ASSESSMENT AND QUANTIFICATION OF FOETAL ELECTROCARDIOGRAPHY AND HEART RATE VARIABILITY OF NORMAL FOETUSES FROM EARLY TO LATE GESTATIONAL PERIOD ELAINE CHIA EE LING (B.Sc. (Hons.), NUS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHYSIOLOGY NATIONAL UNIVERSITY OF SINGAPORE 2006 Acknowledgements i ACKNOWLEDGEMENTS I would like to express my sincere gratitude to the following people, without whose contributions this thesis would not have been possible: • A/Prof. Ho Ting Fei for the invaluable guidance, advice and encouragement that she has provided me throughout my time as her PhD student. • A/Prof. William Yip for his helpful discussions and comments. • A/Prof. Mary Rauff for her guidance and for kindly allowing me to conduct the study at her clinic. • Dr. Chang Ee-Chien and Gao Ping from the Department of Computer Science for their help in the development of F-EXTRACT. • Dr. Zhang Niu for her assistance in acquiring the intrapartum ECG. • A/Prof. YC Wong, A/Prof. PC Wong and A/Prof. Roy Joseph for their help in this study. • Mdm Heng Ye Yong for her assistance in various technical aspects of the study. • All patients who participated in this longitudinal study by allowing serial foetal ECG to be recorded during each antenatal visit. • The nursing and reception staff of NUH Women’s Clinic Emerald for their help in patient recruitment and follow-up, as well as in assessing patients’ medical records. • The admin staff of Department of Physiology for their secretarial support. Publications ii PUBLICATIONS The following publications have resulted from the present study: International Referred Journals: 1) Chia EL, Ho TF, Rauff M, Yip WCL. Cardiac time intervals of normal fetuses using noninvasive fetal electrocardiography. Prenat Diagn. 2005; 25(7): 546-52. 2) Chia EL, Ho TF, Wong YC, Yip WCL. Ventricular bigeminy misdiagnosed as fetal bradycardia by cardiotocography- the value of non-invasive fetal electrocardiography. J Perinat Med. 2004; 32(6): 532-4. Conference Paper: 1) Chia EL, Ho TF, Rauff M, Yip WCL. Cardiac time intervals of normal fetuses using non-invasive fetal electrocardiography. NHG Annual Scientific Congress; October 9, 2004; Singapore. Table of Contents iii TABLE OF CONTENTS ACKNOWLEDGMENTS……………………………………………………… i PUBLICATIONS………………………………………………………………. ii TABLE OF CONTENTS………………………………………………………. iii SUMMARY……………………………………………………………………. x LIST OF TABLES…………………………………………………………… xiii LIST OF FIGURES……………………………………………………………. xiv LIST OF ABBREVIATIONS………………………………………………… xvi Chapter The foetal electrocardiogram……………………………… . Historical development of the foetal ECG…………………………… Measurement of the foetal ECG……………………………………… 2.1 Invasive techniques - foetal scalp electrodes………………… 2.1.1 Clinical application of scalp foetal ECG………… 2.2 Non-invasive techniques - maternal abdominal electrodes… . 2.2.1 Foetal ECG studies utilizing abdominal electrodes… 2.2.2 Technical difficulties with abdominal electrodes… 2.2.3 Vernix caseosa and abdominal foetal ECG signal… 2.2.4 Acquisition and processing of abdominal foetal ECG………………………………………………… 11 2.2.5 Chapter Clinical application of abdominal foetal ECG…… 13 The foetal ECG waveform………………………………… . 14 Morphology and time intervals of the foetal ECG……………………. 15 1.1 P wave………………………………………………………. 15 Table of Contents 1.2 PR interval………………………………………………… iv 18 1.3 QRS complex……………………………………………… 21 1.4 QT interval………………………………………………… 23 1.5 ST segment………………………………………………… 25 1.6 T wave………………………………………………………. 25 Foetal ST segment and T wave- Animal studies……………………… 26 Foetal ST segment and T wave- Human studies……………………… 31 Chapter Heart rate variability……………………………………… . 35 Definition of heart rate variability……………………………………. 36 History of heart rate variability………………………………………. 36 Measurement of heart rate variability……………………………… . 37 3.1 Time-domain methods……………………………………… 38 3.2 Frequency-domain methods………………………………… 40 3.3 Geometrical methods……………………………………… 44 3.4 Non-linear methods…………………………………………. 47 Physiological significance of heart rate variability………………… . 48 4.1 Components of heart rate variability……………………… . 49 4.2 Estimate of vagal activity…………………………………… 50 4.3 Estimate of sympathetic activity……………………………. 51 4.4 Estimate of sympatho-vagal balance………………………… 52 Factors affecting HRV………………………………………………… 52 Clinical application of heart rate variability…………………………… 53 Table of Contents Chapter v Heart rate variability in the foetus………………………… 57 Development of the foetal heart rate………………………………… 58 Regulation of the foetal heart rate…………………………………… . 