Analysis of fetal heart rate fluctuations in women diagnosed with preeclampsia during the latent phase of labor.

Introduction: Fetal heart rate variability (fHRV) is a tool used to investigate the functioning of the fetal autonomic nervous system. Despite the significance of preeclampsia, fHRV during the latent phase of labor has not been extensively studied. This study aimed to evaluate fetal cardiac autonomic activity by using linear and nonlinear indices of fHRV analysis in women diagnosed with preeclampsia without hypertensive treatment during gestation, compared to normotensive women during the latent phase of labor. Methods: A cross-sectional and exploratory study was conducted among pregnant women in the latent phase of labor, forming three study groups: normotensive or control (C, 38.8 ± 1.3 weeks of pregnancy, n = 22), preeclampsia with moderate features (P, 37.6 ± 1.4 weeks of pregnancy n = 10), and preeclampsia with severe features (SP, 36.9 ± 1.2 weeks of pregnancy, n = 12). None of the participants received anti-hypertensive treatment during their pregnancy. Linear and nonlinear features of beat-to-beat fHRV, including temporal, frequency, symbolic dynamics, and entropy measures, were analyzed to compare normotensive and preeclamptic groups. Results: Significantly lower values of multiscale entropy (MSE) and short-term complexity index (Ci) were observed in the preeclamptic groups compared to the C group (p < 0.05). Additionally, higher values of SDNN (standard deviation of R-R intervals) and higher values of low-frequency power (LF) were found in the P group compared to the C group. Conclusion: Our findings indicate that changes in the complexity of fetal heart rate fluctuations may indicate possible disruptions in the autonomic nervous system of fetuses in groups affected by undiagnosed preeclampsia during pregnancy. Reduced complexity and shifts in fetal autonomic cardiac activity could be associated with preeclampsia's pathophysiological mechanisms during the latent phase of labor.

Assessing the effects of oxytocin in changes of core body temperature during LPS-induced endotoxemia: A novel approach using Extended Poincaré Plot Analysis.

Oxytocin has shown cardioprotective effects during inflammation and may modify the core body temperature changes in LPS-induced endotoxemia. Notably, the time series analysis of core body temperature fluctuations may indicate thermoregulation alterations. This study aims to assess the effects of oxytocin on changes in the core body temperature by analyzing the fluctuations of the temperature time series of endotoxemic rats. Twelve hours of continuous core body temperature fluctuations time series were obtained from adult male Dark Agouti rats implanted with a telemetric transmitter under the following treatment: lipopolysaccharide (LPS); oxytocin (O); lipopolysaccharide + oxytocin (LPS + O), and vehicle or control (C). The temperature fluctuations time series were analyzed using the Extended Poincaré Plot Analysis (EPPA), a novel approach for measuring nonlinear features, to compute the autocorrelation by Pearson's correlation coefficient r, the standard deviation perpendicular to the line of identity (SD1), and the standard deviation parallel to the line of identity (SD2). The autocorrelation of the temperature fluctuations assessed by Pearson's coefficient was significantly higher in the LPS group compared to control rats (C). Likewise, the co-administration of oxytocin during endotoxemia (LPS + O) significantly reduced the autocorrelation and increased the short-term variability (SD1) of temperature fluctuations compared to those recorded with a single dose of LPS. Thus, we concluded that oxytocin may introduce thermoregulatory changes under LPS-induced endotoxemia. The EPPA is a simple and powerful approach to assess physiological variability that can provide valuable insights into changes in thermoregulation.

Changes in the autonomic cardiorespiratory activity in parturient women with severe and moderate features of preeclampsia.

