Extrauterine Exposure Research Articles

Hippocampal asymmetry of regional development and structural covariance in preterm neonates

Premature birth is associated with a high prevalence of neurodevelopmental impairments in surviving infants. The hippocampus is known to be critical for learning and memory, yet the putative effects of hippocampal dysfunction remain poorly understood in preterm neonates. In particular, while asymmetry of the hippocampus has been well noted both structurally and functionally, how preterm birth impairs hippocampal development and to what extent the hippocampus is asymmetrically impaired by preterm birth have not been well delineated. In this study, we compared volumetric growth and shape development in the hippocampal hemispheres and structural covariance (SC) between hippocampal vertices and cortical thickness in cerebral cortex regions between two groups. We found that premature infants had smaller volumes of the right hippocampi only. Lower thickness was observed in the hippocampal head in both hemispheres for preterm neonates compared with full-term peers, though preterm neonates exhibited an accelerated age-related change of hippocampal thickness in the left hippocampi. The SC between the left hippocampi and the limbic lobe of the premature infants was severely impaired compared with the term-born neonates. These findings suggested that the development of the hippocampus during the third trimester may be altered following early extrauterine exposure with a high degree of asymmetry.

The impact of premature extrauterine exposure on infants’ stimulus-evoked brain activity across multiple sensory systems

Prematurity can result in widespread neurodevelopmental impairment, with the impact of premature extrauterine exposure on brain function detectable in infancy. A range of neurodynamic and haemodynamic functional brain measures have previously been employed to study the neurodevelopmental impact of prematurity, with methodological and analytical heterogeneity across studies obscuring how multiple sensory systems are affected. Here, we outline a standardised template analysis approach to measure evoked response magnitudes for visual, tactile, and noxious stimulation in individual infants (n = 15) using EEG. By applying these templates longitudinally to an independent cohort of very preterm infants (n = 10), we observe that the evoked response template magnitudes are significantly associated with age-related maturation. Finally, in a cross-sectional study we show that the visual and tactile response template magnitudes differ between a cohort of infants who are age-matched at the time of study but who differ according to whether they are born during the very preterm or late preterm period (n = 10 and 8 respectively). These findings demonstrate the significant impact of premature extrauterine exposure on brain function and suggest that prematurity can accelerate maturation of the visual and tactile sensory system in infants born very prematurely. This study highlights the value of using a standardised multi-modal evoked-activity analysis approach to assess premature neurodevelopment, and will likely complement resting-state EEG and behavioural assessments in the study of the functional impact of developmental care interventions.

Oxygen Toxicity to the Immature Lung-Part I: Pathomechanistic Understanding and Preclinical Perspectives.

In utero, the fetus and its lungs develop in a hypoxic environment, where HIF-1α and VEGFA signaling constitute major determinants of further development. Disruption of this homeostasis after preterm delivery and extrauterine exposure to high fractions of oxygen are among the key events leading to bronchopulmonary dysplasia (BPD). Reactive oxygen species (ROS) production constitutes the initial driver of pulmonary inflammation and cell death, altered gene expression, and vasoconstriction, leading to the distortion of further lung development. From preclinical studies mainly performed on rodents over the past two decades, the deleterious effects of oxygen toxicity and the injurious insults and downstream cascades arising from ROS production are well recognized. This article provides a concise overview of disease drivers and different therapeutic approaches that have been successfully tested within experimental models. Despite current studies, clinical researchers are still faced with an unmet clinical need, and many of these strategies have not proven to be equally effective in clinical trials. In light of this challenge, adapting experimental models to the complexity of the clinical situation and pursuing new directions constitute appropriate actions to overcome this dilemma. Our review intends to stimulate research activities towards the understanding of an important issue of immature lung injury.

