Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity.

AIMS/HYPOTHESIS: Fetal programming plays an important role in the pathogenesis of type 2 diabetes. The aim of the present study was to investigate whether maternal metabolic changes during OGTT influence fetal brain activity. METHODS: Thirteen healthy pregnant women underwent an OGTT (75 g). Insulin sensitivity was determined by glucose and insulin measurements at 0, 60 and 120 min. At each time point, fetal auditory evoked fields were recorded with a fetal magnetoencephalographic device and response latencies were determined. RESULTS: Maternal insulin increased from a fasting level of 67 ± 25 pmol/l (mean ± SD) to 918 ± 492 pmol/l 60 min after glucose ingestion and glucose levels increased from 4.4 ± 0.3 to 7.4 ± 1.1 mmol/l. Over the same time period, fetal response latencies decreased from 297 ± 99 to 235 ± 84 ms (p = 0.01) and then remained stable until 120 min (235 ± 84 vs 251 ± 91 ms, p = 0.39). There was a negative correlation between maternal insulin sensitivity and fetal response latencies 60 min after glucose ingestion (r = 0.68, p = 0.02). After a median split of the group based on maternal insulin sensitivity, fetuses of insulin-resistant mothers showed a slower response to auditory stimuli (283 ± 79 ms) than those of insulin-sensitive mothers (178 ± 46 ms, p = 0.03). CONCLUSIONS/INTERPRETATION: Lower maternal insulin sensitivity is associated with slower fetal brain responses. These findings provide the first evidence of a direct effect of maternal metabolism on fetal brain activity and suggest that central insulin resistance may be programmed during fetal development.

Fetal behavioral states are stable over daytime - evidence by longitudinal and cross-sectional fetal biomagnetic recordings.

AIMS: Fetal behavioral states can be distinguished by biomagnetic recordings. We performed a longitudinal and a cross-sectional study to address the question whether the distribution of fetal behavioral states changes during the daytime. METHODS: For the longitudinal study, 32 magnetocardiographic recordings were performed on a singleton pregnancy on a weekly basis. On each examination day, two recordings were performed at different times between 25 and 40 weeks of gestation. For the cross-sectional study, fetal magnetocardiograms (fMCG) were recorded in a group of 32 singleton pregnancies matched for gestational age and daytime to the longitudinal study. The recordings were separated into two gestational age groups (less and more than 32 weeks). Fetal behavioral states were extracted from actocardiograms generated from MCG. RESULTS: No significant differences in fetal behavioral state distribution were found between morning and afternoon recordings in either the longitudinal or the cross-sectional study. CONCLUSION: This is the first magnetographic approach to show that daytime does not influence the distribution of fetal behavioral states in standardized recordings of 30 min length. This result implies that fetal magnetography recordings at normal daytimes can be combined without a bias and future recordings can be conducted independently of daytime as long as the varying behavioral states are generally taken into account during analysis.

Auditory habituation in the fetus and neonate: an fMEG study.

Habituation--the most basic form of learning--is used to evaluate central nervous system (CNS) maturation and to detect abnormalities in fetal brain development. In the current study, habituation, stimulus specificity and dishabituation of auditory evoked responses were measured in fetuses and newborns using fetal magnetoencephalography (fMEG). An auditory habituation paradigm consisting of 100 trains of five 500 Hz tones, one 750 Hz tone (dishabituator) and two more 500 Hz tones, respectively, were presented to 41 fetuses (gestational age 30-39 weeks) and 22 newborns or babies (age 6-89 days). A response decrement between the first and fifth tones (habituation), an increment between the fifth tone and the dishabituator (stimulus specificity) and an increment between the fifth (last tone before the dishabituator) and seventh tones (first tone after the dishabituator) (dishabituation) were expected. Fetuses showed weak responses to the first tone. However, a significant response decrement between the second and fifth tones (habituation) and a significant increment between the fifth tone and the dishabituator (stimulus specificity) were found. No significant difference was found for dishabituation nor was a developmental trend found at the group level. From the neonatal data, significant values for stimulus specificity were found. Sensory fatigue or adaptation was ruled out as a reason for the response decrement due to the strong reactions to the dishabituator. Taken together, the current study used fMEG to directly show fetal habituation and provides evidence of fetal learning in the last trimester of pregnancy.

Is there a relationship between fetal brain function and the fetal behavioral state? A fetal MEG-study.