60 2.1 Regulation by the sympathetic nervous system…………… . 61 2.2 Regulation by the parasympathetic nervous system…………. 61 2.3 Central control of foetal heart rate………………………… 62 2.4 Different maturation rates of the autonomic branches………. 63 Causes of foetal heart rate variability… …………………………… . 64 Measurement of foetal HRV………………………………………… . 65 Characteristics of foetal HRV…………………………………………. 67 Factors affecting foetal heart rate variability………………………… 68 6.1 Gestational age………………………………………………. 68 6.2 Hypoxia……………………………………………………… 68 6.3 Foetal activity……………………………………………… . 69 6.4 Foetal breathing movements………………………………… 70 6.5 Drugs………………………………………………………… 71 Clinical significance of foetal heart rate variability………………… . 72 Chapter Scope of study……………………………………………… 75 Background…………………………………………………………… 76 Hypotheses……………………………………………………………. 77 Aims and objectives………………………………………………… . 77 Chapter Materials and methods…………………………………… . 80 Patient selection………………………………………………………. 81 Table of Contents vi 1.1 Study subjects………………………………………………. 81 1.2 Exclusion criteria…………………………………………… 81 1.3 Patient withdrawal………………………………………… 81 Methodology………………………………………………………… 82 2.1 Foetal ECG acquisition procedures………………………… 82 2.2 Foetal ECG equipment description and operation………… 86 2.3 Measurement of foetal ECG parameters……………………. 91 2.4 Neonatal ECG acquisition and measurement………………. 93 2.5 Foetal HRV measurement………………………………… 94 2.6 Comparison of F-EXTRACT and Nevrokard HRV softwares…………………………………………………… 96 2.7 Correction of aberrant beats……………………………… . 97 2.8 Statistics……………………………………………………. 97 Cardiac time intervals of healthy foetuses……………… 98 Introduction…………………………………………………………. 99 Study population……………………………………………………. 101 Method……………………………………………………………… 103 Results………………………………………………………………. 103 Chapter 4.1 Success rates of foetal ECG recording……………………. 103 4.2 Cardiac time intervals and gestational age……………… . 105 4.3 Cardiac time intervals and gender………………………… 112 4.4 Intrapartum cardiac time intervals………………………… 112 Discussion…………………………………………………………… 115 Summary…………………………………………………………… 127 Table of Contents Chapter vii Clinical application of foetal electrocardiography………. 128 Introduction…………………………………………………………. 129 Case report of a foetus with premature ventricular contractions…… 129 2.1 Antenatal foetal ECG…………………………………… . 129 2.2 Intrapartum foetal ECG…………………………………… 136 Discussion…………………………………………………………… 138 Chapter Development of a novel HRV software…………………… 140 Introduction………………………………………………………… 141 Overview of F-EXTACT……………………………………………. 141 2.1 Software operating procedures…………………………… 143 2.2 Data input format………………………………………… . 144 2.3 Algorithm to remove artifacts……………………………… 144 2.4 User interface………………………………………………. 146 2.5 Mathematical computation of HRV parameters…………… 146 2.5.1 Time-domain analysis…………………………… 148 2.5.2 Frequency-domain analysis……………………… 148 2.6 Display of HRV results…………………………………… 150 2.7 Software limitations… ……………………………………. 150 Summary…………………………………………………………… 150 Chapter 10 Heart rate variability of healthy foetuses………………… 153 Introduction………………………………………………………… 154 Study population…………………………………………………… 155 Methods……………………………………………………………… 155 Table of Contents viii Results……………………………………………………………… 157 4.1 Foetal HRV (time-domain analysis) at different gestational ages……………………………………………………… . 157 4.2 Foetal HRV (frequency-domain analysis) at different gestational ages ………………… .……………………… 160 4.3 Foetal HRV of male and female foetuses…………………. 164 Discussion…………………………………………………………… 164 Summary…………………………………………………………… 172 Chapter 11 Comparison of novel versus commercial HRV softwares… 174 Introduction…………………………………………………………… 175 Method……………………………………………………………… . 175 2.1 Nevrokard system description/operation……………………. 175 Statistics………………………………………………………………. 182 Results………………………………………………………………… 184 4.1 Mean measurements obtained by Nevrokard and FEXTRACT………………………………………………… 184 4.2 Comparison of time-domain parameters between Nevrokard and F-EXTRACT using Bland-Altman method……………. 187 4.3 Comparison of frequency-domain parameters between Nevrokard and F-EXTRACT using Bland-Altman method… 191 Discussion……………………………………………………………. 195 Summary…………………………………………………………… . 201 Table of Contents Chapter 12 ix Limitations of the study and future directions…………… 203 Clinical applications…………………………………………………. 204 Limitations of study/ equipment…………………………………… . 206 Recommendations for future studies………………………………… 208 REFERENCES…………………………………………………………… . 