Background: Cardiorespiratory coupling (CRC) is a physiological phenomenon that reflects the mutual interaction between the cardiac and respiratory control systems. It is mainly associated with efferent vagal activity from the central autonomic network. Few studies have explored the autonomic changes of CRC in preeclampsia, a critical obstetric complication related to possible autonomic dysfunctions and inflammatory disturbances. This study examined the autonomic mechanisms of CRC in women with severe and moderate preeclampsia and healthy controls by applying nonlinear methods based on information theory, such as mutual information (MI) and Renyi's mutual information (RMI) and the linear and nonlinear analysis of the Pulse-Respiration Quotient (PRQ). Methods: We studied three groups of parturient women in the third trimester of pregnancy with a clinical diagnosis of preeclampsia without severe symptoms (P, 38.5 ± 1.4 weeks of pregnancy, n=19), preeclampsia with severe symptoms (SP, 37.5 ± 0.9 weeks of pregnancy, n=22), and normotensive control women (C, 39.1 ± 1.3 weeks of pregnancy, n=20). 10-minutes of abdominal electrocardiograms (ECG) and respiratory signals (RESP) were recorded in all the participants. Subsequently, we obtained the maternal beat-to-beat (RR) and breath-to-breath (BB) time series from ECG and RESP, respectively. The CRC between RR and BB was quantified by nonlinear methods based on information theory, such as MI and RMI, along with the analysis of the novel index of PRQ. Subsequently, we computed the mean PRQ (mPRQ) and the normalized permutation entropy (nPermEn_PRQ) from the PRQ time series generated from BB and RR. In addition, we examined the vagal activity in the three groups by the logarithm of the median of the distribution of the absolute values of successive RR differences (logRSA). Results: The MI and RMI values were significantly lower (p<0.05) in the preeclamptic groups compared to the control group. However, no significant differences were found between the preeclamptic groups. The logRSA and nPermEn_PRQ indices were significantly lower (p<0.05) in SP compared to C and P. Conclusion: Our data suggest that parturient women with severe and mild preeclampsia may manifest an altered cardiorespiratory coupling compared with normotensive control women. Disrupted CRC in severe preeclampsia could be associated with vagal withdrawal and less complex cardiorespiratory dynamics. The difference in vagal activity between the preeclamptic groups may suggest a further reduction in vagal activity associated with the severity of the disease.

Uterine activity modifies the response of the fetal autonomic nervous system at preterm active labor.

Background: The autonomic nervous system of preterm fetuses has a different level of maturity than term fetuses. Thus, their autonomic response to transient hypoxemia caused by uterine contractions in labor may differ. This study aims to compare the behavior of the fetal autonomic response to uterine contractions between preterm and term active labor using a novel time-frequency analysis of fetal heart rate variability (FHRV). Methods: We performed a case-control study using fetal R-R and uterine activity time series obtained by abdominal electrical recordings from 18 women in active preterm labor (32-36 weeks of gestation) and 19 in active term labor (39-40 weeks of gestation). We analyzed 20 minutes of the fetal R-R time series by applying a Continuous Wavelet Transform (CWT) to obtain frequency (HF, 0.2-1 Hz; LF, 0.05-0.2 Hz) and time-frequency (Flux0, Flux90, and Flux45) domain features. Time domain FHRV features (SDNN, RMSSD, meanNN) were also calculated. In addition, ultra-short FHRV analysis was performed by segmenting the fetal R-R time series according to episodes of the uterine contraction and quiescent periods. Results: No significant differences between preterm and term labor were found for FHRV features when calculated over 20 minutes. However, we found significant differences when segmenting between uterine contraction and quiescent periods. In the preterm group, the LF, Flux0, and Flux45 were higher during the average contraction episode compared with the average quiescent period (p<0.01), while in term fetuses, vagally mediated FHRV features (HF and RMSSD) were higher during the average contraction episode (p<0.05). The meanNN was lower during the strongest contraction in preterm fetuses compared to their consecutive quiescent period (p=0.008). Conclusion: The average autonomic response to contractions in preterm fetuses shows sympathetic predominance, while term fetuses respond through parasympathetic activity. Comparison between groups during the strongest contraction showed a diminished fetal autonomic response in the preterm group. Thus, separating contraction and quiescent periods during labor allows for identifying differences in the autonomic nervous system cardiac regulation between preterm and term fetuses.