AIM: Fetal magnetography enables the recording of biomagnetic fetal signals, including fetal heart and fetal brain signals. These signals allow the determination of fetal behavioral states and functional brain signals with auditory evoked responses (AER). In the current study, we investigated how the behavioral state influences the AER and how stimulation affects fetal state. METHODS: One hundred and four fetuses in three age groups (28-31 weeks, 32-35 weeks and 36-41 weeks) were recorded with and without auditory stimulation. Both sessions were scored for fetal states. The AER latency was determined for each state separately. Forty-five additional subjects were recorded with two sessions of 10 min without stimulation to investigate a possible time effect on state changes. RESULTS: The state distribution was significantly different between stimulation and no stimulation conditions. The AER latencies were significantly shorter in active sleep (P=0.013) and active wakefulness (P=0.004) compared to quiet sleep. CONCLUSION: Auditory stimulation has an effect on fetal states. The state information should be taken into account for the analysis of AER latencies.

Atrioventricular conduction delay in fetuses exposed to anti-SSA/Ro and anti-SSB/La antibodies: a magnetocardiography study.

BACKGROUND: The presence of anti-SSA/Ro and anti-SSB/La antibodies during pregnancy is associated with fetal congenital heart block (CHB), which is primarily diagnosed through fetal echocardiography. Conclusive information about the complete electrophysiology of the fetal cardiac conducting system is still lacking. In addition to echocardiography, fetal magnetocardiography (fMCG) can be used. fMCG is the magnetic analogue of the fetal electrocardiogram (ECG). PATIENTS AND METHODS: Forty-eight pregnant women were enrolled in an observational study; 16 of them tested positive for anti-SSA/Ro and anti-SSB/La antibodies. In addition to routine fetal echocardiography, fMCG was used. Fetal cardiac time intervals (fCTIs) were extracted from the magnetic recordings by predefined procedures. ECGs in the neonates of the study group were performed within the first month after delivery. RESULTS: The PQ segment of the fCTI was significantly prolonged in the study group (P = 0.007), representing a delay of the electrical impulse in the atrioventricular (AV) node. Other fCTIs were within normal range. None of the anti-SSA/Ro and/or anti-SSB/La fetuses progressed to a more advanced heart block during pregnancy or after birth. CONCLUSION: The study identified a low-risk population within antibody positive mothers, where PQ segment prolongation is associated with a lack of progression of the disease.

Fetal magnetocardiography (fMCG): moving forward in the establishment of clinical reference data by advanced biomagnetic instrumentation and analysis.

Cardiotocography and echocardiography are currently standard for fetal heart monitoring. However, both do not provide adequate temporal resolution to measure fetal cardiac time intervals and detect arrhythmias, which can occur during normal sinus rhythm. Fetal magnetocardiography (fMCG) is a non-invasive technique measuring magnetic signals generated by fetal heart activity. Most fMCG devices are installed in research institutions limiting the implementation of this method in a clinical setting. Several institutions made a step forward by installing devices, in particular for fetal investigations, in hospital sites to evaluate the clinical benefit. Based on instrumentation differences which can affect signal quality, there is still no established reference database for fetal cardiac time intervals. A new magnetograph dedicated to fetal recordings was implemented with improved patient comfort. The setting was optimized to establish a standard. A total of 103 healthy fetuses starting as early as possible after the first trimester were recorded and fMCG values of cardiac time intervals were compared to former studies. Data allowed high and reliable detection for all fMCG components starting at 17 weeks. The data were comparable to fMCG multicenter studies, fetal electrocardiography and neonatal ECG results and could serve as a database of norm values for further investigation of fetal arrhythmias.

Maternal Weight, Weight Gain, and Metabolism are Associated with Changes in Fetal Heart Rate and Variability.

OBJECTIVE: Prepregnancy obesity and extensive weight gain can lead to diseases in the offspring later in life. The aim of this study was to evaluate the effect of anthropometric and metabolic factors on the fetal autonomic nervous system (ANS) in uncomplicated pregnancies. METHODS: A total of 184 pregnant women in the second or third trimester were included, and for 104 women, maternal insulin sensitivity (ISI) was determined. Fetal heart rate (HR) and heart rate variability (HRV) were determined by magnetic recording. Associations of maternal prepregnancy BMI, weight gain, and ISI with fetal HR and HRV were evaluated by ANCOVA, partial correlation, and mediation analysis. RESULTS: HR was increased and HRV decreased in fetuses of mothers with overweight or obesity in comparison to normal-weight mothers. Fetal HR was negatively correlated with maternal weight gain. Maternal prepregnancy BMI was positively correlated with fetal high frequency and was negatively correlated with low frequency and low/high frequency ratio. Maternal ISI showed a negative correlation with fetal HR. CONCLUSIONS: The results show that the fetal ANS is sensitive to alterations of prepregnancy BMI, weight changes, and glucose metabolism. These findings highlight the importance of the intrauterine environment on the developing ANS and the possible programming of obesity.