210 APPENDIX A……………………………………………………………… 250 Heart rate variability in the foetus 64 embryonic heart at weeks onwards, and sympathetic nervous innervation of the foetal heart begins around 9-10 weeks. In-utero, the earliest age at which maternally-administered atropine (which crosses the placenta readily) evokes a small increase in fHR is around 15-17 gestational weeks. But the maximum tachycardia response to atropine occurs only between 29-38 weeks. On the other hand, maternally-administered β-adrenergic blockers (also shown to cross the placenta easily) are able to induce foetal bradycardia at 23-28 weeks. The maximum bradycardia response is achieved shortly after that period and remains the same until the end of pregnancy (Papp JG, 1988). Thus, foetal heart rate variability (HRV) appears initially as short-term variability (parasympathetic-origin) and later as long-term variability (sympatheticorigin). Then with advancing gestation, as parasympathetic control of the fHR matures, the fHR progressively decreases and short-term HRV increases. After birth, the parasympathetic tone of the resting heart rate rises to adult levels while adrenergic tone decreases, thereby causing the neonatal heart rate to decline progressively, reaching adult levels within six to eight weeks after birth (Assali NS et al., 1977). Causes of foetal heart rate variability Irregularities in fHR were first observed in the 1960s. These comprise short- term rapid beat-to-beat fluctuations superimposed on long-term oscillations (3-10 cycles per minute) of the fHR. As mentioned, the components of foetal HRV can be Heart rate variability in the foetus 65 summarized as the rapid-acting parasympathetic cardio-decelerator activity and the slower-acting sympathetic cardio-accelerator activity, each superimposed on the tonic level of the respective cardiac innervations. The parasympathetic system fine-tunes the fHR on a beat-to-beat basis because of the almost instantaneous decrease in heart rate that occurs with vagal stimulation and the equally rapid recovery at the end of stimulation. As for cardiac sympathetic stimulation, there is a time lag of seconds from the onset of stimulation to the onset of cardioacceleration, and the return to baseline after the end of impulse is further delayed. Therefore, the parasympathetic and sympathetic branches are responsible for producing the short-term and long-term fluctuations in fHR, respectively (Hainsworth R, 1995). Measurement of foetal heart rate variability Clinical evaluation of foetal HRV is usually performed by visual assessment of the fHR oscillations recorded by cardiotocography (CTG), which is based largely on the qualitative observation of the baseline HR, variability in the baseline rate, the presence, absence and timing of accelerations and decelerations. According to the published research guidelines of National Institute of Child Health and Human Development (NICHD), foetal HRV is defined as absent if the fHR line is flat, minimal (if the short-term fHR varies by ≤ bpm), moderate (6-25 bpm), and marked (>25 bpm) (NICHD, 1997). However, visual interpretation of fHR traces is very subjective and often leads to either unnecessary intervention or unwarranted conservation. The inter- and intra- Heart rate variability in the foetus 66 observer variations of CTG tracings are also unacceptably high. Studies evaluating the reproducibility of CTG classification showed that the overall agreement was fair for normal tracings but poor for suspicious and pathological tracings. Disagreements often occurred over decision-making for clinical interventions when CTG tracings differed from the normal. This may lead to serious implications in medico-legal cases that result in poor foetal outcome, which requires auditing and re-evaluation of CTG tracings, especially if the re-analysis reveals an abnormal CTG tracing that warranted an earlier intervention (Ayres-de-Campos D et al., 1999; Spencer JA et al., 1997; Keith RD et al., 1995). Moreover, the safety of insonating the foetus frequently with ultrasound waves during CTG recording is still somewhat controversial (Newnham JP et al., 1993). Moreover, strictly speaking, beat-to beat variability cannot be recorded on CTG tracings as the equipment uses an averaging technique known as autocorrelation whereby not every beat interval is recorded on the cardiotocogram. Instead, fHR intervals are averaged over an epoch of 3.75 seconds. For a fHR of 140 beats per minute, the foetal heart beats more than two times every second. There is an average of about beats over 3.75 seconds, thus