Differences in the Asymmetry of Beat-to-Beat Fetal Heart Rate Accelerations and Decelerations at Preterm and Term Active Labor.

The fetal autonomic nervous system responds to uterine contractions during active labor as identified by changes in the accelerations and decelerations of fetal heart rate (FHR). Thus, this exploratory study aimed to characterize the asymmetry differences of beat-to-beat FHR accelerations and decelerations in preterm and term fetuses during active labor. In an observational study, we analyzed 10 min of fetal R-R series collected from women during active preterm labor (32-36 weeks of pregnancy, n = 17) and active term labor (38-40 weeks of pregnancy, n = 27). These data were used to calculate the Deceleration Reserve (DR), which is a novel parameter that quantifies the asymmetry of the average acceleration and deceleration capacity of the heart. In addition, relevant multiscale asymmetric indices of FHR were also computed. Lower values of DR, calculated with the input parameters of T = 50 and s = 10, were associated with labor occurring at the preterm condition (p = 0.0131). Multiscale asymmetry indices also confirmed significant (p < 0.05) differences in the asymmetry of FHR. Fetuses during moderate premature labor may experience more decaying R-R trends and a lower magnitude of decelerations compared to term fetuses. These differences of FHR dynamics might be related to the immaturity of the fetal cardiac autonomic nervous system as identified by this system response to the intense uterine activity at active labor.

Phase Entropy Analysis of Electrohysterographic Data at the Third Trimester of Human Pregnancy and Active Parturition.

Phase Entropy (PhEn) was recently introduced for evaluating the nonlinear features of physiological time series. PhEn has been demonstrated to be a robust approach in comparison to other entropy-based methods to achieve this goal. In this context, the present study aimed to analyze the nonlinear features of raw electrohysterogram (EHG) time series collected from women at the third trimester of pregnancy (TT) and later during term active parturition (P) by PhEn. We collected 10-min longitudinal transabdominal recordings of 24 low-risk pregnant women at TT (from 35 to 38 weeks of pregnancy) and P (>39 weeks of pregnancy). We computed the second-order difference plots (SODPs) for the TT and P stages, and we evaluated the PhEn by modifying the k value, a coarse-graining parameter. Our results pointed out that PhEn in TT is characterized by a higher likelihood of manifesting nonlinear dynamics compared to the P condition. However, both conditions maintain percentages of nonlinear series higher than 66%. We conclude that the nonlinear features appear to be retained for both stages of pregnancy despite the uterine and cervical reorganization process that occurs in the transition from the third trimester to parturition.

Analysis of the fetal cardio-electrohysterographic coupling at the third trimester of gestation in healthy women by Bivariate Phase-Rectified Signal Averaging.