Preterm Birth and the Development of Visual Attention During the First 2 Years of Life

<h3>Importance</h3> Preterm birth is associated with an increased risk for long-lasting attention deficits. Early-life markers of attention abnormalities have not been established to date but could provide insights into the pathogenesis of attention abnormalities and could help identify susceptible individuals. <h3>Objective</h3> To examine whether preterm birth is associated with visual attention impairments in early life, and if so, in which attention functions and at which developmental period during the first 2 years of life. <h3>Data Sources</h3> PubMed and PsycINFO were searched on November 17, 2019, to identify studies involving visual attention outcomes in infants born preterm vs full term. <h3>Study Selection</h3> Peer-reviewed studies from the past 50 years met the eligibility criteria if they directly assessed visual attention outcomes until the age of 2 years in generally healthy infants born preterm or full term. The selection process was conducted by 2 independent reviewers. <h3>Data Extraction and Synthesis</h3> The Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline was followed. Random-effects models were used to determine standardized mean differences. The risk of bias was assessed both within and between studies. <h3>Main Outcomes and Measures</h3> Five nascent indices of visual attention were analyzed, including very basic functions—namely, the abilities to follow and fixate on visual targets—and more complex functions, such as visual processing (ie, habituation), recognition memory (ie, novelty preference), and the ability to effortfully focus attention for learning. <h3>Results</h3> A total of 53 studies were included, with 69 effect sizes and assessing a total of 3998 infants (2047 born preterm and 1951 born full term; of the 3376 for whom sex was reported, 1693 [50.1%] were girls). Preterm birth was associated with impairments in various attention indices, including visual-following in infancy (Cohen<i>d</i>, −0.77; 95% CI, −1.23 to −0.31), latency to fixate (Cohen<i>d</i>, −0.18; 95% CI, −0.33 to −0.02), novelty preference (Cohen<i>d</i>, −0.20; 95% CI, −0.32 to −0.08), and focused attention (Cohen<i>d</i>, −0.28; 95% CI, −0.45 to −0.11). In the neonatal period, preterm birth was associated with superior visual<i>-</i>following (Cohen<i>d</i>, 0.22; 95% CI, 0.03 to 0.40), possibly owing to the additional extrauterine exposure to sensory stimulation. However, this early association waned rapidly in infancy (Cohen<i>d</i>, –0.77; 95% CI, –1.23 to –0.31). <h3>Conclusions and Relevance</h3> The findings suggest that preterm birth is associated with impingements to visual attention development in early life, as manifested in basic and then complex forms of attention. Advancements in neonatal care may underlie improvements found in the current era and accentuate several early protective factors.

Nutrition and the developing brain: the road to optimizing early neurodevelopment: a systematic review.

Neonatal intensive care practices have resulted in marked improvements in the survival of premature infants; however, they remain at significant risk for adverse neurodevelopmental outcomes. The impact of current nutritional practices on brain development following early extra-uterine exposure in premature infants is not well known. We performed a systematic review to investigate nutritional effects on postnatal brain development in healthy term and prematurely born infants utilizing advanced magnetic resonance imaging tools. Systematic screen yielded 595 studies for appraisal. Of these, 22 total studies were selected for inclusion in the review, with findings summarized in a qualitative, descriptive fashion. Fat and energy intake are associated with improved brain volume and development in premature infants. While breast milk intake and long-chain polyunsaturated fatty acid supplementation has been proven beneficial in term infants, the impact in preterm infants is less well understood.

Early extra-uterine exposure alters regional cerebellar growth in infants born preterm.

ObjectivesTo compare third trimester global and regional cerebellar volumetric growth at two time-points between very preterm (PT) infants and healthy gestational age-matched fetuses in the PT period and at term equivalent age (TEA).Study designUsing a prospective study design, high resolution anatomic magnetic resonance images (MRI) were acquired in PT infants (gestational age at birth < 32 weeks; birthweight < 1500 g) without cerebellar injury and healthy full-term controls. PT infants completed two MRIs, one as soon as medically stable and the other around TEA. Controls also completed two MRIs, one in utero (i.e. fetal MRI) and a postnatal MRI shortly after birth. The cerebellum of each participant was parcellated into 5 regions: left and right hemispheres, the anterior, neo and posterior vermis. Evidence of differences in regional volumes between term and pre-term infants matched for gestational age (GA) at the time of the first MRI were assessed using multiple linear regression.Results: we studied 76 subjects38 PT infants were matched to 38 healthy fetuses. At MRI-1, PT infants demonstrated decreased cerebellar hemispheric volumes and increased anterior, neo- and posterior vermian regional volumes when compared to healthy fetuses. At TEA, PT infants demonstrated a persistent increase in anterior, neo- and posterior vermian regional volumes but no longer showed reductions in cerebellar hemispheric volume. Only the neovermis volume demonstrated a significant negative association with birthweight, male gender and supratentorial injury.ConclusionsIn the absence of demonstrable cerebellar parenchymal injury evident on conventional MRI, PT birth is associated with cerebellar growth alterations that are regionally- and temporally-specific.