rendering the analysis of beat-to-beat fHR impossible. Accurate measurement of beat-to-beat fHR variability requires the identification of successive R waves of the foetal ECG from electrodes attached to the foetal scalp or maternal abdomen. Heart rate variability in the foetus 67 For quantitative analysis of foetal HRV, power spectral analysis may be performed on the R-to-R interval data obtained from the foetal ECG. The computation of the HRV power spectrum from this technique has been discussed in Chapter 3. Since the sympathetic and parasympathetic nervous systems modulate the fHR at different frequencies, the technique of power spectral analysis is able to identify and quantify the underlying superimposed periodicities corresponding to the two autonomic branches that influence the fHR at their characteristic frequencies. Characteristics of foetal heart rate variability Power spectral analysis of foetal HRV using abdominal ECG reveals two predominant peaks that reflect the frequencies of short-term and long-term fHR oscillations. Ferrazzi et al. (Ferrazzi E et al., 1989) compared the power spectra of foetuses recorded at 26 and 36 weeks of gestation and reported a low frequency (LF) peak concentrated at 0.1 Hz in all foetuses and a high frequency (HF) peak centered around 0.8 Hz that was observed only in 36 week-old foetuses. The HF peak correlated with the foetal breathing movements (determined by ultrasound) in the mature foetus. This relationship between HF power (ranging from 0.2-1.0 Hz) and foetal breathing movements has also been reported by other studies on human foetuses using abdominal fECG (Groome LJ et al., 1994a; Karin J et al., 1993) and foetal magnetocardiography (Zhuravlev YE et al., 2002; Waikai RT et al., 1993; 1995). These findings suggest that analogous to the adult, the foetal HRV power spectrum Heart rate variability in the foetus 68 exhibits a LF, sympathetically-mediated peak and a HF, vagally-mediated peak in the mature foetus. As in the adults, the LF/HF ratio of the foetal power spectrum acts as a quantitative index of the foetal sympathovagal balance. Factors affecting foetal heart rate variability Foetal HRV can be influenced by gestational age, foetal activity, sleep/wake cycles, breathing movements, hypoxia as well as drugs administered to the mother. 6.1 Gestational age Foetal HRV changes with gestation, being low earlier in pregnancy and increases with advancing gestation. Both short-term (HF) and long-term (LF) foetal HRV increase with gestation, but not in the same manner. The LF component of the foetal HRV power spectrum was found to be present in both young and mature foetuses, while the HF component was observed only in mature foetuses (Ferrazzi E et al. 1989). This coincides with the finding that the sympathetic nervous system matures early in gestation while the parasympathetic nervous system matures when the foetus is almost full-term. In addition, the LF/HF ratio decreases as the foetus develops, thus further reflecting the slower maturation of the foetal parasympathetic system as compared to the sympathetic system (Hirsch M et al, 1995). 6.2 Hypoxia In clinical practice, foetal hypoxia is often associated with decreased or absent foetal HRV. However, animal studies showed that acute hypoxia induced a transient Heart rate variability in the foetus 69 rise in foetal HRV, usually accompanied by a fall in fHR. If the hypoxia was prolonged until hypoxic acidosis occurred, then foetal HRV gradually decreased until severe acidosis develops (Bocking AD, 1993; Ikenoue T et al., 1981). A foetus with severe acidosis displays a decreased HRV, suggesting that acidosis and hypoxia result in a diminished control of the fHR by the foetal central nervous system (CNS) (Oppenheimer LW et al., 1994). During intrapartum hypoxia, the initial increase in foetal HRV may be caused by compensatory mechanisms to the transient acute hypoxaemia. The fall in foetal HRV may thus represent decompensation of the CNS that has already been subjected to prolonged and increased hypoxic stress. 