Ekkehard Schleußner

Indices of fetal development derived from heart rate patterns

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.

Nitric oxide donors: effects on fetoplacental blood flow

OBJECTIVE To investigate fetal and uteroplacental blood flow after transdermal administration of glyceroltrinitrate (GTN) in pregnancies at risk for preterm delivery. STUDY DESIGN Twenty-five pregnant women who received GTN patches (Nitroderm TTS 10) with a dosage of 0.8 mg/h, because of risk for preterm delivery, were included in the prospective study. Doppler measurements (resistance index, RI) of the umbilical artery (UA), the middle cerebral artery (MCA) and the uterine arteries of the placental (UTA-P) and the non-placental (UTA-NP) side, with calculation of the mean-RI (UTA-mean), were performed before and after 24, 48 and 72 h of the 1st GTN application. Wilcoxon test and Holm correction were used for statistical analysis. RESULTS The initial RI values were in the normal range. Significant decreases of the RI of UTA-NP ( P = 0.02 ) and UTA-mean ( P = 0.03) were observed 24h after GTN application. The other RI values did not show significant changes. CONCLUSION Transdermal nitroglycerine used for the treatment of preterm labour does only reduce uterine vascular impedance at the non-placental side with primary higher resistance. It does not affect fetal perfusion and uterine perfusion at the placental side with normal blood flow resistance.

Fetal functional brain age assessed from universal developmental indices obtained from neuro-vegetative activity patterns.

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 R2 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.

Fetal magnetocardiography in the investigation of congenital heart defects

OBJECTIVES To investigate the changes of the fetal magnetocardiography (FMCG), a new noninvasive diagnostic tool in the analysis of electrophysiologic changes of the heart, in cases of congenital heart defect (CHD). METHODS The FMCG was analysed and compared to the postnatal ECG in eight cases of CHD: atrial septal defect ASDII (three cases), a combination of atrioventricular-septal-defect (AVSD) and Tetralogy of Fallot (TOF) (one case ), complete transposition of great arteries (d-TGA) (two cases), coarctation of aorta (COA) (one case), stenosis of the pulmonary artery (PS) and right ventricular hypoplasia (one case). RESULTS (1) The following FMCG changes were observed: a split R-wave (AVSD/TOF, ASDII), prolongation of QRS complex (COA, PS). (2) The notch of the R-wave could not be observed in the newborn with AVSD/TOF. (3) Neither the fetal FMCG nor the neonatal ECG revealed any changes in the cases of d-TGA. (4) All other neonatal ECGs were corresponding to the FMCG. CONCLUSIONS The FMCG can unearth changes of the cardiac electrophysiologic activity in the case of CHD. The method provides additional information concerning the effect of a CHD on the cardiac conductory system. As in the neonate, the FMCG changes do not reflect the severity of the CHD. FMCG cannot serve as a primary diagnostic tool in the case of CHD as compared to echocardiography.

Fetal autonomic brain age scores, segmented heart rate variability analysis, and traditional short term variability

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.

Validation of fetal auditory evoked cortical responses to enhance the assessment of early brain development using fetal MEG measurements

The maturation of fetal auditory evoked cortical responses (fAECRs) is an important aspect of developmental medicine, but their reliable identification is limited due to the technical restrictions in prenatal diagnosis. The signal-to-noise ratio of the fAECRs extracted exclusively from fetal magnetoencephalography is a known issue which limits their analysis as markers of brain development. The objective of this work was to develop a signal analysis strategy to address these problems and find appropriate processing steps. In this study, a group of 147 normal fetuses with gestations between 26 and 41 weeks underwent auditory evoked response testing. We combine different approaches that address data cleaning, fAECR determination and statistical fAECR validation to reduce the uncertainty in the detection of the auditory evoked responses. For the statistical validation of the evoked responses, we use parameters computed from bootstrap-based test statistics and the correlation between different averaging modes. Appropriate thresholds for those parameters are identified using linear regression analyses by looking at the maximum correlation coefficients. The results show that by using different validation parameters, the selected fAECRs conduct to similar regression slopes with an average of −13.6 ms/week gestational age which agree with previous studies. Our novel processing framework provides an objective way to identify and eliminate non-physiological variation in the data induced by artifacts. This approach has the potential to produce more reliable data needed in clinical studies for fetal brain maturation as well as extending the investigations to high-risk groups.