Delivery Mode and the Transition of Pioneering Gut-Microbiota Structure, Composition and Predicted Metabolic Function.

Cesarean (C-section) delivery, recently shown to cause excess weight gain in mice, perturbs human neonatal gut microbiota development due to the lack of natural mother-to-newborn transfer of microbes. Neonates excrete first the in-utero intestinal content (referred to as meconium) hours after birth, followed by intestinal contents reflective of extra-uterine exposure (referred to as transition stool) 2 to 3 days after birth. It is not clear when the effect of C-section on the neonatal gut microbiota emerges. We examined bacterial DNA in carefully-collected meconium, and the subsequent transitional stool, from 59 neonates [13 born by scheduled C-section and 46 born by vaginal delivery] in a private hospital in Brazil. Bacterial DNA was extracted, and the V4 region of the 16S rRNA gene was sequenced using the Illumina MiSeq (San Diego, CA, USA) platform. We found evidence of bacterial DNA in the majority of meconium samples in our study. The bacterial DNA structure (i.e., beta diversity) of meconium differed significantly from that of the transitional stool microbiota. There was a significant reduction in bacterial alpha diversity (e.g., number of observed bacterial species) and change in bacterial composition (e.g., reduced Proteobacteria) in the transition from meconium to stool. However, changes in predicted microbiota metabolic function from meconium to transitional stool were only observed in vaginally-delivered neonates. Within sample comparisons showed that delivery mode was significantly associated with bacterial structure, composition and predicted microbiota metabolic function in transitional-stool samples, but not in meconium samples. Specifically, compared to vaginally delivered neonates, the transitional stool of C-section delivered neonates had lower proportions of the genera Bacteroides, Parabacteroides and Clostridium. These differences led to C-section neonates having lower predicted abundance of microbial genes related to metabolism of amino and nucleotide sugars, and higher abundance of genes related to fatty-acid metabolism, amino-acid degradation and xenobiotics biodegradation. In summary, microbiota diversity was reduced in the transition from meconium to stool, and the association of delivery mode with microbiota structure, composition and predicted metabolic function was not observed until the passing of the transitional stool after meconium.

Do Preterm Infants Perceive Temporal Synchrony? An Analysis with the Eye-Tracking System

The aim of this study was to investigate auditory–visual temporal asynchrony in preterm infants using a habituation procedure coupled with an eye-tracking system in order to examine visual behavior accurately and determine specific visual areas of interest. Sixteen term infants, twelve low-risk near-term (LBW) preterm infants and eight Very Low Birth Weight (VLBW) preterm infants were tested at four months post term. Infants were habituated with an auditory–visual synchronic situation: a visual ball bounced back in synchrony with an auditory sound. In the test phase, an asynchronized situation and a synchronized situation were presented alternately three times. The results showed that VLBW infants spent more time looking at the target before being habituated compared to LBW preterm infants and full-term infants. Specific areas of interest showed that VLBW infants spent less time on the target than LBW and full-term infants and had a more heterogeneous visual exploration. Nevertheless, VLBW infants had the same novelty reaction as the other infant groups. Moreover, the study of areas of interest revealed that whatever the age group, infants looked more at the area where the sound was produced during the asynchronized trial. This result suggests that infants perceive asynchrony. We suggest that VLBW preterm infants show the same ability to habituate and novelty recovery through an early learning experience due to earlier additional extra-uterine exposure.

