Ultrasound assessment of fetal cardiac function and risk of ...

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Ultrasound assessment of fetal cardiac function and risk of adverse obstetric

and neonatal outcomes in term fetuses

MD (Res) Thesis

Dr Gowrishankar Paramasivam

CID number: 00681826

Department of Surgery and Cancer

Imperial College

London -U.K

Supervisors: - Professor Phillip Bennett

Professor Sailesh Kumar

Declaration of originality

I declare that this thesis is my original work. I have appropriately referenced where other’s

work has been used in my thesis.

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Commons Attribution, Non-commercial, No derivatives license. Researchers are free to copy,

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ABSTRACT

Aim: To measure the fetal cardiac output prior to labour and assess the risk of adverse

obstetric and neonatal outcome in singleton pregnancies with appropriately grown for

gestational age (AGA) fetuses at term.

Methods: This was a prospective observational study conducted at Queen Charlotte’s and

Chelsea Hospital, London UK. Fetal cardiac output and fetal cerebro-placental ratio (CPR)

was measured within 72 hours before birth in 200 nulliparous women having singleton

pregnancies with AGA fetuses. Scan details were not available to the clinicians and delivery

was managed per the local protocol and guidelines. Obstetric and neonatal outcomes were

obtained from case notes and were correlated with the ultrasound findings.

Results: Delivery was vaginal in 129 (64.5%) cases and by caesarean section in 71 (35.5%),

including 34 (17.0%) for fetal distress and 37 (18.5%) for failure to progress. Fetuses

delivered by caesarean section for fetal distress, compared to the remaining fetuses, had a

lower median left cardiac output (152.3 vs. 191.7 mL/min/kg; p=0.003), higher difference in

the median ratio between the right to left cardiac output (1.925 vs. 1.340; p=0.002) and

lower CPR (1.222 vs. 1.607; p<0.0001). In screening for emergency caesarean section for

fetal distress, for a 10% false positive rate, the detection rate with the ratio of the right to

the left cardiac output was higher that with the left cardiac output (41% vs. 29%) and with

the CPR (41% vs. 27%). Similarly, the positive predictive value for the ratio of right to left

cardiac output (45%) was higher than for left cardiac output (37%) and for the CPR (35%).

Conclusion: In AGA fetuses at term that develop intrapartum distress, there is evidence of

prelabour redistribution of the cardiac output. The ratio of the right to the left cardiac

output is superior to the left cardiac output and CPR in predicting intrapartum fetal distress.

Such assessments may be useful in stratifying patients for intensity of monitoring during

labour.

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ACKNOWLEDGEMENTS

I am grateful to my supervisors, Professors Phillip Bennett and Sailesh Kumar, for their

invaluable help and guidance in my research.

I wish to thank the doctors and midwifes in the Department of Obstetrics at Queen

Charlotte’s and Chelsea Hospital for their immense help in recruiting patients and

supporting my research. My special thanks go out to Dr Tom Prior, for his invaluable help

and suggestions during my period of study.

I thank my parents who guided me to take up this noble profession. My wife, the silver

lining of every cloud in my life, has provided her unwavering support and encouragement

during my study; and my children who have accepted the importance of advancing in my

studies even if this was at the expense of time spent with them.

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STATEMENT OF CANDIDATE CONTRIBUTION

I generated the hypothesis for the studies in this thesis together with my supervisors

Professors Phillip Bennett and Sailesh Kumar. I developed the study design and

methodology with the assistance from my supervisors. I undertook all the ultrasound

assessments, data collection, statistical analysis and wrote this thesis.

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CONTENTS

Chapter 1 Introduction and literature review 12

1.1 Placental development and fetoplacental circulation:

Impact on fetal growth 14

1.2 Intra partum hypoxia and neural injury 15

1.3 Antenatal and intrapartum assessment of fetal well-being 17

1.4 Role of ultrasound to monitor growth and fetal well-being 20

1.5 Amniotic fluid volume 26

1.6 Meconium stained liquor 28

1.7 Doppler ultrasound in assessment of fetal well-being 29

1.8 Fetal cardiac function 40

1.9 Summary 46

Chapter 2 Methods 47

2.1 Introduction 47

2.2 Aim 47

2.3 Hypothesis 47

2.4 Methods 48

2.5 Ultrasound assessment 49

2.6 Fetal cardiac function 52

2.7 Diastolic function 52

2.8 Systolic function 54

2.9 Left ventricular myocardial performance index (LV-MPI) 56

Chapter 3 Pilot study 58

3.1 Introduction 58

3.2 Aims 58

3.3 Materials and Methods 59

3.4 Results 60

3.5 Discussion 65

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Chapter 4 Pre-labour assessment of fetal cardiac function 68

4.1 Introduction 68

4.2 Aims 68

4.3 Hypothesis 69

4.4 Methods 69

4.5 Analysis of data 70

4.6 Results 71

4.7 Maternal demographics and ultrasound parameters 75

4.8 Cerebro -placental ratio (CPR) or Cerebro -umbilical ratio (C-U ratio) 78

4.9 Fetal cardiac function 82

4.10 Summary of fetal cardiac function 118

4.11 Amniotic fluid index (AFI) 119

4.12 Deepest vertical pool of liquor (DVP) 120

4.13 Intrapartum monitoring 122

4.14 Neonatal outcomes 124

4.15 Estimated fetal weight (EFW) and outcome 128

Chapter 5 Cardiac functional parameters, cerebroplacental ratio and risk of

adverse obstetric and neonatal outcomes 132

5.1 Maternal demographics and mode of delivery 132

5.2 Maternal demographics and ultrasound parameters 135

5.3 Ethnicity and ultrasound parameters 136

5.4 Cerebro -placental ratio (CPR) 138

5.5 Fetal cardiac functional parameters 140

5.6 Intrapartum and neonatal outcomes 152

Chapter 6 Fetal cardiac function and cerebroplacental ratio in the prediction

of adverse intrapartum outcome 159

6.1 Performance of screening in prediction of intrapartum fetal distress at term 159

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Chapter 7 Conclusions 163

7.1 Strengths and limitations 163

7.2 Conclusions 167

7.3 Potential clinical application and further research 169

REFERENCES 176

PERMISSIONS 187

APPENDICES 198

ABBREVIATIONS 203

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FIGURES

Figure 1.1: Hypoxic ischemic injury 16

Figure 1.2: Doppler indices 30

Figure 1.3: Umbilical artery waveform 31

Figure 1.4: Umbilical artery Pi 32

Figure 1.5: Umbilical artery Doppler abnormalities 33

Figure 1.6: Middle cerebral artery Doppler 34

Figure 1.7: Middle cerebral artery pulsatility index per gestation 35

Figure 1.8: Cerebroplacental ratio per gestation 37

Figure 1.9: Ductus venosus waveform 39

Figure 1.10: Right cardiac output across gestation 42

Figure 1.11: Left cardiac output across gestation 43

Figure 2.1: 2D Fetal cardiac Doppler-Diastolic function 53

Figure 2.2: 2D Fetal cardiac Doppler-Systolic function 55

Figure 2.3: 2D Fetal cardiac Doppler-MPI 57

Figure 4.1: Flow chart of recruitment 71

Figure 4.2: Maternal age and ultrasound parameters 75

Figure 4.3: BMI and ultrasound parameters 76

Figure 4.4: Gestational age and ultrasound parameters 77

Figure 4.5: CPR distribution 79

Figure 4.6: CPR centile and mode of delivery 81

Figure 4.7: RV stroke volume distribution 85

Figure 4.8: Right cardiac output distribution 88

Figure 4.9: Distribution of Ejection time at Aorta 91

Figure 4.10: Distribution of velocity time integral at Aorta 93

Figure 4.11: Distribution of LV stroke volume 95

Figure 4.12: LV stroke volume centile and M.O.D 97

Figure 4.13: Distribution of LCO/mL/min/kg 99

Figure 4.14: LCO centiles and M.O.D 101

Figure 4.15: Distribution of the difference between RV and LV stroke volume 103

Figure 4.16: Difference between RV and LV stroke volume per centile and M.O.D 105

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Figure 4.17: Distribution of difference between RCO and LCO 106

Figure 4.18: Difference between RCO and LCO by centile and M.O.D 108

Figure 4.19: Ratio of RCO to LCO by centile and M.O.D 111

Figure 4.20: Correlation between RCO and LCO ratio with CPR and EFW 112

Figure 4.21: ROC curve to predict CS for fetal distress by ratio of the RCO to LCO 113

Figure 4.22: Distribution of CCO/mL/min/kg 114

Figure 4.23: Distribution of LV-MPI 116

Figure 4.24: Meconium-stained liquor and M.O.D 123

Figure 4.25: Correlation between estimated and actual birth weight 130

Figure 5.01: Correlation between VTI Aorta and LV stroke volume 143

Figure 5.02: Factors affecting Stroke volume 148

Figure 6.01: Prediction of CS-fetal distress by LCO, CPR and RCO to LCO ratio 160

Figure 6.02: PPV for CS-fetal distress by LCO, CPR and RCO to LCO ratio 161

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TABLES

Table 1.1: NICE guidelines for electronic fetal heart rate monitoring interpretation 18

Table 1.2: Cardiac function parameters 45

Table 3.1: Maternal demographics, ethnicity and onset of labour 61

Table 3.2: Indication and M.O.D 62

Table 3.3: Fetal Doppler and M.O.D 62

Table 3.4: Fetal cardiac function parameters and M.O.D 64

Table 3.5: Inter and Intra observer variability 65

Table 4.1: Maternal demographics, ethnicity and onset of labour 72

Table 4.2: Indication and M.O.D 73

Table 4.3: Maternal demographics, ethnicity and M.O.D 73

Table 4.4: Ethnicity and important ultrasound parameters 78

Table 4.5: Relation between UA Pi, MCA Pi, CPR and M.O.D 78

Table 4.6: Descriptive statistics of CPR 79

Table 4.7: Dunn’s multiple comparison tests – CPR 80

Table 4.8: Fetal cardiac function assessment and M.O.D 83

Table 4.9: Descriptive statistics of RV Stroke volume 86

Table 4.10: Dunn’s multiple comparison tests – RV stroke volume 86

Table 4.11: Descriptive statistics of RCO/mL/min/kg 88

Table 4.12: Dunn’s multiple comparison tests – RCO/mL/min/kg 89

Table 4.13: Descriptive statistics of Ejection time at Aorta 92

Table 4.14: Dunn’s multiple comparison tests – Ejection time at Aorta 92

Table 4.15: Descriptive statistics of VTI Aorta 94

Table 4.16: Dunn’s multiple comparison tests – VTI Aorta 94

Table 4.17: Descriptive statistics of LV Stoke volume 96

Table 4.18: Dunn’s multiple comparison tests – LV Stroke volume 96

Table 4.19: M.O.D and LV stroke volume by centile 97

Table 4.20: Descriptive statistics of LCO/mL/min/kg 99

Table 4.21: Dunn’s multiple comparison tests – LCO/mL/min/kg 100

Table 4.22: M.O.D and LCO/mL/min/kg by centile 101

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Table 4.23: Difference between RV and LV stroke volume 104

Table 4.24: Dunn’s multiple comparison tests – RV and LV stroke volume difference 104

Table 4.25: M.O.D and difference between RV and LV stroke volume by centile 106

Table 4.26: Descriptive statistics of difference between RCO and LCO 107

Table 4.27: Dunn’s multiple comparison tests – Difference between RCO and LCO 107

Table 4.28: Difference between RCO and LCO by centile and M.O.D 109

Table 4.29: Descriptive statistics of ratio of RCO to LCO 110

Table 4.30: Dunn’s multiple comparison tests – ratio of RCO to LCO 110

Table 4.31: Ratio of RCO to LCO by centile and M.O.D 111

Table 4.32: Descriptive statistics of CCO/mL/min/kg 115

Table 4.33: Dunn’s multiple comparison tests of CCO/mL/min/kg 115

Table 4.34: Descriptive statistics of LV-MPI 117

Table 4.35: Dunn’s multiple comparison tests of LV-MPI 117

Table 4.36: Descriptive statistics of AFI 119

Table 4.37: Dunn’s multiple comparison tests of AFI 119

Table 4.38: Descriptive statistics of DVP 120

Table 4.39: Dunn’s multiple comparison tests of DVP 121

Table 4.40: Comparison of CTG with important ultrasound parameters 122

Table 4.41: APGAR score and delivery outcomes 124

Table 4.42: Cord pH and mode of delivery 125

Table 4.43: Arterial pH and delivery outcome 126

Table 4.44: Indication and M.O.D by centiles of the arterial pH 126

Table 4.45: Base excess -descriptive statistics 127

Table 4.46: Dunn’s multiple comparison tests of base excess 127

Table 4.47: Descriptive statistics of EFW and M.O.D 128

Table 4.48: Dunn’s multiple comparison tests of EFW 129

Table 4.49: Difference between EFW and actual birth weight 130

Table 5.01: Correlation of Maternal demographics and ultrasound parameters 135

Table 7.01: Relative risk and likelihood ratios in prediction of CS for fetal distress 167

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Chapter 1 Introduction and literature review

In pregnancies with some degree of uteroplacental insufficiency the fetus may either be

small for gestational age (SGA) or it may be appropriate for gestational age (AGA) but with

reduced nutritional and energy reserves leading to intrapartum compromise and neonatal

complications.(1) Although the traditional methods of antenatal monitoring, such as

measurement of symphysis-fundal height, or even routine ultrasound examination in the

third trimester may to varying degrees identify SGA fetuses, these methods cannot detect

compromised AGA fetuses.

Most neonatal neurological injuries predate labour; however, intrapartum hypoxia is also

associated with a significant risk of asphyxia and asphyxia-related morbidity and mortality.

Most of the malpractice claims analyses suggest that a large proportion may be

preventable.(2) There is a growing epidemic of medical malpractice litigation around the

world. Donn et al. in his article, describing the medico legal implications of hypoxic ischemic

injury concluded that brain damaged infants are among the costliest medical lawsuits in the

United States with an average indemnity claim of around half a million dollars. It is alleged

that extended period of intrapartum asphyxia may be associated with these events resulting

in long-term morbidities such as cerebral palsy and neurodevelopmental delay; however, it

is not possible to clearly establish a link between the duration of Intrapartum asphyxia and

the risk of abnormal neurodevelopmental outcome and mental handicap.(3)

Intrapartum hypoxia/ischemia occurs in around 8–28% of pregnancies,(4) but the majority of

them usually have an uneventful outcome. The majority (65%) of children diagnosed with

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cerebral palsy (CP) are born at term and the incidence of CP has not declined in the past 30

years despite advances in intrapartum care.(5) It still remains as one of the leading causes of

childhood disability with a significant risk of neurodevelopmental delay and mental

handicap.(6)

Cerebral palsy has been monitored in western Sweden for more than 50 years, which

showed a stable incidence of 2 per 1000 live births although; the prevalence is much higher

in babies born before 26 weeks. Himmelmann et al. analysed the birth period from 2003 to

2006 in western Sweden and observed similar findings of CP when compared to earlier

studies and found that hemiplegia was the most common type (44%) of CP followed by

Diplegia (29%). They also noted that 46% of CP in their population group were due to

perinatal causes and 36% of the cases were associated with neonatal causes.(6)

While there is significant progress and improvement in the quality of antenatal, intrapartum

and new-born care, cases of hypoxic-ischemic injury have not decreased. A systematic

review on electronic fetal heart rate monitoring that included 37000 pregnancies from 13

trials concluded that electronic fetal heart rate monitoring assessment during intrapartum

period resulted in a significant increase in the caesarean section and instrumental vaginal

delivery rates with no significant difference in the CP rates.(7) It is still not clear why some of

the AGA fetuses at term do not tolerate labour despite antenatal and intrapartum

surveillance.

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1.1 Placental development and fetoplacental circulation – Impact on fetal growth

Placental development begins in the first week after fertilisation when implantation is

initiated and involves the syncytiotrophoblast, cytotrophoblast, extraembryonic mesoderm

and the uterine (endometrial layer) tissues. Shortly after the blastocyst contacts the uterine

wall, the syncytiotrophoblast invades and erodes the maternal tissue which then forms

lacunae by the 9th day. By the 12th day, these lakes fill with maternal blood as the

syncytiotrophoblast erodes through uterine blood vessels. Placental villi begin to form by

day 13, which consists of a layer of syncytiotrophoblast and a core of cytotrophoblast and

protrude into the lacunae assisting in placental development.(8) Blood vessels from the

embryo continue to grow while the trophoblast continues its vascular invasion into the

uterine wall. The trophoblast cells continue to develop into more placental villi into which

the fetal capillaries grow to establish the fetal-maternal circulation.

Defective modelling of the spiral arteries is associated with an adverse obstetric outcome

resulting in fetal growth restriction and pre-eclampsia.(9) The histological changes which

occur in the placenta complicated by pre-eclampsia include increased number of syncytial

knots, areas of fibrinoid necrosis, proliferation of the media of the vessel wall with areas of

calcification and hyalinization.

Odibo et al. analysed the morphometric analysis of placenta and observed that reduced

volume and surface area of the terminal and intermediate villi were seen in pregnancies

complicated by SGA and pre-eclampsia.(10) Although defective placentation is associated

with abnormal outcome, the degree of abnormalities in deep placentation was found to be

different in the clinical presentations in pregnancies complicated by SGA and pre-eclampsia.

Kovo et al. in their study observed that in pregnancies affected by pre–eclampsia there is

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defective maternal vascular supply lesions while in those with SGA fetuses there is evidence

of defective fetal vascular supply lesions.(11)

1.2 Intrapartum hypoxia and neural injury

Raised intra-uterine pressure during labour also reduces the uterine blood flow velocity by

up to 60% resulting in intrapartum fetal compromise.(12) These changes are more observed

in nulliparous women compared to multiparous women. The fetus responds to the reduced

volume of blood by redistributing to the vital organs, particularly the brain to prevent

cerebral hypoxemia, commonly referred to as “brain sparing effect”. These changes are

commonly seen in SGA fetuses.

Hypoxic ischemic injury (HII) to the brain frequently results in death or profound long-term

disability. Reduced cerebral blood flow results in brain ischemia due to cerebral hypoxemia

(Figure 1.1). Cerebral hypoxemia results in the conversion of oxidative phosphorylation to

anaerobic metabolism. This causes rapid depletion of adenosine triphosphate (ATP)

resulting in lactate accumulation within the cells eventually causing loss of normal cell

membrane function. This process triggers depolarization of presynaptic neuronal cell

membranes causing a massive release of glutamate, which binds to N-methyl d-aspartate

(NMDA) receptors. Activation of the NMDA receptors causes an influx of calcium ions,

triggering several cytotoxic processes and resulting in mitochondrial injury. This results in

further loss of ATP production and energy depletion causing apoptosis. The severity of brain

injury depends on the gestation at which the insult had occurred, the degree of brain

maturity and the duration of the abuse with severe changes occurring in preterm neonates

when compared to term fetuses.(13)

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Figure 1.1: Hypoxic ischemic injury. Taken from--Huang BY, Castillo M. Hypoxic-Ischemic Brain Injury: Imaging Findings from Birth to Adulthood. RadioGraphics 2008; 28: 417-39.

The pattern of brain injury varies depending on gestation and the degree of involvement.

This includes hypoxic-ischemic injury, intraventricular haemorrhage, periventricular

leukomalacia or delayed white matter injury which could then progress to post-anoxic

leukoencephalopathy.

The hypoxic-ischemic injury continues to be one of the leading causes of death and a

significant degree of neurodevelopment disability in term neonates. The earliest changes

are visualised within the deep grey matter affecting predominantly the thalamus, putamen,

hippocampus, dorsal brain stem and lateral geniculate nuclei which contain the highest

concentration of NMDA receptors that are susceptible to maximum injury. The reminder of

the cerebral cortex is usually spared unless there is prolonged insult to the brain.

Periventricular leukomalacia, referred to as white matter injury of prematurity, occurs,

especially in preterm infants. The prevalence of injury is inversely related to the gestation

with severe preterm babies being more affected when compared to the term infants. The

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injury is related principally to the white matter region of the brain which appears to be less

perfused compared to rest of the brain resulting in lesions adjacent to the cerebral lateral

ventricles and foramen of Monro. The neurological injury results in visual impairment and

motor impairment causing spastic diplegia.(13)

1.3 Antenatal and intrapartum assessment of fetal well-being

The earliest evidence of fetal monitoring was in 1818 when Francois–Isaac Mayor of Geneva

reported that the fetal heart rate was audibly different from the maternal pulse by applying

the ear directly to the mother's abdomen. In 1827, Ferguson was the first physician in the

British Isles to describe the fetal heart sounds. The methods of fetal auscultation and

monitoring have significantly improved over the years due to improvement in modern

technology and invention, and we have now progressed from fetal stethoscope to electronic

fetal heart rate monitoring; however, the addition of diagnostic ultrasound with Doppler

applications has made a significant contribution to the current management of clinical

obstetrics.

Electronic fetal heart rate monitoring or commonly known as Cardiotocography (CTG) is a

technical way of recording the fetal heartbeat and the uterine contractions in the third

trimester. It is used to monitor fetal wellbeing and identify fetal distress which is

represented by abnormal tracing and therefore requires active management in labour.

Electronic fetal heart rate monitoring analysis and interpretation is a description of uterine

activity (contractions), baseline fetal heart rate, baseline fetal heart rate variability,

presence of accelerations and periodic or episodic decelerations. Electronic fetal heart rate

monitoring analysis and interpretation is performed in the U.K according to the NICE

guidelines on intrapartum care (Table 1.1).(14)

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Category Definition

Normal All four features fall in the reassuring category

Suspicious One feature is in the non-reassuring category but the other three are reassuring

Pathological >2 feature in the non-reassuring category or <1 in abnormal categories

Feature Baseline (bpm) Variability

(bpm)

Decelerations Accelerations

Reassuring 110-160 >5 None Present

Non-

reassuring

100-109

161-180

< 5 or >40 to

<90 minutes

1.Early decelerations

2.Variable decelerations

3.Single prolonged

deceleration up to 3 minutes

The absence of

accelerations with an

otherwise normal CTG

are of uncertain

significance

Abnormal <100

>180

Sinusoidal

pattern ≥ 10 min

<5 for ≥ 90

minutes

1.Atypical variable

decelerations

2.Late decelerations

3.Single prolonged

4.Single, prolonged

decelerations >3 minutes

The absence of

accelerations with an

otherwise normal CTG

are of uncertain

significance

Table 1.1: NICE guidelines for electronic fetal heart rate monitoring interpretation

Ananth et al. published results of a retrospective study of more than 55 million non-

anomalous live births of fetuses between 24 to 44 weeks of gestation over a period of 15

years (1990 - 2004). They observed that use of electronic fetal monitoring was modestly

associated with a decline in neonatal mortality especially at preterm gestations.(15) Despite

published guidelines by FIGO and NICE there is still a wide variation in inter and

intraobserver variability in interpretation of the electronic fetal heart rate monitoring which

could result in the sub-optimal management leading to various medico – legal claims.(16) A

systematic review by Alfirevic et al. on the effectiveness of continuous electronic fetal

monitoring during labour showed a reduction in neonatal seizures; however, there were no

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significant differences in cerebral palsy, infant mortality rate or other standard measures of

neonatal well – being.(7) Similarly, a Cochrane review on fetal echocardiogram during labour

showed no significant difference to birth by caesarean section, the rate of severe metabolic

acidosis or the number of babies with neonatal encephalopathy.(17)

Fetal blood sampling (FBS) from the fetal scalp is used as an adjunctive diagnostic test when

abnormal electronic fetal heart rate monitoring is noted to quantify fetal hypoxemia or

academia. Studies have shown that FBS with a pH of less than 7.20 has a higher specificity

than a pathological electronic fetal heart rate monitoring to predict low APGAR score at 1

minute.(18) Although FBS is a useful additional investigation in the evaluation of intrapartum

hypoxia, it is still an invasive procedure which could be technically challenging at times, and

is not possible to obtain sample in all the cases.

A systematic review by East et al. in 2010 on fetal blood sampling observed that successful

fetal blood sample on the first attempt could only be achieved in around 80% of the cases.(19)

The average time from procedure to obtain the results after FBS was reported to be around

18 minutes which could delay the crucial time in delivery of a previously distressed fetus

posing a greater risk to intrapartum hypoxia. Furthermore, there was also a high risk of

sample contamination due to the complexity of the procedure affecting the accuracy of the

results.(19)

The NICE guidelines recommend the use of FBS in the presence of a pathological heart trace

unless there is clear evidence of acute fetal compromise or in cases of suspected fetal

acidosis before contemplating an assisted birth for an abnormal heart trace. Although FBS is

a useful adjunctive test following an abnormal trace, there is no evidence to show that FBS

can improve neonatal outcome or reduce the incidence of caesarean section rates for fetal

compromise.(18)

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Fetal pulse oximetry was introduced in the late 1980's hoping that it would assist in the

intrapartum management and identify fetuses that are at risk of fetal hypoxia following a

non – reassuring electronic fetal heart rate monitoring tracing. Fetal pulse oximetry is

performed by using a probe that rests on the fetal head which is held either by suction or

clip while the head is still within the maternal pelvis. It can also be positioned over the fetal

cheek or against the fetal temporal bone or to lie on the fetal back. The sensors measure

the proportion of the fetal haemoglobin, which is used to calculate the percentage of

oxygen saturation. Lower oxygen saturation readings can occur with reduced arterial

perfusion suggestive of fetal acidosis. Typical normal values range between 58 to 68%.

Values less than 30% are considered significant and warrant intervention ranging from a

change in maternal posture to emergency delivery by caesarean section.(20)

Systematic review studies by East et al. in 2007 reported no significant difference in the

overall caesarean section rates among the group of fetuses that were monitored with fetal

oximetry when compared with the group those not monitored.(21) Recent systematic review

in 2014 performed by the same study group concluded that the addition of fetal pulse

oximetry did not reduce overall caesarean section rates suggesting that fetal pulse oximetry

does not contribute to overall clinical practice.(22)

1.4 Role of ultrasound to monitor growth and fetal well-being

History of ultrasound

Evidence suggest that the use of ultrasound in medicine began during or shortly after the

second world war although initial discoveries in ultrasound date back as early as 1794 by

Lazaro Spallanzani when analysing the spatial orientation of the bats observed that there

was another mechanism in addition to the visual -ophthalmic system. In 1826 Jean –Daniel

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Colladon, could determine the speed of sound in water. Many researchers by then were

working towards defining the fundamental physics of sound vibrations and its properties of

transmission, propagation and refraction. However, in 1877, Lord Rayleigh described sound

wave as a mathematical equation thus forming the basis of future practical work in

acoustics.(23)

Pierre Curie and Jacques Curie in 1880 discovered that individual rare earth crystals like lead

zirconate titanate can resonate when subjected to vibration by electrical stimulation or

mechanical stress. This is called the piezo–electric effect which formed the basis in evolution

of high-frequency echo-sounding techniques.(24)The medical use of ultrasound began in

1920's when it was mostly therapeutic due to its initial thermal and disruptive effects noted

in animal tissue experiments.

Langevin et al. in the initial studies indicated that pain could be induced in the hand when

placed in a water insonated with high-intensity ultrasound. This technique progressively

evolved to be used in neurosurgical applications when its thermal effects were used to

destroy parts of the basal ganglia and the frontal lobe to alleviate pain in patients suffering

from carcinomatosis. Ultrasound has also been used in physical and rehabilitation medicine

in 1953 in the treatment of rheumatoid arthritis and Meniere's disease.

The work of Ian Donald in 1956 resulted in the significant transfer of ultrasound technology

into clinical practice. His findings of the Investigation of abdominal masses by pulsed

ultrasound in 1958 is still considered the most important paper ever published in medical

ultrasound.(25) His first invention and follow up work by many researchers have thus paved

the way for modern medical imaging resulting in significant developments in the ultrasound

technology starting from the basic ‘A' mode static scanner to the present real-time

imaging.(26)

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The principle component of the ultrasound equipment is the ultrasound transducer or the

probe, which has a series of piezo –electric crystals that function both as transmitter and

receiver. Ultrasound equipment uses frequency range above 20,000 Hz that is not audible to

the human ear. The frequencies used in medical ultrasound can vary between 2MHz to

18MHz depending upon its clinical use. It is known that higher ultrasound frequency has a

lower penetration with improved resolution while lower frequencies have greater

penetration with a compromise on the image resolution. There are selections of probes

available with different frequencies to choose for appropriate application in modern clinical

practice.

Doppler ultrasound

The principle of Doppler ultrasonography is based on the “Doppler effect” proposed by the

Austrian physicist Christian Doppler in 1842. It is defined as the “change in the apparent

frequency of a wave as the observer and source move towards or away from each other”.

To explain this phenomenon, it is common to observe that the frequency of the ambulance

siren is more audible as the vehicle approaches towards the observer rather than away from

the observer. The emitted frequency from the ambulance siren is the same; however, when

the ambulance approaches towards the observer, the sound waves have a shorter

wavelength and higher frequency, making it more audible. While the ambulance is away

from the observer, the emitted sound waves will have a longer wavelength and lower

frequency making it less loud. This principle of Doppler shift has been used in diagnostic

imaging to study the movement of blood flow within the blood vessels. In Obstetrics, it is

particularly used to investigate changes that occur in the feto–placental and utero –

placental circulation.(27)

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Safety of Ultrasound

Ultrasound has now been in the clinical practice for over 40 years and is the safest imaging

modality in pregnancy. Unlike X-rays or CT scans that use ionising radiation, ultrasound

technology uses sound waves which are non –ionising for image acquisition. It was not long

after its clinical applications that concerns were raised regarding its safety in pregnancy due

to the properties of heating and cavitation and its effects while using in the first trimester.

Absorption of ultrasound energy into bone and soft tissue produces heat, which is measured

by the thermal index. Thermal index is defined as a measure of an ultrasound beam’s

thermal bioeffects. Thermal index represents the ratio of the power used in relation to the

power required to raise the temperature by 10 C.

