Use of Multiscale Entropy to Characterize Fetal Autonomic Development

The idea that uterine environment and adverse events during fetal development could increase the chances of the diseases in adulthood was first published by David Barker in 1998. Since then, investigators have been employing several methods and methodologies for studying and characterizing the ontological development of the fetus, e.g., fetal movement, growth and cardiac metrics. Even with most recent and developed methods such as fetal magnetocardiography (fMCG), investigators are continuously challenged to study fetal development; the fetus is inaccessible. Finding metrics that realize the full capacity of characterizing fetal ontological development remains a technological challenge. In this thesis, the use and value of multiscale entropy to characterize fetal maturation across third trimester of gestation is studied. Using multiscale entropy obtained from participants of a clinical trial, we show that MSE can characterize increasing complexity due to maturation in the fetus, and can distinguish a growing and developing fetal system from a mature system where loss of irregularity is due to compromised complexity from increasing physiologic load. MSE scales add a nonlinear metric that seems to accurately reflect the ontological development of the fetus and hold promise for future use to investigate the effects of maternal stress, intrauterine growth restriction, or predict risk for sudden infant death syndrome

Physiological responses of preterm infants in the neonatal intensive care unit to repeated stressors: moderating effect of skin-to-skin care

Technological advances in neonatal care have resulted in a dramatic rise in the survival rate of premature infants. However, knowledge is limited regarding the preterm infant\u27s stress reactivity and the most effective methods to reduce the stress response. This research was designed to investigate stress reactivity in preterm infants and to determine the effect of the intervention strategy of Skin-to-Skin Care (SSC) on the stress response. Twelve preterm infants meeting eligibility criteria established by the approved guideline for SSC in a level HI neonatal intensive care unit (NICU) participated in this study. The cardiopulmonary parameters of heart rate, blood pressure, and respiratory rate were monitored. Adrenocortical responses were determined by changes in levels of concentration of salivary cortisol. Stress reactivity was determined by changes in cardiopulmonary parameters and adrenocortical responses to an invasive stressor, defined in this study as a routine heelstick procedure. Stress reactivity was evaluated under the following test conditions: baseline measures of dependent variables in bed, SSC without invasive stressor, invasive stressor in bed, and invasive stressor in SSC. Changes in the values of the cardiopulmonary parameters and salivary cortisol concentration levels indicated that the preterm infants regulated their responses to aversive stressors differently when they were in SSC than when they were not in SSC. The differences found under these test conditions supported the research hypotheses that providing organizing postural support during SSC reduces stress reactivity in preterm infants in the NICU as reflected by changes in adrenocortical function. Significant changes in cardiopulmonary measures were not demonstrated. The results of this study improved understanding of the mechanism undergirding the process of co-regulation. The clinical implications provide valuable information for medical professionals challenged to implement care in the NICU in a way that reduces destabilizing stress responses of premature infants to the repeated intrinsic and extrinsic stressors experienced during the hospitalization period following a premature birth

Neurodevelopmental Outcomes of High Risk Infants

Background: Infant developmental research has revealed amazing physical, cognitive, and social capacities of the human infant. Along with this knowledge is a growing appreciation of numerous factors that have the potential to impact the individual infant\u27s developmental trajectory, either enhancing or compromising the eventual outcome. Enhanced understanding of those factors that shape infant developmental trajectories will provide an evidence base for the establishment of a supportive environment for the youngest members of society. Purpose: To determine the relationship between neurodevelopmental outcome and gestational age, birth weight, Apgar scores, NICU admission, infant gender, maternal depression, home environment, and parent-child interaction. Methodology: This study utilized a descriptive, correlational design and secondary analysis of data from the Healthy Families San Diego (HFSD) randomized controlled clinical trial conducted by Landsverk and colleagues (2002). Data Analysis: Multiple linear regression was utilized to produce the best combination of predictors of neurodevelopmental outcome, which was measured by the Bayley Scales of Infant Development, 2nd ed. (BSID-II) (Bayley, 1993). Results: The model of predictor variables significantly predicted all three BSID-II developmental outcomes (MDI, PDI, and BRS) measured at year 2. Mental Development: The model explained 34% of variance in the BSID-II MDI. MDI scores at year 1, parent-child interaction (NCAST) scores at year 2, and infant gender significantly contributed to the model. Motor Development: The model explained 16% of variance in the Y2 BSID-II PDI. PDI scores at year one, BRS scores at year 1, birth weight, and infant gender significantly contributed to the model. Behavioral Development: The model explained 20% of variance in the Y2 BSID-II BRS. Y2 NCAST scores, Y2 home inventory (HOME) scores, birth weight, gestational age, and infant gender significantly contributed to the model. Conclusions: Optimal development of a community\u27s children is a vital component of a healthy and sustainable society. Based on the results of this study, future research may focus on the unique contribution of gender to developmental dynamics. Also of interest is the significance of early parent-child interaction, the home environment, birth weight, and gestational age in shaping infant developmental trajectories. Research efforts may focus on determining which of these risk factors are most amenable to preventative and interventional strategies, and identifying the stage of development where these strategies would be most effective