Developing fetal motor-cardiovascular coordination analyzed from multi-channel magnetocardiography

Fetal movements (FM) related heart rate accelerations (AC) are an important maturation criterion. Since Doppler-based time resolution is not sufficient for accompanying heart rate variability analysis, the work is aimed at a comprehensive FM-AC analysis using magnetocardiographic recordings from fetuses during sleep.We identify FM and AC by independent component analysis and automatic recognition algorithms. We investigate associations between FM and AC of different magnitude by means of event coincidence and time series cross-correlation over the maturation period of 21-40 weeks of gestation (WGA).FM related AC appear with increasing AC magnitude and WGA. Vice versa, AC related FM appear independent of WGA, but more frequently with increasing AC amplitude. The FM-AC correlation exists already at 21 WGA and further increases with WGA while the variability of its time delay decreases. Hence, FM and AC are clearly associated over the whole investigated maturation period. The increase of FM related AC runs parallel to the increasing AC magnitude.The MCG methodology was confirmed and results from previous Doppler-based analyses reproduced. Hence, MCG recordings allow the collective analysis of heart rate variability based maturation indices and FM related AC. This synergism may improve the diagnosis of fetal developmental disorders.

Validation of functional fetal autonomic brain age score fABAS in 5 min short recordings

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.

Medikamentöse Therapie bei drohender Frühgeburt

Die Behandlung der drohenden Fruhgeburt dient nicht der Schwangerschaftsverlangerung an sich, sondern der Verbesserung der Chancen des Fruhgeborenen fur ein moglichst komplikationsfreies Uberleben. Eine medikamentose Wehenhemmung (Tokolyse) ist immer nur eine symptomatische Therapie, zu der als Tokolytika Betamimetika, Oxytozinantagonisten, Kalziumantagonisten, NO-Donoren und Prostaglandinsynthesehemmer eingesetzt werden konnen. Eine Neuroprotektion erscheint mit Magnesiumsulfat moglich. Es wird jeweils auf Indikation, Kontradindikation, Effektivitat, Nebenwirkungen und Therapieempfehlungen eingegangen.

Heterotaxy Syndrome: An Embryologic Study

Heterotaxy is a clinically and genetically heterogeneous disorder with two main settings - left or right isomerism. Important diagnostic pointers like viscerocardiac heterotaxy, complex cardiac malformations, anomalies of the inferior vena cava may provide the prenatal diagnosis. Special signs of heterotaxy were sonographically detected in 5 human foetuses. Following the termination of the pregnancy a detailed examination according to the guidelines of the sequential segmental approach was performed. The main findings include multiple failures in the formation of the heart resulting from the dysfunctional viscerocardiac arrangement. The discontinuity and malposition of the inferior vena cava as well as the duplication of the superior vena cava are based on disorders of the left-right determination of the paired primitive veins in early embryonic development. The malrotation and malfixation of the bowel seem to be induced by the abnormal process of the embryonic duodenal loop with subsequent malpositioning of the portal vein and the superior mesenteric vessels. We demonstrate the wide variety of cardiac and extracardiac congenital malformations with considerable overlap in left and right isomerism. As a consequence, the differentiation between left or right isomerism may be sometimes difficult. Highly skilled sonographers and radiologists should be familiar with the corresponding embryonic development, which is essential for understanding the complex malformation pattern. Complete evaluation of each individual case is mandatory for adequate parental counselling with regard to further diagnostic steps and the planning of perinatal management.