Fetal autonomic cardiac response during pregnancy and labour

Timely recognition of fetal distress, during pregnancy and labour, in order to intervene adequately is of major importance to avoid neonatal morbidity and mortality. As discussed in chapter 1, the cardiotocogram (CTG) might be a useful screening test for fetal monitoring but it has insufficient specificity and requires additional diagnostic tests in case of suspected fetal compromise to avoid unnecessary operative deliveries. Potential additional techniques used in clinical practice are fetal scalp blood sampling (FBS) and ST-waveform analysis of the fetal electrocardiogram (ECG; STAN®). However, publications on these techniques provide limited support for the use of these methods in the presence of a non-reassuring CTG for reducing caesarean sections. In addition, these techniques are invasive and can therefore only be used during labour at the term or the near term period. Consequently, it is of great clinical importance that additional methods are developed that contribute to more reliable assessment of fetal condition. Preferably, this information is obtained non-invasively. Valuable additional information on the fetal condition can possibly be obtained by spectral analysis of fetal heart rate variability (HRV). The fetal heart rate fluctuates under the control of the autonomic part of the central nervous system. The autonomic cardiac modulation is discussed in chapter 2. The sympathetic and parasympathetic nervous systems typically operate on partly different timescales. Time-frequency analysis (spectral analysis) of fetal beat-to-beat HRV can hence quantify sympathetic and parasympathetic modulation and characterise autonomic cardiac control . The low frequency (LF) component of HRV is associated with both sympathetic and parasympathetic modulation while the high frequency (HF) component is associated with parasympathetic modulation alone2. Spectral estimates of HRV might indirectly reflect fetal wellbeing and increase insight in the human fetal autonomic cardiac response. In chapter 3, technical details for retrieving fetal beat-to-beat heart rate and its spectral estimates are provided. In this thesis spectral analysis of fetal HRV is investigated. The first objective is to study the value of spectral analysis of fetal HRV as a tool to assess fetal wellbeing during labour at term. The second objective is to monitor spectral estimates of fetal HRV, non-invasively, during gestation to increase insight in the development of human fetal autonomic cardiac control. Since Akselrod reported the relation between autonomic nervous system modulation and LF and HF peaks in frequency domain1, frequency analysis of RR interval fluctuations is widely performed . For human adults, standards for HRV measurement and physiological interpretation have been developed2. Although HRV parameters are reported to be highly prognostic in human adults in case of cardiac disease, little research is done towards the value of these parameters in assessing fetal distress in the human fetus, as shown in chapter 4. In this chapter, the literature about time-frequency analysis of human fetal HRV is reviewed in order to determine the value of spectral estimates for fetal surveillance. Articles that described spectral analysis of human fetal HRV and compared the energy in spectral bands with fetal bloodgas values were included. Only six studies met our inclusion criteria. One study found an initial increase in LF power during the first stage of fetal compromise, which was thought to point to stress-induced sympathetic hyperactivity3. Five out of six studies showed a decrease in LF power in case of fetal distress , , , , ,. This decrease in LF power in case of severe fetal compromise was thought to be the result of immaturity or decompensation of the fetal autonomic nervous system. These findings support the hypothesis that spectral analysis of fetal HRV might be a promising method for fetal surveillance. All studies included in the literature review used absolute values of LF and HF power. Although absolute LF and HF power of HRV provide useful information on autonomic modulation, especially when considering fetal autonomic development, LF and HF power may also be measured in normalised units. Normalised LF (LFn) and normalised HF power (HFn) of HRV represent the relative value of each power component in proportion to the total power2. Adrenergic stimulation can cause a sympathetically-modulated increase in fetal heart rate . A negative correlation however exists between heart rate and HRV . As a result, the sympathetic stimulation can decrease the total power of HRV and even the absolute LF power. When normalising the absolute LF (and HF) with respect to the total power, a shift in activity from HFn to LFn might become visible, revealing the expected underlying sympathetic activity. Thus, because changes in total power influence absolute spectral estimates in the same direction, normalised values of LF and HF power seem more suitable for fetal monitoring. In other words, normalised spectral estimates detect relative changes that are no longer masked by changes in total power2. LFn and HFn power are calculated by dividing LF and HF power, respectively, by total power and represent the controlled and balanced behaviour of the two branches of the autonomic nervous system2. In chapter 5 we hypothesised that the autonomic cardiovascular control is functional in fetuses at term, and that LFn power increases in case of distress due to increased sympathetic modulation. During labour at term, ten acidaemic fetuses were compared with ten healthy fetuses. During the last 30 minutes of labour, acidaemic fetuses had significantly higher LFn power and lower HFn power than control fetuses, which points to increased sympathetic modulation. No differences in absolute LF or HF power were found between both groups. The observed differences in normalised spectral estimates of HRV were not observed earlier in labour. In conclusion, it seems that the autonomic nervous system of human fetuses at term responds adequately to severe stress during labour. Normalised spectral estimates of HRV might be able