The World Federation of Ultrasound in medicine and biology stated that “a diagnostic

exposure that produces a maximum in situ temperature of 1.50C above normal physiological

level might be used without reservations on thermal grounds”. They also stated that “a

diagnostic procedure that elevates embryonic and fetal in situ temperature above 410 C for

5 minutes should be considered potentially hazardous”.(28) Research on animal studies by

Zhu et al. showed that using diagnostic levels of colour Doppler in pregnant rats did not

affect the DNA content in any phase of the cell cycle confirming its safety in the first

trimester.(29) Most of the present-day ultrasound machines are enabled with a safety

feature to manually set the thermal index to 1 so that it automatically shuts down the

equipment if the thermal index is raised above 1 degree. There have not been any published

studies explaining the safety of ultrasound performed at early gestation, so it would be

prudent to avoid using Doppler studies during early pregnancy to prevent risk to the

developing fetus.

24

Cavitation is another property of ultrasound resulting in gaseous bubble formation when

there is an air–water interface. The collapse of these bubbles releases heat into the adjacent

tissues that may disrupt the cell membrane. Cavitation is not a primary concern in

mammalian tissues because for the most part; there is no air–water interface that is needed

for cavitation to occur.

Long-term effect of prenatal ultrasound

Despite its clinical use in Obstetrics for over 40 years, there has always been a concern

about the risks of its usage in pregnancy relating to fetal growth, mental development,

congenital malformations or chromosomal aberrations. However, there has not been any

published reports citing concerns on the long-term adverse following its clinical application.

Torloni et al. in 2009 performed a WHO systematic review and meta-analysis on the safety

of ultrasonography in pregnancy and concluded that ultrasonography in pregnancy

appeared to be safe and was not associated with adverse maternal or perinatal outcome. It

was also not associated with increased risk of malignancy in childhood, subnormal

intelligence or mental illness. However, some of the studies in the analysis showed a weak

association between exposure to ultrasonography and left-handedness.(30)

Despite the safety of ultrasound in clinical practice, we are still unaware of the long-term

outcomes. Safety and departmental guidelines must therefore be strictly adhered when

performing ultrasound examination at any gestation; with emphasis on keeping the

mechanical and thermal index at optimum levels and the appropriate use of fetal Doppler. It

is good practice adhering to the ALARA (As Low As Reasonably Achievable) principle, which

would also apply to the ultrasound examinations like any other imaging investigation.

25

Obstetric ultrasound – from conception to delivery

Obstetric ultrasound is an essential complementary tool in modern obstetric practice, and

widely used across all gestations from conception to delivery. The use of ultrasound begins

as early as 4 - 5 week’s post-conception to confirm the pregnancy location, calculate the

period of gestation and to confirm the presence of fetal pole and cardiac activity. Follow-up

scans are performed in the first trimester for calculation of the gestational age by the

crown-rump length of the fetus (CRL) and to complete the fetal risk assessment for

aneuploidy. Second-trimester scans are usually performed between 18 to 22 weeks to check

for fetal biometry, assessment for fetal abnormalities and soft markers for fetal aneuploidy,

cervical screening and evaluation of uterine artery Doppler. Third-trimester scans are

performed to check for fetal growth, placental localisation, amniotic fluid volume, and the

estimated fetal weight to formalise the delivery plan.(31)

Doppler evaluation of uteroplacental and fetoplacental circulation is performed in addition

to the routine scans for fetuses at risk of developing growth restriction to assist in the

clinical management. Ultrasound is also being used in post-dated pregnancies and in fetuses

before induction of labour to confirm the fetal presentation, placental location and amniotic

fluid volume to assist in further clinical management. The markers for fetal wellbeing

include checking the fetal biometry against growth charts for gestation, amniotic fluid

volume and Doppler ultrasound in fetuses to exclude fetal growth restriction. (32)

There are different formulae and nomograms available to calculate the fetal weight using

the biometry measurements. The most commonly used are the Hadlock formula which

could predict the fetal weight with a mean error of 10 -15 % in most of the cases. Estimation

of the fetal weight is important to classify fetuses whether they are appropriately grown,

26

macrosomic, small for gestation (SGA) or FGR. This is important as it would alter the

management of pregnancy depending on the cause.(33)

SGA fetuses describe a population of fetuses with the estimated fetal weight below the 10th

centile or severe if they are below the 3rd centile for the gestation. It is important to note

that FGR fetuses are not synonymous with SGA fetuses in which the reduction in fetal

weight is associated with abnormal Doppler changes. There is enough evidence to suggest

that FGR fetuses have an increased risk of adverse perinatal and intrapartum outcome

compared to appropriately grown fetuses.(34)

Early-onset FGR has a distinct pattern of disease evolution that usually manifest in the 1st or

2nd trimester due to abnormal placentation. Early-onset FGR is primarily due to a vascular

disease of the placenta and can be associated with pre-eclampsia. Late onset FGR manifests

around 32 weeks or later due to suboptimal placental function. In late onset IUGR, the

umbilical artery Doppler findings are normal in contrast to early onset FGR fetuses; however,

there is abnormal middle cerebral artery Doppler and altered cerebro-placental ratio due to

cerebral hypoxemia.

While growth restricted fetuses are identified by potential markers of fetal well-being, there

appears to be a small group of AGA fetuses at term with a sub-optimal placental function

that tolerate labour poorly. It's currently not possible to identify these fetuses at risk of

adverse intrapartum outcome.(35)

1.5 Amniotic fluid volume

Amniotic fluid serves several important functions in the normal development of the embryo

and the fetus. It acts as a cushion for the fetus against physical trauma and helps in the

mobility of the fetus within the uterus during its growth and development. It also provides a

27

thermally stable environment during intrauterine life. Amniotic fluid is also useful in the

normal development of the respiratory, gastrointestinal and the musculoskeletal system of

the fetus.

During early gestation, the chorion –amnion acts as a sieve allowing free passage of water,

solutes and electrolytes constituting the amniotic fluid. Diffusion occurs through the

embryonic skin derived from the epiblast of the b-laminar embryonic disc which occurs

during the mid to late first trimester. In the latter half of the gestation, fetal kidney and

lungs are the primary sources of production with fetal urine constituting the main source of

amniotic fluid. There is a steady increase in the amniotic fluid volume, starting as little as 1

ml at seven weeks to 25 ml at ten weeks and 60 ml at twelve weeks. The amniotic fluid

volume then reaches a maximum (630-817 ml) at mid-trimester and remains through until

39 weeks and then begins to decline due to reduced urine production and reduced placental

function.(36)

Manning and Platt suggested the importance of reduced amniotic fluid in growth restricted

fetus indicating that poor placental function was associated with reduced liquor volume.(37)

In 1980, the same research group used the maximum vertical pool measurement (MVP) in

the calculation of fetal biophysical score assessment for fetal well-being.(38) MVP less than 2

cm was considered as oligohydramnios and MVP greater than 8 cm was considered

polyhydramnios. Chamberlain et al. in 1984 performed a retrospective analysis and

concluded that MVP less than 1 cm was associated with FGR in 78.8 to 89.6% reflecting poor

placental function as a cause for reduced liquor volume.(39) Hypoxemia resulting from a poor

placental function in FGR fetuses can cause redistribution of the cardiac output resulting in

poor renal perfusion explaining the oligohydramnios in these fetuses.

28

Post-term fetuses have increased morbidity with increased risk of meconium aspiration,

fetal post maturity, and fetal death. The cause remains unclear although the likely

explanation would be due to reduced renal perfusion as explained before. Bar-Hava et al.

looked at post-term pregnancies with oligohydramnios to observe if they differed in their

umbilical, middle cerebral and renal blood flow distribution when compared with a control

population of fetuses with normal amniotic fluid volume. They observed that there was no

significant difference when matched for the blood flow; however, fetuses with

oligohydramnios had low birth weights compared with control group concluding that

oligohydramnios was associated with low birth weight rather than renal perfusion.(40)

Follow-up studies by Selam et al. however, disagreed with the previous findings as their

group observed that oligohydramnios in post-term pregnancies is associated with an arterial

distribution of fetal blood flow typical of brain sparing effect evidenced by decreased

resistance in the middle cerebral artery and the fetal IVC.(41)

1.6 Meconium stained liquor

Pregnancies complicated with meconium stained liquor are at risk of adverse outcome. The

amniotic fluid is a relatively clear yellow coloured liquid until later in gestation when it

becomes more turbid due to the shedding of fetal cells and the vernix. Meconium is the

earliest stool of a mammalian infant. It is mainly composed of materials ingested by the

intrauterine fetus. It is rarely passed into the amniotic fluid before 34 week's gestation

which relates to fetal maturity.

There is controversial evidence to suggest that meconium stained liquor is indicative of

intrapartum hypoxia. Numerous studies have shown that passage of meconium is a sign of

fetal maturity reflecting a normal physiological event. Animal experiments have suggested

29

that passage of meconium is physiological and occurs in term fetuses which increased with

advanced gestation.(42) Meconium stained amniotic fluid (MSAF) in the presence of normal

electronic fetal heart rate monitoring is reassuring with no significant risk of adverse

outcome(43) however, meconium stained liquor associated with oligohydramnios and

abnormal electronic fetal heart rate monitoring in a fetus are suggestive of adverse

outcome.

The most important complication of MSAF is meconium aspiration syndrome, which occurs

in 5% of fetuses that have meconium stained liquor. It is a cause for concern as meconium-

stained amniotic fluid is associated with a mortality rate of about 2.5% in the developed

world and up to 35% in the developing countries.(44)

Aspiration of meconium stained amniotic fluid results in chemical pneumonitis and may

progress to persistent pulmonary hypertension.(44) Study by Beligere et al. observed a

significant risk of neurodevelopmental delay in children affected by meconium aspiration

syndrome even though they responded well to conventional ventilator support.(45) Similarly,

preterm fetuses and SGA fetuses with meconium stained liquor are associated with

additional adverse pregnancy outcomes when compared with appropriately grown term

fetuses.(46)

1.7 Doppler ultrasound in assessment of fetal well-being

Doppler ultrasound in clinical practice relies on the movement of red blood corpuscles

within the blood stream. When an ultrasound beam with a specific frequency is used to

insonate a blood vessel, the reflected frequency is directly proportional to the speed with

which the red blood cells are moving within that vessel and is represented as a waveform

for interpretation.

30

The size of the Doppler signal is directly proportional to the velocity of the blood and the

frequency of the ultrasound beam. The frequency shift is also largely dependent on the

angle of insonation of the ultrasound beam with the maximum output obtained when the

sound beam is parallel to the flow.(47, 48)

The common Doppler indices that are used in the clinical practice are (Figure 1.2):

1. Pulsatility Index (Pi) = Peak systolic flow velocity – Trough diastolic flow velocity / Mean

blood flow velocity. This is the most commonly used index because it gives a broader

range of values for analysis and also a series of waveform shapes when there is no end

diastolic flow.(47)

2. Resistive index (Ri) = Peak systolic flow velocity – Trough diastolic velocity / Peak

systolic flow velocity

3. Systolic –Diastolic ratio (S/D ratio) = Peak systolic flow velocity / Trough diastolic

velocity

Figure 1.2: Doppler indices

31

Umbilical artery

The umbilical artery was the first vessel to be assessed by Doppler velocimetry. The

umbilical artery has a characteristic waveform (saw tooth appearance) with systolic and

diastolic components reflecting the cardiac cycle (Figure 1.3). Sampling is usually performed

at either the fetal end or the placental end of the cord insertion, although impedance

indices are noted to be higher close to the fetal cord insertion.(49)

Figure 1.3: Umbilical artery waveform

With advancing gestation, there is a steady progressive decline, in the end diastolic velocity

resulting in decreased pulsatility indices (Figure 1.4).(50) There are no noticeable diurnal

changes in pregnancy that may affect the umbilical artery blood flow; however, the blood

flow decreases with fetal expiration, and therefore it is preferable to obtain the velocity

assessment during fetal quiescence.

32

Figure 1.4: Umbilical artery Pi. Taken from Parra-Cordero M, Lees C, Harris C. Taken from Fetal arterial and venous Doppler pulsatility index and time averaged velocity ranges. Prenatal Diagnosis 2007; 27: 1251-7

Previously published studies have shown an association with abnormal Umbilical artery

Doppler changes with poor placental function relating to an adverse outcome. The blood

flow resistance in the umbilical arteries is a reflection of increased resistance in the fetal

villous vascular tree and therefore poor placental function results in increased impedance to

the umbilical artery blood flow resulting in absent to reverse end diastolic flow (Figure

1.5).(51) The Cochrane review by Alfirevic et al. in 2007 concluded that use of Doppler

ultrasound in high-risk pregnancies was associated with a reduction in the risk of perinatal

deaths and therefore resulted in less obstetric interventions.(52)

33

Figure 1.5: Umbilical artery Doppler abnormalities. Taken from Baschat AA. Examination of the fetal cardiovascular system. Seminars in Fetal and Neonatal Medicine 2011; 16: 2-12.

While abnormal umbilical artery Doppler waveforms are associated with fetal growth

restriction, studies have also shown that fetuses with abnormal electronic fetal heart rate

monitoring tracing in the intrapartum period are associated with abnormal umbilical artery

waveform evidenced by raised pulsatility indices.(53) Similar studies in combination with

other fetal Doppler and electronic fetal heart rate monitoring were shown to be beneficial

in the evaluation of intrapartum fetal hypoxia.(54)Despite initial observations, subsequent

meta-analysis demonstrated that isolated finding of an abnormal umbilical artery was found

to be a poor predictor of adverse perinatal outcome.(48, 55)

34

Middle cerebral artery

Published studies have demonstrated the changes in Middle cerebral artery (MCA) Doppler

flow and the role of brain sparing in the prediction of adverse outcomes in fetal growth

restriction.(56) The MCA is the vessel of choice in intracranial Doppler assessment due to its

ideal anatomical location which allows the Doppler beam to insonate the vessel close to the

angle of zero degrees (Figure 1.6). There are also studies which have looked at the sampling

site of the vessel, and it is best preferred to sample the MCA proximal to its origin from the

internal carotid artery to decrease inter and intra-observer variability.(57) The MCA Pi usually

peaks from 22 weeks onwards up to until 28 weeks and then continues to show a gradual

decline towards term (Figure 1.8).(58) Growth-restricted fetuses had a decreased pulsatility

index of the MCA due to increased cerebral perfusion (Figure 1.7). Many studies support

that reduced MCA Pi is associated with an adverse perinatal outcome.(59, 60)

Figure 1.6: Middle cerebral artery Doppler. Taken from Baschat AA et al. Examination of the fetal cardiovascular system. Seminars in Fetal and Neonatal Medicine 2011; 16: 2-12.

35

Figure 1.7: Middle cerebral artery pulsatility index per gestation. Taken from Parra-Cordero M, Lees C, Missfelder-Lobos H, Seed P, Harris C. Fetal arterial and venous Doppler pulsatility index and time averaged velocity ranges. Prenat Diagn 2007; 27: 1251-7.

Cerebro-Placental ratio (CPR)

During fetal hypoxemia, there is an increase in the blood supply to the brain, myocardium

and the adrenal glands at the expense of reduced perfusion of the kidneys, gastrointestinal

tract and the lower extremities. This phenomenon called as ‘cerebral redistribution' or

‘brain sparing effect' was reported earlier in animal studies by Thornburg et al. in 1991.(61)

Wladimiroff et al. examined the cerebral and umbilical artery Doppler in normal and

growth-restricted fetuses and found that fetuses with growth restriction showed a raised Pi

in the umbilical artery and reduced index values in the internal carotid artery suggesting the

presence of ‘brain sparing effect'.(62)

Cerebroplacental ratio (CPR), which is the ratio of Pi in the MCA to that in the umbilical

artery, reflects both the placental status and the fetal response. The CPR was first reported

36

by Arbeille et al. that fetuses complicated by growth restriction or hypertension had a CPR <

1 compared to appropriately grown fetuses which had a CPR >1.(63) Several studies have

been published since then supporting the usefulness of CPR and it association in predicting

the risk of the adverse perinatal outcome in growth restricted fetuses.(64, 65) Longitudinal

reference ranges are available which show a gradual increase until 34 weeks and then

decline towards term (Figure 1.8).(66)

Bahado-Singh et al. analysed the fetal Doppler in 203 FGR fetuses and showed that lower

CPR was significantly associated with adverse perinatal outcomes associated with low birth

weight, meconium stained liquor, low APGAR scores, perinatal death and neonatal

admissions when compared with isolated umbilical artery Doppler changes.(67)

A multicentre prospective trial (PORTO study) by the Perinatal Ireland Research Consortium

looked at 1,100 consecutive singleton pregnancies over a two-year period. Adverse

perinatal outcome was defined by a composite score consisting of interventricular

haemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotising

enterocolitis, lung complications like bronchopulmonary dysplasia, neonatal sepsis and

death. The study showed that CPR less than 1 was associated with an 11-fold increase in the

risk of adverse outcome compared with normal CPR.(56)

37

Figure 1.8: Cerebroplacental ratio per gestation. Taken from Ebbing C, Rasmussen S, Kiserud T. Middle cerebral artery blood flow velocities and pulsatility index and the cerebroplacental pulsatility ratio: longitudinal reference ranges and terms for serial measurements. Ultrasound Obstet Gynecol 2007; 30: 287-96.

Some studies have shown that combining CPR with electronic fetal heart rate monitoring in

intrapartum surveillance reduces the risk of adverse intrapartum outcome and decreases

the risk of caesarean sections for fetal distress. Sirsistadis et al. in their prospective

controlled study looked at intrapartum outcomes in fetuses that were monitored by

electronic fetal heart rate monitoring alone and in combination with CPR. The results from

the study showed that fetuses with electronic fetal heart rate monitoring combined with

CPR had significantly lower rates of caesarean section for fetal distress and an improved

outcome with a lower risk of neonatal metabolic acidosis.(68)

Prior et al. performed a prospective observational study to predict intrapartum compromise

in AGA fetuses. He observed that fetuses delivered by caesarean section for fetal distress

38

had significantly lower CPR than those born by spontaneous delivery. Fetuses with CPR <10th

centile had a six-fold increased risk to be delivered by caesarean section while fetuses with

CPR >90th centile appeared protective of caesarean section for fetal distress.(69)

Ductus venosus

The venous vasculature in the fetus is primarily responsible in shunting significant amount

of oxygenated blood from the umbilical vein to the heart. The fetal liver along with the

venous vasculature consisting of the umbilical and portal veins, ductus venosus, hepatic vein

and the inferior vena cava play an import role in contributing to the pre-load to the heart.

The Ductus venosus (DV) is unique as it shunts a considerable amount of oxygenated blood

from the umbilical – portal system through the inferior vena cava to the right atrium. The

diameter of the DV is approximately 1/3rd of the umbilical vein. It courses posteriorly and

steeply in a cephalad direction as the original orientation of the umbilical vein and enters

the IVC in a venous vestibule below the diaphragm. The velocity of blood increases as it

passes through the DV due to its course and the narrow lumen.(70) It is estimated that in

normal fetuses, around 20-30% of the oxygenated blood bypasses the hepatic circulation

through the ductus venosus to reach to the right atrium.(26, 71) However, this could increase

up to 60% in fetal hypoxemia and growth restricted fetuses.(70)

The typical waveform in the Ductus venosus consists of a characteristic triphasic waveform

(Figure 1.9). The highest-pressure gradient occurring during ventricle systole between the

venous vessels and the right atrium is represented by the ‘S’ wave. Early diastole with

passive filling of the ventricles is associated with a second peak of forward flow which is

represented by the ‘D’ wave and the ‘a’ wave which represents atrial contraction, prevents

direct blood flow from the ductus venosus to the left atrium during this short period of

closure of foramen ovale. (72)

39

Figure 1.9: Ductus venosus waveform. Taken from Baschat AA. Examination of the fetal cardiovascular system. Seminars in Fetal and Neonatal Medicine 2011; 16: 2-12.

Many studies have shown abnormal ductus venosus flow in association with chromosomal

abnormalities, cardiac defects and adverse perinatal outcome.(73-75) Maiz et al. looked at the

combined data from eight studies and observed that abnormal DV blood flow was

associated with 87% of fetuses with cardiac defects, suggesting the use of DV as a secondary

marker in risk assessment of fetuses with raised nuchal translucency.(74, 76, 77)

Abnormal umbilical artery waveform evidenced by absent or reverse end-diastolic flow

represent an increased fetal-placental resistance. This is secondary to abnormal placental

villous vasculature resulting in poor nutritional transfer across the placenta in FGR fetuses.

Abnormal DV waveform account for a late vascular response in FGR fetuses resulting in

absent or reverse ‘a' wave. Further fetal compromise results in impaired cardiac pre-load

and afterload due to dysfunctional myocardium resulting in severe adverse perinatal

outcome including stillbirth.(72)

40

1.8 Fetal cardiac function

The importance of fetal echocardiography in diagnosing structural cardiac defects in utero is

well known. More recent research has allowed the prenatal cardiac function to be assessed

accurately.(78) Cardiovascular adaptations in utero secondary to placental insufficiency can

lead to altered fetal programming which persists in the form of subclinical cardiac and

vascular dysfunction and cardiac remodelling in neonates and children.(79) There is

substantial evidence that programming of adult cardiovascular disease begins prenatally

and fetal cardiac assessment can identify fetuses at risk of adverse perinatal outcome and

long-term cardiovascular dysfunction.(80)

Cardiac output and blood flow to the fetus in animal models suggest a right ventricular

dominance in the fetus compared to the postnatal life, and the reported ratio of right to left

cardiac output ranged from 1 to 1.5.(81) In the fetal lambs, the biventricular cardiac output in

the second half of pregnancy is approximately 450 mL/min/kg. Of this, about 60-65% of the

cardiac output is ejected by the right ventricle, and 35-40% is ejected by the left ventricle

thus giving a ratio of right to the left cardiac output of 1.5 o 1.85.(81) This cardiac ratio

changes postnatally with an increase in the left cardiac output to 240/mL/min/kg within the

first 2 hours and then stabilises to approximately 190 mL/min/kg. This decreases the left to

right shunt from 62 ml/min/kg to about 14 mL/min/kg.(81)

Studies in animal models have demonstrated changes in the fetal cardiac function in hypoxic

conditions and those with fetal growth restriction.(82) Chronic hypoxia induces adaptive

changes to the fetus in utero. These include erythropoiesis to increase oxygen transport,

angiogenesis in muscle to reduce oxygen diffusion distance, increase catecholamine release

and metabolic changes at a cellular level. Herrera et al. studied the cardiac effects of chronic

41

fetal hypoxia in rats that were independent of changes in nutrition in pregnancy. 30

pregnant rats in each group were housed under normoxic (21% oxygen) and hypoxic

conditions (13% oxygen) from Day 6 to Day 20 of the pregnancy. Pups that were housed

under hypoxic conditions showed a 176% increment in aortic wall thickness and a 170%

increment in the wall to lumen ratio of the fetal aorta when compared to the pups that

were kept under normoxic conditions.(83)(84) Pulgar et al. also observed that mild chronic

hypoxia induced by repeated cord occlusion in sheep showed a detrimental effect on fetal

cardiovascular and neurological outcomes.(85)

Tchirikov et al. measured the cardiac output and blood flow redistribution in fetal sheep

models subjected to hypoxia. He observed a significant reduction the values of p02, fetal pH

and base excess in hypoxic fetuses and a significant increase in the proportion of blood

passing through the ductus venosus in hypoxic fetuses resulting in the reduction in the

placental fraction of cardiac output and the right to left heart ratio.(86) Kiserud et al.

subsequently observed similar results when measuring the cardiac output in fetuses with

intrauterine growth restriction. They found that although the overall cardiac output was

maintained, the placental fraction of blood flow was lower due to increased fetal demands

resulting in increased recirculation of fetal blood flow.(87)

Following animal experiments, there have been studies on the application of conventional

and modern ultrasound techniques to measure fetal cardiac function with longitudinal

reference ranges in fetuses across the gestation. Mielke et al. performed a cross-sectional

study using 2D and Doppler echocardiography in 222 normal singleton fetuses from 13 to 41

week’s gestation (Figure 1.10 and 1.11).(81) The median biventricular cardiac output was

estimated to be 425 mL/min/kg with a clear right heart dominance evidenced by the right

cardiac output contributing to 59% to the total cardiac output. They had also observed that

42

the pulmonary flow to cardiac output was higher when compared to the lamb models. The

average normal cardiac output between 18-41 weeks gestation was about 425 /mL/min/kg

with one-third of the fetal combined cardiac output (CCO) being distributed to the placenta

in most of the second half of the pregnancy.(81)

The most significant change in the precordial veins when cardiac dysfunction occurs is

reflected as reversal or absence of ‘a' wave in the DV. It has been shown that reversed or

absent ‘a' wave is associated with a 63% risk of fetal and neonatal death.(88) Makikallio et al.

have shown that fetuses with elevated levels of markers of myocardial dysfunction

(Troponin or N –Terminal pro –atrial natriuretic peptide) also had abnormal Pulsatility index

of the ductus venosus and the IVC.(89)

Figure 1.10: Right cardiac output across gestation. Taken from G Mielke et al. Cardiac output and central distribution of blood flow in the human fetus. Circulation 2001; 103: 1662-1668.

43

Figure 1.11: Left cardiac output across gestation. Taken from G Mielke et al. Cardiac output and central distribution of blood flow in the human fetus. Circulation 2001; 103: 1662-1668.

Although early onset FGR confers a significant risk of perinatal mortality and morbidity,

constitutionally small fetuses have been considered to have a good prognosis.(90) However,

recent evidence suggests that a proportion of these fetuses that represent late onset fetal

growth restriction beyond 32 weeks also have a mild degree of placental insufficiency that is

not reflected on routine umbilical artery Doppler screening. These babies are at risk of

adverse neurodevelopment and cardiovascular disease in adult life.(91-93)

It is also shown that around 30% of late-onset SGA fetuses with normal umbilical artery

Doppler have increased myocardial perfusion indices suggesting that compromised cardiac

function.(94, 95)

44

M-Mode Echocardiography is the study of the two-dimensional motion of all structures

along the line of the ultrasound beam. This technique is primarily used to record both atrial

and ventricular activity to check for conduction and diagnose atrioventricular block. At late

gestation, shadows from adjacent structures and the ribs result in acoustic shadowing

leading to poor heart tracing and inconsistencies in obtaining the measurements. For these

reasons, we decided not to include the M-Mode assessment in the study of fetal cardiac

function in our studies.

Fetal echocardiographic assessment is routinely performed using 2D ultrasound with

Doppler. New techniques for assessment of fetal cardiac function, including the

spatiotemporal image correlation (STIC), tissue Doppler imaging and speckle tracking may

not be suitable for routine clinical application due to the complexity of the techniques and

the skill required to learn and reproduce with minimal inter and intra-observer variability. In

addition, the reproducibility of using 2D Doppler was better compared to using STIC. (78,96)

The table below illustrates the standard cardiac functional assessments performed by fetal

echocardiography in clinical practice (Table 1.2). For simplicity and if this would make a

difference to the clinical practice, we decided to use the standard 2D fetal echo assessment

of cardiac output in our study.

45

Cardiac functional parameters Definition Technique

Systolic Function

Cardiac output SV x Heart Rate 2D, Doppler, STIC

Systolic annular peak velocity Speed of movement of AV valve in systole Spectral or Colour TDI

Myocardial strain and strain rate Amount and speed of deformation of myocardial segment

Colour TDI or2D speckle tracking

Diastolic Function

Precordial vein blood flow patterns Pattern of blood flow during atrial contraction

Conventional Doppler

E/A Ratio Ratio between early and late ventricular filling velocity

Conventional Doppler

Diastolic annular peak velocity Speed of movement of AV valve at the beginning of and late Diastole

Spectral or Colour TDI

Isovolumetric relaxation time (IRT) Conventional or Spectral Doppler/ Colour TDI

Global Cardiac function

Myocardial performance index ICT + IRT / ET Conventional Doppler or spectral / Colour TDI

STIC – Spatiotemporal image correlation, TDI – Tissue Doppler imaging, IRT – Isovolumetric relaxation time, ICT – Isovolumetric contraction time, MPI – Myocardial performance index, SV – stroke volume, EDV –End diastolic volume, ET – Ejection time

Table 1.2: Cardiac function parameters. Taken from Crispi F et al. Fetal cardiac function: Technical considerations and potential research and clinical applications. Fetal diagnosis and Therapy 2012; 32: 47-64.

46

1.9 Summary

Global hypoxic-ischemic injury to the brain remains a significant cause of mortality and

severe morbidity. Significant improvements in antenatal care management and intrapartum

fetal monitoring has not shown to significantly reduce adverse perinatal outcome for the

last 50 years. Many studies have shown that the current methods of intrapartum monitoring

lack specificity with a high rate of inter-observer variability. These observations could result

in inaccuracies in the diagnosis of intrapartum fetal distress leading to an increased rate of

emergency caesarean sections. Systematic reviews using the combination of various

intrapartum assessment techniques to electronic fetal heart rate monitoring has failed to

show a reduction in caesarean section for fetal distress.

Numerous publications in the past have indicated that addition of intrapartum ultrasound

with fetal Doppler in combination with electronic fetal heart rate monitoring have proved to

improve detection of fetuses that tolerate poorly in-utero. Prior et al. from our research

group has shown that low CPR less than the 10th centile in AGA foetuses at term is

significantly associated with adverse intrapartum outcome.(69)

Studies have also been published on the assessment of cardiac function in fetuses at risk of

compromise due to maternal or fetal causes. However, there had not been any previously

published research in the evaluation of cardiac function of AGA fetuses at term. This is the

first study that has considered measuring the fetal cardiac function before labour in AGA

fetuses and comparing with the obstetric and neonatal outcome.

47

Chapter 2 Methods

2.1 Introduction

Previously published studies have measured the fetal cardiac function in normal and hypoxic

fetuses across the gestation; however, this is the first study that has measured fetal cardiac

output in appropriately grown term singleton fetuses in nulliparous women before labour. It

is also known from previously published studies that there is a change in the fetal cardiac

output in fetuses with chronic hypoxemia and growth restriction in utero; however, there

has not been reported studies that considered the feasibility to conduct assessment of

cardiac output in AGA fetuses at term to identify fetuses at risk of adverse obstetric and

neonatal outcome.

2.2 Aim

To measure fetal cardiac output and fetal Doppler (Cerebroplacental ratio) in singleton AGA

fetuses at term in nulliparous women before labour.