The motor and visual networks in preterm infants: An fMRI and DTI study

Knowledge regarding the association between functional connectivity and white-matter (WM) maturation of motor and visual networks in preterm infants at term equivalent age (TEA) and their association with behavioral outcome is currently limited. Thirty-two preterm infants born <34 weeks gestational-age without major brain abnormalities were included in this study, underwent resting-state fMRI at TEA. Thirteen infants also underwent diffusion tensor imaging (DTI). Neurobehavioral assessments were performed at one and two years corrected age using the Griffiths Mental Developmental Scales. Functional connectivity between homolog motor and visual regions were detected, which may reflect that a level of organization in these domains is present already at TEA. DTI parameters of WM tracts at TEA demonstrated spatial-temporal variability, with the splenium of the corpus-callosum (CC) found to be the most mature fiber bundle. Correlations between DTI parameters, functional connectivity and behavioral outcome were detected, yet did not show the same pattern of diffusivity changes in the different networks. Visual functional connectivity was negatively correlated with radial-diffusivity (RD) in the optic radiation, while motor functional connectivity was positively correlated with RD in the splenium. In addition, axial-diffusivity (AD) and RD in the genu and midbody of the CC were positively correlated with neurobehavioral outcome at one and 2 years of age. This study highlights the importance of understanding the spatial-temporal changes occurring during this sensitive period of development and the potential effect of extrauterine exposure on the microstructural changes as measured by DTI; their correlation with functional connectivity; and their long term relationship with neuro-behavioral development.

Neurodegenerative changes and apoptosis induced by intrauterine and extrauterine exposure of radiofrequency radiation

Adverse health effects of radiofrequency radiation (RFR) on the ongoing developmental stages of children from conception to childhood are scientifically anticipated subject. This study was performed to identify the effects of global system for mobile communications (GSM) modulated mobile phone like RFR in 1800MHz frequency on oxidative DNA damage and lipid peroxidation beside the apoptotic cell formation, using histopathological and immunohistochemical methods in the brain tissue of 1-month-old male and female New Zealand White rabbits that were exposed to these fields at their mother's womb and after the birth. Oxidative DNA damage and lipid peroxidation levels were investigated by measuring the 8-hydroxy-2′-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) levels, respectively. Histopathological changes were observed using by hematoxylin and eosin (HE) staining. Apoptotic cells were detected in the examined organs by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining.For both male and female infants; 8-OHdG levels increased in the group exposed to RFR in both intrauterine and extrauterine periods compared to the infants that were never exposed to RFR and the ones were exposed when they reached one month of age (p<0.05). MDA results were different for male and female rabbits. There was no difference between all female infant groups (p>0.05), while only intrauterine exposure significantly causes MDA level increase for the male infants. HE staining revealed mild lessions in neuronal necrobiosis in brain tissues of female rabbits that had only intaruterine exposure and male rabbits had only extrauterine exposure. Gliosis were mildly positive in brain tissues of rabbits that are exposed only intrauterine period, also the group exposed both intrauterine and extrauterine periods. However, there was no apoptotic change detected by TUNEL staining in the brain tissues of all groups.

Diffuse excessive high signal intensity in low-risk preterm infants at term-equivalent age does not predict outcome at 1 year: a prospective study.

The outcome of premature infants with only diffuse excessive high signal intensity (DEHSI) is not clear. We explored the relationship between DEHSI, white matter (WM) diffusion characteristics, perinatal characteristics, and neurobehavioral outcome at 1 year in a homogenous group of preterm infants without major brain abnormalities. Fifty-eight preterm infants, gestational age 29 ± 2.6 weeks, underwent an MRI at term-equivalent age (TEA). Griffiths Mental Developmental Scales, neurological assessment, and Parental Stress Index (PSI) were performed at 1 year corrected age. These measures were compared between preterm infants according to DEHSI classification (none, mild, moderate). Diffusion tensor imaging was used in major WM volumes of interest to objectively measure the degree of WM maturation. No significant differences were detected in the perinatal risk characteristics, neurobehavioral outcome, and PSI at 1 year between infants with different DEHSI classifications. In infants with DEHSI, increased axial and radial diffusivities were detected in the optic radiations, centrum semiovale, and posterior limb of the internal capsule, indicating less advanced maturation of the WM. Significant correlations were detected between the time interval from birth to MRI and the WM microstructure in infants without DEHSI. DEHSI in premature infants is neither a predictive measure for short-term adverse neurobehavioral outcome nor related to perinatal risk characteristics. Extrauterine exposure time had a differential effect on WM maturational trajectories in infants with DEHSI compared to those without. We suggest DEHSI may represent an alteration in WM maturational characteristics. Further follow-up studies may verify later consequences of DEHSI in premature infants.

