Maternal eating disorder severity is associated with increased latency of foetal auditory event-related brain responses.

OBJECTIVE: Maternal eating disorders (EDs) are associated with adverse pregnancy and child outcomes. There is limited research investigating the influence of maternal EDs on foetal brain development. METHOD: Using foetal magnetoencephalography (fMEG), an auditory sequence was presented for 10 min to assess brain response latencies in foetuses of mothers with (n = 12) and without (n = 11) a history of anorexia nervosa (AN) in the third trimester of pregnancy. ED history and severity were assessed using the structured clinical expert interview eating disorder examination (EDE) and the self-report questionnaire EDE-Q. RESULTS: Foetuses of mothers with AN showed delayed foetal brain responses to auditory stimulation compared to foetuses of control women. Self-reported ED symptom severity explained 34% of variance in foetal brain response latencies in the AN group. CONCLUSIONS: ED pathology was strongly associated with foetal brain response latencies in the third trimester with longer latencies in foetuses of women with a history of AN reporting more ED symptoms. Follow-up on the children is pivotal to investigate if fMEG outcomes are associated with later child development.

Magnetoencephalographic signatures of conscious processing before birth.

The concept of fetal consciousness is a widely discussed topic. In this study, we applied a hierarchical rule learning paradigm to investigate the possibility of fetal conscious processing during the last trimester of pregnancy. We used fetal magnetoencephalography, to assess fetal brain activity in 56 healthy fetuses between gestational week 25 and 40, during an auditory oddball paradigm containing first- and second-order regularities. The comparison of fetal brain responses towards standard and deviant tones revealed that the investigated fetuses show signs of hierarchical rule learning, and thus the formation of a memory trace for the second-order regularity. This ability develops over the course of the last trimester of gestation, in accordance with processes in physiological brain development and was only reliably present in fetuses older than week 35 of gestation. Analysis of fetal autonomic nervous system activity replicates findings in newborns, showing importance of activity state for cognitive processes. On the whole, our results support the assumption that fetuses in the last weeks of gestation are capable of consciously processing stimuli that reach them from outside the womb.

The impact of maternal eating disorders on breastfeeding practices: a systematic review.

Breastfeeding is an effective way to protect and promote the health of the infant and mother. Cultural, social, economic, medical, or psychological factors might interfere with successful breastfeeding. Therefore, maternal eating disorders (EDs) may have detrimental effects on the decision of breastfeeding initiation and on its continuation. There is limited knowledge about the breastfeeding practices of mothers with EDs. We performed a systematic review to generate more evidence in this area. A search was conducted in PubMed and PsycINFO, and several journals were hand searched for relevant publications. Of N = 3904 hits, 13 full texts were included in the qualitative analysis. The findings on total duration of BF between mothers with and without EDs were mixed, but women with EDs showed more negative experiences and emotional problems during BF. There was not enough evidence to conclude on breastfeeding initiation, or on the duration of exclusive breastfeeding. Maternal EDs might have a negative impact on BF practices with possible negative effects on the maternal-child feeding environment. Further studies with comparable data and information on the women's partners' attitudes about breastfeeding are needed.

No Effect of Lifestyle Intervention during Third Trimester on Brain Programming in Fetuses of Mothers with Gestational Diabetes.

Maternal metabolism and intrauterine conditions influence development of health and disease in offspring, leading to metabolic, physiologic, and/or epigenetic adaptation of the fetus. Maternal gestational diabetes (GDM) leads to higher incidence of obesity and type 2 diabetes in offspring. We have previously shown that fetuses of insulin-resistant mothers with GDM have a delayed reaction to auditory stimuli in the postprandial state, indicating a fetal central insulin resistance. We tested whether this effect could be influenced by a lifestyle intervention in mothers with GDM, including diet counselling and regular blood glucose measurements. We measured fetal brain activity over the course of a maternal glucose challenge, at two measurement time points (baseline at an average of 29 weeks of gestation and follow-up after 4 weeks) in mothers with GDM and mothers with normal glucose tolerance (NGT). Data from eight mothers were able to be included. Fetuses of GDM mothers showed longer latencies than those of NGT mothers postprandially at both measurement time points during the third trimester and did not show a difference in response patterns between baseline and after 4 weeks. Maternal postprandial blood glucose and insulin values did not change from baseline to follow-up either. While the overall intervention seems to have been effective, it does not appear to have influenced the fetal postprandial brain responses. This might have been because interventions for GDM take place relatively late in pregnancy. Future research should focus on maternal lifestyle interventions as early as possible during gestation, or even prenatally.

Magnetoencephalographic signatures of hierarchical rule learning in newborns.