2.3 Hypothesis

Fetuses that require emergency caesarean section for intrapartum fetal distress will have

poor cardiac function and low CPR than fetuses who do not. Reliable identification of

fetuses at risk of adverse intrapartum events will assist in the management of these fetuses

during labour.

48

2.4 Methods

This prospective observational study was conducted at Queen Charlotte's and Chelsea

Hospital, London U.K between March 2013 and February 2015. Leaflets describing the study

were provided to pregnant women attending their routine antenatal clinic and midwifery

appointments. Study leaflets were also displayed at the antenatal clinic, antenatal ward,

delivery suite and in the day assessment unit to facilitate recruitment.

Pregnant women who agreed to participate in this study and met the inclusion criteria were

given a copy of the study information sheet (Appendix A). They were given sufficient time to

read the information and to discuss the study with the researcher. Participants who agreed

to the study were then asked to sign the consent form to be included in the research

(Appendix B).

The inclusion criteria were nulliparous women with AGA term singleton fetuses (37-42

weeks inclusive gestation) who were either in early labour or had induction of labour.

Exclusion criteria included cervical dilatation more than 4 cm, pre-eclampsia, maternal

diseases like diabetes, hypertension, diagnosis of fetal growth restriction, fetal anomaly,

chromosomal or genetic abnormality, evidence of congenital fetal infections or maternal

age less than 16 years. All women recruited to the study were delivered within 72 hours.

Ethical approval for this study was granted by the London Research Ethics Committee (Ref

no: REC 10/H0718/26).

Ultrasound examination of the fetal biometry and fetal weight estimation was performed by

calculation of the bi-parietal diameter, head circumference, abdominal circumference and

the femur length. The amniotic fluid volume and the deepest pool of liquor were also

measured as part of the study. Estimated fetal weight was then calculated using the Hadlock

49

formula.(97) Fetal Doppler indices of the umbilical artery and middle cerebral artery were

measured, and the cerebro-placental ratio (CPR) was calculated by dividing the middle

cerebral artery pulsatility index by the umbilical artery pulsatility index.

The fetal cardiac function was measured by conventional 2D and Doppler ultrasound. We

performed the assessment of the systolic and diastolic function of the ventricles and the

flow velocity across the inflow and the outflow tracts of the heart. The results obtained

were then used to calculate the stroke volume, cardiac output and the myocardial perfusion

index.

2.5 Ultrasound assessment

Fetal biometry

The 2D fetal ultrasound and Doppler examination was performed with GE Voluson-E8

ultrasound machine with 4-8 MHz probe (GE Medical Systems, Zipf, Austria and

Buckinghamshire, HP8 4SP, U.K)

Fetal biometry was performed according to guidelines published by the international society

of obstetrics and gynaecology.(98, 99) The fetal presentation was confirmed by ultrasound

examination to ensure that fetuses with cephalic presentation were included in the study

population. Pregnant mother was positioned in a semi supine position rather than left

lateral decubitus position. The head rest was elevated to an angle of 45 degrees to prevent

aorto-caval compression. Studies have shown that this position is associated with minimal

changes in the cardiac output when compared to the lying position.(100)

50

The biparietal diameter and the head circumference were measured after obtaining an axial

sectional plane of the fetal head in the trans-thalamic plane with the falx in the midline. The

biparietal diameter was then calculated by placement of the calliper from the outer table to

the inner table of the fetal calvarium. For the head circumference, elliptical trace method

was used to determine the outer perimeter of the calvarium excluding the soft tissue of the

scalp.

The fetal abdominal circumference was measured by elliptical trace method at the level of

the skin line after obtaining a transverse section of the fetal abdomen at the level of the

junction of the umbilical vein with portal sinus and fetal stomach in the field of view. Femur

length was measured after obtaining a long axis of the bone with the angle of insonation

perpendicular to the shaft of the bone. The callipers were placed along the long axis of the

bone between the metaphysis excluding the femoral epiphysis and the cartilage.

Amniotic fluid volume index and the single deepest pool of liquor was calculated by dividing

the maternal abdomen into four quadrants by an imaginary line drawn across the umbilicus

and another perpendicular from the symphysis pubis below to the xiphoid process above.

Longitudinal measurement of the maximum vertical pool of amniotic fluid was identified

and measured avoiding fetal parts or the umbilical cord in the field of view.

Doppler ultrasound

Doppler indices of the Umbilical artery and middle cerebral artery of the fetus were

obtained before assessment of the fetal cardiac function. The fetal Doppler assessment was

performed according to the standardised published guidelines (27) regarding the technique

and waveform analysis using appropriate pulse repetition frequency and wall motion filter

51

for the vessel under examination. The angle of insonation was kept close to zero degrees at

all times if possible for Doppler evaluation; however, in the assessment of the middle

cerebral artery Doppler, the angle correction was kept to zero degrees at all times.(27) High

pass filter was activated in the machine to limit the noise from vessel wall movement. At

least 5 consecutive waveforms were obtained in a single examination which was repeated

three times for assessment of each vessel. Indices were calculated using automated

software installed in the equipment to prevent errors by manual tracing method and the

mean value was used for data analysis.

Umbilical artery Doppler assessment was performed in the free loop since most of the

published literature with the reference ranges are obtained by free loop examination.(101, 102)

There is a variation in the flow velocity with higher values are seen closer to the fetal cord

insertion. However, it was difficult to assess the Doppler flow close to the fetal cord

insertion at later gestation due to the poor acoustic window and limited views due to the

fetal position.

Middle cerebral artery Doppler was performed after obtaining an axial section of the fetal

brain to visualise the sphenoid wings and the thalami. Colour Doppler is then used to

identify the circle of Willis, and the middle cerebral artery was sampled at the proximal third

according to the criteria in published guidelines.(27)Minimal pressure was obtained while

obtaining the measurements of the MCA Doppler to avoid excessive compression to the

fetal head while obtaining the readings.

52

2.6 Fetal cardiac function

The following systolic and diastolic cardiac functional parameters were measured for

our study.

Diastolic function

a) E/A ratio

Systolic Function

a) Assessment of outflow tracts

b) Stroke volume (SV), Right, left and combined cardiac output

Left ventricular myocardial performance index – assessment of global cardiac function

2.7 Diastolic function

E/A Ratio

The E/A ratio is performed with spectral Doppler through the atrioventricular valves with

the heart either in a posterior or an anterior apical projection (Figure 2.1). The

interventricular septum is aligned at zero degrees with the Doppler beam before obtaining

the measurement, and the angle of insonation is kept below 20 degrees to get the

waveform. The Doppler gate is placed just below the A-V valves and set to 2-3 mm to avoid

contamination with artefacts resulting from wall motion and outflow tracts. The pulse

repetition frequency (PRF) is adjusted so that the waveform occupies at least 75% of the

scale. Three to five symmetrical waveforms were obtained, and the average measurement

was taken for analysis.(103)

The first component of the waveform is the ‘E’ wave related to the process of myocardial

relaxation followed by the second wave (A wave) that represents atrial contraction during

53

ventricular filling. The E/A ratio is obtained by dividing the peak velocities of E over A

waveform as shown below.(103)

Figure 2.1: 2D Fetal cardiac Doppler – Diastolic function. Taken from Hernandez-Andrade E et al. Evaluation of

conventional Doppler fetal cardiac function parameters: E/A ratios, outflow tracts, and myocardial

performance index. Fetal diagnosis and therapy. 2012;32(1-2):22-29.

Ductus venosus flow pattern

Analysis of the venous flow channels contiguous with the right atrium provides a good

approximation of the pressure gradients within the right atrium thus indirectly reflecting

cardiac compliance. An attempt was made to study the waveform from the ductus

venosus(DV) as described in the methods; however, it was not possible to get a consistent

waveform of the DV in our study population. This was due to multiple factors like fetal

position, acoustic shadowing from the spine and ribs, fetal diaphragmatic movements, the

narrow lumen of the vessel diameter at late gestation and a close approximation of the

hepatic veins with the DV that resulted in sampling error and inconsistent waveform for

analysis. Therefore, we were didn’t include the analysis of the Ductus venosus in our study.

54

2.8 Systolic function

Assessment of outflow tracts, Right, left and combined cardiac output

Systolic function of the heart is measured by recording the velocity of blood ejected by the

ventricles, which would allow estimation of stroke volume and the cardiac output (Figure

2.2). Differential cardiac output assessment provides valuable information regarding blood

flow to different regions in the fetus. Measurements of aortic flow reflect changes in the left

ventricle and pulmonary arterial flow reflect that of the right ventricle.(104)

The aortic outflow tract is evaluated on a long axis of the left ventricle. This view is obtained

from an apical 4-chamber view with the transducer turned slightly towards the right

shoulder of the fetus. This technique exposes the aorta as a single vessel in continuity with

the interventricular septum. The pulmonary artery is evaluated either in a short or long axis

view of the right ventricle. The short axis is obtained from the 4-chamber view by rotating

the transducer to the fetal left side; the long axis is achieved by slightly displacing the

transducer from the four chambers towards the fetal head. The angle of insonation is kept

close to zero as possible during Doppler acquisition to obtain the best readings.(103)

The peak systolic velocity, velocity time integral and ejection time is obtained as shown in

the shown in the figure below to calculate the stroke volume, ejection fraction and the

cardiac output.(103)

55

Figure 2.2: 2D Fetal cardiac Doppler-Systolic function. Taken from Hernandez-Andrade E et al. Evaluation of

conventional Doppler fetal cardiac function parameters: E/A ratios, outflow tracts, and myocardial

performance index. Fetal diagnosis and therapy. 2012;32(1-2):22-29.

For assessment of the cardiac output, it is important to measure the valve area and the

velocity time integral of the aortic and the pulmonary valve respectively to obtain the stroke

volume which then multiplied by the heart rate to obtain the cardiac output.

The valve area is calculated by using the formula πr2 or (3.14 x valve diameter/2)2. The

velocity time integral for the aortic and pulmonary valve is calculated by manually tracing

the Doppler signal on the corresponding waveform that provides the ejection velocity,

ejection time, heart rate and the velocity time integral of the corresponding valve. Stroke

volume of the left and the right ventricle is calculated by multiplying the velocity time

integral by the valve area of the aortic and the pulmonary valve respectively. Cardiac output

of the respective ventricles is obtained by multiplying the stroke volume and the heart rate.

56

The weight adjusted cardiac output (mL/min/kg) of the right and left side is calculated by

dividing the corresponding cardiac output by the estimated fetal weight and the combined

cardiac output is the sum of both ventricular outputs.

2.9 Left Ventricular Myocardial Performance Index (LV - MPI)

The left ventricular myocardial performance index is obtained with a cross-sectional view of

the fetal thorax in the apical projection showing a good 4-chamber view (Figure 2.3). The

Doppler gate is then placed to include both the lateral wall of the ascending aorta, and the

mitral valve where the clicks correspond to the opening and closing of the valves are clearly

seen. The sample volume should be 2-4 mm, and the gain is optimised so that the valve

clicks are visualised and appear more echogenic than the E/A wave and aortic

waveforms.(103)

The E/A waveform and the aortic waveform should remain visible always during the process,

and the sweep velocity is set to maximum. The E/A waveform is displayed as a positive flow.

Isovolumetric contraction time (ICT), Isovolumetric relaxation time (IRT) and Ejection time

(ET) are calculated as described in the figure below. The cursor is placed just before the

echo of each valve click with care to avoid overlapping with the echogenic reflection from

the valve.(103) The myocardial performance index is obtained by the adding the isovolumetric

contraction(ICT) and relaxation(IRT) time divided by the ejection time(ET) of the left

ventricle

(LV.MPI = ICT + IRT / ET). Each cardiac parameter was recorded three times, and a mean of

the values was used for analysis.

57

Figure 2.3: 2D Fetal cardiac Doppler -MPI. Taken from Hernandez-Andrade E et al. Evaluation of conventional

Doppler fetal cardiac function parameters: E/A ratios, outflow tracts, and myocardial performance index. Fetal

diagnosis and therapy. 2012;32(1-2):22-29.

The right ventricular MPI can also be obtained in a similar way as the left ventricle by

analysis of the waveforms at the tricuspid and pulmonary artery valves; however due to

their different anatomical configuration; they cannot be captured simultaneously for

waveform analysis. Due to the above limitations, assessment of right ventricular MPI is less

frequently used in clinical practice; therefore, we did not perform the assessment of right

ventricular MPI in our methodology.(105)

All data generated from this study were initially entered to a storage database (Microsoft

Excel – 2013) and subsequently transferred to statistical analysis software (Graph Pad Prism

version 6.03, Graph Pad Software Inc, La Jolla, CA 92037 United States of America) for

further analysis.

58

Chapter 3 – Pilot study

3.1 Introduction

There have not been previously published studies measuring the fetal cardiac output in

appropriate for gestational age fetuses at term prior to labour. We therefore could not

obtain data required for power calculation for our study. It was also intended to evaluate if

this study was feasible to be performed prior to active labour.

Prior et al.(69)from our unit had published his data on the assessment of intrapartum hypoxia

by measurement of the cerebroplacental ratio before labour by performing a similar pilot

study since there had not been previously published reports to generate a sample size. We

therefore decided to recruit similar numbers based on the lack of evidence to obtain the

data for analysis and perform a power calculation for a larger study.

3.2 Aims

1 To measure fetal cardiac function and fetal Doppler (cerebroplacental ratio) in

appropriate for gestational age singleton fetuses at term before labour in nulliparous

women.

2 To generate the mean and standard deviation for cardiac functional parameters

from the data to perform power calculation and calculate a sample size to achieve a

statistical power of >0.80.

59

3.3 Materials and Methods

135 patients were recruited to this prospective observational pilot study at Queen

Charlotte's and Chelsea Hospital, London U. K for nine months from March 2013 until

November 2013. Leaflets describing the study were provided to pregnant women attending

their routine antenatal clinic and midwifery appointments. Study leaflets were also

displayed at the antenatal clinic, antenatal ward, delivery suite and in the day assessment

unit to facilitate recruitment.

Pregnant women who agreed to participate in this study and met the inclusion criteria were

given a copy of the study information sheet (Appendix A). They were given sufficient time to

read the information and to discuss the study with the researcher. Participants agreed to

the study were then asked to sign the consent form to be included in the research

(Appendix B).

The inclusion criteria were nulliparous women with appropriately grown normal term

singleton fetuses (37-42 weeks inclusive gestation) who were either in early labour or had

induction of labour. Exclusion criteria included cervical dilatation more than 4 cm, pre-

eclampsia, maternal diseases like diabetes, hypertension, diagnosis of fetal growth

restriction, fetal anomaly, chromosomal or genetic abnormality, evidence of congenital fetal

infections or maternal age less than 16 years. All women recruited to the study were

delivered within 72 hours. Ethical approval for this study was granted by the London

Research Ethics Committee (Ref no: REC 10/H0718/26).

60

3.4 Results

The patient’s demographic information (Table 3.1) were recorded in the Appendix C before

starting the examination.

The entire ultrasound assessment was completed in about 30 to 45 minutes depending on

the fetal position and the availability of adequate views for assessment. Data obtained from

this study was not made available to the clinicians responsible for the patient’s intrapartum

care and labour was managed as per local protocols and guidelines. All data were initially

stored on the ultrasound machine’s hard drive and subsequently downloaded to an external

hard drive for off-line analysis.

Intrapartum and neonatal outcome were collected from the patients and baby case medical

records. Intrapartum evaluation included details of electronic fetal heart rate monitoring,

fetal blood sampling, meconium stained liquor and intrapartum pyrexia (Table3.1). Delivery

details included the indication and mode of delivery. Immediate puerperal complications

that occurred within the first 48 hours were also recorded.

Neonatal outcome details were obtained from neonatal electronic and clinical case records.

Information about birth weight, APGAR score, cord pH, base deficit and admission if any

were recorded for analysis.

All data generated from this study were entered to a storage database (Microsoft Excel –

2013) and subsequently transferred to statistical analysis software (Graph Pad Prism version

6.03, Graph Pad Software Inc, La Jolla, CA 92037 United States of America) for further

analysis.

61

The primary outcome of this pilot study was to measure the cardiac output in fetuses before

labour and to record the mean and standard deviation of each parameter to enable

accurate power calculation.

For analysis, fetuses were grouped per indication and the mode of delivery into the

following five categories.

1. Spontaneous vaginal delivery (SVD)

2. Emergency caesarean section for intrapartum fetal distress (CS-FD)

3. Emergency caesarean section for prolonged second stage of labour(CS-FTP)

4. Instrumental delivery for intrapartum fetal distress (Ins -FD)

5. Instrumental delivery for prolonged second stage of labour(Ins-FTP)

Maternal demographics

Patient Demographics n =135

Age (median and range) 31 (21-47)

BMI (median and range) kg/m2 25 (18-43)

Smoker 5/135 (3.7%)

Partner as a smoker 23/135 (17%)

Ethnicity

Caucasian 97/135 (72%)

Asian 23/135 (16.8%)

Afro-Caribbean 12/135 (9%)

Other 3/135 (2%)

Onset of labour

Spontaneous 10/135 (7.5%)

Induction of labour 125/135 (92.5%)

Table 3.1: Maternal demographics, ethnicity and onset of labour

62

Mode of delivery (M.O.D)

n =135

44 -- Caesarean section (33%) 35 --SVD (26%) 56 --Instrumental deliveries (41%)

23 -- Fetal distress

(17%)

21 --Failure to

progress (16%)

36 -- Fetal

distress (26%)

20 -- Failure to

progress (15%)

Table 3.2: Indication and M.O.D

All the patients recruited to the study had live births. 26% (35/135) of fetuses were born by

spontaneous vaginal delivery, 33 %( 44/135) of fetuses were delivered by a caesarean

section of which 17 % were delivered for fetal distress, and 16 %were delivered for failure to

progress. Instrumental delivery constituted 41 %( 56/135) of fetuses in our study group of

which 26 % were delivered for fetal distress and 15 % were delivered by Instrumental

delivery for failure to progress (Table 3.2).

Fetal Doppler

Mean and (S.D) CS-FTP CS - FD

Ins-FTP Ins-FD SVD

UA Pi 0.825 (0.151) 0.840 (0.126) 0.816 (0.097) 0.791 (0.134) 0.805 (0.146)

MCA Pi 1.265(0.249) 1.085(0.193) 1.403(0.364)

1.279(0.341) 1.298(0.275)

CPR 1.572(0.371) 1.327(0.360) 1.751(0.475) 1.636(0.454) 1.658(0.432)

Table 3.3: Fetal Doppler and M.O.D

63

Fetal cardiac function

The following systolic and diastolic cardiac function parameters were performed, and results

were analysed and summarised in the table below.

1. Diastolic cardiac function

E/A ratio across the mitral and tricuspid valve

2. Systolic Function

Ejection velocity across the aortic and pulmonary valve

Ejection time across the aortic and pulmonary valve

velocity time integral (VTI) across the aortic and pulmonary valve

Left and right ventricular Stroke volume (SV)

Right cardiac output

Left cardiac output

Combined cardiac output

3. Left Ventricular Myocardial performance index (LV-MPI)

64

Mean and standard deviation (S.D) CS-FTP CS - FD

Ins-FTP Ins-FD SVD

Diastolic function

E/A ratio at Mitral valve 0.81 (0.067) 0.80 (0.088) 0.82 (0.072)

0.81 (0.095) 0.83 (0.089)

E/A ratio at Tricuspid valve 0.78 (0.080) 0.82 (0.092) 0.81 (0.088) 0.82 (0.068) 0.82 (0.071)

Systolic Function

Ejection velocity at the aortic valve 0.775 (0.122) 0.706 (0.127) 0.745 (0.147) 0.778 (0.125) 0.704 (0.106)

Ejection time at aortic valve 0.167 (0.014) 0.156 (0.012) 0.165 (0.012) 0.162 (0.009) 0.160 (0.009)

VTI at aortic valve 0.123 (0.030) 0.099 (0.019) 0.110 (0.029) 0.113 (0.026) 0.102 (0.022)

Ejection velocity -Pulmonary valve 0.713 (0.138) 0.736 (0.149) 0.715 (0.111) 0.703 (0.138) 0.660 (0.115)

Ejection time - Pulmonary valve 0.168 (0.013) 0.168 (0.017) 0.168 (0.016) 0.169 (0.013) 0.166 (0.013)

VTI at pulmonary valve 0.113 (0.026) 0.116 (0.030) 0.111 (0.021) 0.109 (0.023) 0.104 (0.023)

RV –Stroke volume 7.98 (2.42) 8.23 (3.42) 8.07 (2.59) 7.53 (2.57) 7.36 (2.72)

LV – Stroke volume 6.23 (1.85) 4.66 (0.99) 5.80 (2.03) 5.57 (1.76) 5.02 (1.71)

RV -LV difference 1.75 (1.99) 3.57 (3.35) 2.78 (3.51) 1.66 (1.65) 2.33 (2.09)

RCO/mL/min/kg 298.8 (83.55) 301.6 (111.7) 311.6 (105) 297.5 (94.09) 291 (99.68)

LCO/mL/min/kg 229.4 (60.81) 171.5 (30.77) 212.7 (81.87) 228.1 (71.12) 198 (63.87)

CCO/mL/min/kg 528.2 (126.7) 473.1 (121.6) 524.3 (148.1) 525.6 (153.8) 489 (144.5)

LV-MPI 0.60 (0.084) 0.59 (0.070) 0.60 (0.072) 0.60 (0.069) 0.62 (0.068)

Table 3.4: Fetal cardiac function parameters and M.O.D

Inter and Intra –Observer variability

Inter and Intra-observer variability was expressed as correlation coefficients. Fetal Cardiac

function and Doppler measurements were repeated after 15 minutes in a cohort of thirty

patients to assess intra-observer variability (Table 3.5). Similarly, for assessment of inter-

observer variability, the measurements were repeated by another operator in a cohort of 30

65

patients. We had accepted levels of intra and inter-observer variability. One sample t-test

showed no significant difference in the intra observer variability

Intra-observer variability Inter-observer variability

CPR 0.98 0.96

LCO/mL/min/kg 0.96 0.97

RCO/mL/min/kg 0.97 0.96

Table 3.5: Inter and Intra observer variability

3.5 Discussion

The results of this pilot study showed that fetuses delivered by caesarean section for fetal

distress had a lower CPR compared with the rest of the group. The results were comparable

to the previously published by Prior et al.(69)

The results of the umbilical artery Pi, MCA Pi and the CPR were comparable to the standard

published references across the gestation by Parra-Cordero et al.(50) Among the various

cardiac functional parameters analysed in our pilot study, it was evident that fetuses that

were delivered by emergency caesarean section for intrapartum fetal distress had a lower

left stroke volume and left cardiac output and therefore the left cardiac output/mL/min/kg

was used to perform the power calculation.

For power calculation, two aims were considered

1. To compare the incidence of caesarean section for fetal distress in the group of

fetuses with a left cardiac output less than 50th centile and with left cardiac output

greater than 50th centile.

2. To compare the difference in the mean left cardiac output in fetuses delivered by

caesarean section for fetal distress with rest of the study population.

66

Power calculation was performed to achieve a statistical significance of 0.05 by two-tailed T-

Test analysis.

We observed in our pilot study that the incidence of emergency caesarean section for fetal

distress was higher in the group of fetuses with LCO/ml/min/kg less than the 50th centile

(20/68 =29%) when compared with fetuses that had LCO/ml/min/kg greater than the 50th

centile (3/67=4%).

To compare the incidence of caesarean section for fetal distress in the group of fetuses with

the left cardiac output less than 50th centile with fetuses of left cardiac output greater than

the 50th centile, we required a sample size of 67 patients in each group to achieve a power

of 0.8 to reject the null hypothesis. Similarly, to determine a difference in the mean left

cardiac output/min/kg between fetuses delivered by caesarean section for fetal distress

with all other fetuses we required a sample size of 50 patients (25 in each group) to achieve

a power of 0.8 and reject the null hypothesis.

There have not been previously published studies on fetal cardiac function assessment

before labour. The studies available were either performed at earlier gestation or were

limited up to until 41 weeks gestation.(106) Mielke et al. in 2001 performed a prospective

study in 222 fetuses from 13 to 41 weeks gestation and published standard reference ranges

for the cardiac function.(81) They observed that the reference range values were seen to

increase exponentially with advancing gestation.

The median combined cardiac output and left cardiac outputs were 425 mL/min/kg and

179mL/min/kg respectively. The median ratio to the right and the left cardiac output was

1.42. The median ratio of the right cardiac output to the combined cardiac output was 0.59

and median ratio of the left cardiac output to the combined cardiac output was 0.41. This

ratio was not seen to increase exponentially with gestational age.(81)

67

The values of the right, left and the combined cardiac output obtained from our initial pilot

study data were similar and comparable to the values obtained from this study.(81) Although

the initial data from the pilot study was powered to compare the incidence of caesarean

section for fetal distress with the left cardiac output <50th centile, and further to the

recommendations by the reviewers, we decided to increase the recruitment up to 200 that

may help to perform further subgroup analysis.

68

Chapter 4 --Pre-labour assessment of fetal cardiac function

4.1 Introduction

From the results of pilot study, it was evident that to compare the incidence of caesarean

section for fetal distress in those fetuses with left cardiac output <50th centile with fetuses

of left cardiac output>50th centile; we required a sample size of 67 patients in each group to

achieve a power of 0.8 to reject the null hypothesis. Similarly, to determine a difference in

the mean left cardiac output/min/kg between patients delivered by caesarean section for

fetal distress with all other fetuses, we require a sample size of 50 patients (25 in each

group) to achieve a power of 0.8 and reject the null hypothesis. Further to our initial

recruitment and suggestions by the reviewers of the project, it was agreed to increase the

total number of recruited patients to 200 to perform further subgroup analysis and also to

find if other cardiac parameters could become significant by recruiting additional numbers.

4.2 Aims

1. 2D Ultrasound measurement of fetal cardiac function and fetal Doppler

(Cerebroplacental ratio) in AGA singleton fetuses at term in nulliparous women

before labour and correlate with risk of adverse intrapartum and neonatal outcome.

2. To identify the ideal cardiac ultrasound parameter in the prediction of intrapartum

fetal distress.

69

4.3 Hypothesis

1. Fetuses that require emergency caesarean section for intrapartum fetal distress

will have poor cardiac function and low CPR. Reliable identification of fetuses at

risk of adverse intrapartum events will allow risk stratification and appropriate

management of these pregnancies during labour.

4.4 Methods

This is a prospective observational study conducted at Queen Charlotte's and Chelsea

Hospital, London, UK over a period of 15 months from November 2013 to February 2015.

We recruited 200 nulliparous women with appropriately grown term singleton fetuses to

participate in this study. All the study participants were given written information about the

procedure followed by written consent to be recruited into the study as explained in

chapter 2(Methods). Once consent was obtained all the recruited participants in the study

underwent ultrasound assessment as described in the methods section of chapter

2(Methods).

The obstetric staffs were blinded to the ultrasound findings, and labour was managed per

the local departmental guidelines. The intrapartum and neonatal outcome data were

recorded from hospital case notes, electronic databases and correlated with the ultrasound

findings.

The primary outcome was to identify the mode of delivery and to check for presence or

absence of intrapartum fetal distress in our study population. We also considered secondary

outcomes that include electronic fetal heart rate monitoring findings classified according to

the NICE guidelines(107), presence or absence of meconium stained liquor, the neonatal

outcomes which include APGAR score, cord blood pH, base excess at delivery and the

70

neonatal case records to check for neonatal admissions. APGAR score of less than 7 at one

or five minutes, cord blood pH less than 7.20 and base excess less than - 8.0 were defined as

adverse outcome according to the intrapartum guidelines used in the U.K.(108) (109)

4.5 Analysis of Data

The primary data from our study were initially transferred to Microsoft Excel 2013(Microsoft

Systems, Redmond, WA, U.S.A) and subsequent statistical analysis was performed using

Graph Pad Prism version 6.03(Graph Pad Software Inc. La Jolla, CA 92037 USA) and SPSS

version 19(SPSS Inc., Cary NC).

Distribution of the data was evaluated using D' Agostino -Pearson normality test with a

value less than 0.05 suggestive of a non -normal distribution.

Data in this study are represented in the format appropriate to the statistical analysis and

distribution of the data. Non-Gaussian distribution is represented as median and

interquartile range while normal distribution is represented as mean and standard deviation

in our analysis. A probability value less than 0.05 was considered statistically significant.

Data analysis were performed using one-way ANOVA (analysis of variance) as there were

more than three variables and independent sample t-tests were used for normal

distribution of the data. Kruskal -Wallis and Mann-Whitney U significance testing was used

in analysis of non -normal distribution of data. Dunn's multiple comparison tests were used

to find if there was a significant difference in the mean rank difference between the study

groups. Chi square tests and relative risk calculator was used for comparing proportions

between the study groups. Receptor operative characteristics (ROC) curves were

constructed to test the predictive value where appropriate to establish optimal levels of

sensitivity and specificity. Since this study was designed to identify ultrasound parameters of

71

clinical interest and to prevent type II error, the Bonferroni correction for multiple

comparisons was not used in this study. Hence it would be prudent to interpret borderline

significance results with caution.

4.6 Results

Figure 4.1: Flow chart of recruitment

72

Maternal Demographics

The following details were obtained from the obstetric case notes of the patients recruited

to our study (Table 4.1).