Effects of Intrauterine and Extrauterine Exposure to 1800 MHz GSM-Like Radiofrequency Radiation on Liver Regulatory Enzymes Activities in Infant Female Rabbits

Effects of Intrauterine and Extrauterine Exposure to 1800 MHz GSM-Like Radiofrequency Radiation on Liver Regulatory Enzymes Activities in Infant Female Rabbits

Effects of intrauterine and extrauterine exposure to GSM-like radiofrequency on distortion product otoacoustic emissions in infant male rabbits

The aim of this study was to investigate the potential hazardous effects of intrauterine (IU) and/or extrauterine (EU) exposure to 1800 MHz Global System for Mobile Communications-like (GSM-like) radiofrequency (RF) on the cochlear functions of infant rabbits by measuring distortion product otoacoustic emission (DPOAE) response amplitudes. Thirty-six white infant male New Zealand rabbits each 1-month-old were included in the study. The animals were randomly divided into four groups. Nine infant rabbits (Group 1) were not exposed to 1800 MHz GSM-like RF (Control-C). Nine infant rabbits (Group 2) were exposed to 1800 MHz GSM-like RF, 15 min daily for 14 days after they reached 1-month of age (extrauterine-EU). Nine infant rabbits (Group 3) were exposed to 1800 MHz GSM-like RF, 15 min daily for 7 days in the intrauterine period (between 15th and 22nd days of the gestational period) (intrauterine-IU). Nine infant rabbits (Group 4) were exposed to 1800 MHz GSM-like RF, 15 min daily for 7 days in the intrauterine period (between 15th and 22nd days of the gestational period) and 15 min daily for 14 days after they reached to 1-month of age (IU+EU). The cochlear functions were assessed by DPOAEs at 1.0-8.0 kHz. At 1.5 kHz, the mean DPOAE amplitude of Group 3 was higher than that of the controls and Group 2; and the mean DPOAE value of Group 4 was higher than that of the controls and Group 2. At 2.0 kHz, the mean DPOAE amplitude of Group 4 was higher than that of Group 2. At 3.0 kHz, the mean DPOAE amplitude of Group 4 was higher than that of the controls and Group 2. At 4.0 kHz, the mean DPOAE amplitude of Group 2 was lower than that of the controls, while the mean value of Group 4 was higher than the mean value of the controls and Group 2. At 6.0 kHz, the mean DPOAE amplitude of Group 2 was lower than that of the control group; however, the mean value of Group 4 was higher than that of Group 2. At 1.0 and 8.0 kHz, no significant differences were found among the four groups. Prolonged exposure and hyperthermia related to the power density of applied RF, increasing the temperature in the ear canal, may affect DPOAE amplitudes. Harmful effects of RF are mainly observed as a decrease in DPOAE amplitudes at 4.0-6.0 kHz during extrauterine exposure in infancy. During the intrauterine period, the water content of the middle and inner ear and amnion fluid may play a protective role. Therefore, children must be protected from RF exposure. The use of mobile phones at short distances from the ear of the infants should be avoided because of the lower thickness of the anatomical structure in infancy.

Alterations in surfactant protein gene expression associated with premature birth and exposure to hyperoxia

Steady-state levels of mRNAs for the three surfactant-associated proteins, SP-A, SP-B, and SP-C, were measured in a primate model of premature birth and survival. These values were determined by Northern and quantitative slot blot analyses of total lung RNA during both in utero and extrauterine development of the fetus as well as in response to hyperoxic exposure. The composition and surface properties of surfactant were also analyzed to determine the effect of differential expression of the surfactant proteins on the overall composition and function of surfactant. The data clearly demonstrate that the regulation of surfactant mRNA levels in the premature fetus is under complex physiological control. Interruption of in utero development by premature birth results in increased levels of all three surfactant mRNAs, presumably in response to precocious initiation of air breathing. Within the first 24 h after parturition both SP-B and SP-C mRNA levels are increased beyond the levels found in the full-term fetal controls. Expression of mRNA for these genes peaks on day 2 and thereafter drops to levels below that found on day 1. However, response of the SP-A gene to premature birth is slow and transcripts from this gene lag considerably behind values found in the full-term fetus. Furthermore, exposure of the premature fetus to hyperoxia results in an increase in the steady-state levels of SP-B and SP-C mRNA without significant changes in SP-A. Defects in the ability of the SP-A gene to respond to extrauterine exposure and hyperoxia may be contributing to development of bronchopulmonary dysplasia, a common clinical complication of premature birth in humans.