to discriminate between normal and abnormal fetal condition. Although we found significant differences in normalised spectral estimates between healthy and acidaemic fetuses, we wondered whether spectral power of HRV is also related to fetal distress in an earlier stage. The next step in chapter 6 was therefore, to investigate whether spectral estimates are related to fetal scalp blood pH during labour. Term fetuses during labour, in cephalic presentation, that underwent one or more scalp blood samples were studied. Beat-to-beat fetal heart rate segments, preceding the scalp blood measurement, were used to calculate spectral estimates. In total 39 FBS from 30 patients were studied. We found that normalised spectral estimates are related to fetal scalp blood pH while absolute spectral estimates are not related to fetal pH. It was further demonstrated that LFn power is negatively related and HFn power is positively related to fetal pH. These findings point to increased sympathetic and decreased parasympathetic cardiac modulation in human fetuses at term upon decrease of their pH value. This study confirms the hypothesis that normalised spectral values of fetal HRV are related to fetal distress in an early stage. Previous studies showed that absolute LF and HF power increase as pregnancy progresses, which is attributed to fetal autonomic maturation , . Since it is yet unclear how LFn and HFn evolve with progressing pregnancy, before using spectral analysis for fetal monitoring, it has to be determined whether gestational age has to be corrected for. In addition, fetal autonomic fluctuations, and thus spectral estimates of HRV, are influenced by fetal behavioural state . Since these states continue to change during labour , thorough understanding of the way in which these changes in state influence spectral power is necessary for the interpretation of spectral values during labour at term. Therefore, in chapter 7, we examined whether differences in spectral estimates exist between healthy near term and post term fetuses during labour. In case such differences do exist, they should be taken into consideration for fetal monitoring. The quiet and active sleep states were studied separately to determine the influence of fetal behavioural state on spectral estimates of HRV during labour around term. No significant differences in spectral estimates were found between near term and post term fetuses during active sleep. During quiet sleep, LFn power was lower and HF and HFn power were higher in post term compared to near term fetuses, no significant differences in LF power were observed between both groups. LF, HF and LFn power were higher and HFn power was lower during active sleep compared to quiet sleep in both groups. This seems to point to sympathetic predominance during the active state in fetuses around term. In addition, post term parasympathetic modulation during rest seems increased compared to near term. In conclusion, fetal behavioural state and gestational age cause a considerable variability in spectral estimates in fetuses during labour, around term, which should be taken into consideration when using spectral estimates for fetal monitoring. In chapters 4 to 6, spectral estimates of beat-to-beat fetal HRV were studied using fetal ECG recordings that were obtained directly from the fetal scalp during labour. However, the second objective of this thesis is to obtain spectral estimates non-invasively during gestation to increase insight in the development of human fetal autonomic cardiac control. The fetal ECG is also present on the maternal abdomen, although much smaller in amplitude and obscured by the maternal ECG and noise. Chapter 8 focused on non-invasive measurement of the fetal ECG from the maternal abdomen. These measurements allow for obtaining beat-to-beat fetal heart rate non-invasively. Therefore, this method can be used to obtain spectral estimates of fetal HRV throughout gestation. Although abdominal recording of the fetal ECG may offer valuable additional information, it is troubled by poor signal-to-noise ratios (SNR) during certain parts of pregnancy, e.g. during the immature period and during the vernix period. To increase the usability of abdominal fetal ECG recordings, an algorithm was developed that uses a priori knowledge on the physiology of the fetal heart to enhance the fetal ECG components in multi-lead abdominal fetal ECG recordings, before QRS-detection. Evaluation of the method on generated fetal ECG recordings with controlled SNR showed excellent results. The method for non-invasive fetal ECG and beat-to-beat heart rate detection presented in chapter 8 was used for analysis in chapter 9. The feasibility of this method in a longitudinal patient study was investigated. In addition, changes in spectral estimates of HRV during pregnancy were studied and related to fetal rest-activity state to study the development of fetal autonomic cardiac control. We found that approximately 3% of non-invasive fetal ECG recordings could be used for spectral analysis. Therefore, improvement of both equipment and algorithms is still needed to obtain more good-quality data. The percentage of successfully retrieved data depends on gestational age. Before 18 and between 30 and 34 weeks no good-quality beat-to-beat heart rate data were available. We found an increase in LF and HF power of fetal HRV with increasing gestational age, between 21 to 30 weeks of gestation. This increase in LF and HF power is probably due to increased sympathetic and parasympathetic modulation and might be a sign of autonomic development. Furthermore, we found sympathetic predominance during the active state compared to the quiet state in near term fetuses (34 to 41 weeks of gestation), comparable to the results observed during labour around term. During 34 to 41 weeks a (non-significant) decrease in LF and LFn power and a (non-significant) increase in HF and HFn power were observed. These non-significant changes in spectral estimates in near term fetuses might be associated with changes in fetal rest-activity state and increased parasympathetic modulation as pregnancy progresses. However, more research is needed to confirm this

