Search

Adverse prenatal environmental influences to the developing fetus are associated with mental and cardiovascular disease in later life. Universal developmental characteristics such as self-organization, pattern formation, and adaptation in the growing information processing system have not yet been sufficiently analyzed with respect to description of normal fetal development and identification of developmental disturbances. Fetal heart rate patterns are the only non-invasive order parameter of the developing autonomic brain available with respect to the developing complex organ system. The objective of the present study was to investigate whether universal indices, known from evolution and phylogeny, describe the ontogenetic fetal development from 20 weeks of gestation onwards. By means of a 10-fold cross-validated data-driven multivariate regression modeling procedure, relevant indices of heart rate variability (HRV) were explored using 552 fetal heart rate recordings, each lasting over 30 min. We found that models which included HRV indices of increasing fluctuation amplitude, complexity and fractal long-range dependencies largely estimated the maturation age (coefficients of determination 0.61-0.66). Consideration of these characteristics in prenatal care may not only have implications for early identification of developmental disturbances, but also for the development of system-theory-based therapeutic strategies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Monitoring the fetal behavior does not only have implications for acute care but also for identifying developmental disturbances that burden the entire later life. The concept, of 'fetal programming', also known as 'developmental origins of adult disease hypothesis', e.g. applies for cardiovascular, metabolic, hyperkinetic, cognitive disorders. Since the autonomic nervous system is involved in all of those systems, cardiac autonomic control may provide relevant functional diagnostic and prognostic information. The fetal heart rate patterns (HRP) are one of the few functional signals in the prenatal period that relate to autonomic control and, therefore, is predestinated for its evaluation. The development of sensitive markers of fetal maturation and its disturbances requires the consideration of physiological fundamentals, recording technology and HRP parameters of autonomic control. Based on the ESGCO2016 special session on monitoring the fetal maturation we herein report the most recent results on: (i) functional fetal autonomic brain age score (fABAS), Recurrence Quantitative Analysis and Binary Symbolic Dynamics of complex HRP resolve specific maturation periods, (ii) magnetocardiography (MCG) based fABAS was validated for cardiotocography (CTG), (iii) 30 min recordings are sufficient for obtaining episodes of high variability, important for intrauterine growth restriction (IUGR) detection in handheld Doppler, (iv) novel parameters from PRSA to identify Intra IUGR fetuses, (v) evaluation of fetal electrocardiographic (ECG) recordings, (vi) correlation between maternal and fetal HRV is disturbed in pre-eclampsia. The reported novel developments significantly extend the possibilities for the established CTG methodology. Novel HRP indices improve the accuracy of assessment due to their more appropriate consideration of complex autonomic processes across the recording technologies (CTG, handheld Doppler, MCG, ECG). The ultimate objective is their dissemination into routine practice and studies of fetal developmental disturbances with implications for programming of adult diseases.

With the objective of evaluating the functional maturation age and developmental disturbances we have previously introduced the fetal autonomic brain age score (fABAS) using 30 min fetal magnetocardiographic recordings (fMCG, Jena). The score is based on heart rate pattern indices that are related to universal principles of developmental biology. The present work aims at the validation of the fABAS methodology on 5 min recordings from an independent database (fMCG, Bochum).We found high agreement of fABAS obtained from Jena normal fetuses (5 min subsets, n =  364) and Bochum recordings (n =  322, normal fetuses). fABAS of 48 recordings from fetuses with intra-uterine growth restriction (IUGR, Bochum) was reduced in most of the cases, a result consistent with IUGR fetuses from Jena previously reported. fABAS calculated from 5 min snapshots only partly covers the accuracy when compared to fABAS from 30 min recordings. More precise diagnosis requires longer recordings.fABAS obtained from fMCG recordings is a strong candidate for standardized assessment of functional maturation age and developmental disturbances. Even 5 min recordings seem to be valuable for screening for maturation problems.