The Effect of Gestational Age at Birth on Somatosensory -evoked Potentials Performed at Term

Multimodality-evoked potentials are widely used in newborns to assess the maturation and integrity of the sensory pathways. Reliable normative data are needed to maximize the utility of this technique as a diagnostic and research tool. Several electrophysiologic studies on the maturational changes of the auditory brain-stem response have demonstrated that latency measurements decrease as a function of increasing conceptional age. However, maturational studies of the somatosensory-evoked potential, particularly in low-risk premature infants, are limited. The existing evoked potential literature in healthy newborns proposes that maturation of the central nervous system occurs at a predictable rate, irrespective of a given gestational age at birth. Behavioral studies of premature infants suggest that neurologic development may be altered by early extrauterine exposure. The purpose of this study was to determine whether brain-stem auditory- or somatosensory-evoked potential conduction times were comparable in premature and full-term infants matched for conceptional age. The results of this study suggest that myelination is determined by conceptional age, independent of premature birth.

DRUG UTILIZATION DURING THE PERINATAL PERIOD

In a progressive study, 231 gravid females and their progeny were monitored to assess drug utilization during the perinatal period. The patients came from a middle to high socioeconomic population and delivered in a university hospital. Gravid patients were found to take a mean (M) of 9.6 drug preparations (DP) during the prenatal course with a range of 1-37; 6.4 DP (R=0-28) were prescription drugs; 3.2 DP (R=0-12) were over the counter drugs; and .03 drugs (R=0-3) were not identified. Twenty-five percent of patients received a drug chronically throughout pregnancy. Ninety percent were prescribed. The mother received a M = 6.0 (R=0-14) drugs during labor and delivery. Single drugs were administered during L&D, whereas DP containing multiple agents were ingested during the prenatal course. During the post partum course the mother received a M = 8.7 drug preparations (R=1-25). Thirty-nine percent of the mothers were discharged home on medications. Fifty-nine percent of the mothers who were breast feeding were sent home on medications. During the nursery stay the progeny received a M = 3.1 drugs (R=1-15) with 23% of the infants receiving 4-15. In infants who received >6 drugs, 40% were treated because of a direct or indirect effect of maternal drugs. Within the first natal days the average newborn infant had been exposed to a M = 18.7 drugs by intrauterine or extrauterine exposure. Breast fed infants may be exposed to an additional 7.7 (R=2-15) drugs.

THE MECHANISMS OF NEONATAL THYROIDAL HYPERACTIVITY IN THE NEWBORN SHEEP

We have reported data in the human newborn suggesting that the early TSH surge and subsequent hyperthyroid state is due to extrauterine cooling. We now report further studies of this phenomenon in the newborn sheep. Uterotomies were performed on 8 pregnant ewes at term. Three lambs were delivered into room air (21-22° C), five were delivered into 40° C water bath and kept there for 60 min. with cord intact. They were then exposed to room air for an additional 60 min. Rectal and skin temperatures, pulse and blood pressure were monitored serially. T4 and T3 were determined in serum by RIA. Base line T4 values were similar in both groups and did not change significantly during the studies. Mean T3 levels, initially similar in both groups, increased 300% by 60 min. and 672% (p < 0.01) by 120 min. of exposure to room air; mean values in water bath fetuses did not change in or out of the bath. Three/3 exposed fetuses survived and 3/5 of the water bath fetuses died with hypothermia when exposed to room air. The data indicate that neonatal thyroidal hyperactivity is associated with extrauterine cooling but that other factors associated with initial extrauterine exposure must be involved. The T3 response may be important to survival.