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Physiological Reviews Jul 2018Hypoxia is one of the most common and severe challenges to the maintenance of homeostasis. Oxygen sensing is a property of all tissues, and the response to hypoxia is... (Review)
Review
Hypoxia is one of the most common and severe challenges to the maintenance of homeostasis. Oxygen sensing is a property of all tissues, and the response to hypoxia is multidimensional involving complicated intracellular networks concerned with the transduction of hypoxia-induced responses. Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. Hypoxia during gestation impacts both the mother and fetal development through interactions with an individual's genetic traits acquired over multiple generations by natural selection and changes in gene expression patterns by altering the epigenetic code. Changes in the epigenome determine "genomic plasticity," i.e., the ability of genes to be differentially expressed according to environmental cues. The genomic plasticity defined by epigenomic mechanisms including DNA methylation, histone modifications, and noncoding RNAs during development is the mechanistic substrate for phenotypic programming that determines physiological response and risk for healthy or deleterious outcomes. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue. The complex molecular and epigenetic interactions that may impact an individual's physiology and developmental programming of health and disease later in life are discussed.
Topics: Adaptation, Physiological; Adipose Tissue; Animals; Epigenesis, Genetic; Female; Fetal Development; Fetal Heart; Fetal Hypoxia; Heart Diseases; Humans; Hypertension, Pulmonary; Hypothalamo-Hypophyseal System; Maternal Health; Pituitary-Adrenal System; Placental Circulation; Pregnancy
PubMed: 29717932
DOI: 10.1152/physrev.00043.2017 -
Sensors (Basel, Switzerland) Aug 2018This article reviews existing clinical practices and sensor research undertaken to monitor fetal well-being during labour. Current clinical practices that include fetal... (Review)
Review
This article reviews existing clinical practices and sensor research undertaken to monitor fetal well-being during labour. Current clinical practices that include fetal heart rate monitoring and fetal scalp blood sampling are shown to be either inadequate or time-consuming. Monitoring of lactate in blood is identified as a potential alternative for intrapartum fetal monitoring due to its ability to distinguish between different types of acidosis. A literature review from a medical and technical perspective is presented to identify the current advancements in the field of lactate sensors for this application. It is concluded that a less invasive and a more continuous monitoring device is required to fulfill the clinical needs of intrapartum fetal monitoring. Potential specifications for such a system are also presented in this paper.
Topics: Acidosis; Female; Fetal Hypoxia; Fetal Monitoring; Humans; Labor, Obstetric; Lactic Acid; Pregnancy; Scalp
PubMed: 30104478
DOI: 10.3390/s18082648 -
Best Practice & Research. Clinical... Jan 2017Fetal growth restriction remains a challenging entity with significant variations in clinical practice around the world. The different etiopathogenesis of early and late... (Review)
Review
Fetal growth restriction remains a challenging entity with significant variations in clinical practice around the world. The different etiopathogenesis of early and late fetal growth restriction with their distinct progression of fetal severity and outcomes, compounded by doctors and patient anxiety adds to the quandary involving its management. This review summarises the literature around diagnosing and monitoring early onset fetal growth restriction (early onset FGR) with special emphasis on optimal timing of delivery as guided by recent research advances.
