Correlation of fetal heart rate dynamics to inflammatory markers and brain-derived neurotrophic factor during pregnancy.

OBJECTIVES: This study aims to show the relation between biomarkers in maternal and cord-blood samples and fetal heart rate variability (fHRV) metrics through a non-invasive fetal magnetocardiography (fMCG) technique. METHODS: Twenty-three women were enrolled for collection of maternal serum and fMCG tracings immediately prior to their scheduled cesarean delivery. The umbilical cord blood was collected for measurement of biomarker levels. The fMCG metrics were then correlated to the biomarker levels from the maternal serum and cord blood. RESULTS: Brain-derived neurotrophic factor (BDNF) had a moderate correlation with fetal parasympathetic activity (0.416) and fetal sympathovagal ratios (-0.309; -0.356). Interleukin (IL)-6 also had moderate-sized correlations but with an inverse relationship as compared to BDNF. These correlations were primarily in cord-blood samples and not in the maternal blood. CONCLUSIONS: In this small sample-sized exploratory study, we observed a moderate correlation between fHRV and cord-blood BDNF and IL-6 immediately preceding scheduled cesarean delivery at term. These findings need to be validated in a larger population.

Characterizing pelvic floor muscles activities using magnetomyography.

AIMS: To characterize levator ani muscle (LAM) activity in nulligravidas using magnetomyography (MMG) and define MMG characteristics associated with LAM activity with and without accessory muscle contributions. METHODS: MMG data were collected from eight nulligravidas during rest and voluntary LAM contractions (Kegels) of varying intensity. We utilized simultaneous vaginal manometry and surface electromyography (sEMG) to evaluate for accessory muscle recruitment. Moderate Kegel (MK) MMG trials were sub-selected based on the presence or absence of accessory muscle interaction. Amplitude and spectral-related indicators were calculated across MK epochs: root-mean square (RMS) amplitude, percentage amplitude relative to rest, and relative power spectrum density (rPSD) in three frequency bands (low, middle, high). Ternary diagram characterized rPSD from selected Kegels and ROC analysis was performed to identify cut-points to differentiate MKs from interacting MKs. RESULTS: Nineteen MMG recordings were obtained. Amplitude and spectral parameters were significantly different between isolated and interacting MK epochs. Mean RMS and power values of the isolated MK were, respectively, 120.66 ± 43.8 fT and 1.72 ± 1.44 (T2 /Hz)*10-28 . Amplitudes of MK were 64% and 117 higher than baseline activities for the isolated and interacting epochs, respectively. ROC curves reveled cut-off points on low and middle frequency bands that achieved perfect separation (ROC-AUC = 1.0) between isolated and interacting MK. CONCLUSIONS: Our study demonstrates that MMG, a novel biomagnetic technique, allows precise detection and characterization of normal female pelvic floor function. Results show that isolated moderate voluntary contraction of the LAMs produces distinct MMG amplitude and spectral characteristics compared with Kegels involving co-activation of other muscle groups.

Magnetocardiographic identification of prolonged fetal corrected QT interval in women receiving treatment for opioid use disorder.

AIM: Pregnant women undergoing treatment for opioid use disorder (OUD) may be exposed to multiple QT prolonging agents. We used magnetocardiography to measure fetal QT intervals in mothers with OUD on buprenorphine therapy. METHODS: Fetal and maternal magnetocardiography was performed in pregnant women receiving buprenorphine-assisted treatment (Disorder group); these were matched by gestational age to pregnant women who were opiate naïve (Reference group). Corrected QT intervals were determined using Bazett's formula and compared between groups. RESULTS: A total of eight women in the Disorder group matched to eight in the Reference group. Seven of the mothers (88%) in the Disorder group were smokers; there were no smokers in the Reference group. The average fetal corrected QT was significantly longer (P = 0.022) in the Disorder group than that in the Reference group (505 milliseconds [ms] ± 68.6 [standard deviation] vs 383 ms ± 70.3 [standard deviation]). CONCLUSION: Novel data from this small sample demonstrate prolongation of fetal corrected QT in women with OUD participating in buprenorphine assisted therapy. Additional investigation from a larger sample is needed to clarify if fetal buprenorphine and/or tobacco exposure is associated with changes in fetal QT which would warrant further prenatal and postnatal testing.

Fetal magnetocardiography using optically pumped magnetometers: a more adaptable and less expensive alternative?