Fetal brain development involves the development of the neuro-vegetative (autonomic) control that is mediated by the autonomic nervous system (ANS). Disturbances of the fetal brain development have implications for diseases in later postnatal life. In that context, the fetal functional brain age can be altered. Universal principles of developmental biology applied to patterns of autonomic control may allow a functional age assessment. The work aims at the development of a fetal autonomic brain age score (fABAS) based on heart rate patterns. We analysed n = 113 recordings in quiet sleep, n = 286 in active sleep, and n = 29 in active awakeness from normals. We estimated fABAS from magnetocardiographic recordings (21.4-40.3 weeks of gestation) preclassified in quiet sleep (n = 113, 63 females) and active sleep (n = 286, 145 females) state by cross-validated multivariate linear regression models in a cross-sectional study. According to universal system developmental principles, we included indices that address increasing fluctuation range, increasing complexity, and pattern formation (skewness, power spectral ratio VLF/LF, pNN5). The resulting models constituted fABAS. fABAS explained 66/63% (coefficient of determination R(2) of training and validation set) of the variance by age in quiet, while 51/50% in active sleep. By means of a logistic regression model using fluctuation range and fetal age, quiet and active sleep were automatically reclassified (94.3/93.1% correct classifications). We did not find relevant gender differences. We conclude that functional brain age can be assessed based on universal developmental indices obtained from autonomic control patterns. fABAS reflect normal complex functional brain maturation. The presented normative data are supplemented by an explorative study of 19 fetuses compromised by intrauterine growth restriction. We observed a shift in the state distribution towards active awakeness. The lower WGA dependent fABAS values found in active sleep may reflect alterations in the universal developmental indices, namely fluctuation amplitude, complexity, and pattern formation that constitute fABAS.

Development of the fetal autonomic nervous system's integrative capacity in relation to gestational age and emerging behavioral pattern is reflected in fetal heart rate patterns. Conventional indices of vagal and sympathetic rhythms cannot sufficiently reflect their complex interrelationship. Universal behavioral indices of developing complex systems may provide additional information regarding the maturating complex autonomic control. We investigated fetal magnetocardiographic recordings undertaken at 10-min intervals in active (n = 248) and quiet (n = 111) states between 22 and 39 wk gestational age. Standard deviation of heartbeat intervals, skewness, contribution of particular rhythms to the total power, and multiscale entropy were analyzed. The multiscale entropy methodology was validated for 10-min data sets. Age dependence was analyzed by linear regression. In the quiet state, contribution of sympathovagal rhythms and their complexity over a range of corresponding short scales increased with rising age, and skewness shifted from negative to positive values. In the active state, age dependencies were weaker. Skewness as the strongest parameter shifted in the same direction. Fluctuation amplitude and the complexity of scales associated with sympathovagal rhythms increased. We conclude that in the quiet state, stable complex organized rhythms develop. In the active state, however, increasing behavioral variability due to multiple internal coordinations, such as movement-related heart rate accelerations, and external influences develop. Hence, the state-selective assessment in association with developmental indices used herein may substantially improve evaluation of maturation age and early detection and interpretation of developmental problems in prenatal diagnosis.

Aim: To describe developmental aspects of the sympatho-vagal heart rate regulation in the human fetus by applying numerics to visual descriptions of fetal heart rate patterns throughout the third trimester of pregnancy. The focus is to determine potential benefits of this alternative means of assessing the maturation of the fetal autonomic nervous system by analysis of fetal heart rate variability (fHRV)., Subjects and Methods: The magnetocardiograms of 103 normal fetuses between 24+1 and 41+6 weeks of gestation were studied. Fetal heart beat intervals were determined with a temporal precision of 1 ms. The levels of fetal activity were estimated according to characteristic heart rate patterns (I-III) prior to 32, between 32-35 and beyond 35 (groups 1-3) completed weeks. Mean heart rate (mHR), standard deviation of normal-to-normal beat intervals (SDNN) and root mean square of successive differences of normal beats (RMSSD) served as fHRV indices, mean permutation entropy (PE_Mean) as complexity measure. SDNN/RMSSD was introduced as a potential marker for sympatho-vagal balance., Results: Low activity fHRP (I) were characterized by significantly lower level fHRV indices and higher PE_Mean when compared to fHRP II. We found that SDNN/RMSSD decreases with gestation in fHRP I, which suggests increasing vagal influence. In fHRP III (assigned to active awake fetuses only after 32 weeks), highest level SDNN and mHR are associated with a dramatically reduced complexity. fHRV indices cluster characteristically with the activity levels., Conclusions: We conclude that a combined analysis of fHRV, based on SDNN/RMSSD and PE_Mean, and fHRP is advantageous in the assessment of maturation of the fetal autonomic nervous system.