Ethical development of artificial amniotic sac and placenta technology: a roadmap

In this paper we present an initial roadmap for the ethical development and eventual implementation of artificial amniotic sac and placenta technology in clinical practice. We consider four elements of attention: (1) framing and societal dialogue; (2) value sensitive design, (3) research ethics and (4) ethical and legal research resulting in the development of an adequate moral and legal framework. Attention to all elements is a necessary requirement for ethically responsible development of this technology. The first element concerns the importance of framing and societal dialogue. This should involve all relevant stakeholders as well as the general public. We also identify the need to consider carefully the use of terminology and how this influences the understanding of the technology. Second, we elaborate on value sensitive design: the technology should be designed based upon the principles and values that emerge in the first step: societal dialogue. Third, research ethics deserves attention: for proceeding with first-in-human research with the technology, the process of recruiting and counseling eventual study participants and assuring their informed consent deserves careful attention. Fourth, ethical and legal research should concern the status of the subject in the AAPT. An eventual robust moral and legal framework for developing and implementing the technology in a research setting should combine all previous elements. With this roadmap, we emphasize the importance of stakeholder engagement throughout the process of developing and implementing the technology; this will contribute to ethically and responsibly innovating health care.Research into fetal development and medicin

SUGAR-DIP trial: Oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Introduction In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. Methods The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals

Enhancement of low-quality fetal electrocardiogram based on time-sequenced adaptive filtering

Extraction of a clean fetal electrocardiogram (ECG) from non-invasive abdominal recordings is one of the biggest challenges in fetal monitoring. An ECG allows for the interpretation of the electrical heart activity beyond the heart rate and heart rate variability. However, the low signal quality of the fetal ECG hinders the morphological analysis of its waveform in clinical practice. The time-sequenced adaptive filter has been proposed for performing optimal time-varying filtering of non-stationary signals having a recurring statistical character. In our study, the time-sequenced adaptive filter is applied to enhance the quality of multichannel fetal ECG after the maternal ECG is removed. To improve the performance of the filter in cases of low signal-to-noise ratio (SNR), we enhance the ECG reference signals by averaging consecutive ECG complexes. The performance of the proposed augmented time-sequenced adaptive filter is evaluated in both synthetic and real data from PhysioNet. This evaluation shows that the suggested algorithm clearly outperforms other ECG enhancement methods, in terms of uncovering the ECG waveform, even in cases with very low SNR. With the presented method, quality of the fetal ECG morphology can be enhanced to the extent that the ECG might be fit for use in clinical diagnostics. [Figure not available: see fulltext.