INTRODUCTION: The fetal cardio-electrohysterographic coupling (FCEC) is defined as the influence of the uterine electrical activity on fetal heart rate. FCEC has been mainly evaluated by visual analysis of cardiotocographic data during labor; however, this physiological phenomenon is poorly explored during the antenatal period. Here we propose an approach known as Bivariate Phase-Rectified Signal Averaging analysis (BPRSA) to assess such FCEC in the late third trimester of low-risk pregnancies. We hypothesized that BPRSA is a more reliable measure of FCEC than visual analysis and conventional measures such as cross-correlation, coherence, and cross-sample entropy. Additionally, by using BPRSA it is possible to detect FCEC even from the third trimester of pregnancy. MATERIAL AND METHODS: Healthy pregnant women in the last third trimester of pregnancy (36.6 ± 1.8 gestational weeks) without any clinical manifestation of labor were enrolled in the Maternal and Childhood Research Center (CIMIGen), Mexico City (n = 37). Ten minutes of maternal electrohysterogram (EHG) and fetal heart rate (FHR) data were collected by a transabdominal non-invasive device. The FCEC was quantified by the coefficient of coherence, the maximum normalized cross-correlation, and the cross-sample entropy obtained either from the EHG and FHR raw signals or from the corresponding BPRSA graphs. RESULTS: We found that by using BPRSA, the FCEC was detected in 92% cases (34/37) compared to 48% cases (18/37) using the coefficient of coherence between the EHG and FHR raw signals. Also, BPRSA indicated FCEC in 82% cases (30/37) compared to 30% cases (11/37) using the maximum normalized cross-correlation. By comparing the analyses, the BPRSA evidenced higher FCEC in comparison to the coupling estimated from the raw EHG and FHR signals. CONCLUSIONS: Our results support the consideration that in the third trimester of pregnancy, the fetal heart rate is also influenced by uterine activity despite the emerging manifestation of this activity before labor. To quantify FCEC, the BPRSA can be applied to FHR and EHG transabdominal signals acquired in the third trimester of pregnancy.

Comparison of fetal heart rate variability by symbolic dynamics at the third trimester of pregnancy and low-risk parturition.

Fetal heart rate variability (fHRV) is an essential source of information to monitor fetal well-being during pregnancy. This study aimed to apply a nonlinear approach, known as symbolic dynamics (SD), for comparing human fHRV in the third trimester of pregnancy during active fetal state (TT) and active labor at term (P). We performed a longitudinal, prospective, descriptive, and comparative study composed of 42 longitudinal recordings of 5-minutes of fetal heartbeat interval series. Recordings were collected from 21 low-risk, healthy, pregnant women attending the Maternal and Child Research Center (CIMIGen), Mexico City. We calculated relevant linear parameters of fHRV between TT and P stages, such as the percentage of differences between adjacent RR intervals >5 ms (PRR5, related to vagal modulations) and other SD parameters such as the percentage of no variations between three successive symbols (%0V, reflects sympathetic modulations) and the probability of low variability with a threshold of 4 ms (POLVAR4, associated with a low variability). We identified statistical differences for PRR5 between TT and P (37.13% [28.47-47.60%] vs. 28.84% [19.36-36.76%], p = 0.03), respectively. Also, for 0V% (65.66% [59.01-71.80%] vs. 71.14% [65.94-75.87%], p = 0.03) and for POLVAR4 values (0.06 [0.04-0.11] vs. 0.15 [0.09-0.24], p = 0.002), respectively. Our results indicate that during parturition, the short-term fetal fHRV is decreased, showing a decreased vagal modulations and higher adrenergic response of the heart. These autonomic modifications may result from the fetal response to the stressful inflammatory challenge of labor. We thus confirmed that the analysis of the SD applied to fHRV time series could be a potential clinical biomarker to differentiate the fetal autonomic cardiac condition at different stages of pregnancy.

Symbolic analysis of heart rate fluctuations identifies cardiac autonomic modifications during LPS-induced endotoxemia.

The present study aimed to compare linear and symbolic dynamics (SD) indices for detecting the autonomic cardiac changes produced by endotoxemia in freely-moving rats. In this context, we analyzed ECG-derived R-R time series in freely moving Dark Agouti rats, which received lipopolysaccharide (LPS, n = 9), or vehicle (V, n = 7). Five minutes R-R time series were assessed every hour up to +12 h and + 24 h post-LPS injection. We found that SD indices showed significant differences at +7 h between V vs. LPS groups and at +9 h between basal levels of LPS (-3 h) and post-LPS injection (pre-LPS vs. post-LPS). In general, SD seems more appropriate than linear indices to evaluate the autonomic changes of endotoxemic rats. Overall, the symbolic parameters detected decreased R-R variability and complexity, which indicate a modification of the autonomic regulation during LPS-induced endotoxemia. This modification is probably related to a reduced activity of the cholinergic anti-inflammatory pathway at the long term.