Patient Demographics n =200

Age (median and range) 32 (16-45)

BMI (median and range) Kg/m2 25 (18-43)

Smoker 11/200 (5.5%)

Partner as a smoker 44/200 (22%)

Ethnicity

Caucasian 139/200 (69.5%)

Asian 31/200 (15.5%)

Afro-Caribbean 21/200 (10.5%)

Other 9/200 (4.5%)

Onset of labour

Spontaneous or early stage of labour 42/200 (21%)

Induction of labour

158/200(79%)

Table 4.1: Maternal demographics, ethnicity and onset of labour

73

Indication and M.O.D

n =200

Caesarean section

71 (35.5%)

Spontaneous vaginal delivery 50

(25%)

Instrumental deliveries

79 (39.5%)

Fetal distress

34 (17%)

Failure to progress

37 (18.5%)

Fetal distress

46 (23%)

Failure to

progress

33 (16.5%)

Table 4.2: Indication and M.O.D

Maternal demographics, ethnicity and mode of delivery

Mean and S. D CS –FTP CS – FD Ins- FTP Ins –FD SVD p /X2

Maternal age

33.2 (4.99) 32.4 (6.12) 31.4 (4.56) 33.6 (6.62) 31.4 (5.70) 0.314

Maternal BMI 26.47 (4.48) 26.20 (4.65) 25.55 (4.50) 25.48 (3.73) 25.52 (5.29) 0.730

Median G. A 41 (38.42 to 41.71)

41.42 (39 to 42)

41.14 (37 to 41.71)

40.71 (37.42 to 42)

40.85 (37.14 to 42)

0.059

Ethnicity and M.O. D

Caucasian 20 (10%) 21 (10.5%) 24 (12%) 35 (17.5%) 39 (19.5%) 0.65

Asian 8 (4%) 4 (2%) 4 (2%) 8 (4%) 7 (3.5%) 0.80

Afro -Caribbean 7 (3.5%) 6 (3%) 3 (1.5%) 2 (1%) 2 (1%) 0.10

Other 2 (1%) 2 (1%) 2 (1%) 2(1%) 2 (1%) 0.92

Table 4.3: Maternal demographics, ethnicity and M.O.D

74

All the patients in our study gave birth to live singleton infants. The time interval between

the ultrasound assessment and delivery was within 72 hours as specified in the protocol.

The onset of labour was spontaneous in 21 %( 42/200) of the study population while 79%

(158/200) of women had induction of labour in our study group.

Caucasian women constituted 69.5 %( 139/200) of the mothers in our study group followed

by 15.5 %( 31/20) of Asian women. Afro-Caribbean represented 10.5% (20/200), and other

mixed ethnic origin accounted for 4.5% (9/200) in our study population.

Of the study cohort, 35.5% (71/200) of women were delivered by emergency caesarean

section of which 17% of fetuses were delivered by emergency caesarean section for fetal

distress, and 18.5% were delivered by emergency caesarean section for failure to progress.

Instrumental delivery constituted 39.5% (79/200) of women in our study group of which 23%

of fetuses were delivered for fetal distress and 16.5% of fetuses for failure to progress.

Spontaneous vaginal delivery constituted 25% (50/200) of women in our study group.

There was no significant difference between maternal age, BMI, ethnicity and the mean

gestational age in fetuses when grouped per the indication and the mode of delivery.

The relationship between maternal demographics and ethnicity were also correlated with

ultrasound parameters to observe if they affected the ultrasound markers of well-being.

Pearson correlation coefficient was used to observe if there was a correlation between

maternal demographics (Maternal age, BMI and G.A) against EFW,AFI, CPR, LCO, RCO, CCO

and the ratio of the right to left cardiac output.

75

4.7 Maternal demographics and ultrasound parameters

Maternal age and ultrasound parameters

There was a very weak correlation between maternal age and all the ultrasound parameters.

However, this did not reach statistical significance(p>0.05)

Figure 4.2: Maternal age and ultrasound parameters

0

2000

4000

6000

0 10 20 30 40 50

Mat age and EFW ( R2 =0.03)p=0.95

0

10

20

30

0 10 20 30 40 50

Mat age and AFI (R2 =0.001)p=0.63

0

2

4

0 10 20 30 40 50

Mat age and CPR (R2 =0.003)p=0.43

0

200

400

600

0 10 20 30 40 50

Mat age and LCO (R2 =0.005)p=0.30

0

500

1000

0 10 20 30 40 50

Mat age and RCO (R2 =0.01)p=0.06

0

500

1000

1500

0 10 20 30 40 50

Maternal age and CCO (R2 =0.01)p=0.07

0

2

4

6

0 10 20 30 40 50

Mat.age and Ratio of RCO to LCO (R2 =0.001)

p=0.61

76

Maternal BMI and ultrasound parameters

Negative correlation was seen between the BMI and all the ultrasound parameters except

EFW that showed a very weak positive correlation (R2=0.003). However, this did not reach

statistical significance (p>0.05).

Figure 4.3: BMI and ultrasound parameters

0

5000

10000

0 10 20 30 40 50

Mat.BMI and EFW (R2 =0.003)p=0.40

0

20

40

0 10 20 30 40 50

BMI and AFI (R2 = - 0.006)p=0.27

0

2

4

0 10 20 30 40 50

BMI and CPR (R2 = - 0.01)p=0.06

0

500

0 10 20 30 40 50

BMI and LCO (R2 = - 0.0005)p=0.75

0

500

1000

0 10 20 30 40 50

BMI and RCO (R2 = - 0.01)p=0.05

0

1000

2000

0 10 20 30 40 50

BMI and CCO (R2 = - 0.01)p=0.12

0

10

0 10 20 30 40 50

BMI and Ratio of RCO to LCO (R2 = - 0.12)

p=0.08

77

Gestational age and ultrasound parameters

Positive correlation was noted between the gestational age and the EFW (R2=0.20) while

other parameters had a weak negative correlation (R2=<0.1). However, this did not reach

statistical significance (p>0.05).

Figure 4.4: Gestational age and ultrasound parameters

0

2000

4000

6000

36 38 40 42 44

Gestation and EFW (R2 = 0.20)p=0.45

0

10

20

30

36 38 40 42 44

Gestation and AFI (R2 = - 0.04)p=0.06

0

1

2

3

4

36 38 40 42 44

Gestation and CPR (R2 = - 0.001)p=0.43

0

200

400

600

36 38 40 42 44

GA and LCO (R2 = - 0.001)p=0.62

0

200

400

600

800

36 38 40 42 44

GA and RCO (R2 = 0.003)p=0.42

0

500

1000

1500

36 38 40 42 44

GA and CCO (R2 = 0.02)p=0.74

0

2

4

6

36 38 40 42 44

G.A and Ratio of RCO to LCO(R2 = 0.08)p=0.21

78

Ethnicity and ultrasound parameters

Median and I.Q range Caucasian Asian Afro -Caribbean Other p value

CPR 1.556 (1.311 to 1.885)

1.381 (1.132 to 1.519)

1.600 (1.193to 1.852)

1.761 (1.470 to 2.069)

0.007

LCO/mL/min/kg 193 (151.5 to 247.3)

177.7 (134.9 to 216.4)

191.1 (155 to 236.5)

152.4 (146.4 to 186.2)

0.135

RCO/mL/min/kg 268.4 (206.5 to 345.4)

269.3 (205.6 to 343)

258 (226.9 to 310.3)

210.2 (163.8 to 286.4)

0.298

CCO/mL/min/kg 464.7 (374.2 to 589.6)

423.5 (378.7 to 534.5)

470.5 (364.4 to 563.4)

359.3 (308.3 to 483)

0.195

AFI 12.8 (9.35 to 15.3)

12.1 (8.7 to 14.3)

11.9 (9 to 13.9)

12.5 (9.2 to 17.5)

0.64

Estimated fetal weight (grams)

3660 (3355 to 3918)

3289 (3163 to 3648)

3627 (3338 to 3928)

3697 (3358 to 4085)

0.009

Table 4.4: Ethnicity and important ultrasound parameters

When comparing the relationship between the ethnicity and relevant ultrasound

parameters mentioned above, only the CPR and the estimated fetal weight were found to

be significant among fetuses. Women of Asian origin had the lowest estimated fetal weight

and the lowest CPR when compared with the rest of the ethnic population (Table 4.4).

4.8 Cerebro -placental ratio (CPR) or Cerebro -umbilical ratio (C-U ratio)

The Cerebro placental ratio is calculated by dividing the pulsatility index (Pi) of the middle

cerebral artery by the pulsatility index of the umbilical artery.

Median and IQ Range

CS –FTP CS – FD Ins -- FTP Ins –FD SVD p value

UA Pi 0.79 (0.72- 0.86)

0.83 (0.79 - 0.92)

0.81 (0.69 - 0.86)

0.78 (0.68 - 0.89)

0.79 (0.71- 0.90)

0.32

MCA Pi 1.19 (1.07- 1.37)

1.06 (0.89- 1.16)

1.27 (1.12 - 1.52)

1.23 (1.05- 1.55)

1.26 (1.11- 1.48)

0.0004

CPR 1.53 (1.36 – 1.79)

1.22 (1.11 – 1.44)

1.74 (1.42 – 2.06)

1.52 (1.37 – 1.89)

1.62 (1.34 – 1.97)

<0.0001

Table 4.5: Relation between UA Pi, MCA Pi, CPR and M.O.D

79

The CPR was measured in all the fetuses in our study population. The median CPR was

1.532(range 0.77 to 2.89). The median 10th centile value of CPR was 1.008, and the 90th

centile was 2.29. The CPR had a non-Gaussian distribution in our study population

(Skewness =0.03, kurtosis = 0.49, D’agostino-Pearson test of normality p = <0.001)

Figure 4.5: CPR distribution

Descriptive statistics

CS –FTP CS –FD Ins – FTP Ins – FD SVD

n = 200 37 34 33 46 50

Minimum 0.8857 0.8660 1.061 0.8478 0.7755

25% Percentile 1.369 1.113 1.425 1.374 1.342

Median 1.532 1.222 1.740 1.527 1.629

75% Percentile 1.799 1.442 2.069 1.892 1.975

Maximum 2.511 1.775 2.895 2.694 2.350

Mean 1.586 1.266 1.739 1.622 1.649

Std. Deviation 0.3652 0.2363 0.4349 0.4223 0.3818

Std. Error of Mean 0.06004 0.04053 0.07571 0.06226 0.05399

Lower 95% CI 1.465 1.184 1.585 1.496 1.541

Upper 95% CI 1.708 1.349 1.893 1.747 1.758

Mean ranks 102.4 52.29 122.8 104.8 113.2

Table 4.6: Descriptive statistics of CPR

0

2

4

6

8

10

12

14

16

18

20

0.5

0.6

0.7

0.8

0.9 1

1.1

1.2

1.3

1.4

1.5

1.6

1.7

1.8

1.9 2

2.1

2.2

2.3

2.4

2.5

2.6

2.7

2.8

2.9 3

CPR

80

Dunn's multiple comparison tests

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD 50.07 Yes Significant

CS-FTP vs. Ins-FTP -20.39 No Not significant

CS-FTP vs. Ins-FD -2.461 No Not significant

CS-FTP vs. SVD -10.87 No Not significant

CS-FD vs. Ins-FTP -70.46 Yes Significant

CS-FD vs. Ins-FD -52.53 Yes Significant

CS-FD vs. SVD -60.94 Yes Significant

Ins-FTP vs. Ins-FD 17.93 No Not significant

Ins-FTP vs. SVD 9.528 No Not significant

Ins-FD vs. SVD -8.404 No Not significant

Table 4.7: Dunn's multiple comparison tests – CPR

There was a significant difference in the CPR, when fetuses were classified per the indication

and the mode of delivery (p = < 0.0001).

The lowest median CPR was recorded in fetuses that were delivered by emergency

caesarean section for fetal distress (1.222, IQR=1.113 to 1.442) and the highest median CPR

was recorded in fetuses delivered by instrumental delivery for failure to progress (1.740,

IQR=1.425 to 2.069).

Dunn's multiple comparisons tests showed a difference in the mean ranks between fetuses

delivered by emergency caesarean section for fetal distress when compared with fetuses

delivered by caesarean section for failure to progress, spontaneous vaginal delivery and

Instrumental delivery for fetal distress and failure to progress (Table 4.6 and 4.7).

81

Further to the initial analysis, the CPR of fetuses was classified into three groups (CPR -

under the 10th centile, 10 to 90th centile and over 90th centile). The mode of delivery was

analysed in each of this group to observe if there was an association between the centile of

the CPR and the outcome of delivery (Figure 4.24).

Figure 4.6: CPR centile and mode of delivery

In our study, we observed 40% (8/20) of fetuses with CPR <10th centile was delivered by

emergency caesarean section for fetal distress while none (0/20) of the fetuses were

delivered by caesarean section for fetal distress in the group of fetuses with a CPR >90th

centile. Fetuses with CPR < 10th centile were 2.7 times more likely to be delivered by

caesarean section for fetal distress when compared with the rest of the fetuses (R.R -2.769,

95th CI 1.454 to 5.272, p=0.0019).

0

5

10

15

20

25

30

35

40

45

CS-FTP CS-FD Ins -FTP Ins-FD SVD

CPR and mode of delivery according to centile

C-U ratio <10th centile C-U ratio 10th to 90th centile C-U ratio >90th centile

82

There were no fetuses in the group of CPR greater than the 90th centile that had caesarean

section for fetal distress suggesting that fetuses with CPR greater than the 90th centile were

protective of caesarean section for fetal distress (Negative predictive value (NPV) -100%).

These above results were comparable to the previous study by Prior et al.(69)

We did not find any significant difference in the maternal age, BMI, gestational age and the

ethnicity when the CPR of the fetuses was grouped per the different centiles (<10th centile,

10-90th centile and greater than 90th centile).

4.9 Fetal cardiac function

The following systolic and diastolic cardiac function parameters were measured in our study

population (Table 14) and the median and interquartile range are represented in the table

below.

83

Median, (IQR) CS – FTP CS – FD Ins -- FTP Ins --FD SVD p value

Diastolic function

E/A ratio Mitral valve

0.81 (0.77 – 0.84)

0.81 (0.75 – 0.87)

0.82 (0.76 – 0.88)

0.82 (0.76 – 0.88)

0.82 (0.76 – 0.87)

0.80

E/A ratio Tricuspid valve

0.79 (0.75 - 0.84)

0.79 (0.77 – 0.86)

0.84 (0.76 – 0.87)

0.82 (0.79 – 0.86)

0.81 (0.75 – 0.86)

0.14

Left heart function Systolic Function

Heart rate at Aorta 136 (129 -144)

137 (132 - 144)

135 (130 - 143)

139 (134 - 148)

141 (130 - 146)

0.406

Aortic valve diameter 7.85 (7.30 – 8.27)

7.90 (7.40 – 8.40)

8.00 (7.30 – 8.80)

7.70 (7.00 – 8.32)

8.10 (7.30 – 8.60)

0.608

Aortic valve area 48.37 (41.83– 53.75)

48.99 (42.98-55.38)

50.24 (41.83-60.79)

46.54 (38.46–54.40)

51.50 (41.83–51.50)

0.656

Ejection velocity aortic valve

0.805 (0.672-0.897)

0.720 (0.610-0.820)

0.760 (0.680-0.850)

0.790 (0.680-0.850)

0.700 (0.650-0.820)

0.078

Ejection time aortic valve

0.164 (0.156-0.175)

0.156 (0.145-0.160)

0.164 (0.160-0.173)

0.164 (0.156-0.169)

0.160 (0.156-0.168)

0.0005

VTI at aortic valve 0.100 (0.090-0.135)

0.090 (0.070-0.100)

0.100 (0.080-0.120)

0.110 (0.097-0.130)

0.100 (0.080-0.112)

< 0.0001

LV – Stroke volume 5.460 (4.132-6.860)

4.019 (3.411-5.407)

4.753 (4.086-6.247)

5.116 (4.272-6.418)

4.684 (3.893-6.127)

0.028

LCO 191.1 (149.9-251.4)

152.3 (124.3-192.9)

174.4 (150.3-230.7)

204.9 (169.7-256.4)

196.4 (148-232.5)

0.003

Right heart function Systolic Function

Heart rate 140 (133-144) 140 (132- 146) 136 (132- 142) 140(132- 146) 138(134- 144) 0.463

Diameter Pulmonary valve

9.55 (8.60- 9.87)

9.50 (8.80- 10.10)

9.40 (8.50- 10.35)

9.05 (8.17- 10.13)

9.30 (8.55- 10.10)

0.762

Pulmonary valve area

71.59 (58.05- 76.55)

70.84 (60.79- 80.07)

69.36 (56.72- 84.09)

64.29 (52.46- 80.47)

67.89 (57.38- 80.07)

0.762

Ejection velocity Pulmonary. valve

0.660 (0.600- 0.832)

0.740 (0.620- 0.810)

0.700 (0.560- 0.770)

0.660 (0.600-0.750)

0.660 (0.580- 0.740)

0.462

Ejection time at pulmonary valve

0.167 (0.160-0.178)

0.169 (0.158- 0.182)

0.164 (0.160- 0.179)

0.166 (0.158- 0.178)

0.164 (0.160- 0.169)

0.674

VTI pulmonary valve

0.108 (0.090- 0.120)

0.110 (0.090- 0.120)

0.110 (0.080- 0.125)

0.105 (0.090- 0.120)

0.100 (0.080- 0.110)

0.429

RV –Stroke volume 6.659 (5.506- 9.001)

7.495 (6.238- 9.156)

7.084 (5.627- 7.997)

6.916 (5.253- 8.808)

6.346 (5.265- 8.252)

0.560

RCO 259.6 (196.5- 336.0)

273.6 (221.4- 322.0)

233.0 (208.3- 311.2)

279.4 (203.2- 349.7)

262.2 (207.8- 344.8)

0.887

CCO/mL/min/kg 449 (373- 595.5)

426.5 (362.2- 520.0)

448.7 (365.9- 566.9)

483.0 (387.8- 594.9)

445.6 (391.9- 547.6)

0.700

Difference RV -LV stroke volume

1.250 (0.220- 3.276)

3.025 (1.960- 4.574)

2.036 (0.494- 3.892)

1.373 (0.240- 2.692)

1.789 (0.980- 2.931)

0.0113

Difference RCO and LCO

46.17 (12.57- 117.3)

121.6 (74.98- 174.6)

78.42 (18.38- 146.2)

56.02 (14.49- 113.2)

68.25 (28.40- 121.1)

0.0158

Percentage of RCO/mL/min/kg

57.4 (51.1- 61.1)

65.8 (58.4-70.8)

58.6 (52.2- 64.8)

55.6 (51.4- 60.9)

57.6 (52.2- 63.4)

0.0019

Percentage of LCO/mL/min/kg

42.6 (38.8- 48.8)

34.2 (29.1- 41.6)

41.4 (35.1- 47.7)

44.4 (39.0- 48.5)

42.4 (36.5- 47.7)

0.0019

Ratio of RCO to LCO 1.34 (1.04- 1.57)

1.92 (1.40- 2.42)

1.41 (1.09- 1.84)

1.25 (1.06- 1.56)

1.35 (1.09- 1.73)

0.0019

LV -MPI 0.645 (0.570- 0.670)

0.620 (0.580- 0.660)

0.610 (0.570- 0.650)

0.610 (0.550- 0.650)

0.650 (0.590- 0.700)

0.126

Table 4.8: Fetal cardiac function assessment and M.O.D

84

Diastolic function

The diastolic function across the right and left side of the heart was performed by

calculating the E/A ratio across the tricuspid and the mitral valve.

The median value of E/A ratio across the tricuspid valve was 0.81(range 0.60 to 1.10). The

median value of E/A ratio across the mitral valve was 0.82(range 0.59 to 1.19).

There was no significant difference in the right and the left diastolic function among the

fetuses when classified per the indication and the mode of delivery.

Systolic function

Systolic function of the fetal heart involves assessment of the right and the left cardiac

output by above-described methods that include assessment of the heart rate and the

outflow tracts. The results were then mathematically calculated to obtain the stroke volume,

left, right and the combined cardiac output.

Right cardiac functional parameters

The cardiac parameters include measurement of the heart rate, valve diameter and area of

the pulmonary valve. Doppler indices include measurement of ejection velocity, ejection

time and velocity time integral (VTI) at the pulmonary valve which is then used to calculate

the stroke volume and the right cardiac output.

Right ventricular stroke volume is calculated by multiplying the valve area and the velocity

time integral at the pulmonary valve. The cardiac output is then obtained by multiplying the

stroke volume and the heart rate across the pulmonary valve. The median heart rate at the

pulmonary valve was 139(range 116 to 178).

85

Right ventricular stroke volume

Stroke volume (SV) is the difference between the end diastolic volume (EDV) and the end

systolic volume (ESV). The right ventricular stroke volume is obtained by multiplying the

velocity time integral of the pulmonary valve with the valve area of the pulmonary valve.

The right ventricular stroke volume was measured in all the fetuses in our study population.

The median right ventricular stroke volume was 6.98 mL (range 2.05 to 17.23 mL). The right

ventricular stroke volume had a non-normal distribution (skewness = 1.00, kurtosis =1.63,

D’agostino-Pearson test of normality p = <0.001).

Figure 4.7: RV stroke volume distribution

0

5

10

15

20

25

30

1.5 2

2.5 3

3.5 4

4.5 5

5.5 6

6.5 7

7.5 8

8.5 9

9.5 10

10

.5 11

11

.5 12

12

.5 13

13

.5 14

14

.5 15

15

.5 16

16

.5 17

17

.5 18

RV -Stroke volume

86

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Number of values 37 34 33 46 50

Minimum 3.429 2.792 2.649 2.540 2.051

25% Percentile 5.506 6.238 5.627 5.253 5.265

Median 6.659 7.495 7.084 6.916 6.346

75% Percentile 9.001 9.156 7.997 8.808 8.252

Maximum 13.85 17.24 15.92 10.45 14.99

Mean 7.332 7.871 7.509 6.970 6.946

Std. Deviation 2.373 3.198 2.871 2.232 2.522

Std. Error of Mean 0.3956 0.5405 0.4998 0.3291 0.3567

Lower 95% CI 6.528 6.773 6.491 6.307 6.229

Upper 95% CI 8.135 8.970 8.527 7.633 7.663

Mean ranks 102.1 112.5 103.1 98.53 91.06

Table 4.9: Descriptive statistics of RV Stroke volume

Dunn’s multiple comparison test

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD -10.44 No Not significant

CS-FTP vs. Ins-FTP -1.021 No Not significant

CS-FTP vs. Ins-FD 3.537 No Not significant

CS-FTP vs. SVD 11.01 No Not significant

CS-FD vs. Ins-FTP 9.423 No Not significant

CS-FD vs. Ins-FD 13.98 No Not significant

CS-FD vs. SVD 21.45 No Not significant

Ins-FTP vs. Ins-FD 4.558 No Not significant

Ins-FTP vs. SVD 12.03 No Not significant

Ins-FD vs. SVD 7.473 No Not significant

Table 4.10: Dunn's multiple comparison tests – RV stroke volume

87

There was no significant difference in the right ventricular stroke volume between fetuses

when grouped per the indication and mode of delivery (p=0.560). Fetuses delivered by

emergency caesarean section for fetal distress had the highest right ventricular stroke

volume (7.495mL, IQR – 6.238 to 9.156 mL) and the lowest right ventricular stroke volume

was observed in fetuses delivered by spontaneous vaginal delivery (6.346 mL, IQR 5.265 to

8.252mL). Dunn's multiple comparison tests did not find a significant difference in the mean

rank when compared between each mode of delivery with the other group (Table 4.9 and

4.10).

Right cardiac output/mL/min/kg(RCO)

The right cardiac output is obtained by multiplying the right ventricular stroke volume and

the heart rate across the pulmonary valve. The cardiac output/mL/min/kg is obtained by

dividing the cardiac output by the estimated fetal weight.

The RCO was measured in all the fetuses in our study population. The median value was

264.09mL/min/kg (range 87.09 to 593.16 mL/min/kg). The results in our study group

showed a non -Gaussian distribution (skewness =0.73, kurtosis = 0.44, D’agostino-Pearson

test of normality p = <0.001).

88

Figure 4.8: Right cardiac output distribution

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Number of values 37 34 33 46 50

Minimum 125.9 111.6 108.2 114.5 87.10

25% Percentile 196.5 221.4 208.3 203.2 207.8

Median 259.6 273.6 233.0 279.4 262.2

75% Percentile 336.0 322.0 311.2 349.7 344.8

Maximum 469.4 544.9 593.2 514.3 529.7

Mean 273.4 293.7 271.7 281.8 276.2

Std. Deviation 86.84 113.0 100.7 94.68 94.21

Std. Error of Mean 14.47 19.10 17.54 13.96 13.32

Lower 95% CI 244.0 254.9 235.9 253.7 249.5

Upper 95% CI 302.8 332.6 307.4 309.9 303.0

Mean ranks 97.00 107.6 94.67 103.5 99.18

Table 4.11: Descriptive statistics of RCO/mL/min/kg

0

5

10

15

20

25

50 80 110 140 170 200 230 260 290 320 350 380 410 440 470 500 530 560 590 620

RCO/mL/min/kg

89

Dunn’s multiple comparison test

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD -10.60 No Not significant

CS-FTP vs. Ins-FTP 2.333 No Not significant

CS-FTP vs. Ins-FD -6.457 No Not significant

CS-FTP vs. SVD -2.180 No Not significant

CS-FD vs. Ins-FTP 12.93 No Not significant

CS-FD vs. Ins-FD 4.143 No Not significant

CS-FD vs. SVD 8.420 No Not significant

Ins-FTP vs. Ins-FD -8.790 No Not significant

Ins-FTP vs. SVD -4.513 No Not significant

Ins-FD vs. SVD 4.277 No Not significant

Table 4.12: Dunn's multiple comparison tests – RCO/mL/min/kg

There was no significant difference in the RCO between fetuses when grouped per the

indication and the mode of delivery (p= 0.887). The highest median RCO was noted in

fetuses delivered by instrumental delivery for fetal distress (279.4 mL/min/kg, IQR 203.2 to

349.7 mL/min/kg). The lowest median RCO was observed in fetuses delivered by

instrumental delivery for failure to progress (233.0 mL/min/kg, IQR 208.3 to 311.2

mL/min/kg). Dunn's multiple comparisons tests did not find a significant difference in the

mean rank when compared between each mode of delivery with the other group (Table

4.11 and 4.12).

When maternal demographics were assessed to determine the relation to the RCO, we

observed that maternal age and the gestational age had a weak positive correlation with the

right cardiac output; however, this did not reach statistical significance.

90

Left cardiac functional parameters

The left cardiac parameters include measurement of fetal heart rate, valve diameter and

area of the aortic valve. Doppler indices include ejection velocity, ejection time and velocity

time integral (VTI) of the aortic valve which is then used to calculate the stroke volume and

the left cardiac output.

Stroke volume is calculated by multiplying the valve area and the velocity time integral. The

cardiac output is obtained by multiplying the stroke volume and the heart rate across the

aortic valve.

The median heart rate at the aortic valve was 138 (range 116 to 166).

We observed that left cardiac functional parameters were found to be significantly different

between the fetuses when grouped per the indication and the mode of delivery.

The parameters that were statistically significant are the ejection time at the aortic valve,

velocity time integral at aortic valve, left ventricular stroke volume and the left cardiac

output/mL/min/kg and would be discussed in detail.

91

Ejection time at aortic valve

The ejection time is defined as the time of ejection of blood from the left ventricle beginning

with aortic valve opening and ending with aortic valve closure measured in milliseconds.

Ejection time at aortic valve was measured in all our patients which showed a non-normal

distribution in our study population (skewness =0.25, Kurtosis =0.989, D’agostino-Pearson

test of normality p = <0.001). The median value of ejection time at aortic valve was 0.164

milliseconds (range -0.133 to 0.204 milliseconds)

Figure 4.9: Distribution of Ejection time at Aorta

0

10

20

30

40

50

60

70

Aorta -Ejection time

92

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Number of values 37 34 33 46 50

Minimum 0.1430 0.1330 0.1420 0.1420 0.1360

25% Percentile 0.1560 0.1458 0.1600 0.1560 0.1568

Median 0.1640 0.1560 0.1640 0.1640 0.1600

75% Percentile 0.1755 0.1600 0.1730 0.1690 0.1683

Maximum 0.2040 0.1870 0.2000 0.1800 0.1780

Mean 0.1657 0.1548 0.1661 0.1620 0.1607

Std. Deviation 0.01319 0.01213 0.01228 0.009350 0.009280

Std. Error of Mean 0.002168 0.002081 0.002138 0.001379 0.001312

Lower 95% CI 0.1613 0.1506 0.1617 0.1593 0.1581

Upper 95% CI 0.1701 0.1591 0.1704 0.1648 0.1634

Mean ranks 114.9 64.82 121.5 103.4 97.60

Table 4.13: Descriptive statistics of Ejection time at Aorta

Dunn’s multiple comparison test

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD 50.12 Yes Significant

CS-FTP vs. Ins-FTP -6.509 No Not significant

CS-FTP vs. Ins-FD 11.58 No Not significant

CS-FTP vs. SVD 17.35 No Not significant

CS-FD vs. Ins-FTP -56.63 Yes Significant

CS-FD vs. Ins-FD -38.55 Yes Significant

CS-FD vs. SVD -32.78 No Not significant

Ins-FTP vs. Ins-FD 18.08 No Not significant

Ins-FTP vs. SVD 23.85 No Not significant

Ins-FD vs. SVD 5.770 No Not significant

Table 4.14: Dunn's multiple comparison tests – Ejection time at Aorta

There was a significant difference in the ejection time at the aortic valve when fetuses were

grouped per the indication and the mode of delivery (p=0.0005). Fetuses delivery by

emergency caesarean section for fetal distress had the lowest median ejection time in our

study group (0.156 milliseconds, IQR 0.145 to 0.160 milliseconds) when compared with the

rest of the fetuses.

93

Dunn's multiple comparisons tests showed a significant difference in the mean ranks

between fetuses delivered by caesarean section for fetal distress when compared with a

caesarean section for failure to progress, instrumental delivery for failure to progress and

instrumental delivery for fetal distress (Table 4.13 and 4.14).

Velocity time integral at aortic valve (VTI -Aorta)

Velocity time integral is calculated by manually tracing the Doppler signal of the aortic

velocity waveform as described in the methods section. Velocity time integral is then

multiplied by the valve area of the aorta to obtain the stroke volume of the left ventricle.

The velocity time integral was measured in all the fetuses. The median value of the VTI -

aorta was 0.1 (Range 0.05 to 0.18). The values showed a non-normal distribution (skewness

=0.59, Kurtosis =0.08, D’agostino-Pearson test of normality p = <0.001).