Estimating the extent to which newborn humans process input from their environment, especially regarding the depth of processing, is a challenging question. To approach this problem, we measured brain responses in 20 newborns with magnetoencephalography (MEG) in a "local-global" auditory oddball paradigm in which two-levels of hierarchical regularities are presented. Results suggest that infants in the first weeks of life are able to learn hierarchical rules, yet a certain level of vigilance seems to be necessary. Newborns detected violations of the first-order regularity and displayed a mismatch response between 200-400 ms. Violations of the second-order regularity only evoked a late response in newborns in an active state, which was expressed by a high heart rate variability. These findings are in line with those obtained in human adults and older infants suggesting a continuity in the functional architecture from term-birth on, despite the immaturity of the human brain at this age.

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.

Family History of Diabetes Is Associated With Delayed Fetal Postprandial Brain Activity.

Introduction: We have previously shown that fetuses of mothers with gestational diabetes mellitus (GDM) and insulin resistance exhibit a prolongation of fetal auditory event-related brain responses (fAER) compared to fetuses of normal glucose tolerant women during an oral glucose tolerance test (oGTT). This implies that maternal metabolism may program the developing fetal brain. We now asked whether a family history of type 2 diabetes without metabolic programing also impacts fetal brain activity. We therefore investigated brain activity in fetuses of normal glucose tolerant mothers with and without family history of type 2 diabetes (FHD+ and FHD-). Methods: A 75 g oGTT was performed in healthy pregnant women. Plasma glucose and insulin levels were measured after 0, 60, and 120 min. Each blood draw was preceded by fetal magnetoencephalographic (fMEG) recordings of fAER. From a group of 167 participants, a subsample of 52 metabolically healthy women, 37 with a negative, and 15 with a positive FHD (at least one first- or second-degree relative) was carefully selected based on the following inclusion criteria: inconspicuous pregnancy, no GDM, BMI 18.5-30 kg/m2, no preterm birth and at least two fMEG with detectable fetal responses during oGTT. Results: An ANOVA showed a significant interaction between fMEG measurement time during the oGTT and FHD on fAER latency [F (2) = 4.163, p = 0.018]. Fetuses of mothers with FHD+ had a prolonged fAER (273 ± 113 ms) compared to fetuses of mothers with FHD- (219 ± 69 ms) at 60 min during the oGTT [F (1) = 4.902, p = 0.032]. There were no significant differences in age, BMI before pregnancy, weight gain during pregnancy and gestational age between the groups. Maternal glucose levels and insulin sensitivity were also not significantly different. Discussion: In addition to the previously shown influence of maternal metabolism on fetal brain activity, maternal family history of diabetes (FHD) is also linked to fetal postprandial brain activity. This indicates that genetic and/or epigenetic factors modulate the postprandial brain response of the developing fetus.

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.

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.

Development and application of an automated extraction algorithm for fetal magnetocardiography - normal data and arrhythmia detection.

INTRODUCTION: Current standard methods of monitoring fetal heart function are mainly based on echocardiography, which provides indirect information (through mechanical assessment) of the fetal heart rhythm. Fetal magnetocardiography (fMCG) allows a reliable quantification of the temporal structure of fetal heart signals. However, its application in clinical studies is difficult because extracting the fetal heart signal for most current applications requires user intervention. To overcome this limitation, we developed a completely automated extraction algorithm. PATIENTS AND METHODS: The fMCG recordings were acquired using a 156-channel biomagnetic system. To perform an automated analysis, a combination of orthogonal projection and independent component analysis was used. fMCG recordings from 69 healthy uncomplicated singleton pregnancies with normally developing fetuses were included in the study. RESULTS: The normal values achieved by the automated algorithm were comparable to previously published data. The majority of the cardiac time intervals were positively correlated with gestational age (GA). The ST segment, T wave and QT interval did not show any correlation. CONCLUSIONS: The automated detection of fetal heart signals was possible beginning at a GA of 19 weeks. This automated analysis of fMCG recordings might be an objective and easily applicable approach for clinicians to analyze fetal heart signals.

The effect of routine magnesium supplementation on fetal cardiac time intervals: a fetal magnetocardiographic study.

OBJECTIVES: Magnesium deficiency in pregnancy is frequent, and in consequence magnesium supplementation is widely used. As magnesium crosses the placental barrier and since the fetal kidney does not excrete magnesium as efficiently as the mature kidney, effects on fetal cardiac time intervals are probable, but still unknown. STUDY DESIGN: Sixty pregnant women were included in an observational study: 31 patients received oral routine magnesium supplementation. In addition to routine fetal echocardiography, fetal magnetocardiography (fMCG) was used to investigate electrophysiological rhythm patterns with high temporal resolution. fMCG tracings were analyzed according to a predefined procedure for fetal cardiac time interval (CTI)-detection. fCTI findings (P-wave, PQ-segment, PR-interval, QRS complex, ST segment, T-wave and QTc interval) were registered. RESULTS: Significant widening of the QRS-complex (p=0.004) was demonstrated in fetuses whose mothers received magnesium supplementation (240 mg/day) relative to the control group. CONCLUSION: Magnesium exposed fetuses demonstrated a prolonged ventricular arousal, but healthy neonatal outcome was found in all exposed fetuses. Although fMCG is a preclinical method and limited in its availability, the procedure could help to monitor fetuses.

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.

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.