Neuroautonomic activity evidences parturition as a complex and integrated neuro-immune-endocrine process.

Parturition in mammals demands a precise coordination of several neuro-immune-endocrine interactions including: a sterile inflammatory response that involves secretion of inflammation mediators like cytokines/chemokines; changes in the secretion of hormones such as progestogen, estrogens, cortisol, and oxytocin; as well as adjustments of the neuroautonomic function. Specifically, the so-called cholinergic anti-inflammatory pathway seems to play a key role in the homeostasis of the neuro-immune-endocrine axis by adjusting the vagus nerve activity during parturition. Here, we provide insights into the importance of the vagus during parturition from an autonomic, endocrine, and immune interplay perspective, and describe the potential role of heart rate variability analysis to explore these interactions noninvasively, economically, and accessibly.

Women Serum Concentrations of the IL-10 Family of Cytokines and IFN-γ Decrease from the Third Trimester of Pregnancy to Active Labor.

Labor is regarded as increased myometrial activity with a regular contractility pattern. At this final stage of pregnancy, myometrial quiescence is lost, accompanied by altered immune homeostasis. It is well known that the interleukin (IL)-10 family of cytokines modulates immunological responses mainly in epithelial cells, including the endometrium. To investigate their inflammatory profile during labor, we performed a longitudinal study in a group of healthy pregnant women (n = 20) with uncomplicated pregnancies in the third trimester of pregnancy and during active labor. Blood was sampled from pregnant women in the third trimester (gestational age 32-38 weeks, mean 36 ± 2 weeks) and during active labor (39-41 weeks of gestation, mean 40 ± 1 weeks). Serum levels of several cytokines were measured using multiplex immunoassays for both stages, indicating that the concentrations of IL-10, IL-20, IL-22, IL-28A, and interferon (IFN)-γ were significantly decreased during active labor in comparison with third-trimester levels (p < 0.05). Our analysis did not find significant correlations between IL-10, IL-20, IL-22, IL-28A, and IFN-γ levels and gestational age. However, our data suggest that the systemic downregulation of several members of the IL-10 family of cytokines plays an important role in the activation of myometrial smooth cells associated with uterine contractions during active labor. Downregulation of this IL-10 family of cytokines seems to coincide with the well-reported functional progesterone withdrawal during labor. Likewise, lower plasma IFN-γ concentrations may indicate a role for IFN-γ in active labor.

Oxytocin's role on the cardiorespiratory activity of endotoxemic rats.

BACKGROUND: Recent findings concerning oxytocin indicate its anti-inflammatory, cardioprotective and parasympathetic modulating properties. In this study, we investigated the effects of systemically applied oxytocin on the cardiorespiratory activity in a rodent model of moderate endotoxemia. METHODS: Telemetrically recorded electrocardiogram (ECGs) from animals which received lipopolysaccharide (LPS); oxytocin (Ox); lipopolysaccharide+oxytocin (LPS+Ox), or vehicle (V) were analyzed using the ECG-derived respiration (EDR) technique to estimate the respiratory rate. The mean R-R interval and the spectral parameters of heart rate variability (HRV), such as the natural logarithm of the high frequency (lnHF) and low frequency (lnLF) components were also estimated up to 24h after treatment. RESULTS: The endotoxemic animals (LPS) showed an elevated respiratory rate as well as a reduced mean R-R interval, lnHF and lnLF components compared to controls (V) from +5 to +12h after the treatment. The administration of oxytocin significantly attenuated the hyperventilation produced by the LPS-induced endotoxemia (LPS+Ox) and restored the values of the mean R-R interval and such spectral parameters at different time points. CONCLUSIONS: Our results support the existence of a link among the respiratory, cardiovascular, and immune systems in which oxytocin seems to act as a potential cardioprotective peptide by favoring cardiac cholinergic autonomic coupling. As a result, oxytocin diminished animal's endotoxemic tachypnea and restored the cardiorespiratory interactions, which was indicated by the spectral components of HRV.