Introduction: Prenatal exposure to supraphysiological glucocorticoid (GC) levels may lead to long‐lasting developmental changes in numerous biological systems. Our prior study identified an association between prenatal GC prophylaxis and reduced cognitive performance, electrocortical changes, and altered autonomic nervous system (ANS) activity in children aged 8–9 years. This follow‐up study aimed to examine whether these findings persisted into adolescence. Material and Methods: Prospective observational follow‐up study involving twenty‐one 14‐ to 15‐year‐old adolescents born to mothers who received betamethasone for induction of fetal lung maturation in threatened preterm birth, but who were born with a normal weight appropriate for their gestational age (median 37+4 gestational weeks). Thirty‐five children not exposed to betamethasone served as the reference group (median 37+6 gestational weeks). The primary endpoint was cognitive performance, measured by intelligence quotient (IQ). Key secondary endpoints included symptoms of attention‐deficit/hyperactivity disorder (ADHD) and metabolic markers. Additionally, we determined electrocortical (electroencephalogram), hypothalamus–pituitary–adrenal axis (HPAA), and ANS activity in response to a standardized stress paradigm. Results: No statistically significant group difference was observed in global IQ (adjusted mean: betamethasone 103.9 vs references 105.9, mean difference −2.0, 95% confidence interval [CI]: −7.12 to 3.12, p = 0.44). Similarly, ADHD symptoms, metabolic markers, the overall and stress‐induced activity of the HPAA and the ANS did not differ significantly between groups. However, the betamethasone group exhibited reduced electrocortical activity in the frontal brain region (spectral edge frequency–adjusted means: 16.0 Hz vs 17.8 Hz, mean difference −1.83 Hz, 95% CI: −3.21 to −0.45, p = 0.01). Conclusions: In 14‐ to 15‐year‐old adolescents, prenatal GC exposure was not associated with differences in IQ scores or ANS activity compared to unexposed controls. However, decelerated electrocortical activity in the frontal region potentially reflects disturbances in the maturation of cortical and/or subcortical brain structures. The clinical significance of these changes remains unknown. Given the small sample size, selective participation/loss of follow‐up and potential residual confounding, these findings should be interpreted cautiously. Further research is required to replicate these results in larger cohorts before drawing firm clinical conclusions. [ABSTRACT FROM AUTHOR]

Disturbances of fetal autonomic brain development can be evaluated from fetal heart rate patterns (HRP) reflecting the activity of the autonomic nervous system. Although HRP analysis from cardiotocographic (CTG) recordings is established for fetal surveillance, temporal resolution is low. Fetal magnetocardiography (MCG), however, provides stable continuous recordings at a higher temporal resolution combined with a more precise heart rate variability (HRV) analysis. A direct comparison of CTG and MCG based HRV analysis is pending. The aims of the present study are: (i) to compare the fetal maturation age predicting value of the MCG based fetal Autonomic Brain Age Score (fABAS) approach with that of CTG based Dawes-Redman methodology; and (ii) to elaborate fABAS methodology by segmentation according to fetal behavioral states and HRP. We investigated MCG recordings from 418 normal fetuses, aged between 21 and 40 weeks of gestation. In linear regression models we obtained an age predicting value of CTG compatible short term variability (STV) of R2 = 0.200 (coefficient of determination) in contrast to MCG/fABAS related multivariate models with R2 = 0.648 in 30 min recordings, R2 = 0.610 in active sleep segments of 10 min, and R2 = 0.626 in quiet sleep segments of 10 min. Additionally segmented analysis under particular exclusion of accelerations (AC) and decelerations (DC) in quiet sleep resulted in a novel multivariate model with R2 = 0.706. According to our results, fMCG based fABAS may provide a promising tool for the estimation of fetal autonomic brain age. Beside other traditional and novel HRV indices as possible indicators of developmental disturbances, the establishment of a fABAS score normogram may represent a specific reference. The present results are intended to contribute to further exploration and validation using independent data sets and multicenter research structures. [ABSTRACT FROM AUTHOR]