Figure 4.10: Distribution of velocity time integral at Aorta

94

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Number of values 37 34 33 46 50

Minimum 0.0600 0.0600 0.0500 0.0700 0.0600

25% Percentile 0.0900 0.0700 0.0800 0.0975 0.0800

Median 0.1000 0.0900 0.1000 0.1100 0.1000

75% Percentile 0.1350 0.1000 0.1200 0.1300 0.1125

Maximum 0.1800 0.1200 0.1700 0.1700 0.1600

Mean 0.1130 0.08618 0.1037 0.1113 0.0996

Std. Deviation 0.02943 0.01615 0.02895 0.02363 0.02147

Std. Error of Mean 0.004838 0.002769 0.005039 0.003484 0.003037

Lower 95% CI 0.1032 0.08054 0.09347 0.1043 0.09350

Upper 95% CI 0.1228 0.09181 0.1140 0.1183 0.1057

Mean ranks 119.0 61.53 100.7 121.9 93.43

Table 4.15: Descriptive statistics of VTI Aorta

Dunn’s multiple comparison test

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD 57.48 Yes Significant

CS-FTP vs. Ins-FTP 18.30 No Not significant

CS-FTP vs. Ins-FD -2.932 No Not significant

CS-FTP vs. SVD 25.58 No Not significant

CS-FD vs. Ins-FTP -39.18 No Not significant

CS-FD vs. Ins-FD -60.42 Yes Significant

CS-FD vs. SVD -31.90 No Not significant

Ins-FTP vs. Ins-FD -21.23 No Not significant

Ins-FTP vs. SVD 7.282 No Not significant

Ins-FD vs. SVD 28.52 No Not significant

Table 4.16: Dunn's multiple comparison tests – VTI Aorta

There was a significant difference in the velocity time integral at the aortic valve when

fetuses were grouped per the indication and the mode of delivery (p=<0.0001). Fetuses

delivery by emergency caesarean section for fetal distress had the lowest median velocity

time integral (0.090, IQR 0.070 to 0.100) when compared with the rest of the fetuses in our

study population.

95

Dunn's multiple comparisons tests showed a significant difference between fetuses

delivered by emergency caesarean section for fetal distress when compared with an

emergency caesarean section for failure to progress and Instrumental delivery for fetal

distress (Table 4.15 and 4.16).

Left ventricular stroke volume

Stroke volume is the difference between the end diastolic volume and the end systolic

volume expressed in mL/min. The left ventricular stroke volume is calculated by multiplying

the velocity time integral at the aortic valve and the heart rate at the aortic valve.

The median left ventricular (LV) stroke volume in our study population was 4.89 mL (range

1.75 mL to 9.96 mL). The distribution of the LV stroke volume was non -Gaussian in our

study population (skewness = 0.72, kurtosis = 0.23, D’agostino-Pearson test of normality p =

<0.001).

Figure 4.11: Distribution of LV stroke volume

0

2

4

6

8

10

12

1.6

1.9

2.2

2.5

2.8

3.1

3.4

3.7 4

4.3

4.6

4.9

5.2

5.5

5.8

6.1

6.4

6.7 7

7.3

7.6

7.9

8.2

8.5

8.8

9.1

9.4

9.7 10

LV stroke volume

96

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Number of values 37 34 33 46 50

Minimum 2.720 1.752 2.704 2.732 2.572

25% Percentile 4.132 3.411 4.086 4.272 3.893

Median 5.460 4.019 4.753 5.116 4.684

75% Percentile 6.860 5.407 6.247 6.418 6.127

Maximum 9.966 7.234 9.947 9.505 9.602

Mean 5.532 4.348 5.235 5.347 5.069

Std. Deviation 1.759 1.415 1.810 1.676 1.625

Std. Error of Mean 0.2891 0.2426 0.3151 0.2472 0.2298

Lower 95% CI 4.946 3.854 4.593 4.849 4.607

Upper 95% CI 6.119 4.841 5.877 5.845 5.531

Mean ranks 114.8 73.59 102.3 109.5 98.76

Table 4.17: Descriptive statistics of LV Stoke volume

Dunn’s multiple comparison test

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD 41.22 Yes Significant

CS-FTP vs. Ins-FTP 12.54 No Not significant

CS-FTP vs. Ins-FD 5.311 No Not significant

CS-FTP vs. SVD 16.05 No Not significant

CS-FD vs. Ins-FTP -28.68 No Not significant

CS-FD vs. Ins-FD -35.91 No Not significant

CS-FD vs. SVD -25.17 No Not significant

Ins-FTP vs. Ins-FD -7.227 No Not significant

Ins-FTP vs. SVD 3.513 No Not significant

Ins-FD vs. SVD 10.74 No Not significant

Table 4.18: Dunn's multiple comparison tests – LV Stroke volume

Statistically significant differences were observed in the LV stroke volume when fetuses

were grouped per the indication and mode of delivery (p=0.0289). Fetuses delivered by

emergency caesarean section for fetal distress had the lowest median LV stroke volume

(4.019mL, IQR 3.411 to 5.407 mL) while fetuses delivered by caesarean section for failure to

progress had the highest median LV stroke volume (5.460mL, IQR 4.132 to 6.860 mL).

97

Dunn's multiple comparisons tests showed significant mean rank difference between

fetuses delivered by emergency caesarean section for fetal distress compared with fetuses

delivered by emergency caesarean section for failure to progress (Table 4.17 and 4.18)

The fetuses in our study population were then divided into three groups per the centiles (LV

stroke volume under the 10th centile, 10 to 90th centile and over 90th centile). The delivery

outcome data were further analysed to observe if there was an association between the

centiles of LV stroke volume and the outcome of delivery.

Figure 4.12: LV stroke volume centile and M.O.D

LV stroke volume CS -FTP CS-FD Ins –FTP Ins – FD SVD

< 10th centile (n=20) 2 6 3 5 4

10-90th centile(n=160) 31 28 25 35 41

>90th centile(n=20) 5 0 5 6 4

Table 4.19: M.O.D and LV stroke volume by centile

98

30% of fetuses (6/20) with LV stroke volume under the 10th centile was delivered by

caesarean section for fetal distress while none of the fetuses (0/20) was delivered by

caesarean section for fetal compromise in the group of LV stroke volume that was greater

than the 90th centile (Table 4.19).

Fetuses with Left ventricular (LV) stroke volume less than the 10th centile were 1.9 times

more likely to be delivered by caesarean section for fetal distress when compared with the

rest of the fetuses (R.R 1.928, 95th CI 0.910 to 4.087, p=0.086).

However, we did not have any fetuses with LV stroke volume greater than the 90th centile

that were delivered by caesarean section for fetal suggesting that fetuses with LV stroke

volume greater than the 90th centile were protective of caesarean section for fetal distress

(NPV -100%).

Left cardiac output/mL/min/kg (LCO)

The left cardiac output is obtained by multiplying the left ventricular stroke volume and the

heart rate across the aortic valve. The cardiac output/mL/min/kg is obtained by dividing the

cardiac output by the estimated fetal weight.

The LCO was measured in all the fetuses in our study population. The median value was

187.44mL/min/kg (range 79.24 to 401.84 mL/min/kg). The results in our study group

showed a non -Gaussian distribution (skewness =0.72, kurtosis = 0.30, D’agostino-Pearson

test of normality p = <0.001).

99

Figure 4.13: Distribution of LCO/mL/min/kg

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Number of values 37 34 33 46 50

Minimum 101.0 79.25 95.19 107.5 96.41

25% Percentile 149.9 124.3 150.3 169.7 148.0

Median 191.1 152.3 174.4 204.9 196.4

75% Percentile 251.4 192.9 230.7 256.4 232.5

Maximum 332.2 256.8 401.8 397.8 365.7

Mean 204.3 160.9 192.4 216.4 200.8

Std. Deviation 63.71 48.26 72.18 68.82 59.19

Std. Error of Mean 10.47 8.276 12.56 10.15 8.370

Lower 95% CI 183.1 144.1 166.8 196.0 184.0

Upper 95% CI 225.6 177.7 218.0 236.9 217.7

Mean ranks 107.4 68.38 93.64 117.7 105.9

Table 4.20: Descriptive statistics of LCO/mL/min/kg

0

5

10

15

20

257

0

75

90

10

5

12

0

13

5

15

0

16

5

18

0

19

5

21

0

22

5

24

0

25

5

27

0

28

5

30

0

31

5

33

0

34

5

36

0

37

5

39

0

40

5

42

0

43

5

45

0

46

5

LCO/mL/min/kg

100

Dunn’s multiple comparison test

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD 39.02 Yes Significant

CS-FTP vs. Ins-FTP 13.77 No Not significant

CS-FTP vs. Ins-FD -10.33 No Not significant

CS-FTP vs. SVD 1.505 No Not significant

CS-FD vs. Ins-FTP -25.25 No Not significant

CS-FD vs. Ins-FD -49.36 Yes Significant

CS-FD vs. SVD -37.52 Yes Significant

Ins-FTP vs. Ins-FD -24.10 No Not significant

Ins-FTP vs. SVD -12.26 No Not significant

Ins-FD vs. SVD 11.84 No Not significant

Table 4.21: Dunn's multiple comparison tests – LCO/mL/min/kg

Statistically, significant difference in the LCO was observed in the fetuses when classified per

the indication and the mode of delivery (p=0.003). Fetuses delivered by emergency

caesarean section for fetal distress had the lowest median LCO while fetuses that were

delivered by instrumental delivery for fetal distress had the highest median LCO (204.9

mL/min/kg, IQR 169.7 to 256.4 mL/min/kg). Dunn’s multiple comparison tests showed a

significant mean rank difference in fetuses delivered by caesarean section for fetal distress

when compared with fetuses delivered by caesarean section for failure to progress, fetuses

delivered by instrumental delivery for fetal distress and fetuses with normal vaginal delivery

(Table 4.20 and 4.21).

The incidence of caesarean section for fetal distress was higher (25/100 =25%) in the fetuses

which had LCO <50th centile when compared with fetuses that had LCO >50th centile

(9/100=9%). Fetuses with LCO less than 50th centile were around three times more likely to

be delivered by emergency caesarean section for fetal distress when compared with fetuses

101

with LCO greater than the 50th centile. Our results correlated with observations from the

initial pilot study.

Further to the initial analysis, we divided the fetuses into three groups (Figure 4.32) per the

centiles (LCO under the 10th centile, 10 to 90th centile and over the 90th centile). The mode

of delivery was then analysed in the groups to observe if there was an association between

the centiles of LCO/mL/min/kg and the mode of delivery.

Figure 4.14: LCO centiles and M.O.D

LCO/mL/min/kg CS -FTP CS-FD Ins –FTP Ins – FD SVD

< 10th centile (n=20) 2 8 4 4 2

10-90th centile(n=160) 30 26 26 34 44

>90th centile(n=20) 5 0 3 8 4

Table 4.22: M.O.D and LCO/mL/min/kg by centile

0

5

10

15

20

25

30

35

40

45

50

CS-FTP CS-FD Ins-FTP Ins-FD SVD

LCO/mL/min/kg and mode of delivery according to centile

<10th centile 10-90th centile >90th centile

102

We observed 40% (8/20) of fetuses with LCO <10th centile was delivered by emergency

caesarean section for fetal distress. It was interesting to observe that none of the fetuses

was delivered by caesarean section for fetal distress with LCO above the 90th centile (Table

4.22).

Fetuses with LCO < 10th centile were 2.7 times more likely to be delivered by caesarean

section for fetal distress when compared with the rest of the fetuses (R.R -2.769, 95th CI

1.454 to 5.272, p=0.0019). We did not find any fetuses with LCO greater than the 90th

centile to be delivered by caesarean section for fetal distress suggesting that fetuses with

LCO greater than the 90th centile were protective of caesarean section for fetal distress

(Negative predictive value 100%). We also did not find any significant difference in the

maternal age, BMI, gestational age and the ethnicity when the left cardiac output of the

fetuses was grouped per the different centiles (<10th centile, 10-90th centile and greater

than 90th centile).

We then performed a Binary logistic regression with the Caesarean section for fetal distress

as the dependent variable which adjusts for the influence of the potentially confounding

variable. The left cardiac output remained significant even when the cerebro -placental ratio

was included in the model suggesting that they are independent predictors for caesarean

section for fetal distress. For the same reason, there was not a strong linear correlation

between the LCO and the CPR.

Difference between Right and left ventricular stroke volume

From our initial analysis, it was evident that although the right ventricular stroke volume

was not significantly different, the right ventricular stroke volume was higher in fetuses

delivered by emergency caesarean section for fetal distress compared with the rest of the

103

group. We, therefore, decided to analyse if there was a difference between the right and

the left ventricular stroke volume if fetuses were grouped per the indication and the mode

of delivery.

The difference between the right and the left ventricular stroke volume was measured in all

the fetuses in our study population. The median value of the difference between the RV and

LV stroke volume was 1.93 mL (range -4.28 mL to 12.57 mL). The distribution was non -

Gaussian in our study group (skewness =1.02, kurtosis =2.82, D’agostino-Pearson test of

normality p = <0.001)

Figure 4.15: Distribution of the difference between RV and LV stroke volume

0

5

10

15

20

25

-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13

Difference between RV and LV stroke volume

104

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Number of values 37 34 33 46 50

Minimum -2.348 -0.6690 -4.280 -1.374 -3.173

25% Percentile 0.2205 1.960 0.4943 0.2408 0.9800

Median 1.250 3.025 2.036 1.373 1.789

75% Percentile 3.276 4.574 3.892 2.692 2.931

Maximum 5.551 12.21 12.57 6.076 7.780

Mean 1.703 3.644 2.274 1.623 1.877

Std. Deviation 1.838 3.018 3.034 1.783 2.166

Std. Error of Mean 0.3022 0.5177 0.5281 0.2629 0.3063

Lower 95% CI 1.090 2.591 1.198 1.094 1.262

Upper 95% CI 2.316 4.697 3.350 2.153 2.493

Mean ranks 91.73 130.7 104.2 86.91 96.54

Table 4.23: Difference between RV and LV stroke volume

Dunn’s multiple comparison test

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD -38.95 Yes Significant

CS-FTP vs. Ins-FTP -12.45 No Not significant

CS-FTP vs. Ins-FD 4.817 No Not significant

CS-FTP vs. SVD -4.810 No Not significant

CS-FD vs. Ins-FTP 26.49 No Not significant

CS-FD vs. Ins-FD 43.76 Yes Significant

CS-FD vs. SVD 34.14 No Not significant

Ins-FTP vs. Ins-FD 17.27 No Not significant

Ins-FTP vs. SVD 7.642 No Not significant

Ins-FD vs. SVD -9.627 No Not significant

Table 4.24: Dunn's multiple comparison tests –RV and LV stroke volume difference

105

Statistically, a significant difference between RV and LV stroke volume was observed

between the fetuses when grouped per the indication and the mode of delivery (p=0.011).

Fetuses delivered by emergency caesarean section for fetal distress had the highest

difference between the RV and LV stroke volume (3.025 mL, IQR 1.960 to 4.574 mL). The

lowest difference was observed in fetuses delivered by caesarean section for failure to

progress (1.250 mL, IQR 0.220 to 3.276 mL). Dunn’s multiple comparison tests showed a

significant mean rank difference in fetuses delivered by caesarean section for fetal distress

when compared with fetuses delivered by caesarean section for failure to progress and

fetuses delivered by instrumental delivery for fetal distress (Table 4.23 and 4.24).

Further to the initial analysis, the fetuses per the centiles were divided into three groups per

the centiles (difference between RV and LV stroke volume under the 10th centile, 10 to 90th

centile and over 90th centile). The mode of delivery was then analysed in this groups to

observe if there was an association between the difference in the stroke volume and the

outcome of delivery (Figure 4.34).

Figure 4.16: Difference between RV and LV stroke volume per centile and M.O.D

0

5

10

15

20

25

30

35

40

45

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Difference between RV and LV stroke volume according to centile and M.O.D

<10th centile 10-90th centile >90th centile

106

Difference between RV and LV stroke volume

CS -FTP CS-FD Ins –FTP Ins – FD SVD

< 10th centile (n=20) 4 3 4 3 6

10-90th centile(n=160) 31 24 25 40 40

>90th centile(n=20) 2 7 4 3 4

Table 4.25: M.O.D and difference between RV and LV stroke volume by centile

There was a significant difference between the right and the left ventricular stroke volume

among fetuses grouped per the centile (p=0.011). Fetuses with the highest difference were

2.3 times more likely to be delivered by caesarean section for fetal distress (Table 4.25)

compared to the rest of the fetuses (R.R =2.33, 95th CI =1.169 TO 4.657, p=0.0163)

Difference between right and left cardiac output/mL/min/kg

From our initial analysis, we observed that fetuses delivered by caesarean section for fetal

distress had significantly lower left cardiac output and a high right cardiac output when

compared with rest of the fetuses. We, therefore, decided to find if there was a significant

difference between the right and the left cardiac output in fetuses when grouped per the

indication and the mode of delivery.

Figure 4.17: Distribution of difference between RCO and LCO

0

5

10

15

20

25

-200 -160 -120 -80 -40 0 40 80 120 160 200 240 280 320 360 400

Difference between RCO and LCO/mL/min/kg

107

The difference between the RCO and LCO /mL/min/kg was measured in all the fetuses in our

study population. The median value was 70.53 mL/min/kg (range -176 mL/min/kg to 399

mL/min/kg). The results of our study showed a non -Gaussian distribution (skewness =0.67,

kurtosis = 1.15, D’agostino-Pearson test of normality p = <0.001).

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Number of values 37 34 33 46 50

Minimum -83.37 -34.12 -176.3 -59.92 -104.8

25% Percentile 12.57 74.98 18.38 14.49 28.40

Median 46.17 121.6 78.42 56.02 68.25

75% Percentile 117.3 174.6 146.2 113.2 121.1

Maximum 213.5 399.0 351.0 245.7 281.4

Mean 65.62 137.2 79.28 65.37 75.39

Std. Deviation 67.18 109.2 102.1 67.74 87.01

Std. Error of Mean 11.04 18.73 17.78 9.988 12.31

Lower 95% CI 43.22 99.05 43.07 45.25 50.66

Upper 95% CI 88.02 175.3 115.5 85.49 100.1

Mean ranks 90.81 130.8 100.8 89.39 97.12

Table 4.26: Descriptive statistics of difference between RCO and LCO

Dunn’s multiple comparison test

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD -39.98 Yes Significant

CS-FTP vs. Ins-FTP -9.947 No Not significant

CS-FTP vs. Ins-FD 1.420 No Not significant

CS-FTP vs. SVD -6.309 No Not significant

CS-FD vs. Ins-FTP 30.04 No Not significant

CS-FD vs. Ins-FD 41.40 Yes Significant

CS-FD vs. SVD 33.67 No Not significant

Ins-FTP vs. Ins-FD 11.37 No Not significant

Ins-FTP vs. SVD 3.368 No Not significant

Ins-FD vs. SVD -7.729 No Not significant

Table 4.27: Dunn's multiple comparison tests – Difference between RCO and LCO

108

The difference between the RCO and LCO was significantly different between the fetuses

when classified per the indication and the mode of delivery (p=0.0158). Fetuses delivered by

emergency caesarean section for fetal distress had the highest median difference

(121.6mL/min/kg, IQR 74.98 to 174.6). The lowest median difference (46.16mL/min/kg, IQR

12.57 to 117.3 mL) was observed in fetuses delivered by emergency caesarean section for

failure to progress. Dunn’s multiple comparison tests showed a significant mean rank

difference in fetuses delivered by caesarean section for fetal distress when compared with

fetuses delivered by caesarean section for failure to progress and fetuses delivered by

instrumental delivery for fetal distress (Table 4.26 and 4.27). Significant differences were

observed between the RCO and the LCO when grouped per the indication and mode of

delivery.

Following this preliminary analysis, the difference between the RCO and LCO was divided

into three groups (less than 10th centile, 10 to 90th centile and greater than 90th centile) to

observe if there was a significant difference in these groups per the indication and the mode

of delivery (Figure 4.36).

Figure 4.18: Difference between RCO and LCO by centile and M.O.D

0

10

20

30

40

50

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Difference between RCO and LCO/mL/min/kg according to centile and M.O.D

<10th centile 10 to 90th centile >90th centile

109

Difference between RCO and LCO

CS -FTP CS-FD Ins –FTP Ins – FD SVD

< 10th centile (n=20) 2 3 4 4 7

10-90th centile(n=160) 33 24 26 40 37

>90th centile(n=20) 2 7 3 2 6

Table 4.28: Difference between RCO and LCO by centile and M.O.D

Fetuses with the highest difference between the RCO and LCO were 2.3 times more likely to

be delivered by caesarean section for fetal distress (Table 4.28) compared to the rest of the

fetuses (R.R =2.33, 95th CI =1.169 to 4.657, p=0.0163).

Ratio of right to left cardiac output/mL/min/kg

There have been studies reporting a right ventricular dominance in fetal life compared to

postnatal life, and the reported ratio of right to left cardiac output ranged from 1 to 1.5.(81)

We observed a significant difference in the right to left cardiac output in our study and

therefore decided to see if there was a difference in the ratio of the right to left cardiac

output.

The median ratio of the right to left cardiac output/mL/min/kg was 1.40 (range 0.45 to 5.49).

The distribution was non -Gaussian in our study population (skewness =1.15, kurtosis =1.77,

D’agostino-Pearson test of normality p = <0.001).

The ratio of the RCO to LCO was statistically significant when fetuses were classified by the

indication and the mode of delivery (p=0.0019).

110

CS-FTP CS-FD Ins-FTP Ins -FD SVD

Number of values 37 34 33 46 50

Minimum 0.6814 0.8102 0.5612 0.7065 0.4538

25% Percentile 1.048 1.404 1.095 1.061 1.096

Median 1.350 1.925 1.419 1.252 1.359

75% Percentile 1.573 2.426 1.849 1.564 1.735

Maximum 2.574 5.493 4.212 3.275 2.928

Mean 1.368 1.981 1.543 1.349 1.438

Std. Deviation 0.3957 0.9229 0.7173 0.4467 0.5033

Std. Error of Mean 0.06505 0.1583 0.1249 0.06586 0.07118

Lower 95% CI 1.236 1.658 1.289 1.216 1.295

Upper 95% CI 1.500 2.303 1.797 1.481 1.581

Mean ranks 90.51 135.8 101.7 85.52 96.86

Table 4.29: Descriptive statistics of ratio of RCO to LCO

Dunn’s multiple comparison test

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD -45.28 Yes Significant

CS-FTP vs. Ins-FTP -11.21 No Not significant

CS-FTP vs. Ins-FD 4.992 No Not significant

CS-FTP vs. SVD -6.346 No Not significant

CS-FD vs. Ins-FTP 34.07 No Not significant

CS-FD vs. Ins-FD 50.27 Yes Significant

CS-FD vs. SVD 38.93 Yes Significant

Ins-FTP vs. Ins-FD 16.21 No Not significant

Ins-FTP vs. SVD 4.867 No Not significant

Ins-FD vs. SVD -11.34 No Not significant

Table 4.30: Dunn's multiple comparison tests – ratio of RCO to LCO

Fetuses delivered by emergency caesarean section for fetal distress had the highest median

ratio (1.92, IQR 1.40 to 2.42) while fetuses delivered by instrumental delivery for fetal

distress had the lowest median ratio (1.25, IQR 1.06 to 1.56). Dunn’s multiple comparison

tests showed significant mean rank difference in fetuses delivered by caesarean section for

fetal distress when compared with fetuses delivered by emergency caesarean section for

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failure to progress, fetuses delivered by instrumental delivery for fetal distress and those

delivered by spontaneous vaginal delivery (Table 4.29 and 4.30).

The ratio of the RCO and LCO was divided into three groups by the centile (less than 10th

centile, 10 to 90th centile and greater than 90th centile) to observe if there was the

significant difference between the groups on the indication and the delivery outcome

(Figure 4.37).

Figure 4.19: Ratio of RCO to LCO by centile and M.O.D

Ratio of RCO to LCO CS -FTP CS-FD Ins –FTP Ins – FD SVD

< 10th centile (n=20) 2 3 5 3 7

10-90th centile(n=160) 34 20 24 41 41

>90th centile(n=20) 1 11 4 2 2

Table 4.31: Ratio of RCO to LCO by centile and M.O.D

0

5

10

15

20

25

30

35

40

45

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Ratio of right to left cardiac output and M.O.D

<10th centile 10 to 90th centile >90th centile

112

There was a significant difference in the ratio of the RCO and LCO among fetuses grouped

per the centile (p=0.0019).

Fetuses with the highest difference in the ratio were 4.3 times more likely to be delivered by

caesarean section for fetal distress (Table 4.31) compared to the rest of the fetuses (relative

risk =4.304, 95th CI =2.482 to 7.462, p < 0.0001).

We did not find any significant difference in the maternal age, BMI, gestational age and the

ethnicity when the difference in the ratio of the right to the left cardiac output of the

fetuses was grouped per the different centiles (<10th centile, 10-90th centile and greater

than 90th centile). Similarly, we did not observe any correlation between the fetal weight

and the ratio of the right to left cardiac output.

Correlation of RCO to LCO ratio with CPR and EFW

We performed a Pearson correlation coefficient to find out the relation between the RCO to

LCO ratio with the CPR and the EFW.

Figure 4.20: Correlation between RCO and LCO ratio with CPR and EFW

There was weak negative correlation with the CPR and a weak positive correlation with the

EFW in our study. However, they were not found to be significantly different (p >0.05).

0

2

4

6

0 1 2 3 4

CPR and ratio of RCO to LCO R2= -0.21p=0.07

0

2

4

6

0 1000 2000 3000 4000 5000 6000

Ratio of RCO to LCO and EFW R2=0.014p=0.32

113

Binary logistic regression was performed with the caesarean section for fetal distress as the

dependent variable which adjusts for the influence of the potential confounding variable.

The CPR and the ratio of the right to left cardiac output remained significant even when

both are included in the model (p=<0.0001 and 0.001 respectively) suggesting that they are

independent predictors of caesarean section for fetal distress (Odds ratio – 0.057 and 2.820

respectively)

We also constructed a receiver operating characteristic curve( ROC) curve to check the

sensitivity of the ratio of the RCO and LCO to predict fetuses that were delivered by

emergency caesarean section for fetal distress and is represented below (Figure 4.40). The

area under the curve(AUC) was found to be 0.709 (confidence interval = 0.603 to 0.814)

Figure 4.21: ROC curve to predict CS for fetal distress by ratio of the RCO to LCO

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Combined cardiac output /mL/min/kg (CCO)

The overall fetal cardiac output is calculated by adding the right and left cardiac output

respectively.

Figure 4.22: Distribution of CCO/mL/min/kg

The CCO/mL/min/kg was measured in all the fetuses in our study population. The median

value was 457 ml/min/kg (range 233 ml to 968 ml/min/kg). The results in our study group

showed a non -Gaussian distribution (skewness =0.73, kurtosis = 0.40, D’agostino-Pearson

test of normality p = <0.001).

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115

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Number of values 36 35 33 46 50

Minimum 259.8 239.2 233.5 248.8 277.7

25% Percentile 373.0 362.2 365.9 387.8 391.9

Median 449.1 426.5 448.7 483.0 445.6

75% Percentile 595.5 520.0 566.9 594.9 547.6

Maximum 801.6 779.7 968.6 912.1 834.9

Mean 479.0 454.6 464.0 498.2 477.1

Std. Deviation 137.3 133.6 142.4 151.0 131.1

Std. Error of Mean 22.88 22.58 24.79 22.27 18.54

Lower 95% CI 432.6 408.7 413.5 453.4 439.8

Upper 95% CI 525.5 500.4 514.5 543.1 514.3

Mean ranks 102.4 92.06 94.00 108.9 101.6

Table 4.32: Descriptive statistics of CCO/mL/min/kg

Dunn’s multiple comparison test

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD 10.30 No Not significant

CS-FTP vs. Ins-FTP 8.361 No Not significant

CS-FTP vs. Ins-FD -6.574 No Not significant

CS-FTP vs. SVD 0.761 No Not significant

CS-FD vs. Ins-FTP -1.943 No Not significant

CS-FD vs. Ins-FD -16.68 No Not significant

CS-FD vs. SVD -9.543 No Not significant

Ins-FTP vs. Ins-FD -14.93 No Not significant

Ins-FTP vs. SVD -7.600 No Not significant

Ins-FD vs. SVD 7.335 No Not significant

Table 4.33: Dunn's multiple comparison tests of CCO/mL/min/kg

There was no significant difference in the CCO/mL/min/kg between fetuses when grouped

per the indication and the mode of delivery (p=0.70). The highest median CCO/mL/min/kg

(483.0 mL/min/kg, IQR 387.8 to 594.9 mL/min/kg) was noted in fetuses delivered by

Instrumental delivery for fetal distress. The lowest median CCO/mL/min/kg (426.5

mL/min/kg, IQR 362.2 to 520 mL/min/kg) was measured in fetuses delivered by emergency

116

caesarean section for fetal distress. Dunn's multiple comparisons tests, however, did not

find a significant difference in the mean rank when compared to each mode of delivery with

the other group (Table 4.32 and 4.33).

Left Ventricular Myocardial Performance Index (LV MPI)

The MPI is calculated using by adding the Isovolumetric contraction time (ICT) with the

isovolumetric relaxation time (IRT) and dividing by the ejection time (ET) at the aortic valve

(ICT + IRT / ET).

Figure 4.23: Distribution of LV-MPI

The LV-MPI was calculated in all our fetuses in the study population. The median LV- MPI

measured 0.62 (range 0.43 to 0.80). The LV-MPI showed a non-Gaussian distribution

(skewness = -0.19, kurtosis= -0.25, D’agostino-Pearson test of normality p = <0.001).