Fetal magnetocardiography provides the requisite precision for diagnostic measurement of electrophysiological events in the fetal heart. Despite its significant benefits, this technique with current cryogenic based sensors has been limited to few centers, due to high cost of maintenance. In this study, we show that a less expensive non-cryogenic alternative, optically pumped magnetometers, can provide similar electrophysiological and quantitative characteristics when subjected to direct comparison with the current technology. Further research can potentially increase its clinical use for fetal magnetocardiography. © 2016 John Wiley & Sons, Ltd.

Multicompare tests of the performance of different metaheuristics in EEG dipole source localization.

We study the use of nonparametric multicompare statistical tests on the performance of simulated annealing (SA), genetic algorithm (GA), particle swarm optimization (PSO), and differential evolution (DE), when used for electroencephalographic (EEG) source localization. Such task can be posed as an optimization problem for which the referred metaheuristic methods are well suited. Hence, we evaluate the localization's performance in terms of metaheuristics' operational parameters and for a fixed number of evaluations of the objective function. In this way, we are able to link the efficiency of the metaheuristics with a common measure of computational cost. Our results did not show significant differences in the metaheuristics' performance for the case of single source localization. In case of localizing two correlated sources, we found that PSO (ring and tree topologies) and DE performed the worst, then they should not be considered in large-scale EEG source localization problems. Overall, the multicompare tests allowed to demonstrate the little effect that the selection of a particular metaheuristic and the variations in their operational parameters have in this optimization problem.

Fetal magnetocardiographic recordings with a prototype bed-based array system of optically-pumped magnetometers.

OBJECTIVE: To record and extract features of fetal cardiac activities with a semi-rigid prototype optically-pumped magnetometers (OPM) sensor array. METHODS: Fetal magnetocardiography (fMCG) data were collected from 15 pregnant women between 28 and 40 weeks gestation. Mothers were lying flat in a customized bed with sensors touching their abdomen from below using a prototype grid. fMCG was extracted to perform standard fetal heart rate variability (FHRV) analysis. RESULTS: fMCG was observed in 13 of the 15 pregnant women. OPM FHRV indicators were in the range of previous SQUID studies. CONCLUSION: Semi-rigid prototype OPM system has the ability to record quality fMCG. fMCG is capable of identifying lethal cardiac rhythm disturbances in the fetus. Our novel application of OPM technology may lower costs and increase maternal comfort, thus expanding fMCG's generalizability.

Exploring the Influence of Fetal Sex on Heart Rate Dynamics Using Fetal Magnetocardiographic Recordings.

Fetal sex has been associated with different development trajectories that cause structural and functional differences between the sexes throughout gestation. Fetal magnetocardiography (fMCG) recordings from 123 participants (64 females and 59 males; one recording/participant) from a database consisting of low-risk pregnant women were analyzed to explore and compare fetal development trajectories of both sexes. The gestational age of the recordings ranged from 28 to 38 weeks. Linear metrics in both the time and frequency domains were applied to study fetal heart rate variability (fHRV) measures that reveal the dynamics of short- and long-term variability. Rates of linear change with GA in these metrics were analyzed using general linear model regressions with assessments for significantly different variances and GA regression slopes between the sexes. The fetal sexes were well balanced for GA and sleep state. None of the fHRV measures analyzed exhibited significant variance heterogeneity between the sexes, and none of them exhibited a significant sex-by-GA interaction. The absence of a statistically significant sex-by-GA interaction on all parameters resulted in none of the regression slope estimates being significantly different between the sexes. With high-precision fMCG recordings, we were able to explore the variation in fHRV parameters as it relates to fetal sex. The fMCG-based fHRV parameters did not show any significant difference in rates of change with gestational age between sexes. This study provides a framework for understanding normal development of the fetal autonomic nervous system, especially in the context of fetal sex.

Comparison of non-invasive magnetomyography to Brink score for assessment of pelvic floor muscle strength.

Objective.Levator ani muscles undergo significant stretching and micro-trauma at childbirth. The goal was to assess the neuromuscular integrity of this muscle group by means of magnetomyography (MMG) and correlate with Brink score-a commonly used digital assessment of pelvic floor muscle strength.Approach.Non-invasive MMG data was collected on 22 pregnant women during rest and voluntary contraction of the pelvic-floor muscles (Kegels). The mean amplitude and power spectral density (PSD) of the Kegels were correlated to Brink pressure score.Main Results.The modified Brink pressure score demonstrated medium correlations (⩾0.3) with MMG amplitude and PSD with the average Kegel of medium intensity and rest. Data showed that the 'resting state' of the pelvic floor is, in actuality, quite dynamic and may have implications for pelvic floor disorder propensity postpartum.Significance.These results confirm the ability of non-invasive MMG to reliably capture pelvic floor contraction as these signals correlate with clinical measure.

