Early Biomarkers and Intervention Programs for the Infant Exposed to Prenatal Stress

Functional development of affective and reward circuits, cognition and response inhibition later in life exhibits vulnerability periods during gestation and early childhood. Extensive evidence supports the model that exposure to stressors in the gestational period and early postnatal life increases an individual's susceptibility to future impairments of functional development. Recent versions of this model integrate epigenetic mechanisms of the developmental response. Their understanding will guide the future treatment of the associated neuropsychiatric disorders. A combination of non-invasively obtainable physiological signals and epigenetic biomarkers related to the principal systems of the stress response, the Hypothalamic-Pituitary axis (HPA) and the Autonomic Nervous System (ANS), are emerging as the key predictors of neurodevelopmental outcomes. Such electrophysiological and epigenetic biomarkers can prove to timely identify children benefiting most from early intervention programs. Such programs should ameliorate future disorders in otherwise apparently healthy children. The recently developed Early Family-Centered Intervention Programs aim to influence the care and stimuli provided daily by the family and improving parent/child attachment, a key element for healthy socio-emotional adult life. Although frequently underestimated, such biomarker-guided early intervention strategy represents a crucial first step in the prevention of future neuropsychiatric problems and in reducing their personal and societal impact.Comment: 18 pages-Revie

Detection of Maternal and Fetal Stress from the Electrocardiogram with Self-Supervised Representation Learning

In the pregnant mother and her fetus, chronic prenatal stress results in entrainment of the fetal heartbeat by the maternal heartbeat, quantified by the fetal stress index (FSI). Deep learning (DL) is capable of pattern detection in complex medical data with high accuracy in noisy real-life environments, but little is known about DL's utility in non-invasive biometric monitoring during pregnancy. A recently established self-supervised learning (SSL) approach to DL provides emotional recognition from electrocardiogram (ECG). We hypothesized that SSL will identify chronically stressed mother-fetus dyads from the raw maternal abdominal electrocardiograms (aECG), containing fetal and maternal ECG. Chronically stressed mothers and controls matched at enrolment at 32 weeks of gestation were studied. We validated the chronic stress exposure by psychological inventory, maternal hair cortisol and FSI. We tested two variants of SSL architecture, one trained on the generic ECG features for emotional recognition obtained from public datasets and another transfer-learned on a subset of our data. Our DL models accurately detect the chronic stress exposure group (AUROC=0.982+/-0.002), the individual psychological stress score (R2=0.943+/-0.009) and FSI at 34 weeks of gestation (R2=0.946+/-0.013), as well as the maternal hair cortisol at birth reflecting chronic stress exposure (0.931+/-0.006). The best performance was achieved with the DL model trained on the public dataset and using maternal ECG alone. The present DL approach provides a novel source of physiological insights into complex multi-modal relationships between different regulatory systems exposed to chronic stress. The final DL model can be deployed in low-cost regular ECG biosensors as a simple, ubiquitous early stress detection and monitoring tool during pregnancy. This discovery should enable early behavioral interventions.Comment: ClinicalTrials.gov registration number: NCT03389178. Code repo: https://code.engineering.queensu.ca/17ps21/ssl-ecg-v

Gestational Diabetes: Physical Activity Before Pregnancy and Its Influence on the Cardiovascular System

Objectives:Gestational diabetes mellitus (GDM) is a common complication in pregnancy, affecting around 14% of all pregnancies each year. It will likely further increase, as obesity becomes more prevalent. The impact of GDM on cardiovascular changes in pregnant women and her child is still unclear. The aim of the study was to measure the effects of physical activity before pregnancy on the cardiovascular system in patients with GDM in pregnancy. Methods:Two hundred and six pregnant women were included in this observational study. All participants were recruited at the tertiary level teaching University Hospital "Klinikum rechts der Isar" between 28 and 32 weeks gestation. Questionnaires dealing with pre-pregnancy daily and physical activity (PA) were evaluated. The cardiovascular status of the mothers included measurements of the intima-media thickness (IMT) of the carotid arteries. PA level was performed with a standardized 6-min-walking-test. Results:Ninety-nine women with GDM with a mean age of 33.84 (+/- 4.7) years were examined. One hundred seven healthy pregnant women aged 32.6 (+/- 4.2) years served as controls. The mean weight in the study group was 73.0 (+/- 20.3) kg and 61.7 (+/- 9.5) kg in the control group. Based on the higher weight in the study group, the Body Mass Index (BMI) was also significantly higher than in the control group (26.3 +/- 7.1 vs. 21.6 +/- 3;p< 0.001). The frequency of PA was significantly higher in the control group (p< 0.001). The objective fitness level was worse in pregnant women with GDM compared to healthy controls (472 vs. 523 m,p< 0.001). PA before and during pregnancy was less performed in the study group (86 vs. 64.5%,p= 0.002;69 vs. 45.7%,p= 0.003). Women who were physically inactive before pregnancy had a 3-times higher risk to develop GDM compared to active women (OR = 2.67). The IMT was significantly thicker in the study group (0.48 +/- 0.042 mm vs. 0.45 +/- 0.042) mm;p= 0.006). Conclusion:Physical activity before pregnancy and a lower initial weight reduces the risk of developing GDM and cardiovascular risk factors in pregnancy. The development of prevention programs is certainly necessary