6.3 Foetal activity Foetal HRV is affected by the activity state of the CNS. The output from the foetal CRC varies with foetal sleep/wake cycles. The foetal power spectrum is sensitive to changes in the activity state of the foetus. Episodes of foetal activity are associated with an increase in both short-term and long-term HRV, while a decrease in both short-term and long-term HRV occurs during episodes of foetal rest. This variation in fHR is organized into episodes of high and low variability that occur at an average frequency of 20 minutes, with a wide variation between foetuses and within the individual foetus. In addition, gross body movements in the awake, mature foetus have been linked with increase in long-term oscillations (accelerations) in fHR. As such, foetal HRV may be used to characterize normal foetal behaviour, as well as the decrease in foetal body movements in the compromised foetus, who will tend to restrict its activity. Heart rate variability in the foetus 70 The application of a vibroacoustic stimulus to the maternal abdomen leads to increased foetal HRV, often due to a change in foetal state from resting to awake (Magenes G et al., 2004). Foetal HRV also differs between quiet sleep and rapid eye movement (REM) sleep. In a study on foetal sheep, it has been observed that beat-tobeat HRV increases during quiet sleep whereas long-term HRV increases during active REM sleep (Bauer R et al., 1997). Hence, analysis of the foetal HRV may provide a quantitative score of the foetal arousal state. 6.4 Foetal breathing movements Motions of the foetal chest wall known as foetal breathing movements are known to be present approximately 30% of the time in the late gestation human and ovine foetus (Patrick J et al., 1980 Dawes GS et al., 1972). A predominant pattern of rapid, irregular (in rate and amplitude) episodic breathing movements interspersed with episodes of apnoea accounts for more than 90 percent of the breathing activity. The rate of foetal breathing movements was found to correspond to the frequency of fHR variations (Brown JS et al., 1992; Divon MY et al., 1985a; 1985b). Beat-to-beat heart rate variability, together with the HF component of the foetal HRV power spectrum, is increased during episodes of foetal breathing movements and decreased during periods of foetal apnoea (Groome LJ et al., 1994a; 1994b). This indicates the existence of respiratory sinus arrhythmia (RSA) in the human foetus, similar to that observed previously in foetal lambs (Donchin Y et al., 1984; Dalton KJ et al., 1977). Heart rate variability in the foetus 71 RSA is defined as HRV that occurs in synchrony with respiration, whereby RR interval shortens with inspiration and lengthens with expiration, due to modulation of the vagal inhibition of the heart. The origins of RSA are partly central, due to the interaction between the respiratory center and vagal motor neurons. The other part arises from peripheral feedback such as the pulmonary stretch receptors. Since the foetal lungs are not yet inflated, the origin of foetal RSA is mainly from the CNS. As such, RSA may provide a useful non-invasive indicator of foetal well-being, reflecting normal neurological or CNS development. Evidence in support of this, neonates with abnormal neurological development was found to exhibit diminished or absent RSA (Rother M et al., 1987). 6.5 Drugs Maternal medications can have an effect on the foetal HRV. Drugs that depress the CNS, such as barbiturates, opiates and most tranquilizers also depress foetal HRV. Antihypertensives cause decreased foetal HRV, while corticosteroids decreases the incidence of fHR accelerations. Drugs that affect the autonomic nervous system can also alter foetal HRV. Betamimetics result in an increased baseline fHR and decreased foetal HRV. Parasympatholytic agents cause a reduction in foetal HRV, whereas beta-adrenergic blockers usually not cause a noticeable difference in foetal HRV in doses used clinically (Martin C, 1982). In addition, intrapartum drug-induced depression of foetal HRV is mainly responsible for the smoothing pattern of fHR lasting for more than 30 to 40 minutes without associated decelerations. Heart rate variability in the foetus 72 Clinical significance of foetal heart rate variability Alterations in autonomic functions are associated with a variety of physiological and pathophysiological processes, and may contribute to morbidity and mortality. There is a clear association between reduced foetal HRV and intrauterine death, foetal acidosis and low Apgar scores (Martin C, 1982). During the intrapartum period, the foetal sympathovagal balance (LF/HF ratio) increases during contractions and decreases between contractions (Divon MY et al., 1984). This change in autonomic balance, which indicates sympathetic activation during contractions, is the response of a healthy foetus to the normal stress of contractions. If the foetus is severely acidotic, there is no change in foetal autonomic balance during and between