Topics: Acidosis; Amniotic Fluid; Cardiotocography; Female; Fetal Growth Retardation; Fetal Hypoxia; Gestational Age; Humans; Middle Cerebral Artery; Pregnancy; Pregnancy Trimester, Second; Ultrasonography, Doppler; Ultrasonography, Prenatal; Umbilical Arteries; Umbilical Veins
PubMed: 27693119
DOI: 10.1016/j.bpobgyn.2016.08.005 -
Current Molecular Medicine Oct 2010Fetal hearts show a remarkable ability to develop under hypoxic conditions. The metabolic flexibility of fetal hearts allows sustained development under low oxygen... (Review)
Review
Fetal hearts show a remarkable ability to develop under hypoxic conditions. The metabolic flexibility of fetal hearts allows sustained development under low oxygen conditions. In fact, hypoxia is critical for proper myocardial formation. Particularly, hypoxia inducible factor 1 (HIF-1) and vascular endothelial growth factor play central roles in hypoxia-dependent signaling in fetal heart formation, impacting embryonic outflow track remodeling and coronary vessel growth. Although HIF is not the only gene involved in adaptation to hypoxia, its role places it as a central figure in orchestrating events needed for adaptation to hypoxic stress. Although "normal" hypoxia (lower oxygen tension in the fetus as compared with the adult) is essential in heart formation, further abnormal hypoxia in utero adversely affects cardiogenesis. Prenatal hypoxia alters myocardial structure and causes a decline in cardiac performance. Not only are the effects of hypoxia apparent during the perinatal period, but prolonged hypoxia in utero also causes fetal programming of abnormality in the heart's development. The altered expression pattern of cardioprotective genes such as protein kinase c epsilon, heat shock protein 70, and endothelial nitric oxide synthase, likely predispose the developing heart to increased vulnerability to ischemia and reperfusion injury later in life. The events underlying the long-term changes in gene expression are not clear, but likely involve variation in epigenetic regulation.
Topics: Coronary Vessels; Epigenomics; Fetal Development; Fetal Heart; Fetal Hypoxia; Fetus; Gene Expression; HSP70 Heat-Shock Proteins; Heart; Humans; Hypoxia-Inducible Factor 1; Myocardial Ischemia; Myocardium; Nitric Oxide Synthase Type III; Organogenesis; Oxygen; Protein Kinase C-epsilon; Vascular Endothelial Growth Factor A
PubMed: 20712587
DOI: 10.2174/156652410792630643 -
BMC Veterinary Research May 2021Mechanisms of fetal death following maternal PRRSV2 infection remain uncharacterized, although hypoxia from umbilical cord lesions and/or placental detachment due to...
BACKGROUND
Mechanisms of fetal death following maternal PRRSV2 infection remain uncharacterized, although hypoxia from umbilical cord lesions and/or placental detachment due to apoptosis are hypothesized. We performed two experiments examining hypoxia and apoptosis in PRRSV-infected and non-infected, third-trimester fetuses to elucidate possible associations with fetal death. Fetuses were selected based on four phenotypic infection groups: fetuses from non-challenged control gilts (CTRL); low viral load fetuses (LVL; Exp 1) or uninfected fetuses (UNINF; Exp 2) from inoculated gilts; viable high viral load fetuses (HVL-VIA); and HVL meconium-stained fetuses (HVL-MEC).
RESULTS
In experiment 1, paraffin embedded fetal tissues collected 21 days post maternal infection (DPI) were examined for DNA fragmentation associated with apoptosis. Positively stained foci were larger and more numerous (P < 0.05) in heart, liver, and thymus of HVL-VIA and HVL-MEC compared to CTRL and LVL fetuses. In experiment 2, group differences in gene expression within the hypoxia (HIF1a, IDO1, VEGFa, LDHA, NOS2, NOX1) and apoptosis (CASP3, CASP7, CASP8, CASP9, RIPK1, RIPK3) pathways were assessed by RT-qPCR in fetal tissues collected at 12 DPI. High viral load fetuses showed differential expression relative to the CTRL and UNINF (P < 0.05 for all). Brain tissue from HVL-VIA and HVL-MEC fetuses presented increased expression of CASP7, CASP8, RIPK3, HIF1a and IDO1. Fetal heart showed increased expression of CASP8, HIF1a, IDO and NOX1 and a decrease in NOS2 expression in infected groups. CASP7, CASP9, RIPK1 and RIPK3 were only increased in the heart of HVL-VIA while VEGFa was only increased for HVL-MEC fetuses. Thymus from HVL-MEC had decreased expression of CASP9 and there was increased IDO1 in all infected fetuses.