Prenatal stress perturbs fetal iron homeostasis in a sex specific manner

The adverse effects of maternal prenatal stress (PS) on child’s neurodevelopment warrant the establishment of biomarkers that enable early interventional therapeutic strategies. We performed a prospective matched double cohort study screening 2000 pregnant women in third trimester with Cohen Perceived Stress Scale-10 (PSS-10) questionnaire; 164 participants were recruited and classified as stressed and control group (SG, CG). Fetal cord blood iron parameters of 107 patients were measured at birth. Transabdominal electrocardiograms-based Fetal Stress Index (FSI) was derived. We investigated sex contribution to group differences and conducted causal inference analyses to assess the total effect of PS exposure on iron homeostasis using a directed acyclic graph (DAG) approach. Differences are reported for p < 0.05 unless noted otherwise. Transferrin saturation was lower in male stressed neonates. The minimum adjustment set of the DAG to estimate the total effect of PS exposure on fetal ferritin iron biomarkers consisted of maternal age and socioeconomic status: SG revealed a 15% decrease in fetal ferritin compared with CG. Mean FSI was higher among SG than among CG. FSI-based timely detection of fetuses affected by PS can support early individualized iron supplementation and neurodevelopmental follow-up to prevent long-term sequelae due to PS-exacerbated impairment of the iron homeostasis.Fil: Zimmermann, Peter. Technische Universitat München; AlemaniaFil: Antonelli, Marta Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Sharma, Ritika. Technische Universitat München; AlemaniaFil: Müller, Alexander. Technische Universitat München; AlemaniaFil: Zelgert, Camilla. Technische Universitat München; AlemaniaFil: Fabre, Bibiana. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; ArgentinaFil: Wenzel, Natasha. University of Washington; Estados UnidosFil: Wu, Hau Tieng. University of Duke; Estados UnidosFil: Frasch, Martin Gerbert. University of Washington; Estados UnidosFil: Lobmaier, Silvia M.. Technische Universitat München; Alemani

Maternal–fetal stress and DNA methylation signatures in neonatal saliva: an epigenome-wide association study

Background: Maternal stress before, during and after pregnancy has profound effects on the development and lifelong function of the infant’s neurocognitive development. We hypothesized that the programming of the central nervous system (CNS), hypothalamic–pituitary–adrenal (HPA) axis and autonomic nervous system (ANS) induced by prenatal stress (PS) is reflected in electrophysiological and epigenetic biomarkers. In this study, we aimed to find noninvasive epigenetic biomarkers of PS in the newborn salivary DNA. Results: A total of 728 pregnant women were screened for stress exposure using Cohen Perceived Stress Scale (PSS), 164 women were enrolled, and 114 dyads were analyzed. Prenatal Distress Questionnaire (PDQ) was also administered to assess specific pregnancy worries. Transabdominal fetal electrocardiograms (taECG) were recorded to derive coupling between maternal and fetal heart rates resulting in a ‘Fetal Stress Index’ (FSI). Upon delivery, we collected maternal hair strands for cortisol measurements and newborn’s saliva for epigenetic analyses. DNA was extracted from saliva samples, and DNA methylation was measured using EPIC BeadChip array (850 k CpG sites). Linear regression was used to identify associations between PSS/PDQ/FSI/Cortisol and DNA methylation. We found epigenome-wide significant associations for 5 CpG with PDQ and cortisol at FDR < 5%. Three CpGs were annotated to genes (Illumina Gene annotation file): YAP1, TOMM20 and CSMD1, and two CpGs were located approximately lay at 50 kb from SSBP4 and SCAMP1. In addition, two differentiated methylation regions (DMR) related to maternal stress measures PDQ and cortisol were found: DAXX and ARL4D. Conclusions: Genes annotated to these CpGs were found to be involved in secretion and transportation, nuclear signaling, Hippo signaling pathways, apoptosis, intracellular trafficking and neuronal signaling. Moreover, some CpGs are annotated to genes related to autism, post-traumatic stress disorder (PTSD) and schizophrenia. However, our results should be viewed as hypothesis generating until replicated in a larger sample. Early assessment of such noninvasive PS biomarkers will allow timelier detection of babies at risk and a more effective allocation of resources for early intervention programs to improve child development. A biomarker-guided early intervention strategy is the first step in the prevention of future health problems, reducing their personal and societal impact.Fil: Sharma, Ritika. Technische Universitat München; AlemaniaFil: Frasch, Martin Gerbert. University of Washington; Estados UnidosFil: Zelgert, Camila. Technische Universitat München; AlemaniaFil: Zimmermann, Peter. Technische Universitat München; AlemaniaFil: Fabre, Bibiana. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; ArgentinaFil: Wilson, Rory. Helmholtz Zentrum Munich; AlemaniaFil: Waldenberger, Melanie. Helmholtz Zentrum Munich; AlemaniaFil: MacDonald, James W.. University of Washington; Estados UnidosFil: Bammler, Theo K.. University of Washington; Estados UnidosFil: Lobmaier, Silvia M.. Technische Universitat München; AlemaniaFil: Antonelli, Marta Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentin

Differential changes in myocardial performance index and its time intervals in donors and recipients of twin-to-twin transfusion syndrome before and after laser therapy.

OBJECTIVE: To evaluate left myocardial performance index (MPI) and time intervals in fetuses with twin-to-twin transfusion syndrome (TTTS) before and after laser surgery. METHODS: Fifty-one fetal pairs with TTTS and 47 uncomplicated monochorionic twin pairs were included. Left ventricular isovolumetric contraction time (ICT), ejection time (ET), and isovolumetric relaxation time (IRT) were measured using conventional Doppler. RESULTS: Recipients showed prolonged ICT (46 ± 12 vs. 31 ± 8 vs. 30 ± 5 ms; p < 0.001) and IRT (51 ± 9 vs. 43 ± 8 vs. 43 ± 5 ms; p < 0.001) and higher MPI (0.57 ± 0.12 vs. 0.47 ± 0.09 vs. 0.44 ± 0.05; p < 0.001) than donors and controls. Donors showed shorter ET than recipients and controls (157 ± 12 vs. 169 ± 10 vs. 168 ± 10 ms; p < 0.001) and higher MPI than controls (0.47 ± 0.09 vs. 0.44 ± 0.05; p = 0.006). Preoperative MPI changes were observed in all TTTS stages. Time intervals partially improved after surgery. CONCLUSION: Donor and recipient twins had higher MPI due to different changes in the time intervals, possibly reflecting the state of hypovolemia in the donor and hypervolemia and pressure overload in the recipient

The challenges for women's health in sub-Saharan Africa: Lessons learned from an integrative multistakeholder workshop in Gabon.

The sub-Saharan African (SSA) region is home to more than 230 million females of reproductive age who face multiple intersecting health, social, gender and economic challenges [1]. Neglected tropical diseases (NTDs) are a group of chronic disabling, almost exclusively communicable diseases affecting the poorest of the poor, especially in Africa, which alone bears about 40% of the global burden of NTDs [2- 4]. While both men and women are impacted, biological and sociocultural biases mean that NTDs disproportionately affect women and girls [5]. In recent decades, there has been a global shift from communicable toward non-communicable diseases (NCDs), which cause almost 32 million deaths in low-and lower- middle- income countries (LMIC) [6]. It is expected that by 2030, 85% of NCD-related deaths among women will occur in LMICs, including many countries of SSA region [7]. For women older than 50, NCDs are the leading cause of both death and disability-adjusted life years (DALYs) [8]. Important disparities persist in access to maternal and reproductive health services both within and between countries in SSA [9]; it is estimated that almost half of the women in SSA do not have access to essential health care during pregnancy and childbirth. In 2017, SSA accounted for roughly two-thirds of all maternal deaths in the world [10]. Hence, it is evident that many, if not most, women and girls in SSA carry a triple burden of vulnerability to NTDs, NCDs and poor reproductive health outcomes. Here, we report on the outcomes of an integrative, multistakeholder workshop held in Gabon, Central Africa, to help develop a framework for synergistic, sustainable and gender- and context-appropriate interventions to manage the NTD-NCD complex and additionally reproductive health

How to monitor pregnancies complicated by fetal growth restriction and delivery below 32 weeks: a post-hoc sensitivity analysis of the TRUFFLE-study.

