Detection Of Hypoxia Research Articles

Dual‐Emissive Platinum(II) Metallacage with a Sensitive Oxygen Response for Imaging of Hypoxia and Imaging‐Guided Chemotherapy

Imaging of hypoxia in vivo helps with accurate cancer diagnosis and evaluation of therapeutic outcomes. A PtII metallacage with oxygen-responsive red phosphorescence and steady fluorescence for in vivo hypoxia imaging and chemotherapy is reported. The therapeutic agent and diagnostic probe were integrated into the metallacage through heteroligation-directed self-assembly. Nanoformulation by encapsulating the metallacage into nanoparticles greatly enhanced its stability the in physiological environment, rendering biomedical applications feasible. Apart from enhanced red phosphorescence upon hypoxia, the ratio between red and blue emissions, which only varies with intracellular oxygen level, provides a more precise standard for hypoxia imaging and detection. Moreover, in vivo explorations demonstrate the promising potential applications of the metallacage-loaded nanoparticles as theranostic agents for tumor hypoxia imaging and chemotherapy.

Fail-safe aspects of oxygen supply.

A fall in oxygen supply releases a remedial response that is otherwise prevented when the oxygen supply is sufficient; for example, the remedial function of HIF-1α is released when oxygen levels fall. the physiological responses initiated when oxygen supply is compromised operate in a fail-safe manner. This concept is applied to two cases: the control of cerebral blood flow, and the detection of hypoxia by the carotid body. The fail-safe oxygen supply concept was tested with simple computer simulations to demonstrate its function and verify the ability to reproduce measured data. The computer model reproduced published observations, suggesting that the fail-safe concept can be considered as a principle that provides novel insight into the physiology of oxygen supply in these cases. An engineered fail-safe system automatically prevents or mitigates the consequences of a system failure. This operational concept can be applied both to the delivery of oxygen to the brain during hypoxia and anaemia, and to the carotid body response to hypoxia and hypercapnia. I aimed to develop simple mathematical models of these fail-safe processes and examine their ability to replicate experimental observations. The intent is to demonstrate the validity of applying the fail-safe concept, not to reveal the details of the physiology involved. The model calculations are based on a single compartment of the relevant tissue in each case that is challenged with a decrease in oxygen supply. The model equation parameters were adjusted to reproduce experimental observations. The fail-safe model of cerebral blood flow control yielded results similar in form to published experimental observations of the cerebral blood flow responses to hypoxia and anaemia. The fail-safe model of carotid body glomus cell control of intracellular hydrogen ion concentration also yielded results similar in form to observations of carotid sinus nerve responses to hypoxia and hypercapnia. The ability of these simple models to simulate experimental observations demonstrates the applicability of the fail-safe concept to oxygen delivery. I suggest that a fail-safe view of oxygen delivery provides novel physiological insight.

Development of a Mouse Reporter Strain for the Purinergic P2X2 Receptor.

The ATP-sensitive P2X2 ionotropic receptor plays a critical role in a number of signal processes including taste and hearing, carotid body detection of hypoxia, the exercise pressor reflex and sensory transduction of mechanical stimuli in the airways and bladder. Elucidation of the role of P2X2 has been hindered by the lack of selective tools. In particular, detection of P2X2 using established pharmacological and biochemical techniques yields dramatically different expression patterns, particularly in the peripheral and central nervous systems. Here, we have developed a knock-in P2X2-cre mouse, which we crossed with a cre-sensitive tdTomato reporter mouse to determine P2X2 expression. P2X2 was found in more than 80% of nodose vagal afferent neurons, but not in jugular vagal afferent neurons. Reporter expression correlated in vagal neurons with sensitivity to α,β methylene ATP (αβmATP). P2X2 was expressed in 75% of petrosal afferents, but only 12% and 4% of dorsal root ganglia (DRG) and trigeminal afferents, respectively. P2X2 expression was limited to very few cell types systemically. Together with the central terminals of P2X2-expressing afferents, reporter expression in the CNS was mainly found in brainstem neurons projecting mossy fibers to the cerebellum, with little expression in the hippocampus or cortex. The structure of peripheral terminals of P2X2-expressing afferents was demonstrated in the tongue (taste buds), carotid body, trachea and esophagus. P2X2 was observed in hair cells and support cells in the cochlear, but not in spiral afferent neurons. This mouse strain provides a novel approach to the identification and manipulation of P2X2-expressing cell types.