Correlating maternal and cord-blood inflammatory markers and BDNF with human fetal brain activity recorded by magnetoencephalography: An exploratory study.

Background: During gestation, the brain development of the fetus is affected by many biological markers, where inflammatory processes and neurotrophic factors have been of particular interest in the past decade. Aim: This exploratory study is the first attempt to explore the relationships between biomarker levels in maternal and cord-blood samples and human fetal brain activity measured with non-invasive fetal magnetoencephalography (fMEG). Method: Twenty-three women were enrolled in this study for collection of maternal serum and fMEG tracings immediately prior to their scheduled cesarean delivery. Twelve of these women had a preexisting diabetic condition. At the time of delivery, umbilical cord blood was also collected. Biomarker levels from both maternal and cord blood were measured and subsequently analyzed for correlations with fetal brain activity in four frequency bands extracted from fMEG power spectral densities. Results: Relative power in the delta, alpha, and beta frequency bands exhibited moderate-sized correlations with maternal BDNF and cord-blood CRP levels before and after adjusting for confounding diabetic status. These correlations were negative for the delta band, and positive for the alpha and beta bands. Maternal CRP and cord-blood BDNF and IL-6 exhibited negligible correlations with relative power in all four bands. Diabetes did not appear to be a strong confounding factor affecting the studied biomarkers. Conclusions: Maternal BDNF levels and cord-blood CRP levels appear to have a direct correlation to fetal brain activity. Our findings indicate the potential use of these biomarkers in conjunction with fetal brain electrophysiology to track fetal neurodevelopment.

Assessing uterine electrophysiology prior to elective term induction of labor.

Objective: The purpose of this study was to determine if uterine electrophysiological signals gathered from 151 non-invasive biomagnetic sensors spread over the abdomen were associated with successful induction of labor (IOL). Study design: Uterine magnetomyogram (MMG) signals were collected using the SARA (SQUID Array for Reproductive Assessment) device from 33 subjects between 37 and 42 weeks gestational age. The signals were post-processed, uterine contractile related MMG bursts were detected, and parameters in the time and frequency domain were extracted. The modified Bishop score calculated at admission was used to determine the method of IOL. Wilcoxon's rank-sum test was used to compare IOL successes and failures for differences in gestational age (GA), parity, modified Bishop's score, maximum oxytocin, and electrophysiological parameters extracted from MMG. Results: The average parity was three times (3x) higher (1.53 versus 0.50; p = 0.039), and the average modified Bishop score was 2x higher (3.32 versus 1.63; p = 0.032) amongst IOL successes than failures, while the average GA and maximum oxytocin showed a small difference. For the MMG parameters, successful IOLs had, on average, 3.5x greater mean power during bursts (0.246 versus 0.070; p = 0.034) and approximately 1.2x greater mean number of bursts (2.05 versus 1.68; p = 0.036) compared to the failed IOLs, but non-significant differences were observed in mean peak frequency, mean burst duration, and mean duration between bursts. Conclusion: The study showed that inductions of labor that took less than 24 h to deliver have a higher mean power in the baseline electrophysiological activity of the uterus when recorded prior to planned induction. The results are indicative that baseline electrophysiological activity measured prior to induction is associated with successful induction.

The effect of maternal pregestational diabetes on fetal autonomic nervous system.

Heart rate variability assessment of neonates of pregestational diabetic mothers have shown alterations in the autonomic nervous system (ANS). The objective was to study the effect of maternal pregestational diabetes on ANS at the fetal stage by combining cardiac and movement parameters using a non-invasive fetal magnetocardiography (fMCG) technique. This is an observational study with 40 participants where fetuses from a group of 9 Type 1, 19 Type 2 diabetic, and 12 non-diabetic pregnant women were included. Time and frequency domain fetal heart rate variability (fHRV) and coupling of movement and heart rate acceleration parameters related to fetal ANS were analyzed. Group differences were investigated using analysis of covariance to adjust for gestational age (GA). When compared to non-diabetics, the Type 1 diabetics had a 65% increase in average ratio of very low-frequency (VLF) to low-frequency (LF) bands and 63% average decrease in coupling index after adjusting for GA. Comparing Type 2 diabetics to non-diabetics, there was an average decrease in the VLF (50%) and LF bands (63%). Diabetics with poor glycemic control had a higher average VLF/LF (49%) than diabetics with good glycemic control. No significant changes at p < 0.05 were observed in high-frequency (HF) frequency domain parameters or their ratios, or in the time domain. Fetuses of pregestational diabetic mothers exhibited some differences in fHRV frequency domain and heart rate-movement coupling when compared to non-diabetics but the effect of fHRV related to fetal ANS and sympathovagal balance were not as conclusive as observed in the neonates of pregestational diabetic mothers.