Effect of tocolytic drugs on fetal heart rate variability: a systematic review

Introduction: Tocolytics may cause changes in fetal heart rate (HR) pattern, while fetal heart rate variability (HRV) is an important marker of fetal well-being. We aim to systematically review the literature on how tocolytic drugs affect fetal HRV. Materials and methods: We searched CENTRAL, PubMed and EMBASE up to June 2016. Studies published in English, using computerized or visual analysis to describe the effect of tocolytics on HRV in human fetuses were included. Studies describing tocolytics during labor, external cephalic version, pre-eclampsia and infection were excluded. Eventually, we included six studies, describing 169 pregnant women. Results: Nifedipine, atosiban and indomethacin administration show no clinically important effect on fetal HRV. Following administration of magnesium sulfate decreased variability and cases of bradycardia are described. Fenoterol administration results in a slight increase in fetal HR with no changes in variability. After ritodrine administration increased fetal HR and decreased variability is seen. The effect of co-administration of corticosteroids should be taken into account. Conclusion: In order to prevent iatrogenic preterm labor, the effects of tocolytic drugs on fetal HRV should be taken into account when monitoring these fetuses. Keywords: Tocolytic therapy, calcium channel blocker, oxytocin receptor antagonist, prostaglandin antagonist, beta-adrenergic agonist, fetal heart rate variabilit

Beat-to-beat heart rate detection in multi-lead abdominal fetal ECG recordings

Reliable monitoring of fetal condition often requires more information than is provided by cardiotocography, the standard technique for fetal monitoring. Abdominal recording of the fetal electrocardiogram may offer valuable additional information, but unfortunately is troubled by poor signal-to-noise ratios during certain parts of pregnancy. To increase the usability of abdominal fetal ECG recordings, an algorithm was developed that enhances fetal QRS complexes in these recordings and thereby provides a promising method for detecting the beat-to-beat fetal heart rate in recordings with poor signal-to-noise ratios. The method was evaluated on generated recordings with controlled signal-to-noise ratios and on actual recordings that were performed in clinical practice and were annotated by two independent experts. The evaluation on the generated signals demonstrated excellent results (sensitivity of 0.98 for SNR=1.5). Only for SN

Electrohysterographic analysis of uterine contraction propagation with labor progression: a preliminary study

Monitoring the uterine contractions provides important prognostic information during pregnancy and delivery. In particular, the propagation of uterine activity is closely related to the contraction efficiency. In the present study, a propagation analysis of uterine contraction is carried out by simultaneously recording the electrohysterogram (EHG) and the internal uterine pressure (TUP) on one woman in the last 4 hours of labor. The EHG, recorded in a monopolar multi- electrode configuration, was first processed in each channel in order to provide an accurate estimate of the IUP. The IUP estimate resulted in a correlation coefficient with the simultaneously recorded IUP r=0.74. Eventually, in order to evaluate the propagation of the muscular electrical activity, the delays among the IUP estimates in each channels were calculated by cross correlation function maximization. In agreement with previous studies, no preferred direction of propagation was singled out and pacemaker areas changed from contraction to contraction. However, by analyzing the occurrences of each pacemaker area, the uterine upper part resulted the most frequent location. Moreover, the close agreement between the number of simultaneously active electrodes and the IUP peak values (r=0.76) revealed a relationship between the spreading of action potentials and the maximum amplitude of contraction

Objective and non-invasive detection of fetal movement.

Abstract onl