Identification and validation of a combined hypoxia and immune index for triple-negative breast cancer.

The interaction between hypoxia and immune status has been confirmed in various cancer settings, and corresponding treatments have been investigated. However, reliable biomarkers are needed for individual treatment, so we sought to develop a novel scoring system based on hypoxia and immune status. Prognostic hypoxia–immune status‐related signatures of patients with triple‐negative breast cancer (TNBC) were identified in The Cancer Genome Atlas (TCGA) (N = 158), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (N = 297), and GSE58812 (N = 107). LASSO Cox regression was used for model construction. Hypoxia and immune status expression profiles were analyzed, and infiltrating immune cells were compared. Quantitative real‐time PCR (qRT‐PCR) was used for validation in the Sun Yat‐sen University Cancer Center (SYSUCC) cohort, and immunofluorescence was applied for the detection of hypoxia and immune markers in cancer tissues. Ten cross‐cohort prognostic hypoxia–immune signatures were included to construct the comprehensive index of hypoxia and immune (CIHI) in the METABRIC cohort. Two subgroups of patients with distinct hypoxia–immune status conditions were identified using CIHI: hypoxiahigh/immunelow and hypoxialow/immunehigh, with a significantly better overall survival (OS) rate in the latter (P < 0.01). The prognostic value of CIHI was further validated in the TCGA, GSE58812, and SYSUCC cohorts (P < 0.01). Hypoxia–immune signatures were significantly differentially expressed between the two groups, and more active immune responses were observed in the hypoxialow/immunehigh group. Cytotoxic lymphocytes were inversely correlated with CIHI in silico. Differentially expressed CA‐IX and stromal PD‐L1 were detected between subgroups of the SYSUCC cohort. A hypoxia–immune‐based cross‐cohort classifier for predicting prognosis was developed and validated, which may guide hypoxia modifier treatment and immunotherapy for TNBC.

Branched Au Nanoparticles on Nanofibers for Surface-Enhanced Raman Scattering Sensing of Intracellular pH and Extracellular pH Gradients.

The development of plasmonic-active nanosensors for surface-enhanced Raman scattering (SERS) sensing is important for gaining knowledge on intracellular and extracellular chemical processes, hypoxia detection, and label-free detection of neurotransmitters and metabolites, among other applications in cell biology. The fabrication of SERS nanosensors for optophysiology measurements using substrates such as nanofibers with a uniform distribution of plasmonic nanoparticles (NPs) remains a critical hurdle. We report here on a strategy using block copolymer brush-layer templating and ligand exchange for fabricating highly reproducible and stable SERS-active nanofibers with tip diameters down to 60 nm and covered with well-dispersed and uniformly distributed branched AuNPs, which have intrinsic hotspots favoring inherently high plasmonic sensitivity. Among the SERS sensors investigated, those with Au nanostars with short branches [AuNS(S)s] exhibit the greatest SERS sensitivity, as verified also by COMSOL Multiphysics simulations. Functionalization of the AuNS(S)s with the pH-sensitive molecule, 4-mercaptobenzoic acid, led to SERS nanosensors capable of quantifying pH over a linear range of 6.5-9.5, covering the physiological range. These pH nanosensors were shown to be able to detect the intracellular pH as well as extracellular pH gradients of in vitro breast cancer cells with minimal invasiveness and improved SERS sensitivity, along with a high spatial resolution capability.