Reduced osteoprotegerin expression by osteocytes may contribute to rebound resorption after denosumab discontinuation.

Denosumab is an anti-RANKL Ab that potently suppresses bone resorption, increases bone mass, and reduces fracture risk. Discontinuation of denosumab causes rapid rebound bone resorption and bone loss, but the molecular mechanisms are unclear. We generated humanized RANKL mice and treated them with denosumab to examine the cellular and molecular conditions associated with rebound resorption. Denosumab potently suppressed both osteoclast and osteoblast numbers in cancellous bone in humanized RANKL mice. The decrease in osteoclast number was not associated with changes in osteoclast progenitors in bone marrow. Long-term, but not short-term, denosumab administration reduced osteoprotegerin (OPG) mRNA in bone. Localization of OPG expression revealed that OPG mRNA is produced by a subpopulation of osteocytes. Long-term denosumab administration reduced osteocyte OPG mRNA, suggesting that OPG expression declines as osteocytes age. Consistent with this, osteocyte expression of OPG was more prevalent near the surface of cortical bone in humans and mice. These results suggest that new osteocytes are an important source of OPG in remodeling bone and that suppression of remodeling reduces OPG abundance by reducing new osteocyte formation. The lack of new osteocytes and the OPG they produce may contribute to rebound resorption after denosumab discontinuation.

Recording and quantifying fetal magnetocardiography signals using a flexible array of optically-pumped magnetometers.

OBJECTIVE: Fetal magnetocardiography (fMCG) is a non-invasive biomagnetic technique that provides detailed beat-to-beat fetal heart rate analysis, both in normal rhythm as well as in fetal arrhythmias. New cryogenic-free sensors called optically pumped magnetometers (OPMs) have emerged as a less expensive and more geometrically flexible alternative to traditional Superconducting Quantum Interference Device (SQUID) technology for performing fMCG. The objective of the study was to show the ability of OPMs to record fMCG using flexible geometry while seeking to preserve signal quality, and to quantify fetal heart rate variability (FHRV). APPROACH: Biomagnetic measurements were performed with OPMs in 24 healthy pregnant women with uncomplicated singleton pregnancies between 28 and 38 weeks gestation (GA). A total of 96 recordings were analyzed from OPM data that was collected using sensors placed in two different maternal configurations over the abdomen. The fMCG signals were extracted and the quality of the recordings were quantified by peak amplitudes and signal-to-noise ratio (SNR). R peaks were used to perform both time and frequency domain FHRV analysis. FHRV measures obtained from OPMs were compared descriptively to the same measures obtained from GA-matched existing SQUID data. MAIN RESULTS: The fMCG derived from OPMs were observed in 21 of the 24 participants. Higher detection rates (85%) of fMCG signals were observed in the data sets recorded at GA >32 weeks. Peak amplitudes and SNR values were similar between two maternal configurations, but peak amplitudes were significantly higher (p = 0.013) in late GA compared to early GA. FHRV indicators were successfully extracted and their values overlapped substantially with those obtained from SQUID recordings. SIGNIFICANCE: Taking advantage of the geometric flexibility of the OPMs, we have demonstrated their ability to record and quantify fMCG in different maternal positions as opposed to rigid SQUID configurations.

Adaptable Sensor Arrays for Fetal Magnetocardiographic Measurements Using Optically-Pumped Magnetometers: A Pilot Study.

