo.com

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