Early indicators for adverse development of cardiovascular, renal and metabolic function in children born with low birth weight

Prematurity affects more than 10% of infants worldwide and is the main reason for neonatal mortality. Improvements in neonatal care have led to higher survival rates into adulthood. Adverse events during organogenesis and development, intra-or extrauterine, can increase the risk for chronic disease later in life. Developmental origins of health and disease is the epidemiologic research field linking early life events to related clinical phenotypes. In this thesis, we present 4 studies designed to follow up consequences of prematurity or low birth weight at term compared to term controls with normal birth weight in two different cohorts. The first cohort of children, studied at a mean age of 9.7 and again at 12.6 years (studies I-III), were born either very preterm (<32 weeks gestational age) or at term but small for gestational age. We studied kidney volume and function, the autonomous nervous system using heart rate variability and identified markers for insulin resistance. The second cohort of children, studied at a mean age of 7.7 years (study IV), were born extremely preterm (<28 weeks gestational age). We measured kidney volume and function and divided the group into those who developed and those who did not developed nephrocalcinosis during the neonatal period. We also studied blood pressure at the time of their visit, including 24-h ambulatory blood pressure measurements. Kidney volume or function was not significantly different between the three groups in study I. In study IV we found that children born extremely premature had smaller kidneys then children born at term, in particular the right sided kidney volume was significantly smaller compared to controls. Preterm born girls had smaller kidneys than full-term born girls (controls) but preterm born boys were not different to controls. Among preterm born children without nephrocalcinosis girls, had smaller kidney volumes than boys. Kidney function was normal and not affected by kidney volume. Paper II showed signs for insulin resistance in very preterm born children and children born small for gestational age. Preterm born children presented signs for hepatic insulin resistance while small for gestational age born children had a decreased peripheral insulin sensitivity. Both, very preterm and full-term small for gestational age born children had a generalized depression of heart rate variability compared to controls indicating an impaired function of the autonomous nervous system (study III). Office blood pressure as well as 24-hour ambulatory blood pressure were in the normal range for children born very or extremely preterm as well as for children born small for gestational age at term. Circadian blood pressure regulation was adversely affected in 50% of children born extremely preterm illustrated by the absence of normal day-to-night dipping in 24-hour ambulatory blood pressure measurements (study IV). In conclusion, children born preterm or full-term but small for gestational age showed several morphological or functional changes at early school age. The detected changes are indicating a possible development towards impaired kidney function, hypertension and the metabolic syndrome

Cortical pain processing in the infant brain.

Premature infants are exposed to multiple invasive procedures as part of their essential medical care. It is not known, however, if nociceptive information is processed by the cortex at this age. The fundamental question to be addressed by this thesis is whether premature infants display cortical responses to noxious stimulation. This thesis describes a series of studies where the question of cortical pain processing is addressed by directly measuring cortical responses to noxious stimulation using near-infrared spectroscopy (NIRS) and electroencephalography (EEG). The NIRS results show that, following an acute noxious event, the contralateral somatosensory cortex is functionally activated in infants from 25 weeks postmenstrual age (PMA). Awake infants have a larger cortical response than asleep infants and, in the awake group, the size of the response increases with PMA. The magnitude of the haemodynamic response correlates with pain scores calculated using the premature infant pain profile (PIPP), although infants who do not display a change in facial expression can still process noxious stimuli at the cortical level. Latency to response is longest in the youngest infants using either the haemodynamic response or change in facial expression as an output measure. The underlying pain-related neuronal activity in the cortex has been investigated using EEG. Nociceptive-specific event related potentials have been observed in infants from 31-42 weeks PMA, with a recognisable N-P complex visible in the contralateral somatosensory cortex in 82% of studies. Noxious stimulation can evoke specific patterns of neural activity within the cortex of preterm and term infants that can be observed on a single-trial basis. The studies represent the first measurements of cortical activation in the immature preterm cortex following a noxious event. The fact that noxious information is transmitted to higher levels of the central nervous system highlights the importance of developing a systematic approach to reduce pain and improve analgesic strategies in this vulnerable population