Abstract: The increasing functional integrity of the organism during fetal maturation is connected with increasing complex internal coordination. We hypothesize that time scales of complexity and dynamics of heart rate patterns reflect the increasing inter-dependencies within the fetal organism during its prenatal development. We investigated multi-scale complexity, time irreversibility and fractal scaling from 73 fetal magnetocardiographic 30min recordings over the third trimester. We found different scale dependent complexity changes, increasing medium scale time irreversibility, and increasing long scale fractal correlations (all changes p<0.05). The results confirm the importance of time scales to be considered in fetal heart rate based developmental indices. [Copyright &y& Elsevier]

Abstract: Background: Steroid administration to accelerate fetal lung maturation reduces neonatal morbidity and mortality in the case of preterm delivery. Behavioral observations suggest effects on fetal cardiovascular regulation. Aim: We hypothesize that beat to beat heart rate variability (fHRV) derived from fetal magnetocardiography (fMCG) will reveal a direct, acute steroidal effect on fetal autonomic heart rate regulation. Subjects: Eight patients between 29 and 34weeks of gestation at risk for preterm birth who were treated with betamethasone (2×12mg within 24h). Study design: Subjects were studied prior to the first and within 6h after the second administration. Continuous fMCG was recorded with a 31-channel-SQUID biomagnetometer. Each dataset was processed by subtracting maternal cardiac artefacts and determining the time instants of the fetal heart beats. fHRV analysis was applied to periods of fetal quiescence of 4min length. Outcome measures: We compared fHRV prior versus post steroid administration. Results: Steroid exposure reduced all parameters of overall fHRV significantly. The fHRV parameters representing short term variability remained unaffected. Mean fetal heart rate significantly decreased. The complexity of the heart rate patterns increased. Conclusion: Our results suggest an acute shift in the symptaho-vagal balance of fetuses exposed to betamethasone in utero toward sympathetic suppression. [Copyright &y& Elsevier]

Abstract: Background: The fetal precursors of mental and cardiovascular disease caused by adverse prenatal environmental influences and manifesting in later age are an important issue of developmental medicine. However the number of measurable functional parameters of a fetus is limited. Evaluation of key parameters involving fetal autonomic control could permit an earlier detection of developmental problems and improved therapeutic strategies. Thus far, however, even the maturation of normal autonomic control has not been sufficiently assessed. Aim: The objective of the present work is to describe normal fetal maturation based on indices of autonomic heart rate modulation. Study design: Heart beat interval series were magnetocardiographically recorded with 1 kHz sampling rate over 30 min in 78 normal fetuses, gestational age (GA) 23–40 weeks. Indices considered were: number of accelerations (AC) and decelerations (DC), RMSSD, SDNN, and short-term/long-term autonomic information flows (AIF_NN, AIF_fVLF). These were measured from the entire 30 min data sets and from activity-specific subsets (10 min). Results: In the 30 min recordings: the number of AC increased, number of DC decreased, rMSSD and SDNN increased and AIF_fVLF increased with GA, but AIF_NN remained constant. In the 10 min subsets: SDNN increased in the active state but remained constant in the quiet state and AIF_NN decreased with GA in the quiet state. Conclusion: Heart rate patterns from 30 min biomagnetic recordings may provide new indices with which to assess the normal and abnormal maturation of fetal autonomic control and to identify risk of possible disorders in later life. [Copyright &y& Elsevier]