Exogenous oxytocin reduces signs of sickness behavior and modifies heart rate fluctuations of endotoxemic rats.

Besides the well-known roles of oxytocin on birth, maternal bonding, and lactation, recent evidence shows that this hypothalamic hormone possesses cardioprotective, anti-inflammatory and parasympathetic neuromodulation properties. In this study, we explore the heart rate fluctuations (HRF) in an endotoxemic rodent model that was accompanied by the administration of exogenous oxytocin. The assessment of HRF has been widely used as an indirect measure of the cardiac autonomic function. In this context, adult male Dark Agouti rats were equipped with a telemetric transmitter to continuously and remotely measure the electrocardiogram, temperature, and locomotion. In a between-subjects experimental design, rats received the following peripheral treatment: saline solution as a vehicle (V); lipopolysaccharide (LPS); oxytocin (Ox); lipopolysaccharide + oxytocin (LPS+Ox). Linear and non-linear parameters of HRF were estimated starting 3h before to 24h after treatments. Our results showed that exogenous oxytocin does not modify by itself the HRF of oxytocin-treated rats in comparison to vehicle-treated rats. However, in animals undergoing endotoxemia it: a) provokes a less anticorrelated pattern in HRF, b) decreased mean heart rate, c) moderated the magnitude and duration of the LPS-induced hyperthermia, and d) increased locomotion, up to 6h after the LPS injection. The less anticorrelated pattern in the HRF and decreased mean heart rate may reflect a cardiac pacemaker coupling with cholinergic influences mediated by oxytocin during LPS-induced endotoxemia. Finally, the anti-lethargic and long-term temperature moderating effects of the administration of oxytocin during endotoxemia could be a consequence of the systemic anti-inflammatory properties of oxytocin.

A comparison of heart rate variability in women at the third trimester of pregnancy and during low-risk labour.

Heart rate variability (HRV) has been recognised as a non-invasive method for assessing cardiac autonomic regulation. Aiming to characterize HRV changes at labour in women, we studied 10 minute ECG recordings from young mothers (n=30) at the third trimester of pregnancy (P) or during augmentation of labour (L) (n=30). Data of the L group were collected when no-contractions (L-NC) or the contractile activity (L-C) was manifested. Accordingly, the inter-beat interval (IBI) time series were processed to estimate relevant parameters of HRV such as the mean IBI (IBI¯), the mean heart rate HR¯, the root mean square of successive differences (RMSSD) in IBIs, the natural logarithm of high-frequency component (LnHF), the short-term scaling parameters from detrended fluctuation and magnitude and sign analyses such as (α1, α1(MAG), α1(SIGN)), and the sample entropy (SampEn). We found statistical differences (p<0.05) for RMSSD among P and L-NC/L-C groups (25 ± 13 vs. 36 ± 14/34 ± 16 ms) and for LnHF between P and L-NC (5.37 ± 1.15 vs. 6.05 ± 0.86 ms(2)). Likewise, we identified statistical differences (p<0.05) for α1(SIGN) among P and L-NC/L-C groups (0.19 ± 0.20 vs. 0.32 ± 0.17/0.39 ± 0.13). By contrast, L-NC and L-C groups showed statistical differences (p<0.05) in α1(MAG) (0.67 ± 0.12 vs. 0.79 ± 0.12), and SampEn (1.62 ± 0.26 vs. 1.20 ± 0.44). These results suggest that during labour, despite preserving a concomitant non-linear influence, the maternal short-term cardiac autonomic regulation becomes weakly anticorrelated (as indicated by α1(SIGN)); furthermore, an increased vagally mediated activity is observed (as indicated by RMSSD and LnHF), which may reflect a cholinergic pathway activation owing to the use of oxytocin or the anti-inflammatory cholinergic response triggered during labour.