0

5

10

15

20

25

30

0.4 0.420.440.460.48 0.5 0.520.540.560.58 0.6 0.620.640.660.68 0.7 0.720.740.760.78 0.8 0.820.84

LV - MPI

117

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Number of values 37 34 33 46 50

Minimum 0.4300 0.4300 0.4600 0.5100 0.4700

25% Percentile 0.5700 0.5800 0.5700 0.5500 0.5900

Median 0.6450 0.6200 0.6100 0.6100 0.6500

75% Percentile 0.6700 0.6600 0.6500 0.6650 0.7000

Maximum 0.7500 0.7400 0.7300 0.7500 0.8000

Mean 0.6217 0.6143 0.6064 0.6133 0.6422

Std. Deviation 0.07308 0.07289 0.06576 0.06899 0.07098

Std. Error of Mean 0.01218 0.01232 0.01145 0.01017 0.01004

Lower 95% CI 0.5969 0.5892 0.5830 0.5928 0.6220

Upper 95% CI 0.6464 0.6393 0.6297 0.6337 0.6624

Mean ranks 103.7 95.93 88.21 91.78 117.5

Table 4.34: Descriptive statistics of LV-MPI

Dunn’s multiple comparison test

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD 7.808 No Not significant

CS-FTP vs. Ins-FTP 15.52 No Not significant

CS-FTP vs. Ins-FD 11.95 No Not significant

CS-FTP vs. SVD -13.76 No Not significant

CS-FD vs. Ins-FTP 7.716 No Not significant

CS-FD vs. Ins-FD 4.146 No Not significant

CS-FD vs. SVD -21.57 No Not significant

Ins-FTP vs. Ins-FD -3.570 No Not significant

Ins-FTP vs. SVD -29.29 No Not significant

Ins-FD vs. SVD -25.72 No Not significant

Table 4.35: Dunn’s multiple comparison tests of LV-MPI

There was no significant difference in the LV-MPI between fetuses when they were grouped

per the indication and mode of delivery(p=0.126). The highest median LV-MPI (0.65, IQR

0.59 to 0.70) was observed in fetuses delivered by spontaneous vaginal delivery, and the

lowest median LV-MPI (0.610, IQR 0.570 to 0.650) was measured in fetuses delivered by

Instrumental delivery for fetal distress and failure to progress. Dunn's multiple comparisons

test, however, did not find a significant difference in the mean rank when compared to each

mode of delivery with the other group (Table 4.34 and 4.35).

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4.10 Summary of fetal cardiac function

Diastolic function: There was no significant difference in the diastolic function when

fetuses were grouped per the indication and the mode of delivery

Systolic function:

Right cardiac output: The right cardiac function was not significantly different between the

fetuses when grouped per the indication and the mode of delivery.

Left cardiac output: There was a significant difference in the left cardiac function in

fetuses delivered by emergency caesarean section for fetal distress when compared with

the rest of the fetuses.

Fetuses delivered by emergency caesarean section for fetal distress had lower left

ventricular stroke volume and left cardiac output/mL/min/kg. There was no significant

difference in the combined cardiac output in fetuses when classified per the indication and

the mode of delivery. Fetuses delivered by emergency caesarean section for fetal distress

had the highest difference between the right and left ventricular stroke volume, the highest

difference between the right and left cardiac output/mL/min/kg and the highest difference

in ratio between the right and left cardiac output.

Left ventricular Myocardial Performance Index (LV-MPI)

There was no significant difference observed in the LV-MPI when fetuses were grouped per

the indication and the mode of delivery.

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4.11 Amniotic fluid index

The amniotic fluid index (AFI) and the deepest pool of liquor (DVP) were recorded in all our

patients. The median AFI was 12.5 cm (Range = 3 to 22.5 cm). The total liquor volume(AFI)

showed a non-normal distribution (kurtosis = -0.20, skewness = -0.04, D’agostino-Pearson

test of normality p = <0.001)

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Number of values 37 34 33 46 50

Minimum 1.000 1.900 1.400 3.600 3.600

25% Percentile 11.75 7.875 9.625 9.930 8.725

Median 13.90 10.70 13.10 12.15 12.00

75% Percentile 16.10 14.25 16.40 13.73 16.33

Maximum 20.00 18.10 20.80 20.80 22.50

Mean 13.56 10.87 13.08 11.73 12.55

Std. Deviation 3.952 3.742 4.311 3.580 4.517

Std. Error of Mean 0.6497 0.6417 0.7504 0.5278 0.6388

Lower 95% CI 12.24 9.567 11.55 10.67 11.26

Upper 95% CI 14.88 12.18 14.61 12.79 13.83

Mean ranks 120.1 78.81 112.4 91.41 101.3

Table 4.36: Descriptive statistics of AFI

Dunn’s multiple comparison test

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD 41.30 Yes Significant

CS-FTP vs. Ins-FTP 7.729 No Not significant

CS-FTP vs. Ins-FD 28.70 No Not significant

CS-FTP vs. SVD 18.85 No Not significant

CS-FD vs. Ins-FTP -33.57 No Not significant

CS-FD vs. Ins-FD -12.60 No Not significant

CS-FD vs. SVD -22.45 No Not significant

Ins-FTP vs. Ins-FD 20.97 No Not significant

Ins-FTP vs. SVD 11.12 No Not significant

Ins-FD vs. SVD -9.847 No Not significant

Table 4.37: Dunn's multiple comparison tests of AFI

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The amniotic fluid volume was statistically significant when fetuses were grouped per the

indication and mode of delivery (p=0.0210). Fetuses delivered by emergency caesarean

section for fetal distress had the lowest median amniotic fluid volume (10.7 cm, IQR 7.87 to

14.25 cm) while fetuses that were delivered by emergency caesarean section for failure to

progress had the highest median amniotic fluid volume (13.90cm, IQR 11.75 to 16.10 cm).

Dunn’s multiple comparison tests showed a significant mean rank difference in fetuses

delivered by caesarean section for fetal distress when compared with fetuses delivered by

caesarean section for failure to progress (Table 4.36 and 4.37).

The amniotic fluid volume also had a weak positive correlation with maternal age and a

negative correlation with BMI and the gestational age of our study population.

4.12 Deepest vertical pool of liquor (DVP)

The median deepest pool of liquor (DVP) measured 4.1 cm (range 1.5 cm to 7.9 cm). The

DVP showed a non-Gaussian distribution (skewness 0.14, kurtosis -0.35, D’agostino-Pearson

test of normality p = <0.001).

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Number of values 37 34 33 46 50

Minimum 1.000 1.900 1.400 1.100 1.200

25% Percentile 3.550 2.575 3.700 3.075 3.100

Median 4.600 3.600 4.900 3.900 4.100

75% Percentile 5.750 4.225 5.400 4.675 5.258

Maximum 7.200 5.900 7.300 7.200 7.900

Mean 4.611 3.547 4.618 3.920 4.164

Std. Deviation 1.479 1.126 1.340 1.225 1.445

Std. Error of Mean 0.2431 0.1931 0.2333 0.1806 0.2043

Lower 95% CI 4.118 3.154 4.143 3.556 3.754

Upper 95% CI 5.104 3.940 5.093 4.283 4.575

Mean ranks 119.1 74.04 120.5 90.90 100.4

Table 4.38: Descriptive statistics of DVP

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Dunn’s multiple comparison test

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD 45.09 Yes Significant

CS-FTP vs. Ins-FTP -1.319 No Not significant

CS-FTP vs. Ins-FD 28.23 No Not significant

CS-FTP vs. SVD 18.78 No Not significant

CS-FD vs. Ins-FTP -46.41 Yes Significant

CS-FD vs. Ins-FD -16.86 No Not significant

CS-FD vs. SVD -26.32 No Not significant

Ins-FTP vs. Ins-FD 29.55 No Not significant

Ins-FTP vs. SVD 20.09 No Not significant

Ins-FD vs. SVD -9.458 No Not significant

Table 4.39: Dunn’s multiple comparison tests of DVP

The DVP was statistically significant between fetuses when grouped per the indication and

mode of delivery (p=0.0028). Fetuses delivered by emergency caesarean section for fetal

distress had the lowest DVP (3.6 cm, IQR 2.57 to 4.22 cm) while fetuses that were delivered

by Instrumental delivery for failure to progress had the highest DVP (4.9 cm, IQR 3.7 to 5.4

cm). Dunn’s multiple comparison tests showed a significant mean rank difference between

fetuses delivered by caesarean section for fetal distress when compared with fetuses

delivered by caesarean section for failure to progress and Instrumental delivery for failure to

progress (Table 4.38 and 4.39).

There was a significant difference in the amniotic fluid volume and the deepest vertical pool

of liquor among fetuses when grouped per the indication and mode of delivery. Fetuses

delivered by emergency caesarean section for fetal distress had the lowest median amniotic

fluid volume and a lowest median deepest pool of liquor when compared with the rest of

the fetuses in our study population. Dunn's multiple comparisons also showed a significant

difference in the mean rank difference between these two groups.

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4.13 Intrapartum monitoring

Intrapartum monitoring consists of assessment of electronic fetal heart rate monitoring(CTG)

to identify the presence or absence of meconium stained liquor.

Electronic fetal heart rate monitoring (CTG)

Electronic fetal heart rate monitoring analysis was performed in all our patients enrolled in

our study and was classified as normal or pathological per the NICE guidelines. 80 patients

were classified as having pathological electronic fetal heart rate monitoring and 120

patients were classified to have non-pathological electronic fetal heart rate monitoring

tracings in our study population.

The fetuses were grouped into two categories (pathological or non-pathological), and

median values of the relevant parameters (CPR, LCO/ml/min/kg and the ratio of the right to

left cardiac output) were analysed in these fetuses (Table 4.40).

CPR (Median and range) LCO/ml/min/kg (Median and range)

Ratio of RCO to LCO (Median and range)

Non-Pathological CTG (n= 120)

1.649 (0.77 to 2.89) 188.30(95.19 to 401) 1.38(0.45 to 4.21)

Pathological CTG (n=80)

1.434(0.84 to 2.69) 184.98(79.24 to 397) 1.43(0.70 to 5.49)

Table 4.40: Comparison of CTG with important Doppler parameters

From the above table, it is evident that fetuses delivered for pathological electronic fetal

heart rate monitoring tracings had a lower cerebroplacental ratio, lower left cardiac

output/mL/min/kg and a higher ratio of the right to left cardiac output when compared with

the fetuses delivered by non-pathological electronic fetal heart rate monitoring. These

results were however not statistically significant.

Sub group analysis showed increased number of fetuses in the pathological electronic fetal

heart rate monitoring group that were delivered by emergency caesarean section for fetal

123

distress. These fetuses had lower CPR, LCO less than the 10th centile and a higher ratio (>90th

centile) of the right to the left cardiac output. On the contrary, fetuses with higher CPR and

the Left cardiac output greater than the 90th centile in the pathological electronic fetal heart

rate monitoring group appeared protective for caesarean section for fetal distress.

Meconium stained liquor

Assessment of the colour of the amniotic fluid at delivery was recorded in all the fetuses

enrolled in our study population. Meconium stained liquor was observed in 18 cases (9%)

with a normal appearance in 182 cases (91%). There was no significant difference when

compared with maternal demographics, fetal weight and ethnicity although it was more

commonly associated in fetuses with advanced gestation in 72% (13/18) of fetuses that

were delivered between 41to42 week’s gestation.

Fetuses with meconium stained amniotic fluid were then sub-grouped per the indication

and mode of delivery further analysis.

Figure 4.24: Meconium-stained liquor and M.O.D

0

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CS-FTP CS-FD Ins-FTP Ins-FD SVD

Meconium and MOD

124

We observed that the highest number of fetuses with meconium stained liquor were

delivered by caesarean section for fetal distress (33%) when compared with the rest of the

study population. However, the results were not statistically significant (Figure 55).

Critical ultrasound parameters like CPR and the LCO/ml/min/kg were then analysed after

grouping the fetuses per the centile measurements to observe if there were any significant

differences between the groups.

Fetuses delivered by emergency caesarean section for fetal distress with meconium stained

liquor were found to be higher in the group of fetuses with CPR and the LCO <10th centile.

None of the fetuses had meconium stained liquor in the group of fetuses with CPR and LCO

over 90th centile that was delivered for the same indication suggesting higher CPR and LCO

were protective against fetuses with abnormalities in liquor. Since the numbers were small,

they did not undergo further statistical analysis.

4.14 Neonatal outcomes

Neonatal outcome details were obtained from the postnatal and neonatal case records. The

findings included APGAR scores, cord blood gases, actual birth weight and history of

neonatal complications and admissions.

APGAR score

Mean (S.D) CS-FTP CS-FD Ins-FTP Ins-FD SVD p value

1 min 8.16 (1.81) 8.28 (1.82) 8.54 (1.09) 8.32 (1.53) 8.64 (0.94) 0.97

5 min 9.63 (0.83) 9.34(1.71) 9.57 (0.79) 9.71(0.72) 9.82(0.43) 0.64

10 min 9.88(0.39) 9.77(0.84) 9.84(0.56) 9.95(0.20) 10(0) 0.27

Table 4.41: APGAR score and delivery outcomes

125

The records of APGAR score were obtained from the neonatal case notes and compared

amongst fetuses classified per the indication and mode of delivery.

There was no significant difference in the mean APGAR score at 1, 5 and 10 minutes

amongst the fetuses in our study group (Table 4.41). Fetuses delivered by emergency

caesarean section for fetal distress had comparatively low APGAR score at 5 minutes when

compared with rest of the group although the results did not reach statistical significance.

Similarly, there was no significant association between the APGAR scores and the relevant

cardiac functional parameters when fetuses were grouped per the indication and the mode

of delivery. There were no cases in our study population that were either admitted to the

neonatal unit or had developed complications before discharge.

pH (arterial and venous)

The arterial and venous pH was measured in all the fetuses in our study population, and the

mean values are tabulated below. There was no significant difference between the mean

arterial and venous pH when fetuses were grouped per the indication and the mode of

delivery (Table 4.42). Most of the fetuses delivered in our study group had the mean arterial

pH in between 7.2 to 7.3. There was no significant difference in the pH values when fetuses

were grouped per the indication and mode of delivery.

Mean (S. D) CS-FTP CS—FD Ins-FTP Ins-FD SVD p value

Arterial pH 7.23(0.08) 7.21(0.09) 7.24(0.06) 7.20(0.06) 7.20(0.16) 0.11

Venous pH 7.25(0.08) 7.24(0.07) 7.28(0.06) 7.26(0.07) 7.25(0.06) 0.21

Table 4.42: Cord pH and mode of delivery

We classified the fetuses per the indication and mode of delivery in the fetuses with arterial

pH less than 7.2 and greater than 7.2 to analyse outcomes. Similarly, we also grouped the

126

fetuses per the centiles of the arterial pH (<10th, 10-90th and >90th) and observed the

indication and the mode of delivery.

Arterial pH CS-FTP CS-FD Ins-FTP Ins-FD SVD Total

<7.2 10 13 5 18 20 66

>7.2 27 21 28 28 30 134

Total 37 34 33 46 50 200

Table 4.43: Arterial pH and delivery outcome

Arterial pH (mean) CS -FTP CS-FD Ins –FTP Ins – FD SVD

< 10th centile (n=20), mean value = 7.01 2 6 3 5 4

10-90th centile(n=160), mean value = 7.22 30 28 25 35 41

>90th centile(n=20), mean value = 7.36 5 0 5 6 5

Table 4.44: Indication and M.O.D by centiles of the arterial pH

We observed that 20 %( 13/66) of fetuses with arterial pH in <7.2 were delivered by

caesarean section for fetal distress while only 15.6 %( 21/134) of fetuses were delivered in

the group with an arterial pH greater than 7.2.

Similarly, 30% of fetuses were delivered by emergency caesarean section for fetal distress in

the group of fetuses with arterial pH less than the 10th centile while none of the fetuses

were delivered for the same reason in the group of fetuses with arterial pH greater than the

90th centile (Table 4.43 and 4.44). These results were not statistically significant and hence

did not undergo further statistical analysis.

Base excess

The base excess was measured in all the fetuses in our study population with a median

value of -6.5(range between -6.5 to -16). There was non-normal distribution in our study

population (skewness =0.72, kurtosis =2.87, D’agostino-Pearson test of normality p =

<0.001).

127

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Number of values 37 34 33 46 50

Minimum -16.00 -12.00 -9.800 -10.90 -10.40

25% Percentile -6.350 -7.925 -6.550 -9.525 -8.300

Median -5.100 -6.350 -6.200 -7.100 -7.200

75% Percentile -2.300 -4.125 -4.300 -5.600 -6.250

Maximum 1.700 -0.6000 -0.6000 6.700 -3.500

Mean -4.516 -5.841 -5.670 -7.043 -7.220

Std. Deviation 3.218 2.691 1.859 3.027 1.529

Std. Error of Mean 0.5290 0.4614 0.3236 0.4463 0.2163

Lower 95% CI -5.589 -6.780 -6.329 -7.942 -7.655

Upper 95% CI -3.443 -4.902 -5.011 -6.144 -6.785

Mean ranks 139.2 108.3 118.5 77.28 76.00

Table 4.45: Base excess -descriptive statistics

Dunn’s multiple comparison test

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD 33.23 No Significant

CS-FTP vs. Ins-FTP 22.02 No Not significant

CS-FTP vs. Ins-FD 67.47 Yes Not significant

CS-FTP vs. SVD 68.95 Yes Not significant

CS-FD vs. Ins-FTP -11.20 No Not significant

CS-FD vs. Ins-FD 34.25 No Not significant

CS-FD vs. SVD 35.72 No Not significant

Ins-FTP vs. Ins-FD 45.45 Yes Not significant

Ins-FTP vs. SVD 46.92 Yes Not significant

Ins-FD vs. SVD 1.475 No Not significant

Table 4.46: Dunn’s multiple comparison tests of base excess

The base excess was statistically significant when fetuses were grouped per the indication

and the mode of delivery (p<0.0001). The highest median base excess (-4.65, IQR -6.37 to -

2.30) was seen in fetuses delivered by caesarean section for failure to progress while fetuses

delivered by spontaneous vaginal delivery had the lowest median base excess (-7.220, IQR -

8.30 to -6.35).

128

Dunn’s multiple comparison tests showed a significant mean rank difference in fetuses

delivered by caesarean section for failure to progress with spontaneous vaginal delivery and

instrumental delivery for fetal distress. Differences in the mean ranks were also observed

between instrumental delivery for failure to progress and instrumental delivery for fetal

distress and spontaneous vaginal delivery (Table 4.45 and 4.46).

4.15 Estimated fetal weight (EFW) and outcome

Estimated fetal weight was calculated by the Hadlock formula using the Biparietal diameter,

Head circumference, abdominal circumference and the femur length in all our fetuses. The

median estimated fetal weight was 3629 grams (range 2626 to 4856 grams). The results in

our study population showed a non- Gaussian distribution (skewness 0.25,

Kurtosis = -0.017, D’agostino-Pearson test of normality p = <0.001).

CS-FTP CS-FD Ins-FTP Ins-FD SVD

Number of values 36 35 33 46 50

Minimum 3070 3045 3098 2886 2626

25% Percentile 3446 3397 3336 3155 3262

Median 3705 3651 3764 3480 3531

75% Percentile 3960 4047 4005 3739 3822

Maximum 4396 4713 4856 4356 4401

Mean 3719 3737 3755 3472 3512

Std. Deviation 324.1 448.3 432.3 378.5 420.8

Std. Error of Mean 54.02 75.78 75.26 55.81 59.51

Lower 95% CI 3609 3583 3602 3360 3392

Upper 95% CI 3829 3891 3909 3585 3632

Mean ranks 116.8 113.4 116.6 78.89 88.93

Table 4.47: Descriptive statistics of EFW and M.O.D

129

Dunn’s multiple comparison test

Mean rank difference Significant? Summary

CS-FTP vs. CS-FD 3.391 No Not significant

CS-FTP vs. Ins-FTP 0.183 No Not significant

CS-FTP vs. Ins-FD 37.93 Yes Significant

CS-FTP vs. SVD 27.89 No Not significant

CS-FD vs. Ins-FTP -3.208 No Not significant

CS-FD vs. Ins-FD 34.54 No Not significant

CS-FD vs. SVD 24.50 No Not significant

Ins-FTP vs. Ins-FD 37.75 Yes Significant

Ins-FTP vs. SVD 27.71 No Not significant

Ins-FD vs. SVD -10.04 No Not significant

Table 4.48: Dunn's multiple comparison tests of EFW

The EFW was statistically significant between fetuses when grouped per indication and the

mode of delivery (p=0.0036). Fetuses delivered by spontaneous vaginal delivery had the

lowest median EFW (3531 grams, IQR 3262 to 3822 grams) while fetuses that were

delivered by Instrumental delivery for failure to progress had the highest median EFW (3764

grams, IQR 3155 to 3739 grams).

Dunn’s multiple comparison tests showed a significant mean rank difference between

fetuses delivered by caesarean section for failure to progress and Instrumental delivery for

fetal distress and between instrumental delivery for failure to progress and Instrumental

delivery for fetal distress (Table 4.47 and 4.48).

As described earlier in the demographics data, there was a positive correlation between

gestational age and the estimated fetal weight. Similarly, when fetuses were grouped per

ethnicity, it was noted that fetuses of Asian ethnic origin had the lowest median estimated

130

fetal weight (3289 grams, IQR 3163 to 3648 grams) when compared to the other ethnic

groups and was statistically significant (p=0.009).

Difference between the estimated fetal weight and actual fetal weight

The estimated fetal weight (EFW) was initially calculated using the Hadlock formula (BPD,

HC, AC and FL) and was compared to the actual birth weight (ABW) at delivery.

CS -FTP CS-FD Ins –FTP Ins – FD SVD

Median and IQR(grams) 108 (-130 to 318)

200 (-25 to 413)

70 (-99.5 to 290)

58.5 (-124 to 247)

108 (-47 to 268)

Median Percentage of difference

3.3 % (-3.4 to 9.1)

5.5% ( -0.6 to 10.6)

1.7% (-2.7 to 8.2)

1.8% (-3.4 to 8)

2.9% (-1.4 to 8.2)

Table 4.49: Difference between EFW and actual birth weight

Figure 4.25: Correlation between estimated and actual birth weight

0

1000

2000

3000

4000

5000

6000

0 1000 2000 3000 4000 5000 6000

EFW and Actual birth weight R2=0.83p=0.85

131

The lowest median difference between fetal weights (58 grams, IQR -124 to 247 grams) was

observed in fetuses delivered by instrumental delivery for fetal distress (Table 4.49). The

highest median difference in fetal weight was seen in fetuses delivered by emergency

caesarean section for fetal distress (200 grams, IQR -25 to 413 grams). There was a strong

positive correlation (R2 =0.83) between the estimated birth weight and the actual birth

weight. The mean absolute error difference in the fetal weight was 110 grams, and the

mean percentage of error was 3.68% in our study population which are within the

acceptable range of normal variation. Similarly, Pearson correlation analysis did not show a

significant positive correlation between the EFW and important ultrasound parameters (CPR,

Left cardiac output, right cardiac output, combined cardiac output and the ratio of the right

to left cardiac output ratio).

132

Chapter 5 -- Cardiac functional parameters, cerebroplacental ratio and risk of

adverse obstetric and neonatal outcomes

This study was performed to identify if Prelabour cardiac function and cerebroplacental

ratio prior to active labour could predict the risk of adverse intrapartum and neonatal

outcome in appropriately grown term singleton pregnancies.

We recruited 200 nulliparous women with appropriately grown term fetuses for our study.

Our results demonstrated that there was a significant difference in the fetal cardiac function

and the cerebroplacental ratio when fetuses were grouped per the indication and the mode

of delivery. We also observed that fetuses delivered by emergency caesarean section for

fetal distress had a significant difference in the fetal cardiac function and the

cerebroplacental when compared with the rest of the fetuses.

5.1 Maternal demographics and mode of delivery

Most of our study population (69.5%) consisted of Caucasian mothers, followed by Asian

women (15.5%) and the remaining by African, Afro-Caribbean and mixed ethnic groups. The

difference reflects the perceptions of medical research across different ethnic groups as

there is a much wider acceptance to research among the Caucasian population when

compared with other ethnic groups. Women with non-English background had difficulties in

understanding the patient information leaflet and the research methodology and hence

were not able to actively participate in the study.

There was no significant difference in the maternal age, BMI and the mean gestational week

at delivery when fetuses were grouped per the indication and mode of delivery.

133

The median gestation age at delivery in our study population was 41 weeks and one day

(range 40+5 to 41+3 weeks). The lowest mean gestational age at delivery was observed in

the spontaneous vaginal delivery group and the highest mean gestational age at delivery

was observed in fetuses delivered by emergency caesarean section for fetal distress.

However, the absolute difference in the mean gestational age at delivery between the

fetuses was very small (five days) which is less likely to influence the outcome.

There are published reports of increased rate of caesarean section for fetal distress in

women of advanced maternal age.(110) however, we could not find a significant difference in

our study due to relatively small numbers recruited for our project.

Fetuses delivered by emergency caesarean section in our study constituted for

35.5%( 71/200) of the total population out of which 18.5% of fetuses (34/71) were delivered

for fetal distress, and 17 % (37/71) were delivered for failure to progress.

The rate of caesarean section was found to be slightly higher in our study group when

compared to the national average of 26.2% of which 13.2% contributed for elective

caesarean sections, and 13% contributed towards emergency caesarean sections.(111)

About one in four children (25%) born in the U.K are delivered by caesarean section.

However, there are regional differences between District Hospitals and tertiary maternity

units. The tertiary maternity units report a slightly increased rate of caesarean sections

when compared to other hospitals due to the complexity of the cases referred to them.

Recent publications on the outcome following induction of labour have also shown

conflicting results. While reviews of observational studies showed an increase in caesarean

section, consideration of the postdates and term pre-labour rupture of membrane trials

suggested either no difference or a reduction in risk.(112)

134

Nippitta et.al performed a population-based cohort study to observe the variation in

hospital caesarean section rates and obstetric outcome among nulliparous women at term.

The team followed 67239 nulliparous women and found 7.3% had a Prelabour caesarean

section, 58% of mothers laboured spontaneously and 35% of them were induced(IOL). The

overall caesarean section rates were 28.1%; however, women with IOL were twice likely to

have intrapartum caesarean section compared with women with a spontaneous onset of

labour (34% vs. 15.5%). The published evidence summarised that differences in clinical

practice and prediction of intrapartum hypoxia were substantial contributors to variation in

intrapartum caesarean section rates.(113)

We compared our data with the caesarean section rates among nulliparous women in our

hospital those were in spontaneous or induced beyond 37 weeks. 10.5% of nulliparous

women in spontaneous labour had an emergency caesarean section, while 29% of the

women had an emergency caesarean section following induction of labour. We were not

able to obtain further details regarding the indication for caesarean section in these women

i.e. if it was either for fetal distress or failure to progress. Similarly, we were also not able to

get information about intact or ruptured membranes before induction was commenced in

these women which would explain the difference in the caesarean section rates.

All the women recruited in our study population in the induction of labour group had intact

membranes. This could also explain the slightly increased risk of caesarean section from our

study when compared with results from our hospital. Previously published studies have

shown that there is a significant increase in caesarean section rates in nulliparous women,

compared to multiparous women due to increased duration of labour and also with higher

intrauterine pressure in nulliparous women when compared to multiparous women.(110, 114)

135

Nine out of ten women recruited in our study (90.5% - 181/200) had induction of labour.

This variation in sample size may have also have contributed to the slight increase in

caesarean section rates in our study. This difference could become less observed when

equal numbers of women in spontaneous labour are also recruited in prospective future

studies to eliminate selection bias.

5.2 Maternal demographics and ultrasound parameters

Ultrasound parameters were analysed alongside the maternal demographics in our study to

observe correlation between them (Table 5.01). The maternal demographics included

maternal age, BMI and the gestation age at delivery

EFW AFI CPR LCO RCO CCO RCO to LCO Ratio

Maternal age Weak positive

Weak positive

Weak positive

Weak positive

Weak positive

Weak positive

Weak positive

Maternal BMI Weak positive

Weak negative

Weak negative

Weak negative

Weak negative

Weak negative

Weak negative

Gestational age

Weak positive

Weak negative

Weak negative

Weak negative

Weak negative

Weak negative

Weak positive

Table 5.01: Correlation of Maternal demographics and ultrasound parameters

We observed a weak positive correlation between the maternal age and the important

ultrasound parameters in our study. Maternal BMI and gestational age showed a weak

positive correlation with the estimated fetal weight while other parameters showed a weak

negative correlation. The ratio of the right to the left cardiac output showed a weak positive

correlation with the maternal age and the gestational age; however, the values were not

statistically significant (p=>0.05).

136

Women of Asian origin had the lowest estimated fetal weight while the highest estimated

fetal weight was observed in the fetuses born to Caucasian mothers. Published studies have

shown significant differences in birth weight born to women of Asian origin compared to

other ethnic groups suggesting an underlying genetic component is responsible for lower

birth weight rather than under nutrition in these mothers.(115, 116)

Wells et al. in their study found that there was a significant difference between the birth

weights of children born to Caucasian couples when compared with Asian couples. Similar

differences were also observed between couples of mixed ethnic backgrounds suggesting

that maternal and paternal ethnicity contributed to the difference in the fetal growth.(117)

Similarly, another large study by Zipursky et al. examined 692,301 live births of different

ethnic origins in Canada and observed that paternal and maternal ethnic background

influence new-born weight.(118) Fetuses are expected to significantly gain weight in the last

trimester especially after 32 weeks, and various growth charts have shown a gradual

increase in the growth velocity pattern. This pattern was reflected in our study showing a

positive correlation between the estimated fetal weight and the gestation at delivery.

5.3 Ethnicity and ultrasound parameters

Maternal ethnicity was compared against important ultrasound parameters (CPR, fetal

cardiac output, amniotic fluid volume and estimated fetal weight) to check if they varied

significantly between different ethnic populations.

Apart from CPR and the estimated fetal weight, none of the other parameters were found to

be significantly different between the various ethnic groups. As discussed earlier, the fetal

weight was found to be significantly different among the ethnic groups.

137

The CPR was found to be significantly different among the various ethnic groups with the

highest ratio observed in the Caucasian and mixed ethnic groups, and the lowest ratio was

seen in the Asian mothers.

Akolekar et al. observed the effects of maternal characteristics that influenced the fetal

Doppler findings in the assessment of fetal well-being.(119) His study demonstrated a

significant decrease in the pulsatility index of the middle cerebral artery at third trimester

and was found to be particularly lower in women of East Asian origin.

Spencer et.al measured free Beta hCG and PAPP-A as part of first-trimester screening for

combined screening test and observed that differences in the median PAPP-A and Beta hCG

existed amongst Afro-Caribbean, South Asian and Chinese women that resulted in a

difference in the screen-positive rates.(120) Pregnancy-associated plasma protein A (PAPP-A)

produced by the placenta aids in maintaining adequate fetal growth. Studies have shown

that low PAPP–A levels in the first trimester can be associated with abnormal placentation

which could result in an adverse outcome regarding fetal growth and well-being.(121)

The Royal College of Obstetricians and Gynaecologists (RCOG-UK, Green-top Guideline

No .31) have published guidelines on the investigation and the management of the small for

gestational age fetus. The guidelines suggest that a low level of PAPP-A (less than 0.415

MoM) is considered a major risk factor for delivery of a small for gestational age fetus.(122)

However, Kumar et al. in his observational study found that B hcG and PAPP-A measured in

the first trimester were not predictive of intrapartum compromise in AGA fetuses.(123) We

analysed our data and did not find any fetus with low PAPP-A values in our study population.