Exploring the impact of COVID-19 on newborn neurodevelopment: a pilot study.

The COVID-19 pandemic can seize the opportunity to explore the hypothesis of prenatal exposure to viral infections increases the risk for neurodevelopmental disorders. Advancing our knowledge in this regard would improve primary prevention of mental disorders in children. For this pilot study, six-week-old infants born to mothers exposed (n = 21) or unexposed (n = 21) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were assessed in Santander-Cantabria (Spain) using the Neonatal Behavioral Assessment Scale (NBAS). Groups comparisons were performed to explore the effects that infection and timing of exposure (in terms of the three trimesters of pregnancy). The infants' competencies and performances on the NBAS were generally similar in the exposed and unexposed to SARS-CoV-2 groups. The most significant difference found was a less optimally response to cuddliness (item on the state regulation domain) particularly in infants born to mothers exposed in the third trimester of pregnancy, and in pull-to-sit (item on the motor system domain). Although our interpretations must be careful, these preliminary results highlight the possible association between prenatal SARS-CoV-2 exposure and poorer development in motor skills and infant interactive behavior. Further longitudinal studies are needed to explore these relationships and disentangle the biological mechanisms implicated

MATERNAL ADIPOSITY, INSULIN SENSITIVITY AND INFLAMMATION, AND INFANT ADIPOSITY: ASSOCIATIONS WITH OFFSPRING AUTONOMIC NERVOUS SYSTEM DEVELOPMENT

Objective: The prevalence of maternal overweight and obesity is high and the impact is far reaching. Recent studies suggest that fetal exposure to maternal obesity is related to poor neurodevelopmental outcomes in childhood. However, limited data have been collected on the developing fetus. Studies also suggest that the adverse effect was mediated through insulin resistance (IR) and inflammation. We investigated if maternal pre-pregnancy BMI, gestational weight gain (GWG) and newborn adiposity, were associated with fetal autonomic nervous development as indicated by fetal heart rate variability (HRV) and newborn behavior. We also investigated if maternal IR and inflammation were associated with fetal HRV. Material and methods: A total of 48 mother-offspring pairs were analyzed. Short-term (SD1) and overall (SD2) fetal HRV were measured at 32 and 36 weeks of pregnancy using fetal magnetocardiogram. Maternal plasma levels of glucose, insulin, and inflammatory cytokines (TNF-α and IL-6) were analyzed from maternal peripheral blood collected at 36 weeks of pregnancy. Newborn body composition was measured using air-displacement plethysmography (PeaPod®). Multiple linear regression models predicted fetal HRV measures (SD1 and SD2 at 36 week, and SD1 and SD2 change between 32 and 36 week) and NBAS clusters from maternal and newborn factors. Infant gender and pre-pregnancy BMI were included as confounders. Results: In the adjusted regression model, greater GWG was associated with greater SD1 (β=0.442; R2=0.19; p=0.003) and with SD1 change (β =0.511; R2=0.27; p=0.007). Lower newborn %fat was associated with greater SD2 change, but the association was diminished in the adjusted model (β=-0.426; R2=0.17; p=0.055). No correlation was found between any of NBAS cluster scores and maternal or infant predictors, and between fetal HRV and maternal IR and blood inflammatory markers. Conclusions: Greater GWG was associated with better fetal autonomic nervous development, while greater newborn %fat was associated with poorer fetal autonomic nervous development. Further studies are needed to elucidate the impact of maternal and fetal/newborn adiposity on fetal neurodevelopment