CONCLUSIONS
There is strong evidence of apoptosis occurring in the heart, liver and thymus of highly viral load fetuses at 21 DPI. Furthermore, there was clear upregulation of apoptotic genes in the heart of high viral load infected fetuses and less prominent upregulation in the brain of PRRSV-infected fetuses, whereas thymus appears to be spared at 12 DPI. There was no strong evidence of hypoxia at 12 DPI in brain and thymus but some indication of hypoxia occurring in fetal heart.
Topics: Animals; Apoptosis; Brain; Female; Fetal Hypoxia; Fetus; Gene Expression; Myocardium; Porcine Reproductive and Respiratory Syndrome; Porcine respiratory and reproductive syndrome virus; Pregnancy; Pregnancy Complications, Infectious; Sus scrofa; Swine; Thymus Gland; Viral Load
PubMed: 33933084
DOI: 10.1186/s12917-021-02883-0 -
The Journal of Physiology Mar 2017Premature fetuses and babies are at greater risk of mortality and morbidity than their term counterparts. The underlying causes are multifactorial, but include exposure... (Review)
Review
Premature fetuses and babies are at greater risk of mortality and morbidity than their term counterparts. The underlying causes are multifactorial, but include exposure to hypoxia. Immaturity of organs and their functional control may impair the physiological defence responses to hypoxia and the preterm fetal responses, or lack thereof, to moderate hypoxia appear to support this concept. However, as this review demonstrates, despite immaturity, the preterm fetus responds to asphyxia in a qualitatively similar manner to that seen at term. This highlights the importance in understanding metabolism versus homeostatic threat when assessing fetal responses to adverse challenges such as hypoxia. Data are presented to show that the preterm fetal adaptation to asphyxia is triphasic in nature. Phase one represents the rapid institution of maximal defences, designed to maintain blood pressure and central perfusion at the expense of peripheral organs. Phase two is one of adaptive compensation. Controlled reperfusion partially offsets peripheral tissue oxygen debt, while maintaining sufficient vasoconstriction to limit the fall in perfusion. Phase three is about decompensation. Strikingly, the preterm fetus generally performs better during phases two and three, and can survive for longer without injury. Paradoxically, however, the ability to survive can lead to longer exposure to hypotension and hypoperfusion and thus potentially greater injury. The effects of fetal sex, inflammation and drugs on the triphasic adaptations are reviewed. Finally, the review highlights the need for more comprehensive studies to understand the complexity of perinatal physiology if we are to develop effective strategies to improve preterm outcomes.
Topics: Adaptation, Physiological; Animals; Anti-Inflammatory Agents; Asphyxia; Fetal Hypoxia; Fetus; Glucocorticoids; Homeostasis; Humans; Infant, Newborn; Infant, Premature
PubMed: 28094441
DOI: 10.1113/JP272999 -
American Journal of Physiology.... Sep 2015In utero, hypoxia is a significant yet common stress that perturbs homeostasis and can occur due to preeclampsia, preterm labor, maternal smoking, heart or lung disease,... (Review)
Review
In utero, hypoxia is a significant yet common stress that perturbs homeostasis and can occur due to preeclampsia, preterm labor, maternal smoking, heart or lung disease, obesity, and high altitude. The fetus has the extraordinary capacity to respond to stress during development. This is mediated in part by the hypothalamic-pituitary-adrenal (HPA) axis and more recently explored changes in perirenal adipose tissue (PAT) in response to hypoxia. Obvious ethical considerations limit studies of the human fetus, and fetal studies in the rodent model are limited due to size considerations and major differences in developmental landmarks. The sheep is a common model that has been used extensively to study the effects of both acute and chronic hypoxia on fetal development. In response to high-altitude-induced, moderate long-term hypoxia (LTH), both the HPA axis and PAT adapt to preserve normal fetal growth and development while allowing for responses to acute stress. Although these adaptations appear beneficial during fetal development, they may become deleterious postnatally and into adulthood. The goal of this review is to examine the role of the HPA axis in the convergence of endocrine and metabolic adaptive responses to hypoxia in the fetus.