138

5.4 Cerebro placental ratio (CPR)

The CPR was measured in all the patients enrolled in our study population. The median CPR

was 1.53, and the range was between 0.77 and 2.89. The median 10th centile value of CPR

was 1.008, and the median 90th centile was 2.29. The CPR had a non -Gaussian distribution

in our study population (Skewness =0.03, kurtosis =0.49). There have also been publications

using the umbilical- cerebral ratio (U/C ratio) and the vertebro-umbilical ratio in the

assessment of fetal hypoxia. (124)

Umbilical -cerebral ratio has been previously reported as a better predictor of placental

dysfunction in fetuses with fetal growth restriction with chronic hypoxia resulting in adverse

neonatal outcome including neurodevelopmental impairment when compared to the

cerebro placental ratio.(124) (125)However most of the published studies are regarding the

cerebro placental ratio. Our study population consisted of appropriate for gestational age

fetuses at term and the number of cases with severe placental dysfunction is likely to be low.

Hence using the U/C ratio may be of less benefit in our research scenario and therefore we

used the calculation of cerebroplacental ratio in our study population.

Wladimiroff et al. in 1987 measured the pulsatility index (Pi) of the umbilical artery, middle

cerebral artery and cerebro -umbilical ratio in 156 normal and 42 fetuses with intrauterine

growth restriction. He observed a gradual fall in values of CPR with advanced gestation in

the normal fetuses. Fetuses with growth restriction with brain sparing effect showed a

raised Pi in the umbilical artery and low Pi of the middle cerebral artery resulting in a

reduced cerebro placental ratio.(62) These values were significantly different when compared

with normally grown fetuses.

Our study showed a significant difference (p=<0.0001) in the CPR between fetuses when

grouped per the indication and mode of delivery. Fetuses that were delivered by emergency

139

caesarean section had the lowest CPR among the rest of the fetuses delivered by other

modes of delivery. Significant mean rank differences were observed between the fetuses

delivered by emergency caesarean section for fetal distress when compared with fetuses

delivered by caesarean section for failure to progress, spontaneous vaginal delivery and

Instrumental delivery for fetal distress and failure to progress.

Significant differences were also observed when fetuses were classified by the CPR per the

centiles (<10th centile, 10-90th centile and >90th centile). 40% (8/20) of fetuses with CPR

<10th centile was delivered by emergency caesarean section for fetal distress while none

(0/20) of fetuses were delivered by caesarean section for fetal distress in the group of

fetuses with CPR >90th centile (Negative predictive value-100%). CPR<10th centile were 2.7

times more likely to be delivered by emergency caesarean section for fetal distress when

compared to the rest of the fetuses.

CPR is an important finding used in the management of fetal growth restriction at late

gestation. Many published studies have shown its importance in identifying fetuses that are

at risk of fetal compromise.(54, 68, 126-128) Ropacka et al. observed 148 women in

uncomplicated pregnancies between 40-42 weeks. The fetuses were divided into two

groups for analysis of the intrapartum and neonatal outcomes based on presence or the

absence of brain sparing effect. They observed that abnormal CPR was identified in 62.3% of

cases with brain sparing effect while only 19% of fetuses in the control group showed

abnormal CPR. Abnormal CPR also showed the highest sensitivity in the prediction of both

the intrapartum (abnormal FHR in 74% of cases) and risk of the adverse neonatal outcome

(87.8%) suggesting that the CPR showed the highest sensitivity in prediction of fetal heart

rate abnormalities and adverse neonatal outcome in uncomplicated pregnancies.(129)

140

Twomey et al. showed that CPR less than one between 30 to 34 weeks had a greater risk of

an emergency caesarean section for fetal distress (33.3%), and adverse perinatal outcomes.

This observation was also strongly associated with low birth weight babies.(130)

Our results correlate with previously published reports suggesting low CPR can predict the

risk of intrapartum fetal distress in AGA fetuses at term. We also observed that high CPR

was found to be protective for emergency caesarean section in the same cohort.

5.5 Fetal cardiac functional parameters

The fetal heart circulation is different to the adult where two circulations efficiently run in

parallel with two shunts (ductus arteriosus and the foramen ovale) connecting them. It is

also different to the adults that fetal oxygenation occurs at the placenta and not at the fetal

lungs. Despite the low partial pressure of oxygen in fetal circulation, the fetus is still able to

maintain oxygen delivery to its tissues due to the presence of fetal haemoglobin and high

combined ventricular output.(131)

There had been many studies on animal models describing the fetal cardiac circulation and

the response of cardiac function to fetal hypoxia.(82, 83, 85-87, 132)The combined biventricular

cardiac output is approximately 450mL/kg/min at birth of which 60-65% is ejected by the

right ventricle and the remaining 35-40% is ejected by the left ventricle. The ratio of the

right to left cardiac output is 1.5:1 since the right ventricle is the dominant systemic

ventricle during fetal life.

The fetal heart rate at the aorta and pulmonary valve appeared similar with the median

heart rate measuring 138 at the aorta and 139 beats per minute at the pulmonary artery

respectively. Fetal heart rate is higher at earlier gestations and gradually decline to 155

beats per minute and stays at around 140 beats per minute beyond 30 weeks. Our results

141

correlated with the standard reference range across the gestation published in the

literature.(81)

There was no difference in the diastolic function when fetuses were grouped per indication

and the mode of delivery. However, significant difference in the systolic function was

observed in these fetuses. Fetuses delivered by emergency caesarean section for fetal

distress had lower left cardiac systolic function indices (ejection time at aortic valve, velocity

time integral at aortic valve, left ventricular stroke volume and left cardiac

output/mL/min/kg) when compared with the rest of the fetuses.

There was no significant difference in the right ventricular systolic function between fetuses

when grouped per the indication and mode of delivery. However, significant differences in

the ratio of the right to left stroke volume and the right to left cardiac output was observed

in fetuses delivered by caesarean section for fetal distress. While there was no change in the

overall combined cardiac output, there was a shift in the individual ventricular output

suggesting redistribution between ventricles while still maintaining the overall cardiac

output.

The important cardiac function indices that were significantly different among the fetuses

when grouped per the indication and mode of delivery are listed below.

1 Ejection time at the aortic valve

2 Velocity time integral at aortic valve

3 Left ventricular stroke volume

4 Left cardiac output/mL/min/kg

5 Difference between right and left ventricular stroke volume

6 Difference between right and left cardiac output/mL/min/kg

7 Ratio of right to left cardiac output/mL/min/kg

142

Ejection time at aortic valve

Ejection time at the aortic valve is when blood is ejected from the left ventricle beginning

with the opening of the aortic valve and ending with the closure of the aortic valve

measured in milliseconds. Fetuses delivered by emergency caesarean section had the lowest

median ejection time (0.156, IQR 0.145 to 0.160) when compared with the rest of the

fetuses and was statistically significant (p=0.0005).

Dunn's multiple comparisons test showed a significant difference between fetuses delivered

by caesarean section for fetal distress when compared with the caesarean section for failure

to progress, instrumental delivery for failure to progress and instrumental delivery for fetal

distress.

The ejection time is analysed in paediatric and adult cardiology in the evaluation of patients

with various cardiovascular disorders. In an average individual, ejection time varied

inversely with the heart rate and directly with the stroke volume. Prolongation of the

ejection relative to stroke volume was observed in patients with aortic insufficiency.(133) We

observed a weak, but positive correlation between the ejection time and the left ventricular

stroke volume (R2=0.05) which is expected as a normal observation in fetuses.

Velocity time integral at Aortic valve

Measurement of the velocity time integral in 2D fetal echocardiography is an important

parameter to calculate the stroke volume. It is obtained by manually tracing the Doppler

signal of the aortic or the pulmonary valve and then multiplied by the corresponding valve

area to get the stroke volume of the ventricles respectively.

143

Our study showed a significant difference in the velocity time integral at the aortic valve

when fetuses were grouped per the indication and mode of delivery (p=<0.0001). Fetuses

delivery by emergency caesarean section for fetal distress had the lowest median velocity

time integral value in our study group (0.090, IQR 0.070to 0.100). Dunn's multiple

comparisons test showed a significant difference between fetuses delivered by emergency

caesarean section for fetal distress when compared with emergency caesarean section for

failure to progress and instrumental delivery for fetal distress.

The cardiac output is calculated on 2D ultrasound by multiplying the stroke volume with the

heart rate. The LVOT diameter closely approximates a circle in shape and undergoes

minimal change during ventricular systole and diastole and is therefore assumed to be a

constant. Stroke volume is calculated by multiplying the velocity time integral and the valve

area. If the LVOT diameter is assumed constant, the velocity time integral (VTI) should be

directly proportional to the stroke volume which means that an increase in the VTI is

associated with an increase in the stroke volume. We observed this finding in our data

analysis (Figure 5.01) evidenced by a moderate positive correlation between the VTI and the

stroke volume of the left ventricle (R2=0.487) as described in the figure below.

Figure 5.01: Correlation between VTI Aorta and LV stroke volume

0

0.05

0.1

0.15

0.2

0 2 4 6 8 10 12

Correlation between VTI Aorta and LV stroke volume (R2=0.487)

144

Left ventricular stroke volume

Stroke volume is the difference between the end diastolic volume and the end systolic

volume expressed in mL. It defines the amount of blood pumped from the left ventricle per

beat.

Statistically, a significant difference was observed in the LV stroke volume in our study when

fetuses were grouped per the indication and mode of delivery (p=0.0289). Fetuses delivered

by emergency caesarean section for fetal distress had the lowest median LV stroke volume

(4.019mL, IQR 3.411 to 5.407) while fetuses delivered by caesarean section for failure to

progress had the highest median LV stroke volume (5.460mL, IQR 4.132 to 6.860 mL) with

significant mean rank difference between fetuses delivered by emergency caesarean section

for fetal distress when compared with fetuses delivered by emergency caesarean section for

failure to progress. Fetuses with LV stroke volume <10th centile was twice more likely to be

delivered by caesarean section for fetal distress while fetuses with LV stroke volume greater

than the 90th centile were protective of caesarean section for fetal distress.

Left cardiac output/mL/min/kg (LCO)

The left cardiac output is obtained by multiplying the left ventricular stroke volume and the

heart rate across the aortic valve. The cardiac output/mL/min/kg is obtained by dividing the

cardiac output by the estimated fetal weight. Statistically significant variation in the LCO was

observed in the fetuses when classified per the mode of delivery (p=0.003). Fetuses

delivered by emergency caesarean section for fetal distress had the lowest median LCO

(152.3 mL/min/kg, IQR 124.3 to 192.9 mL/min/kg) while fetuses that were delivered by

145

instrumental delivery for fetal distress had the highest median LCO (204.9 mL/min/kg, IQR

169.7 to 256.4 mL/min/kg).

Fetuses were grouped by the centiles (<10th centile, 10-90th centile and >90th centile) and

the mode of delivery was analysed in our study. 40% (8/20) of fetuses with LCO <10th centile

was delivered by emergency caesarean section for fetal distress while none of (0/20) of

fetuses were delivered by caesarean section for fetal distress in the group of fetuses with

LCO >90th centile (Negative predictive value-100%).

Fetuses with LCO <10th centile were 2.7 times more likely to be delivered by caesarean

section for fetal distress when compared with fetuses with LCO >90th centile.

Binary logistic regression was performed with caesarean section as the dependent variable

which adjusts for the influence of the potentially confounding variable. We observed that

left cardiac output remained significant even when the cerebroplacental ratio was included

in the model suggesting that they are independent predictors for caesarean section for fetal

distress. For the same reason, there was not a strong linear correlation between the

LCO/mL/min/kg and the CPR.

Difference between Right and Left ventricular stroke volume

Statistically significant difference between RV and LV stroke volume was observed between

the fetuses when classified per the indication and the mode of delivery (p=0.011). Fetuses

delivered by emergency caesarean section for fetal distress had the highest median

difference between the RV and LV stroke volume (3.025 mL/min, IQR 1.960 to 4.574

mL/min). Fetuses with higher difference (>90th centile) were 2.3 times more likely to be

delivered by emergency caesarean section for fetal distress.

146

Difference between RCO and LCO/mL/min/kg

The difference between the right and the left cardiac output /mL/min/kg was measured in

all the fetuses in our study population. The median value was 70.53 mL/min/kg (range -176

mL/min/kg to 399 mL/min/kg). The difference between the right and left cardiac output was

significantly different between the fetuses when classified per the indication and mode of

delivery (p=0.0158). Fetuses delivered by emergency caesarean section for fetal distress had

the highest median difference (121.6mL/min/kg, IQR 74.98 to 174.6 mL/min/kg). The lowest

median difference (46.17 mL/min/kg, IQR 12.57 to 117.3 mL/min/kg) was found in fetuses

delivered by emergency caesarean section for failure to progress. We observed 15% (3/20)

of fetuses were delivered by emergency caesarean section for fetal distress < 10th centile

while 35% (7/20) of fetuses were delivered by caesarean section for fetal distress in the

group of >90th centile suggesting that fetuses with the highest difference were 2.3 times

more likely to be delivered by emergency caesarean section for fetal distress compared to

the rest of the fetuses in our study.

Ratio of right to left cardiac output/mL/min/kg

Studies in animal models suggest a right ventricular dominance in fetal life compared to

postnatal life which was also evident in our study. The median ratio of the right to left

cardiac output/mL/min/kg in our study was 1.4: 1 that was comparable to previously

published data. We observed a significant difference in the ratio of the right to the left

cardiac output among our fetuses when classified per the indication and the mode of

delivery (p=0.0019). Fetuses delivered by caesarean section for fetal distress had the highest

median ratio (1.925, IQR 1.048 to 1.573) while fetuses delivered by instrumental delivery for

fetal distress had the lowest median ratio (1.252, IQR 1.061 to 1.561).

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We also observed a significant difference in the delivery outcome when fetuses were

grouped per the centiles (10th centile, 10-90th centile and >90th centile). 15% (3/20) of

fetuses were delivered by emergency caesarean section for fetal distress in the group with

ratio less than 10th centile while 55% (11/20) of fetuses were delivered by caesarean section

for fetal distress in the group with ratio greater than 90th centile. Fetuses with higher ratio

difference (greater than the 90th centile) were 4.3 times more likely to be delivered by

caesarean section for fetal distress when compared with rest of the fetuses.

Binary logistic regression with the caesarean section for fetal distress as the dependent

variable which adjusts for the influence of the potential confounding variable was

performed. The CPR and the ratio of the right to left cardiac output remained significant

even when both are included in the model (p=<0.0001 and 0.001 respectively) suggesting

that they are independent predictors of caesarean section for fetal distress (Odds ratio –

0.057 and 2.820 respectively).

We also constructed a receiver operating characteristic curve( ROC) curve to check the

sensitivity of the ratio of the right to left cardiac output to predict fetuses that were

delivered by emergency caesarean section for fetal distress. The area under the curve(AUC)

was found to be 0.709 (confidence interval = 0.603 to 0.814).

The principle component in the assessment of the cardiac output is the stroke volume which

is defined as the amount of blood ejected by the heart in a single contraction. Ventricular

stroke volume is the difference between the end diastolic volume (EDV) and the end systolic

volume (ESV).

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End-diastolic volume (EDV) is the volume of the blood in the ventricle before the onset of

ventricular ejection. End-systolic volume (ESV) is the remaining volume of blood in the

ventricle after ventricular ejection. The difference between these two could affect the

stroke volume. For example, an increase in the EDV increases the stroke volume, while an

increase in ESV reduces the stroke volume. The three principle mechanisms that regulate

the EDV, ESV and the stroke volume are cardiac preload, afterload and myocardial

contractility (Figure 5.02).

Figure 5.02: Factors affecting Stroke volume

Cardiac afterload is defined as to the pressure against which the cardiac muscle fibres can

shorten. The cardiac preload is the end diastolic volume before ventricular contraction.

Cardiac preload increase with exercise, increased sympathetic tone, and increased venous

return to the heart resulting in an increased stroke volume.

In the adult heart, beat to beat variation in the amount of blood pumped by the ventricles is

determined by the amount of blood returning to the heart. By the Frank-Starling mechanism,

the stroke volume of the heart increases in response to an increase in end diastolic volume

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resulting in an increased preload. This increase in the volume causes stretching of the

ventricular wall resulting in much forceful contraction to eject the blood even when all other

factors remain constant. However, in contrast to the adult heart, the fetal heart has little

functional reserve. Weil et.al studied the pressure volume relationship of the fetal heart in

lambs by increasing the ventricular preload while maintaining the afterload. They observed

that left ventricular end diastolic pressure and the peak systolic pressure increased in

proportion to the preload suggesting that mechanism of Frank starling effect. This study also

concluded that cardiac preload plays an important, but limited function in cardiac

reserve.(134) Kirkpatrick et.al performed similar studies in fetal lambs and observed a

significant association between the stroke volume and left ventricular shortening suggesting

that frank starling mechanism is operative and effective within physiological conditions.(135)

There are published studies that have looked at the effects on cardiac function in chronic

hypoxemic fetuses as part of the assessment of fetal growth restriction or pregnancies with

placental dysfunction.(136, 137)

Cardiac flow is significantly influenced by changes in vascular flow to the fetus and placenta

that affect the stroke volume. In fetuses with chronic hypoxia, there is a decrease in the left

ventricular afterload secondary to cerebral vasodilatation and an increase in the right

ventricular afterload due to increased placental vascular resistance.

Fetal hypoxemia results in adaptive changes in the fetus that include erythropoiesis to

increase oxygen transport, angiogenesis in muscle to reduce oxygen diffusion distance,

increase catecholamine release and metabolic changes at a cellular level. The fetal heart

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also reacts to damage differently from the adult heart by responding with cardiac myocyte

proliferation in addition to ventricular hypertrophy.(138)

Longitudinal studies have suggested that in growth restricted fetuses, the cardiac output

gradually declined to indicate a progressive worsening of the cardiac function. It is

important to understand that these changes occur gradually over a period when the fetal

heart undergoes adaptive response to the hypoxic environment.

Alonso et.al(137) examined the right ventricular function in fetal sheep following long-term

hypoxemia by infusing nitrogen gas into the maternal trachea. Six cases were housed under

hypoxic conditions while another six cases were housed in a non-hypoxemic environment as

controls. The right ventricular stroke volume and cardiac output were measured in all the

cases for two weeks with electromagnetic flow probe placed in the pulmonary artery by

intravascular catheters. Cardiac preload was assessed by volume infusion of 5%

(weight/volume) dextrose, and afterload was studied by administering methoxamine (alpha

adrenergic agonist). In hypoxic fetuses, the right ventricular output and stroke volume were

not seen to be affected during the first two days but then reduced to 30% on day three.

Hypoxic fetuses also showed an increase in the fetal arterial pressure by 20% and the

haemoglobin concentration by approximately 30% with minimal changes in the heart rate.

There was no change in the cardiac enzyme levels in both the groups. The researchers also

found that the fetal heart in both the groups always worked on the plateau of its function

curve at any given afterload with right ventricular output remaining constant.

The study concluded that in fetuses with prolonged hypoxemia, right ventricular function

showed a triphasic response. There is an initial primary maintenance phase during 1 to 3

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days followed by a reduced output that lasts up to 7 days and recovery occurs by the end of

two weeks. This study showed that fetal cardiac function was not found to be affected

during the first 48 hours of hypoxemia as there was no significant difference in the atrial

pressure and the fetal heart rate. Besides, circulating catecholamine during short-term

hypoxia could maintain cardiac function by direct inotropic stimulation. The hypoxic fetuses

after two weeks achieved a new steady state to be able to pump against increased afterload

resulting from the polycythaemia and elevated arterial pressure.(139)

The results of the fetal cardiac output to short-term fetal hypoxemia appear variable

depending on the severity and duration of the insult. Adachi et al(140) reported changes in

the fetal cardiac function during short-term hypoxemia by an increase in the stroke volume

and raised cardiac output in spite of associated bradycardia. Similar study by Cohn et.al(141)

in lamb fetuses showed a difference in the cardiac output depending on moderate or severe

hypoxemia. Fetuses with moderate hypoxemia showed no significant change in cardiac

output while decreased cardiac output was observed in fetuses exposed to severe

hypoxemia.

This is the first study that has considered the measurement of fetal cardiac output prior to

labour in appropriate for gestational age fetuses at term. While we found no significant

change in the overall cardiac output, there was clearly a dominance of the right cardiac

output compared to the left in fetuses delivered by emergency caesarean section for fetal

distress while maintaining the overall cardiac output. We know from previous studies that

fetuses normally exhibit a right heart dominance prior to delivery which then converts to

left ventricular dominance after birth. We could therefore hypothesise that babies that

show transition from right to left ventricular dominance and those who show the healthiest

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transition are likely to withstand labour the best. However, fetuses with significant right

ventricular dominance with reduced left ventricular dominance during labour may show

difficulty in adaptation and these are the babies that respond worse to the stress of the

labour and have a higher incidence of developing intrapartum fetal distress.

The observations in our study could therefore be attributed to the failure of adaptation of

the fetus to changes in the physiological activity of the fetal heart in response to

intrapartum fetal distress rather than due to direct consequence of hypoxic changes that

occur during labour resulting in increased incidence of emergency caesarean section for

fetal distress.

5.6 Intrapartum and neonatal outcomes

Electronic fetal heart rate monitoring and outcome

This study was not powered to analyse the intrapartum and neonatal outcomes. However,

we present our analysis on the findings we observed in our study. We had 80 patients that

were classified as having pathological electronic fetal heart rate monitoring tracing in our

study population. We observed that fetuses delivered with pathological electronic fetal

heart rate monitoring tracings also had a lower CPR, lower LCO and a higher ratio of the

right to left cardiac output when compared with rest of the fetuses. Sub group analysis

showed increased number of fetuses in the pathological electronic fetal heart rate

monitoring group that were delivered by emergency caesarean section for fetal distress.

These fetuses had lower CPR, LCO less than the 10th centile and a higher ratio (>90th centile)

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of the right to the left cardiac output. On the contrary, fetuses with higher CPR and the Left

cardiac output greater than the 90th centile in the pathological electronic fetal heart rate

monitoring group appeared protective for caesarean section for fetal distress.

Prediction of intrapartum fetal hypoxia still appears challenging despite improvements in

the assessment of the fetus during labour. Despite standard published guidelines, there is

still a wide variation of inter and intra observer variability in the interpretation of

intrapartum fetal distress leading to sub-optimal management and complications resulting

in medico-legal claims.(16) Systematic reviews on continuous electronic fetal heart rate

monitoring for intrapartum fetal assessment have failed to show significant difference in

cerebral palsy rate, infant mortality rate or other standard measures of neonatal well-

being.(7) Sirsistadis et al. in his prospective controlled study looked at intrapartum outcomes

in fetuses that were monitored by electronic fetal heart rate monitoring alone and in

combination with CPR. They observed that electronic fetal heart rate monitoring together

with CPR showed a lower risk of neonatal metabolic acidosis and had significantly lower

rates of caesarean section for fetal distress and improved outcome rather when used in

isolation.(68)

Our findings correlate with the previously published reports; however, we also observed

that fetuses delivered by emergency caesarean section for fetal distress following abnormal

electronic fetal heart rate monitoring also had a reduced left cardiac output suggesting that

underlying reduced cardiac function in these fetuses predispose them to subsequent risk of

intrapartum fetal distress.

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Amniotic fluid volume

Measurement of the deepest pool of liquor and the amniotic fluid index is part of routine

assessment of fetal well-being. Previously published studies have shown that reduced

amniotic fluid volume is seen in growth restricted fetuses secondary to poor placental

function and reduced renal perfusion secondary to cerebral hypoxemia (37, 39, 142) although

Kushtagi et al. (52) in their study concluded that amniotic fluid index is not a reliable

screening test to predict intrapartum fetal compromise. Post-term fetuses have increased

morbidity due to increased risk of meconium aspiration, fetal post maturity syndrome and

fetal death. Amniotic fluid gradually decreases with advanced gestation nearing term with a

further decline after 40 weeks. Many theories have been proposed for this observation. The

most common belief is that placental insufficiency in post-term fetuses results in cerebral

redistribution leading to impaired renal perfusion resulting in oligohydramnios. However,

Bar-Hava et al. showed that there is increased secondary renal absorption rather than

impaired renal perfusion resulting in reduced liquor volume in post-term fetuses.(40) Clinical

practitioners equally use the amniotic fluid index and the deepest vertical pool of liquor in

the assessment of amniotic fluid volume and abnormalities in either of them is considered

to be associated with adverse intrapartum outcome.

Our results showed that fetuses delivered by emergency caesarean section for fetal distress

had the lowest amniotic fluid volume index and the lowest deepest vertical pool of liquor.

This was statistically significant (p=0.02) when fetuses were grouped per the indication and

mode of delivery. The results suggest that even in the cohort of normally grown term

fetuses, sub-optimal placental function may cause reduced amniotic fluid volume and be

associated with adverse intrapartum outcome.

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Meconium stained liquor was observed in 18 cases in our study group with no significant

difference when compared with maternal demographics, fetal weight and ethnicity. We

observed meconium stained liquor was more associated in fetuses with advanced gestation

beyond 41 weeks. Since the numbers were small, they did not undergo significant statistical

analysis; however, interesting findings were observed in the fetuses that had meconium

stained liquor.

Among the fetuses with meconium stained liquor, 33 %( 6/18) were delivered by emergency

caesarean section for fetal distress. Further analysis was performed after sub-classifying the

fetuses per the centile measurements based on relevant cardiac functional parameters.

We observed that fetuses delivered by emergency caesarean section for fetal distress with

meconium stained liquor also had a low CPR and the LCO < 10th centile. None of the fetuses

was delivered for the same reason in the group of fetuses of measurements above the 90th

centile.

Intrauterine passage of fetal bowel contents occurs in around 8 to 20% of term pregnancies.

There is an increased association of meconium-stained liquor in post-term pregnancies and

in fetuses with intrauterine hypoxia for which the mechanism is poorly understood.

Meconium-stained amniotic fluid has been associated with an increased risk for operative

delivery and adverse perinatal outcome.(143-145)

Hiersch et al(146) performed a retrospective cohort study of women with meconium-stained

amniotic fluid in low-risk pregnancies that were delivered between 37 to 41+6 week's

gestation. They observed that 10.9% of their population were diagnosed with meconium

stained liquor. When matched with controls, the incidence of meconium-stained liquor was

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increased in primiparous women, fetuses with advanced gestation and following induction

of labour. Meconium stained liquor was also increased in fetuses with non-reassuring heart

trace and in fetuses delivered by caesarean section. These fetuses were also found to be at

greater risk for respiratory distress and short-term neonatal morbidity.

Our study findings correlate with previously published reports. We have observed that

abnormal fetal Doppler and cardiac function in fetuses in addition to meconium stained

liquor can be associated with adverse intrapartum outcome resulting in caesarean section

for fetal distress.

Neonatal outcomes

This study was not powered to detect differences in the neonatal outcome. We did not find

a significant difference in the mean APGAR score at 1, 5 and 10 minutes in our study

population; however, fetuses delivered by emergency caesarean section for fetal distress

had comparatively low APGAR scores at 5 minutes when compared with the rest of the

fetuses. Similarly, there was no significant association between the APGAR scores and the

important cardiac functional parameters when fetuses were grouped per the indication and

the mode of delivery.

We did not observe significant differences in the mean arterial and venous pH when fetuses

were classified per the indication and mode of delivery. Most the fetuses that were

delivered in our study population had a mean pH between 7.2 and 7.3. However, when the

arterial pH was grouped per the centile, we observed that arterial pH above the 90th centile

was protective for fetal distress.

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Arterial pH less than seven was observed in 3 fetuses (caesarean section for failure to

progress (1), caesarean section for fetal distress (1) and spontaneous vaginal delivery (1).

Further analysis of these cases showed no significant correlation to the gestational age,

estimated fetal weight, CPR or the left cardiac output when compared with rest of the

fetuses that were either delivered for similar reasons. The fetus with a low arterial pH that

was delivered by vaginal delivery also had a lower fetal weight (3321 vs. 3512 grams), higher

CPR (1.77 vs. 1.64) and was delivered at earlier gestation (37+5 vs. 40+6) when compared

with rest of the fetuses in the spontaneous vaginal delivery group.

Similarly, there were no neonatal admissions for the fetuses that were delivered with cord

pH less than 7. Low arterial pH <7 have been observed in fetuses with an adverse neonatal

outcome. However, these parameters by itself are poor identifiers of intrapartum

compromise as they reflect the neonatal condition at delivery rather than the time of

intrapartum insult to the fetus.

Results of the base excess were obtained from the neonatal case noted for all our fetuses.

The base excess was statistically significant when fetuses were grouped per the indication

and mode of delivery (p<0.0001). Fetuses delivered by caesarean section for failure to

progress had the highest median base excess (-4.65, IQR -6.37 to -2.30) while fetuses that

were delivered by spontaneous vaginal delivery had the lowest median base excess (-7.220,

IQR -8.30 to -6.35).