Impact of Intrauterine Growth Restriction on Cognitive and Motor Development at 2 Years of Age.

Intrauterine growth restriction (IUGR), which is already known to be a risk factor for pathological intrauterine development, perinatal mortality, and morbidity, is now also assumed to cause both physical and cognitive alterations in later child development. In the current study, effects of IUGR on infantile brain function were investigated during the fetal period and in a follow-up developmental assessment during early childhood. During the fetal period, visual and auditory event-related responses (VER and AER) were recorded using fetal magnetoencephalography (fMEG). VER latencies were analyzed in 73 fetuses (14 IUGR fetuses) while AER latencies were analyzed in 66 fetuses (11 IUGR fetuses). Bayley Scales of Infant Development, Second Edition (BSID-II) were used to assess the developmental status of the infants at the age of 24 months. The Mental Development Index (MDI) was available from 66 children (8 IUGR fetuses) and the Psychomotor Development Index (PDI) from 63 children (7 IUGR fetuses). Latencies to visual stimulation were more delayed in IUGR than in small for gestational age (SGA) or appropriate for gestational age (AGA) fetuses, albeit not to any significant extent (p = 0.282). The MDI in former IUGR infants was significantly lower (p = 0.044) than in former SGA and AGA infants. However, IUGR had no impact on PDI (p = 0.213). These findings support the hypothesis that IUGR may constitute a risk factor for neurodevelopmental delay. Further investigation of the possible underlying mechanisms, as well as continued long-term developmental research, is therefore necessary.

Neuromagnetic signatures of syllable processing in fetuses and infants provide no evidence for habituation.

BACKGROUND: Habituation, as a basic form of learning, is characterized by decreasing amplitudes of neuronal reaction following repeated stimuli. Recent studies indicate that habituation to pure tones of different frequencies occurs in fetuses and infants. AIMS: Neural processing of different syllables in fetuses and infants was investigated. STUDY DESIGN: An auditory habituation paradigm including two different sequences of syllables was presented to each subject. Each sequence consisted of eight syllables (sequence /ba/: 5× /ba/, 1× /bi/ (dishabituator), 2× /ba/; sequence /bi/: 5× /bi/, 1× /ba/ (dishabituator), 2× /bi/). Each subject was stimulated with 140 sequences. Neuromagnetic signatures of auditory-evoked responses (AER) were recorded by fetal magnetoencephalography (fMEG). SUBJECTS: Magnetic brain signals of N=30 fetuses (age: 28-39weeks of gestation) and N=28 infants (age: 0-3months) were recorded. Forty-two of the 60 fetal recordings and 29 of the 58 infant recordings were included in the final analysis. OUTCOME MEASURES: AERs were recorded and amplitudes were normalized to the amplitude of the first stimulus. RESULTS: In both fetuses and infants, the amplitudes of AERs were found not to decrease with repeated stimulation. In infants, however, amplitude of syllable 6 (dishabituator) was significantly increased compared to syllable 5 (p=0.026). CONCLUSIONS: Fetuses and infants showed AERs to syllables. Unlike fetuses, infants showed a discriminative neural response to syllables. Habituation was not observed in either fetuses or infants. These findings could be important for the investigation of early cognitive competencies and may help to gain a better understanding of language acquisition during child development.

Gestational Diabetes Impairs Human Fetal Postprandial Brain Activity.

CONTEXT: Gestational diabetes (GDM) influences the fetal phenotype. OBJECTIVE: In the present study, our aim was to determine the effect of GDM specifically on fetal brain activity. DESIGN: Pregnant participants underwent an oral glucose tolerance test (OGTT, 75 g). At 0, 60, and 120 minutes, maternal metabolism was determined, and fetal auditory evoked fields were recorded with a fetal magnetoencephalographic device. SETTING: All measurements were performed at the fMEG Center in Tübingen. PARTICIPANTS: Twelve women with GDM and 28 normal glucose-tolerant (NGT) pregnant women participated on a voluntary basis. INTERVENTIONS: OGTT (75 g, 120 minutes) was used in this study. MAIN OUTCOMES AND MEASURES: Fetal auditory evoked response latencies were determined for this study. RESULTS: In the fetuses of NGT women, latencies decreased between 0 and 60 minutes from 260 ± 90 to 206 ± 74 ms (P = .008) and remained stable until 120 minutes (206 ± 74 vs 230 ± 79, P =.129). In fetuses of women with GDM, there was no change in response latencies during OGTT (P = .11). Sixty minutes after glucose ingestion, fetal latencies in the GDM group were longer than in the NGT group (296 ± 82 vs 206 ± 74 ms, P = .001). Linear regression revealed a significant effect of maternal glucose, insulin levels, and insulin sensitivity on response latencies after 60 minutes. CONCLUSIONS: Fetal postprandial brain responses were slower in the offspring of women with GDM. This might indicate that gestational diabetes directly affects fetal brain development and may lead to central nervous insulin resistance in the fetus.