Topics: Acute Disease; Adaptation, Physiological; Adipose Tissue; Altitude Sickness; Animals; Chronic Disease; Disease Models, Animal; Female; Fetal Development; Fetal Hypoxia; Fetus; Humans; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Pregnancy; Sheep
PubMed: 26173460
DOI: 10.1152/ajpendo.00126.2015 -
American Journal of Physiology.... Jul 2019The availability of oxygen to the fetus is limited by the route taken by oxygen from the atmosphere to fetal tissues, aided or diminished by pregnancy-associated changes... (Review)
Review
The availability of oxygen to the fetus is limited by the route taken by oxygen from the atmosphere to fetal tissues, aided or diminished by pregnancy-associated changes in maternal physiology and, ultimately, a function of atmospheric pressure and composition of the mother's inspired gas. Much of our understanding of the fetal physiological response to hypoxia comes from experiments designed to elucidate the cardiovascular and endocrine responses to transient hypoxia. Complementing this work is equally impactful research into the origins of intrauterine growth restriction in which animal models designed to restrict the transfer of oxygen from the maternal to the fetal circulation were used. A common assumption has been that outcomes measured after a period of hypoxia are related to cellular deprivation of oxygen and reoxygenation: an assumption based on a focus on what we can see "under the streetlights." Recent studies demonstrate that availability of oxygen may not tell the whole story. Transient hypoxia in the fetal sheep stimulates transcriptomics responses that mirror inflammation. This response is accompanied by the appearance of bacteria in the fetal brain and other tissues, likely resulting from a hypoxia-stimulated release of bacteria from the placenta. The appearance of bacteria in the fetus after transient hypoxia complements the recent discovery of bacterial DNA in the normal human placenta and in the tissues of fetal sheep. An understanding of the mechanism of the physiological, cellular, and molecular responses to hypoxia requires an appreciation of stimuli other than cellular oxygen deprivation: stimuli that we would have never known about without looking "between the streetlights," illuminating direct responses to the manipulated variables.
Topics: Animals; Brain; Female; Fetal Development; Fetal Hypoxia; Maternal-Fetal Exchange; Models, Biological; Oxygen Consumption; Pregnancy; Sheep
PubMed: 31017808
DOI: 10.1152/ajpregu.00008.2019 -
Respiratory Physiology & Neurobiology Aug 2011High-altitude studies offer insight into the evolutionary processes and physiological mechanisms affecting the early phases of the human lifespan. Chronic hypoxia slows... (Review)
Review
High-altitude studies offer insight into the evolutionary processes and physiological mechanisms affecting the early phases of the human lifespan. Chronic hypoxia slows fetal growth and reduces the pregnancy-associated rise in uterine artery (UA) blood flow. Multigenerational vs. shorter-term high-altitude residents are protected from the altitude-associated reductions in UA flow and fetal growth. Presently unknown is whether this fetal-growth protection is due to the greater delivery or metabolism of oxygen, glucose or other substrates or to other considerations such as mechanical factors protecting fragile fetal villi, the creation of a reserve protecting against ischemia/reperfusion injury, or improved placental O(2) transfer as the result of narrowing the A-V O(2) difference and raising uterine P(v)O₂. Placental growth and development appear to be normal or modified at high altitude in ways likely to benefit diffusion. Much remains to be learned concerning the effects of chronic hypoxia on embryonic development. Further research is required for identifying the fetoplacental and maternal mechanisms responsible for transforming the maternal vasculature and regulating UA blood flow and fetal growth. Genomic as well as epigenetic studies are opening new avenues of investigation that can yield insights into the basic pathways and evolutionary processes involved.
Topics: Adaptation, Physiological; Altitude; Female; Fetal Hypoxia; Humans; Oxygen Consumption; Placenta; Pregnancy
PubMed: 21536153
DOI: 10.1016/j.resp.2011.04.017 -
The Journal of Physiology Mar 2016
Topics: Fetal Hypoxia; History, 19th Century; History, 20th Century; Humans; Neonatology; Physiology; United Kingdom
PubMed: 26926314
DOI: 10.1113/JP272000