Blood supply to the fetus is challenged to its maximum during the intrapartum period when

maternal oxygenation is compromised, maternal perfusion to the placenta is reduced and

the oxygenated blood flowing from the placenta to the fetus is impeded resulting in cerebral

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redistribution. Further reduction in fetal oxygenated blood flow results in activation of the

anaerobic pathway with accumulation of lactic acid resulting in metabolic acidosis. Although

low arterial pH <7 and base excess greater than -12 are associated with adverse neonatal

outcome, these parameters only reflect the neonatal condition at delivery rather than the

time of intrapartum insult to the fetus.(147)

Estimated fetal weight and obstetric outcome

Estimated fetal weight was recorded in all the fetuses in our study population before labour

and was correlated with postnatal weight obtained from the neonatal case records. The

median estimated fetal weight was 3629 grams (range 2626 to 4856 grams). The estimated

fetal weight was significantly different (p=0.003) when fetuses were classified per the

indication and the mode of delivery. The lowest median fetal weight was recorded in fetuses

delivered by spontaneous vaginal delivery (3531 grams, IQR 3262 to 3822 grams) and the

highest median fetal weight was recorded in fetuses that were delivered by instrumental

delivery for failure to progress (3764 grams, IQR 3336 to 4005 grams). Significant mean rank

differences in fetal weight were observed between fetuses delivered by caesarean section

for failure to progress and Instrumental delivery for fetal distress and between instrumental

delivery for failure to progress and Instrumental delivery for fetal distress. There was a

strong positive correlation (R2 =0.83) between the estimated birth weight and the actual

birth weight. The mean absolute error difference in the fetal weight was 110 grams, and the

mean percentage of error was 3.68% which is within the acceptable range of average values

as documented in many studies.(148, 149) There was no correlation observed between the

fetal weight and the cardiac parameters (LCO and ratio of the RCO to LCO).

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Chapter 6 – Fetal cardiac function and cerebroplacental ratio in the

prediction of adverse intrapartum outcome

6.1 Performance of screening in prediction of intrapartum fetal distress at term

Following the findings from our data analysis, we looked at the performance of screening

methods in the prediction of fetal distress at term by assessment of the fetal cardiac output

and to compare with the cerebro placental ratio. Amongst the cardiac functional

parameters, the most significant differences were observed in the left cardiac output and

the ratio of the right to the left cardiac output when fetuses were grouped per the

indication and the mode of delivery. We, therefore, decided to use the two parameters

along with CPR to compare the detection rate and the positive predictive value of these

parameters in the prediction of intrapartum fetal distress at term in appropriate for

gestational age fetuses.

Detection rate of intrapartum fetal distress at term

To look at the performance of screening in the prediction of intrapartum fetal distress, we

grouped the fetuses and took the 10th or the 90th centile of the different cut-offs of the

fetuses that did not have caesarean section for fetal distress (Figure 6.01).

The 90th centile cut-off for the RCO to LCO ratio was ≥2.05. The 10th centile cut-off for the

CPR was≤1.13 and the 10th centile cut-off for the LCO/mL/min/kg was ≤128mL min/kg.

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The detection rate in the prediction of fetal distress for a 10% false positive rate using the

ratio of the RCO to LCO greater than the 90th centile was 41%. This was found superior when

comparing to the LCO <10th centile which was 29 %. These two cardiac parameters by

comparison were found to be superior to the cerebro placental ratio that had a detection

rate of 27%.

Figure 6.01: Prediction of CS-fetal distress by LCO, CPR and RCO to LCO ratio

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Positive predictive value in the prediction of intrapartum fetal distress

We also analysed our data to look at the positive predictive value of the important cardiac

parameters in comparison with cerebroplacental ratio in the prediction of intrapartum fetal

distress (Figure 6.02).

The positive predictive value in prediction of intrapartum fetal distress by using the ratio of

RCO to LCO was 45%. This value was higher when compared to the LCO which had a

detection rate of 37% and by comparison was found to be superior to the cerebroplacental

ratio with a detection rate of 35%.

Figure 6.02: PPV for CS-fetal distress by LCO, CPR and RCO to LCO ratio

32%

33%

34%

35%

36%

37%

38%

39%

40%

41%

42%

Ratio of RCO toLCO>90th centile

LCO/mL/min/kg <10th centile

CPR <10th centile

Positive predictive value (PPV)

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Logistic regression analysis

We then performed a Binary logistic regression with the Caesarean section for fetal distress

as the dependent variable which adjusts for the influence of the potentially confounding

variable. The LCO remained significant even when the CPR was included in the model

suggesting that they are independent predictors for caesarean section for fetal distress. For

the same reason, there was not a strong linear correlation between the LCO and the CPR.

Similarly, we also performed a binary logistic regression with the caesarean section for fetal

distress as the dependent variable which adjusts for the influence of the potential

confounding variable. The CPR and the ratio of the RCO to LCO remained significant even

when both are included in the model (p=<0.0001 and 0.001 respectively) suggesting that

they are independent predictors of caesarean section for fetal distress (Odds ratio – 0.057

and 2.820 respectively). For the same reason, there was not a strong linear correlation

between the CPR and the ratio of the right to left cardiac output.

We constructed a receiver operating characteristic curve( ROC) curve to check the sensitivity

of the ratio of the RCO to LCO to predict fetuses that were delivered by emergency

caesarean section for fetal distress . The area under the curve(AUC) was found to be 0.709

(confidence interval = 0.603 to 0.814).

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Chapter 7 – Conclusions

7.1 Strengths and limitations

Despite significant improvements in intrapartum assessment of fetuses during labour, the

prediction of intrapartum fetal distress remains a challenge in modern obstetrics

management. Diagnosis of intrapartum fetal distress is usually made by a combination of

clinical findings and electronic fetal heart rate monitoring abnormalities. Many studies and

systematic reviews on continuous intrapartum fetal monitoring have failed to show

significant difference in standard measures of neonatal well-being. The combination of four

systematic reviews comparing electronic fetal heart rate monitoring with pulse oximetry

and isolated electronic fetal heart rate monitoring analysis showed no difference in the

overall caesarean section rates (22)

Visser et al. in 2015 published the FIGO consensus guidelines on intrapartum fetal

monitoring. The study group looked at the combination of adjunctive technologies in

addition to electronic fetal heart rate monitoring to assess fetal oxygenation to reduce the

false positive cases resulting in unnecessary fetal interventions. The study concluded that

there was still much uncertainty regarding the use of different adjunctive technologies in

intrapartum fetal monitoring. The guidelines also suggest that in order to improve the

intrapartum fetal monitoring is to learn and understand the pathophysiology of the fetal

response following reduced oxygenation during labour.(150)

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Studies that have included fetal Doppler in addition to electronic fetal heart rate monitoring

have shown to be more predictive of adverse intrapartum outcome rather than using

electronic fetal heart rate monitoring in isolation.(129) Our study has shown that assessment

of fetal cardiac function in AGA fetuses at term in addition to the fetal Doppler could

identify fetuses at risk of intrapartum fetal distress.

Fetal echocardiographic assessment is routinely performed using 2D echo with Doppler.

There have been significant improvements in the assessment of fetal cardiac function by

modern techniques alongside M mode, conventional 2D echo and Doppler ultrasound. The

newer modern cardiac assessment techniques are not practically suitable for day to day

clinical application due to the complexity of the techniques and the skill required to learn

and reproduce with minimal inter and intra-observer variability.(96)

Previous publications have shown that although 3D and 4D ultrasound techniques are

reliable than standard 2D and Doppler assessment for calculating the stroke volume and

cardiac output(151-153); However, there are many disadvantages in the implementation of this

method as a choice for screening due to the following reasons.

The newer 3D and 4D imaging methods involve complex post processing technology that is

not available with standard ultrasound equipment in day to day clinical practice. It may also

require a longer period of learning as every clinician or sonographer is not competent in

performing 3D ultrasound in routine clinical practice. 3D ultrasound can also be technically

challenging at late gestation due to fetal breathing movements which may compromise

image quality. Finally, it is important to note that the clinical expertise to post process and

review images from these new imaging modalities is not available in every clinical setting.

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While 2D fetal echo and Doppler evaluation require additional skills and training, integrating

these additional examinations should be relatively easy to the existing clinical practice since

most of the doctors and sonographers are familiar with routine assessment of the fetal

heart as part of the fetal anomaly screening programme. Given the technical limitations and

complexity of the assessment of cardiac function by the newer imaging methods, it is

probably wiser to use the simplest and most validated techniques and gain experience with

these techniques for clinical assessment and can be implemented on a large scale screening

if found to be effective.(154)The whole examination was completed in 30-45 minutes which

would roughly be the time required to perform a routine obstetric scan suggesting the

convenience of using this technique in a regular clinical setting

All the scans in our study were conducted by an experienced single operator, and each

measurement was taken three times with the average of the measurements used in analysis.

The technique and measurements were performed per the standard published guidelines

thereby eliminating examination bias.

Analysis of the venous flow channels contiguous with the right atrium provide a good

approximation of the pressure gradients within the right atrium thus indirectly reflecting

cardiac compliance. An attempt was made to study the waveform from the Ductus

venosus(DV) as described in the methods earlier. However, it was not possible to consistent

wave form for analysis in all our population in the pilot study. This was due to multiple

factors like fetal position, acoustic shadowing from the spine and ribs obstructing the view

of the ductus on axial and sagittal planes, fetal diaphragmatic movements resulting in poor

sampling in addition to the narrow lumen of the vessel diameter at late gestation. The

hepatic veins near the ductus venosus also led to inadequate sampling leading resulting in

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an incorrect waveform for analysis. Hence for the above reasons we could not include the

Ductus venosus analysis in our study.

Induction of labour constituted 79% of our recruited population, and the remaining 21% of

the women recruited were in spontaneous or early labour. Despite information of the study

available to patients, most of the women interested in participating in the study had either

progressed into active labour before recruitment and hence could not be enrolled into our

study. This study was performed by a single operator, and it was not possible to recruit the

patients, who arrived in early labour to triage during different times of the day and night.

Observational studies have supported the argument that induction of labour increases the

rate of caesarean sections, whereas reviews of post-date pregnancies and term prelabour

rupture of membranes suggest either no difference or reduction in the risk of caesarean

section. Wood et al.(112)performed a systematic review and meta-analysis of trials in women

with intact membranes. They reviewed 37 RCT’s of which 27 were trials of uncomplicated

pregnancies at 37-42 week’s gestation. The authors concluded that a policy of induction was

associated with a reduction in the risk of caesarean section compared with expectant

management (O.R =0.83, 95th CI 0.76 to 0.92).

A critical aspect of any new intervention or investigation is the acceptability of the

technique to patients. However, we observed very high rate of patient acceptance for

ultrasound examination before labour. Patients find an additional ultrasound examination

before delivery as an enjoyable and reassuring experience because additional scans are

currently not offered to low-risk pregnant women on the NHS antenatal screening

programme. The few patients who declined to participate in the study prior to enrolment

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have cited reasons as being uncomfortable due to pain from active contractions or

unwillingness to undergo examination by a male doctor for religious/ethical reasons. These

issues are unlikely to persist if multiple operators can be trained to perform the study to

translate the evidence from research towards clinical practice.

7.2 Conclusions

This study was aimed to measure the fetal cardiac output before the onset of active labour

and to correlate with obstetric and neonatal outcome. This study is also the first study to

measure fetal cardiac function in AGA term fetuses before active labour in nulliparous

women.

Positive predictive parameters Relative risk Positive LR

CPR <10th centile 2.7 3.25

LCO/ml/min/kg <10th centile 2.7 3.25

Ratio of RCO to LCO >90th centile 4.3 5.97

Table 7.01: Relative risk and likelihood ratios in prediction of CS for fetal distress

Results from the Doppler study of cerebro placental ratio showed that fetuses delivered by

emergency caesarean section for fetal distress had a significantly low CPR compared to the

rest of the fetuses(p<0.0001). Fetuses with CPR less than 10th centile were 2.7 times more

likely to be delivered by caesarean section for fetal distress when compared to the rest of

the fetuses (Table 7.01). Fetuses with CPR >90th centile was protective for fetal distress

(NPV-100%).

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The results of our study have shown that pre-labour assessment of cardiac function in

appropriately grown term singleton fetuses can identify fetuses at risk of subsequent

intrapartum fetal distress.

In fetuses that develop intrapartum fetal distress in utero, we observed a difference in the

prelabour cardiac function.

There was no difference in the diastolic function of the heart in these fetuses; however

significant differences were observed in the systolic function. The left cardiac output and

the difference between the right and left cardiac output were significantly different when

fetuses were grouped per the indication and mode of delivery. Fetuses with left cardiac

output < 10th centile were 2.7 times more likely to be delivered by caesarean section for

fetal distress when compared to the rest of the fetuses. However, fetuses with LCO >90th

centile appeared to be protective for caesarean section for fetal distress (NPV-100%).

Significant difference in the ratio of the right to the left cardiac output was also observed in

fetuses that were delivered by emergency caesarean section for fetal distress.

While there was no change in the overall cardiac output, fetuses delivered by caesarean

section for fetal distress had the highest ratio difference between the right and the left

cardiac output when compared with rest of the fetuses(p=0.0019). Fetuses with highest

ratio difference >90th centile were 4.3 times more likely to be delivered by emergency

caesarean section for fetal distress when compared with rest of the fetuses in our study

population.

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The ratio of the right to the left cardiac output was also found to be superior in the

prediction of intrapartum distress when compared to the left cardiac output and the

cerebro placental ratio.

The detection rate in the prediction of fetal distress for a 10% false positive rate using the

ratio of the RCO to LCO >90th centile was 41%. This was higher when compared to the LCO

less than 10th centile (29 %) which was higher than the CPR with a detection rate of 27%.

The positive predictive value in prediction of intrapartum fetal distress by using the ratio of

RCO to LCO was 45%. This was higher when compared to the LCO<10th centile that had a

detection rate of 37% and by comparison was found to be superior to the CPR <10th centile

with a detection rate of 35%.

Results from the binary logistic regression that adjusts for the influence of the potentially

confounding variables showed the LCO and the ratio of the RCO to LCO remained significant

even when the CPR was included in the model suggesting that they are independent

predictors for caesarean section for fetal distress. For the same reason, there was not a

strong linear correlation between the CPR and the LCO and between the CPR and the ratio

of the right to the left cardiac output.

7.3 Potential clinical application and further research

Despite significant advances in intrapartum fetal monitoring, there has not been a

significant decrease in the overall rate of caesarean sections for the past three decades. One

in 4 babies (25%) is currently delivered by caesarean section making it the most commonly

170

performed operation in the world. There is a wide variation in the caesarean section rates

across the countries and continents around the world with numbers as little as 2% to as high

as 50%. (155, 156) Luz Gibbons et al. in their world health report published in the year 2010

obtained data from 137 countries performing caesarean sections. The results from the data

showed that 54 countries had caesarean section rates below 10%, whereas 69 countries had

shown rates above 15%. Around 10%(14) of the countries had caesarean rates between 10

to 15%.(157)The cost of global excess due to these procedures was estimated approximately

2.32 billion U.S Dollars, while the expense of the global need for caesarean section

approximated a modest amount of 432 million U.S Dollars.

There is an inverse relation between the caesarean section rates and the maternal and

infant mortality rates. However, the caesarean section above a certain limit have not shown

to provide additional benefit while some studies have shown that higher caesarean section

rates could be linked to negative consequences in maternal and child health.(157) Molina et al.

in 2015 published her results after examining the relationship between population level

caesarean delivery rates compared with maternal and neonatal mortality in 194 WHO

member states. The results showed that national caesarean delivery rates of up to

approximately 19 per 100 live births were associated with a lower maternal or neonatal

mortality among the member states.(158)

Caesarean section is being considered as one of the safety operative procedures although

it's not without the risk of surgical complications and adverse outcome. Liu et al. compared

spontaneous vaginal delivery with elective caesarean sections and found that caesarean

section had three times higher risk of severe maternal morbidity compared to spontaneous

vaginal delivery. This included major complicates like cardiac arrest, venous

171

thromboembolism, haemorrhage resulting in hysterectomy or infection. There was also an

increased rate of respiratory distress syndrome in fetuses that were delivered by caesarean

section compared to vaginal delivery.(159)

The observations in our study regarding fetal hemodynamics in AGA fetuses at term provide

information regarding the sub optimal placental function may enable better monitoring of

these fetuses. Despite significant advances in the obstetric care, it is not possible to

significantly reduce the overall rate of stillbirth. A global study by Lawn et al. showed an

estimated 2.6million third trimester stillbirth occurred in 2015. Although the etiology is

multifactorial with no obvious cause identified in majority of the cases, most of them are

linked to placental complications, either with fetal growth restriction or preterm labour or

both. They also observed in their study that prolonged pregnancies contribute to 14% of the

still birth rates.(160)

From the recent data published by the office of the national statistics -U. K, there were

695,233 live births in England and Wales in 2015. 161 The stillbirth rate was 4.5 per 1000

total births with no significant change compared to previous years. The rate of still birth is

still high in the U.K when compared with other wealthy developed countries around the

world.(161) United Kingdom is ranked 21 out of 35 of the world's richest countries and is

currently ranked behind Croatia, Poland and the Czech Republic in still birth rates. The

United Kingdom's reduction in the annual rate of reduction of stillbirth is at 1.4% which

places the country at the 114th place in the global list for the progress made on the decrease

in still birth.(160)The report from MBRRACE -UK (Mothers and babies: reducing risk through

audits and confidential enquiries across the U.K) have observed a big variation in stillbirth

across the U.K by region with the highest rate of still births observed in Yorkshire, Humber,

172

West Midlands and Wales (5 to 5.2%). Similarly, a higher rate of still birth was observed with

women of poorer backgrounds and when classified by ethnicity with Asian and African/Afro-

Caribbean mothers at greater risk when compared to the Caucasian population.

The National Health Service (NHS) in the U.K is currently able to offer two scans for pregnant

women. The first scan is offered between 11 to 14 weeks as part of dating the pregnancy

and combined screening test risk assessment for common trisomies. The second scan is

offered between 18-23 weeks for fetal anomaly evaluation in the context of the Fetal

antenatal screening programme. There are no additional scans offered for pregnant women

for rest of the pregnancy unless there are clinical indications or previous obstetric history of

adverse outcome. However, some NHS trusts in the U.K are able to provide additional third

trimester scans to pregnant women.

There have been many publications with conflicting observations regarding additional scans

in the third trimester. The latest Cochrane database of Systematic reviews by Bricker et al. in

2015(162) concluded that there was no difference in the primary outcomes of perinatal

mortality, preterm birth less than 37 weeks, caesarean section rates and induction of labour

rates if ultrasound in late pregnancy was performed routinely or not. However, the data was

lacking for the other primary outcomes that included preterm birth less than 34 weeks,

maternal psychological effects and neurodevelopment at the age of two. However, the POP

study in 2015 published in the LANCET showed that screening of nulliparous women with

universal third-trimester scan roughly tripled the detection of SGA infants that were at

increased risk of neonatal morbidity.(163) Similarly, another study by Roma et.al compared

the use of routine third-trimester ultrasound at 32 and 36 weeks in predicting the outcome.

They observed that there were no significant differences in the perinatal outcome between

173

the scans performed at different gestations; however, the detection rate for fetal growth

restriction was superior at 36 weeks scan when compared with 32 weeks scan.(164)

suggesting that sub optimal placental function at advancing gestation can result in adverse

intrapartum outcome in a small cohort of AGA fetuses at term. It is currently not possible to

identify this group of fetuses at risk of adverse intrapartum outcome.

Fetal growth restriction as discussed before is a significant risk factor for adverse outcome

including the risk of stillbirth. However, approximately two-thirds of the still born fetuses at

term have a birth weight greater than the 10th centile. Hence it is important to understand

that most the fetuses at risk of adverse intrapartum outcome at term are not small, but are

appropriate for gestational age. Sub-optimal placental function rather than abnormal

placenta at late gestation may contribute to the adverse outcome in these fetuses.

Many studies have been published regarding the usefulness of CPR in predicting the risk of

adverse outcome. Khalil et al. showed that the combination of estimated fetal weight, CPR

and uterine Doppler in the third trimester could identify the majority of fetuses at risk of

stillbirth.(64) Similarly, Akolekar et al. looked at the performance of screening for all stillbirth

due to impaired placentation, unexplained or other causes by a combination of maternal

factors, fetal biometry and uterine artery pulsatility index and then compared with the

screening by the uterine artery Pi alone. His research involved 70,003 singleton pregnancies

and observed that combined screening predicted 55% of all stillbirths, including 75% of

cases due to impaired placentation and 23% due to other causes for a false positive rate of

10%. The detection rate was higher by the combined screening approach rather than using

uterine artery Pi in isolation.(165)

174

Induction of labour is currently offered in our unit beyond 41 weeks in most of the

uncomplicated postdate pregnancies. Apart from presentation and liquor volume

assessment, there are no specific Doppler techniques to facilitate a fetus specific approach

in the management of these pregnancies. Risk assessment for an individual fetus for

intrapartum distress is therefore limited by its inherent poor specificity with current clinical

practices. Recently published studies have shown that combination of CPR in addition to

intrapartum electronic fetal heart rate monitoring is useful in the prediction of both the

intrapartum and subsequent risk of the adverse neonatal outcome.(129)Prelabour

assessment of cardiac function in addition with CPR combined with existing clinical practice

of intrapartum monitoring may help to identify fetuses at risk for appropriate obstetric

management.

Identification of fetuses that are at high or low risk of intrapartum distress by these

assessments would allow informed decisions to be made regarding the mode and the place

of delivery. Prior risk stratification of pregnancies may also allow safer allocation of women

to be delivered outside of obstetric units. This will reduce transfer rates as well as the

associated financial costs to the NHS. For example, fetuses that are classified as high risk of

developing intrapartum fetal distress may opt for elective caesarean section, reducing the

risks and costs associated with an emergency procedure, as well as the psychological and

emotional impact of emergency delivery on the woman and the partner.

Previously published reports have shown elevated levels of N -terminal peptide of the pro-

atrial natriuretic peptide (NT -pro ANP) and Cardiac Troponin-T (cTnT) in post-natal fetal

blood samples in fetuses with placental insufficiency. These fetuses also showed a change in

the distribution of the cardiac output with increased left cardiac output consistent with

175

chronic hypoxemia.(89) Similarly, another prospective cross-sectional study by Girsen et

al.(166) looked at 42 fetuses with growth restriction that had Doppler assessment of

cardiovascular hemodynamics within seven days before delivery. Fetuses with severe

growth restriction and abnormal umbilical and DV Doppler showed significantly increased

NT -pro ANP levels. These fetuses also showed a change in distribution of the cardiac output

consistent with chronic hypoxemia.

Our results have shown that prelabour assessment of cardiac function in addition to the CPR

in AGA fetuses at term can identify fetuses at risk of subsequent intrapartum fetal distress.

While the overall cardiac output was maintained, there was a significant difference in the

ratio of the right to the left cardiac output in fetuses that were delivered by emergency

caesarean section for fetal distress. Further investigation of this technique using randomised

controlled trials would be essential before considering its application in clinical practice.

176

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APPENDICES Appendix A: Information sheet for volunteers Study title: “Ultrasound assessment of fetal cardiac function and risk of adverse obstetric and neonatal outcomes in term fetuses." Invitation to take part You are invited to participate in a research study. Before you decide, it is important for you to understand why the research is being done and what it will involve. Please take the time to read the following information. Ask us if there is anything that is not clear or if you would like more information. What is the purpose of this study? Blood flow to baby’s organs is known to change during periods of stress. These changes are particularly marked in small fetuses. Some babies become stressed during labour. We want to determine if ultrasound assessment of blood flow in the umbilical artery, brain and to the heart at the start of labour are predictive of obstetric and neonatal complications. If we have a way of identifying babies likely to become distressed in labour, it will help us better manage these pregnancies and hopefully improve the outcome for these babies. Why have I been chosen? You have been selected because you are in early labour or are likely to go into labour within 48 -72 hours. Do I have to take part? It is up to you to decide whether to participate. If you do, you will be asked to sign a consent form. If you choose not to, you will continue to receive standard management and will not affect the care you receive during the pregnancy. What will happen to me if I take part? If you decide to participate, you will be given this information sheet to keep, and we will ask you to sign a consent form. We will then perform a short ultrasound scan of your baby (lasting around 15-20 minutes). We will measure the size of your baby, amniotic fluid volume, blood flow in various vessels and fetal cardiac output. Once this is done your labour will be managed in the usual manner. The information obtained from the ultrasound scan will not be available to either the doctors or midwives looking after you. We would also take a drop of blood from your baby’s heel (heel prick test) within the first 24 hours after birth. This method of taking blood from a baby is very safe and is used routinely. You may be contacted following delivery regarding the development of the baby. All babies born to mothers recruited in this study will have heel prick samples performed at 24 hours of life to obtain dried blood spots for later analysis. Are there any side effects of obstetric ultrasound? There are no published serious side effects with antenatal ultrasound.

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What are the possible benefits of taking part? There are no immediate benefits to you from taking part. However, the information gathered from this study may be of benefit for other pregnancies. Will my participation in this study kept confidentially? The information obtained from your study is covered by the Data Protection Act. The digital information is protected by software and hardware barrier, and the records are handled in the same way as hospital records. We also seek permission to include clinical details about your pregnancy in the study, for instance, your gestation and medical history. Who is organising the research? The Centre for Fetal Care at Queen Charlotte’s and Chelsea Hospital, Imperial College Healthcare Trust is organising this research. Who has reviewed this study? This study has been reviewed by the principal investigator and his collaborators. The London Research Ethics Committee has approved this research. What if something goes wrong? In the unlikely event of suffering adverse effects because of your participation in the study, you will be compensated through the Imperial College London's "No-fault Compensation scheme." What will happen to the results of the research study? The results from this study may be published in the medical literature. No patient's names or identifiable data will be included in the publication. Contact for Further Information Dr Gowri Paramasivam Clinical Research Fellow Centre for Fetal Care, Queen Charlotte’s and Chelsea Hospital Du Cane Road, London –W12 0HS Phone: 0208 3833998, Fax: 0208 3833507 Email: [email protected] Dr Sailesh Kumar Senior Lecturer/Consultant in Maternal and Fetal Medicine Centre for Fetal Care, Queen Charlotte’s and Chelsea Hospital Email: [email protected] Prof Phillip Bennett Consultant in Obstetrics Queen Charlotte’s and Chelsea Hospital Phone: 0208 3833998, Fax: 0208 3833507 Email: [email protected]

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Appendix B Patient Consent form for inclusion in UA/MCA ratio and Fetal cardiac function assessment study. I …………………………………. have read the attached information sheet regarding the study

“Ultrasound assessment of fetal cardiac function and risk of adverse obstetric and neonatal

outcomes in term fetuses” and I would like to participate.

Signed Patient______________________________ Date______________________ Person taking Consent__________________ Date______________________

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Appendix C Fetal Doppler/ Fetal cardiac function study Maternal Demographics Hospital Number__________ DOB___________

Age____________ Ethnicity_________ BMI____________ Smoker YES/NO Partner Yes/No Weight in Labour_______ Parity__________ Previous SB/IUGR______ Booking BP____ Raised BP in pregnancy___ Pre-existing medical condition ___________________________ Date of booking Scan ___________________________ Labour Details Spontaneous labour YES/NO Induction YES/NO If Yes Indication ___________________________ Gestation at IOL/onset of labour ____________ Membranes: Intact/Ruptured At ROM Liquor: CLEAR/MECI/MECII/MECIII Cervical Dilatation at time of USS ___________ Electronic fetal heart rate monitoring pre-labour YES/NO If Yes describe _________________________ Mode of Delivery: SVD/Forceps/Vacuum/Em.LSCS If instrumental/Em.LSCS why _____________________________ Intrapartum Hypertension YES/NO Meconium during labour YES/NO Intra-partum Pyrexia YES/NO Intrapartum Antibiotics YES/NO Associated Fetal Tachycardia YES/NO If Yes BR Rate_____________ Electronic fetal heart rate monitoring abnormalities YES/NO If yes describe___________________________________________________ FBS YES/NO Number_________ Results________________ Intrapartum haemorrhage YES/NO Intrapartum USS details Date of Scan____________

BPD HC AC

FL AFI DVP

EFW

Fetal Doppler Indices

Umbilical artery 1 2 3 MCA 1 2 3

PI PI

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Cerebro Placental Ratio (CPR) = (MCA Pi /Umbilical artery Pi)

MCA Pi UA Pi CPR

MCA Pi UA Pi CPR

MCA Pi UA Pi CPR

Fetal Cardiac Function

Cardiac parameters 1 2 3

ICT

IRT

ET

MPI = ICT + IRT / ET

E/A Ratio Mitral valve

E/A Ratio Tricuspid valve

1 2 3 1 2 3

Heart rate at Aorta Heart rate at Pulmonary artery

Valve diameter Valve diameter

Valve area Valve area

Aortic Ejection velocity Pulmonary Ejection velocity

Aortic Ejection Time Pulmonary Ejection Time

VTI - Aorta VTI - Pulmonary artery

LV Stroke volume RV Stroke volume

Cardiac output (SV x HR) Cardiac output (SV x HR)

LCO/mL/min/kg RCO/mL/min/kg

Labour Outcome Date of Delivery __________ Gestation at delivery _______ Birth Weight__________ Apgar score: ____at 1m_____at 5min ______at 10 min_______ Cord Gases: pH_____ BE ______ Admission to NNU YES/NO Reason for admission ________________

Length of stay ________________ Ventilation ________________ Sepsis ________________ NEC ________________

Cranial USS/MRI ______________ Other complications ______________

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Abbreviations FGR Fetal growth restriction

HII Hypoxic ischemic injury

ATP adenosine triphosphate

NMDA N-methyl d-aspartate

CTG Cardiotocography

bpm beats per minute

FHR Fetal heart rate

NICE National Institute for Health and Care Excellence

FBS Fetal blood sampling

ALARA As Low As Reasonably Achievable

SGA small for gestation age

MVP maximum vertical pool measurement

AFI Amniotic fluid index

MSAF Meconium stained amniotic fluid

Pi Pulsatility index

PSV Peak systolic velocity

MCA Pi Middle cerebral artery Pulsatility index

UA Pi Umbilical artery Pulsatility index

DV Ductus venosus

CPR Cerebroplacental ratio

C-U ratio cerebro-umbilical ratio

SV Stroke volume

LCO Left cardiac output

RCO Right cardiac output

CCO Combined cardiac output

MPI Myocardial performance index

EV Ejection velocity

ET Ejection time

VTI Velocity time integral

CS-FTP Emergency caesarean section for prolonged second stage of labour

CS-FD Emergency caesarean section for intrapartum fetal distress

Ins -FTP Instrumental delivery for prolonged second stage of labour

Ins -FD Instrumental delivery for intrapartum fetal distress

SVD Spontaneous vaginal delivery

M.O. D Mode of delivery

EFW Estimated fetal weight

ABW Actual birth weight

AFI Amniotic fluid index

DVP Deepest vertical pool

S.D Standard deviation

IQR Inter Quartile range

C.I Confidence interval

p value Probability value

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