Fetal magnetocardiography (fMCG) is a noninvasive method of measuring magnetic signals generated by the depolarizing heart. fMCG has proved to have superior signal-to-noise ratio characteristics and enables precise detection of the R-R intervals for fetal heart rate variability (FHRV) analysis. FHRV is one of the most useful clinical indicators for investigating fetal neurodevelopment. Currently, fMCG recordings rely on superconducting quantum interference devices (SQUIDs) which require cryogenics leading to a high cost device. New cryogenic-free sensors called optical pump magnetometers (OPMs) have emerged as alternative to SQUIDs. To take advantage of the flexibility of the OPM sensors, we explored the ability of OPM sensors to measure the fMCG at different maternal positions and sensor locations. Data were collected with a 14-channel OPM array using different sitting positions (mother leaning forward, backward, and prone). Projection operator algorithm based on minimum norm (POMN) was applied to extracted fMCG. R peaks were obtained to perform standard FHRV analysis. We were able to configure a standalone array of the OPMs that conforms to the shape of the maternal abdomen to obtain signals with sufficient quality. We extracted and quantified FHRV parameters in three low-risk fetuses. Results showed that FHRV values are in the range of previous SQUID studies.

Studying the Effect of Maternal Pregestational Diabetes on Fetal Neurodevelopment Using Magnetoencephalography.

Background. Developmental origin of health and disease states that an adverse intrauterine environment can lead to different diseases in later life. In this study, we aimed to explore the effect of maternal pregestational diabetes on the fetal brain activity using magnetoencephalography (MEG). Methods. Forty participants were included in an observational study with 9 type 1 and 19 type 2 diabetic pregnant women compared with data from 12 nondiabetic participants. Spontaneous fetal MEG signals were recorded and power spectral density was computed in 4 standard frequency bands. Group differences were investigated using analysis of covariance. Results. Our results showed that type 1 group was significantly different (P < .05) from the reference group for 3 of the 4 brain activity frequency bands, while in type 2 group, 2 bands exhibited this trend. When dichotomized based on the maternal glycemic control, significant differences in all bands were observed between the poor-control and reference groups. Conclusion. The fetal background brain activity parameters appear to be altered in diabetic pregnancy in comparison with the reference low-risk group. The study showed that maternal pregestational diabetes could potentially influence in utero neurodevelopment.

Magnetomyographic Recordings of Pelvic Floor Activity During Pregnancy and Postpartum: A Novel Non-invasive Approach.

The levator ani muscles (LAM) are integral to pelvic floor support and injury to this muscle complex has been associated with pelvic floor disorders, but our ability to evaluate their neuromuscular integrity is limited. During pregnancy, gravidas undergo systemic functional and anatomic modifications, including pelvic floor muscular adaptations. Magnetomyography (MMG) is a novel and non-invasive tool to passively measure the magnetic fields generated by depolarization activity of muscles and offers a unique method to evaluate the LAM. We collected serial MMG data in a pregnant woman with singleton gestation. Pregnant woman performed LAM contractions (Kegels) with intervening rest periods. Kegel signals were isolated by using the frequency dependent subtraction (SUBTR) and independent component analysis (ICA) methods. Concurrent body-surface electromyography (EMG) was used to evaluate for accessory-muscle recruitment by placing bipolar electrodes on the perineum, abdomen, and thigh. Amplitude and spectral-related indicators were computed across moderate intensity MMG Kegel epochs: root-mean square (RMS) amplitude, power spectrum density (PSD) and relative PSD (rPSD) in three frequency bands. Indicators were extracted from two pregnancy recordings and one postpartum. Parameters were represented in terms of gestation and postpartum weeks. We observed that postpartum RMS Kegel amplitudes had lower values than seen in pregnancy. Changes in spectral indicators were observed between pregnancy and postpartum.

Fully Automated Subtraction of Heart Activity for Fetal Magnetoencephalography Data.

Fetal magnetoencephalography (fMEG) is a method to record human fetal brain signals in pregnant mothers. Nevertheless the amplitude of the fetal brain signal is very small and the fetal brain signal is overlaid by interfering signals mainly caused by maternal and fetal heart activity. Several methods are used to attenuate the interfering signals for the extraction of the fetal brain signal. However currently used methods are often affected by a reduction of the fetal brain signal or redistribution of the fetal brain signal. To overcome this limitation we developed a new fully automated procedure for removal of heart activity (FAUNA) based on Principal Component Analysis (PCA) and Ridge Regression. We compared the results with an orthogonal projection (OP) algorithm which is widely used in fetal research. The analysis was performed on simulated data sets containing spontaneous and averaged brain activity. The new analysis was able to extract fetal brain signals with an increased signal to noise ratio and without redistribution of activity across sensors compared to OP. The attenuation of interfering heart signals in fMEG data was significantly improved by FAUNA and supports fully automated evaluation of fetal brain signal.