contractions and the LF/HF is perpetually high (Siira SM et al., 2005), reflecting the depression of the CNS in fHR control (Oppenheimer LW and Lewinsky RM, 1994). Clinically, a reduction in HRV is also associated with foetal hypoxia or pharmacological depression of the foetal CNS activity. Foetal HRV, being an important correlate of foetal neurological development, is a major diagnostic parameter. A normal foetal HRV indicates an intact autonomic feedback between the CNS and SA node. Measurement of foetal HRV may thus provide a non-invasive method of assessing the integrity of the foetal neurological systems. Thus, intrapartum analysis of foetal HRV using power spectral analysis has the potential to be used as an index of central autonomic function and to reflect foetal well-being in labour. This is because this technique enables the quantitative evaluation of small changes in fHR that may remain undetected by visual interpretation of fHR. Heart rate variability in the foetus 73 In addition, the measurement of HRV in the healthy foetus may provide more information on the chronological order of the functional maturation of foetal autonomic nervous system. This is because the two branches of the autonomic nervous system operate at different frequencies, which can be quantified using power spectral analysis of the fHR. Evaluation of foetal HRV throughout gestation provides information on the normal development and maturation of the foetal sympathetic and parasympathetic systems, which may be used to correlate with the histological, pharmacological and in-vitro evidence for the presence and function of these systems. During the postnatal period, HRV continues to increase. Pre-term infants have lower HRV than term infants (Nakamura T et al., 2005). This difference is still present when pre-term infants reach term post-conception age. This has been explained by an alteration in the sympathovagal balance with a diminished parasympathetic component of heart rate control in pre-term infants as compared to term infants (Eiselt M et al., 1993). By using the foetal RSA as a specific measure of vagal tone, it was shown that foetuses who were parasympathetically-dominated were more efficient regulators of homeostasis than those who were sympathetically-dominated (Groome LJ et al., 1999). The beneficial effects of a higher basal vagal tone relative to sympathetic tone seem to extend into infanthood and childhood. As a measure of vagal activity, RSA reflects the infant’s ability to coordinate physiological systems in response to spontaneous fluctuations in internal demands, so a greater vagal tone is thought to Heart rate variability in the foetus 74 indicate a more optimal physiological state (Porges SW, 1996). Infants with a high vagal tone at 40 post-conception weeks were more likely to have positive developmental outcomes at and 12 months of age (Fox NA and Porges SW, 1985). Children with relatively greater vagal tone are more sociable, resilient, joyful, attentive, more reactive to challenges, and exhibit better regulation of emotion and behaviour resulting in fewer verbal and physical conflicts (Movius HL and Allen JJ, 2005; El-Sheikh M et al., 2001; Huffman LC et al., 1998). The predictive value of foetal RSA also been extended to sudden infant death syndrome (SIDS). It has been shown that autonomic dysfunction or autonomic maturational delay is a feature of some infants who succumb to SIDS (Schwartz PJ et al., 2004; 1998; Taylor BJ et al., 1996; Schechtman VL et al., 1992). This has been postulated to be due to an imbalance between the sympathetic and parasympathetic input to the heart, which increases its vulnerability to insidious arrhythmias, resulting in SIDS. Although it has not yet been studied in the foetus, it would be useful to find out if the measurement of foetal RSA (HF spectral power of foetal HRV) can be used to monitor the development and maturation of the autonomic system and thus identify prenatally the infants who may be at risk of SIDS. 75 Scope of the study CHAPTER SCOPE OF THE STUDY Scope of the study 76 Background The foetal heart rate (fHR) signal is the primary indication of foetal viability and well-being. The techniques of fHR monitoring have not changed for the past two decades and are performed using Doppler ultrasound devices such as the cardiotocography (CTG). These techniques are based on detection of the mechanical activity of the foetal heart, and gives only an averaged fHR which renders the data produced unsuitable for true beat-to-beat analysis