OBJECTIVES: In the recent TRUFFLE study it appeared that, in pregnancies complicated by fetal growth restriction (FGR) between 26 and 32 weeks, monitoring of the ductus venosus (DV) combined with computerised cardiotocography (cCTG) as a trigger for delivery, increased the chance of infant survival without neurological impairment. However, concerns in interpretation were raised as DV monitoring appeared associated with a non-significant increase in fetal death, and part of the infants were delivered after 32 weeks, after which the study protocol was no longer applied. This secondary sensitivity analysis focuses on women who delivered before 32 completed weeks, and analyses fetal death cases in detail. METHODS: We analysed the monitoring data of 317 women who delivered before 32 weeks, excluding women with absent infant outcome data or inevitable perinatal death. The association of the last monitoring data before delivery and infant outcome was assessed by multivariable analysis. RESULTS: The primary outcome (two year survival without neurological impairment) occurred more often in the two DV groups (both 83%) than in the CTG-STV group (77%), however the difference was not statistically significant (p = 0.21). Nevertheless, in surviving infants 93% was free of neurological impairment in the DV groups versus 85% in the CTG-STV group (p = 0.049). All fetal deaths (n = 7) occurred in women allocated to DV monitoring, which explains this difference. Assessment of the monitoring parameters that were obtained shortly before fetal death in these 7 cases showed an abnormal CTG in only one. Multivariable regression analysis of factors at study entry demonstrated that higher gestational age, larger estimated fetal weight 50th percentile ratio and lower U/C ratio were significantly associated with the (normal) primary outcome. Allocation to the DV groups had a smaller effect, but remained in the model (p < 0.1). Assessment of the last monitoring data before delivery showed that in the CTG-STV group abnormal fetal arterial Doppler was significantly associated with adverse outcome. In contrast, in the DV groups an abnormal DV was the only fetal monitoring parameter that was associated with adverse infant outcome, while fetal arterial Doppler, STV below CTG-group cut-off or recurrent fetal heart rate decelerations were not. CONCLUSIONS: In accordance with the results of the overall TRUFFLE study of the monitoring-intervention management of very early severe FGR we found that the difference in the proportion of infants surviving without neuroimpairment (the primary endpoint) was non-significant when comparing timing of delivery with or without changes in the DV waveform. However, the uneven distribution of fetal deaths towards the DV groups was likely by chance, and among surviving children neurological outcomes were better. Before 32 weeks, delaying delivery until abnormalities in DVPI or STV and/or recurrent decelerations occur, as defined by the study protocol, is therefore probably safe and possibly benefits long-term outcome

Longitudinal study of computerised cardiotocography in early fetal growth restriction.

OBJECTIVES: To explore if in early fetal growth restriction (FGR) the longitudinal pattern of short-term fetal heart rate (FHR) variation (STV) can be used for identifying imminent fetal distress and if abnormalities of FHR registration associate with two-year infant outcome. METHODS: The original TRUFFLE study assessed if in early FGR the use of ductus venosus Doppler pulsatility index (DVPI), in combination with a safety-net of very low STV and / or recurrent decelerations, could improve two-year infant survival without neurological impairment in comparison to computerised cardiotocography (cCTG) with STV calculation only. For this secondary analysis we selected women, who delivered before 32 weeks, and who had consecutive STV data for more than 3 days before delivery, and known infant two-year outcome data. Women who received corticosteroids within 3 days of delivery were excluded. Individual regression line algorithms of all STV values except the last one were calculated. Life table analysis and Cox regression analysis were used to calculate the day by day risk for a low STV or very low STV and / or FHR decelerations (DVPI group safety-net) and to assess which parameters were associated to this risk. Furthermore, it was assessed if STV pattern, lowest STV value or recurrent FHR decelerations were associated with two-year infant outcome. RESULTS: One hundred and fourty-nine women matched the inclusion criteria. Using the individual STV regression lines prediction of a last STV below the cCTG-group cut-off had a sensitivity of 0.42 and specificity of 0.91. For each day after inclusion the median risk for a low STV(cCTG criteria) was 4% (Interquartile range (IQR) 2% to 7%) and for a very low STV and / or recurrent decelerations (DVPI safety-net criteria) 5% (IQR 4 to 7%). Measures of STV pattern, fetal Doppler (arterial or venous), birthweight MoM or gestational age did not improve daily risk prediction usefully. There was no association of STV regression coefficients, a last low STV or /and recurrent decelerations with short or long term infant outcomes. CONCLUSION: The TRUFFLE study showed that a strategy of DVPI monitoring with a safety-net delivery indication of very low STV and / or recurrent decelerations could increase infant survival without neurological impairment at two years. This post-hoc analysis demonstrates that in early FGR the day by day risk of an abnormal cCTG as defined by the DVPI protocol safety-net criteria is 5%, and that prediction of this is not possible. This supports the rationale for cCTG monitoring more often than daily in these high-risk fetuses. Low STV and/or recurrent decelerations were not associated with adverse infant outcome and it appears safe to delay intervention until such abnormalities occur, as long as DVPI is in the normal range