Heart rate variability parameters and fetal movement complement fetal behavioral states detection via magnetography to monitor neurovegetative development.

Fetal behavioral states are defined by fetal movement and heart rate variability (HRV). At 32 weeks of gestational age (GA) the distinction of four fetal behavioral states represented by combinations of quiet or active sleep or awakeness is possible. Prior to 32 weeks, only periods of fetal activity and quiesence can be distinguished. The increasing synchronization of fetal movement and HRV reflects the development of the autonomic nervous system (ANS) control. Fetal magnetocardiography (fMCG) detects fetal heart activity at high temporal resolution, enabling the calculation of HRV parameters. This study combined the criteria of fetal movement with the HRV analysis to complete the criteria for fetal state detection. HRV parameters were calculated including the standard deviation of the normal-to-normal R-R interval (SDNN), the mean square of successive differences of the R-R intervals (RMSSD, SDNN/RMSSD ratio, and permutation entropy (PE) to gain information about the developing influence of the ANS within each fetal state. In this study, 55 magnetocardiograms from healthy fetuses of 24-41 weeks' GA were recorded for up to 45 min using a fetal biomagnetometer. Fetal states were classified based on HRV and movement detection. HRV parameters were calculated for each state. Before GA 32 weeks, 58.4% quiescence and 41.6% activity cycles were observed. Later, 24% quiet sleep state (1F), 65.4% active sleep state (2F), and 10.6% active awake state (4F) were observed. SDNN increased over gestation. Changes of HRV parameters between the fetal behavioral states, especially between 1F and 4F, were statistically significant. Increasing fetal activity was confirmed by a decrease in PE complexity measures. The fHRV parameters support the differentiation between states and indicate the development of autonomous nervous control of heart rate function.

Magnetoencephalographic signatures of numerosity discrimination in fetuses and neonates.

Numerosity discrimination has been demonstrated in newborns, but not in fetuses. Fetal magnetoencephalography allows non-invasive investigation of neural responses in neonates and fetuses. During an oddball paradigm with auditory sequences differing in numerosity, evoked responses were recorded and mismatch responses were quantified as an indicator for auditory discrimination. Thirty pregnant women with healthy fetuses (last trimester) and 30 healthy term neonates participated. Fourteen adults were included as a control group. Based on measurements eligible for analysis, all adults, all neonates, and 74% of fetuses showed numerical mismatch responses. Numerosity discrimination appears to exist in the last trimester of pregnancy.

Sensitivity to Auditory Spectral Width in the Fetus and Infant - An fMEG Study.

Auditory change detection is crucial for the development of the auditory system and a prerequisite for language development. In neonates, stimuli with broad spectral width like white noise (WN) elicit the highest response compared to pure tone and combined tone stimuli. In the current study we addressed for the first time the question how fetuses react to "WN" stimulation. Twenty-five fetuses (M age = 34.59 weeks GA, SD ± 2.35) and 28 healthy neonates and infants (M age = 37.18 days, SD ± 15.52) were tested with the first paradigm, wherein 500 Hz tones, 750 Hz tones, and WN segments were randomly presented and auditory evoked responses (AERs) were measured using fetal magnetoencephalography (fMEG). In the second paradigm, 12 fetuses (M age = 25.7 weeks GA, SD ± 2.4) and 6 healthy neonates (M age = 23 days and SD ± 6.2) were presented with two auditory oddball conditions: condition 1 consisted of attenuated WN as standard and 500 Hz tones and WN as deviants. In condition 2, standard 500 Hz tones were intermixed with WN and attenuated WN. AERs to volume change and change in spectral width were evaluated. In both paradigms, significantly higher AER amplitudes to WN than to pure tones replicated prior findings in neonates and infants. In fetuses, no significant differences were found between the auditory evoked response amplitudes of WN segments and pure tones (both paradigms). A trend toward significance was reached when comparing the auditory evoked response amplitudes elicited by attenuated WN with those elicited by WN (loudness change, second paradigm). As expected, we observed high sensibility to spectral width in newborns and infants. However, in the group of fetuses, no sensibility to spectral width was observed. This negative finding may be caused by different attenuation levels of the maternal tissue for different frequency components.