of fHR variability (Shakespeare SA et al., 2001). A more accurate method to obtain the fHR is by the use of foetal electrocardiography, which detects the electrical activity of the heart. In adults, children and neonates, the ECG gives valuable diagnostic information in a wide variety of cardiac conditions. Similarly in foetuses, such data will provide information regarding the foetal cardiac status and well-being. Unfortunately, monitoring of the foetal ECG (fECG) during pregnancy is largely done by an invasive method during labour (after the rupture of membranes) with the use of an electrode attached to the foetal scalp. This study utilizes a non-invasive fECG monitor known as FEMO (Medco Electronic Systems Ltd., Israel), which allows the detection of fECG from as early as 18 weeks of gestation, up to labour and delivery. FEMO detects the electrical activity of the foetal cardiac cycle via electrodes placed on the maternal abdomen. It provides an accurate true beat-to-beat fHR and foetal ECG morphology. Scope of the study 77 Hypotheses It is known that there is a progressive increase in cardiac time intervals from neonatal period through childhood and adolescence due to the progressive age-related changes in cardiac anatomy and physiology that occur during this period of growth (Dickinson DF, 2005). It has also been found that gender does not have a major influence on ECG intervals in pre-pubertal children (Dickinson DF, 2005). In the first part of this thesis, there are hypotheses. Firstly, it is hypothesized that foetal cardiac time intervals will increase with increasing foetal age and heart growth. Secondly, it is hypothesized that foetal cardiac intervals not differ in male and female foetuses. In the second part of this thesis, the hypothesis is that the sympathetic and parasympathetic components of the autonomic nervous system develop at different stages of gestation, such that the sympathetic system develops and matures earlier in gestation than the parasympathetic system. Aims and objectives Firstly, the aim of the study was to conduct longitudinal measurement of fECG in healthy singleton pregnancies from 18 weeks of gestation to full-term, and to determine the normal pattern of foetal cardiac time intervals for the different stages of gestation, as well as whether these cardiac intervals differ in male and female foetuses. Scope of the study 78 In this study, the durations of various cardiac time intervals such as that of the P wave, PR interval, QRS interval, QT interval, QTc interval and T wave were determined from fECG complexes. The fECG cardiac time intervals of normal foetuses were correlated with foetal gestational age and foetal gender. A single ECG using the standard 12-lead ECG was also recorded within the first 1-2 days postpartum to compare with fECG patterns. Secondly, the HRV of normal foetuses was determined by spectral analysis of the R-R interval obtained from the fECG signal. HRV was used to evaluate the foetal cardiac autonomic profile. Although much is known about the adult HRV, there are still many questions regarding the normal foetal HRV spectrum, the frequency bandwidths, how the spectral power changes as gestation increases, and if they differ in male and female foetuses. Hence, this study aims to evaluate the normal pattern of foetal HRV power spectrum and to determine the relationship between foetal HRV and gestational age, as well as between foetal HRV and gender of the healthy human foetus from 18 to 41 weeks of gestation. A novel HRV software (F-EXTRACT) was developed in collaboration with signal-processing expertise at the National University of Singapore. HRV analysis of the recorded fECG signals was performed using F-EXTRACT. Since HRV is a noninvasive measure of autonomic nervous system activity on the sinus node, by analyzing the HRV of the foetus progressively, the pattern of development and maturation of foetal cardiac autonomic control may be determined. Scope of the study 79 Finally, the HRV measurements derived from F-EXTRACT were compared to those obtained by a commercial HRV software, Nevrokard HRV System (Medistar Inc., Slovenia). Since different HRV programs employ different algorithms for the computation of HRV, as well as for artifact rejection and correction, differences between the two systems in the determination of foetal HRV may be delineated. [...]... on Nevrokard software ……… 17 7 Figure 11 -2 Artifact-correction on Nevrokard software …………….……… 17 8 Figure 11 -3 HRV power spectrum and results on Nevrokard software …… 18 1 Figure 11 -4 Time-domain HRV from Nevokard and F-EXTRACT ……… 18 5 Figure 11 -5 Frequency-domain HRV from Nevokard and F-EXTRACT …… 18 6 Figure 11 -6 Bland-Altman plots (absolute bias) for time-domain HRV …… 19 0 Figure 11 -7 Bland-Altman plots... ……….……………………… 15 1 Figure 10 -1 Time-domain HRV at various gestational ages ……….……… 15 9 Figure 10 -2 HRV power spectra of foetuses at 20 and 37 weeks ………… 16 1 Figure 10 -3 Frequency-domain HRV at various gestational ages ………… 16 3 List of Figures xv Figure 10 -4a Relationship between time-domain HRV and gender …… … 16 6 Figure 10 -4b Relationship between frequency-domain HRV and gender … 16 7 Figure 11 -1 Graph of RR-interval... ECG strip, heart rates and averaged foetal ECG complex … 92 Figure 7 -1 Foetal cardiac time intervals at various gestational ages ……… 10 9 Figure 7-2 Scatter plots of cardiac time intervals versus gestational age … 11 0 Figure 7-3 Relationship between foetal cardiac time intervals and gender … 11 3 Figure 8 -1 Foetal heart rate as shown by CTG …… ……………………… 13 1 Figure 8-2 Maternal and foetal heart rates as... intervals …………………………… 11 4 Table 7-6 Cardiac time intervals measured by fECG and fMCG …….… 11 8 Table 9 -1 HRV parameters calculated by F-EXTRACT ………………… 14 9 Table 10 -1 Time-domain variables in relation to gestational age ……… 15 8 Table 10 -2 Frequency-domain variables in relation to gestational age … 16 2 Table 10 -3 Mean HRV parameters in male and female foetuses ………… 16 5 Table 11 -1 Time-domain statistics... HRV.……… 19 2 Figure 11 -8 Bland-Altman plots (absolute bias) for frequency-domain HRV 19 3 Figure 11 -9 Bland-Altman plots (percent bias) for frequency-domain HRV 19 4 Appendix Figure 1 Average foetal ECG complexes of different foetuses 211 Appendix Figure 2 Average foetal ECG complexes of a single foetus…… 215 List of abbreviations xvi LIST OF ABBREVIATIONS ANOVA Analysis of variance ANS Autonomic... displayed by Nevrokard software … 18 0 Table 11 -2 Bland-Altman analysis (mean difference) ….…………………… 18 8 Table 11 -3 Bland-Altman analysis (mean percent difference) ….………… 18 9 List of Figures xiv LIST OF FIGURES Figure 2 -1 Reference points for measurement of foetal ECG ……… … … 16 Figure 3 -1 A typical HRV power spectrum in a resting adult ……………… 43 Figure 4 -1 The changes in foetal heart rates during gestation... Wharton’s jelly into the amniotic fluid Hence, it is again not necessary to include the umbilical cord in a volume conduction model The conductivity of the vernix was found to be (1. 8 ± 0.3) x10-6 Ω -1 m -1, being of the same order as the value of 1. 4 x 10 -6 Ω -1 m -1 (at 37˚C) as found by Bolte in a German literature in 19 61 Hence, the conductivity of vernix differs by a factor of roughly one million from. .. 2004; Khamene A and Negahdaripour S, 2000), singular value decomposition (SVD) techniques (Kanjilal PP et al., 19 97; Callaerts D et al., 19 90, 19 89, 19 86; Vanderschoot J et al., 19 87), matched and spatial filtering (Gibson NM et al., 19 97; van Oosterom A, 19 86; Bergveld P et al., 19 86, 19 81) autoand cross-correlation (Budin N and Abboud S, 19 94; Abboud S et al., 19 92; van Bemmel JH, 19 68), blind source... of these high-risk foetuses 14 The foetal ECG waveform CHAPTER 2 THE FOETAL ECG WAVEFORM The foetal ECG waveform 1 15 Morphology and time intervals of the foetal ECG Like the adult ECG, the foetal ECG consists of P, QRS and T waves, separated by PR and ST segments These waves represent the summation of electrical events within the heart as seen from the body’s surface Figure 2 -1 shows the clinically... CHD Congenital heart defect CHF Congestive heart failure CNS Central nervous system CRC Cardioregulatory center CTG Cardiotocography ECG Electrocardiogram fECG Foetal ECG FEMO Foetal ECG monitor (Medco Electronic Systems Ltd., Israel) FFT Fast Fourier transformation fHR Foetal heart rate fMCG Foetal magnetocardiography GA Gestational age HF High frequency HR Heart rate HRV Heart rate variability IUGR . ASSESSMENT AND QUANTIFICATION OF FOETAL ELECTROCARDIOGRAPHY AND HEART RATE VARIABILITY OF NORMAL FOETUSES FROM EARLY TO LATE GESTATIONAL PERIOD ELAINE. 3 Foetal ST segment and T wave- Human studies……………………… 31 Chapter 3 Heart rate variability …………………………………… 35 1 Definition of heart rate variability …………………………………. 36 2 History of heart rate. male and female foetuses ………… 16 5 Table 11 -1 Time-domain statistics displayed by Nevrokard software … 18 0 Table 11 -2 Bland-Altman analysis (mean difference) ….…………………… 18 8 Table 11 -3 Bland-Altman