Predicting fetal hypoxia using common spatial pattern and machine learning from cardiotocography signals

Cardiotocography (CTG) is a screening tool used in daily obstetric practice to determine fetal wellbeing. Its interpretation is generally performed visually by the field experts, and this visual inspection is an error-prone and subjective process. In addition, it leads to several drawbacks, such as variability among the observers and low reproducibility rates. To tackle these drawbacks, a novel computer-aided diagnostic (CAD) model is proposed. As novel diagnostic indices, the features provided by the common spatial patterns (CSP) were considered in this study. The experiments were carried out on a publicly available CTU-UHB Intrapartum CTG database. Four different data division criteria were evaluated individually. The proposed model relied upon a combination of the conventional as well as the CSP features and machine learning models such as an artificial neural network (ANN), support vector machine (SVM), and k-nearest neighbor (kNN). To validate the successes of the models, the five-fold cross-validation method was employed. The results validated that the CSP features ensured an increase in the performances of the machine learning models in the fetal hypoxia detection task. Also, the most effective results were provided by the SVM classifier with an accuracy of 94.75%, a sensitivity of 74.29% and a specificity of 99.55%. Consequently, thanks to the proposed model, a novel, consistent, and robust diagnostic model ensured for predicting fetal hypoxia.

Activatable fluorescent probe based on aggregation-induced emission for detecting hypoxia-related pathological conditions

Hypoxia, as a condition in which a region of body has low oxygen tension, is closely related to a variety of pathological conditions, and in many diseases local hypoxia occurs that would further increase the severity of diseases. Hence the extent of hypoxia could reflect the related pathological conditions and diseases, and the detection of hypoxia is of great significance. In hypoxia, the elevated level of nitroreductase (NTR) usually occurs, which could serve as a biomarker for hypoxia and thus the related diseases. Herein, an activatable fluorescent probe TPAQS-NO2 based on aggregation-induced emission (AIE) was designed for hypoxia detection via responding to NTR. The probe consists of an electron acceptor quinolinium and an electron donor triphenylamine group. The activated probe shows a large Stokes shift (186 nm). The probe TPAQS-NO2 was successfully used for detecting the early-stage and the advanced-stage tumors via NTR detection in 4T1 tumor-bearing mouse model. Furthermore, the probe TPAQS-NO2 was applied for detecting NTR in the cerebral ischemia (CIS) mouse model. The probe could offer an effective approach for detecting hypoxia-related pathological conditions.

Study of early warning for desaturation provided by Oxygen Reserve Index in obese patients

Acute hemoglobin desaturation can reflect rapidly decreasing PaO2. Pulse oximetry saturation (SpO2) facilitates hypoxia detection but may not significantly decrease until PaO2 < 80 mmHg. The Oxygen Reserve Index (ORI) is a unitless index that correlates with moderately hyperoxic PaO2. This study evaluated whether ORI provides added arterial desaturation warning in obese patients. This IRB approved, prospective, observational study obtained written informed consent from Obese (body mass index (BMI) kg m−2; 30 < BMI < 40) and Normal BMI (19 < BMI < 25) adult patients scheduled for elective surgery requiring general endotracheal anesthesia. Standard monitors and an ORI sensor were placed. Patient’s lungs were pre-oxygenated with 100% FiO2. After ORI plateaued, general anesthesia was induced, and endotracheal intubation accomplished using a videolaryngoscope. Patients remained apneic until SpO2reached 94%. ORI and SpO2 were recorded continuously. Added warning time was defined as the difference between the time to SpO2 94% from ORI alarm start or from SpO2 97%. Data are reported as median; 95% confidence interval. Complete data were collected in 36 Obese and 36 Normal BMI patients. ORI warning time was always longer than SpO2 warning time. Added warning time provided by ORI was 46.5 (36.0–59.0) seconds in Obese and 87.0 (77.0–109.0) seconds in Normal BMI patients, and was shorter in Obese than Normal BMI patients difference 54.0 (38.0–74.0) seconds (p < 0.0001). ORI provided what was felt to be clinically significant added warning time of arterial desaturation compared to SpO2. This added time might allow earlier calls for help, assistance from other providers, or modifications of airway management.Trial registration ClinicalTrials.gov NCT03021551.

EVALUATION OF FETAL OUTCOME BY USG COLOUR DOPPLER IN PATIENTS OF PIH WITH AND WITHOUT FETAL GROWTH RESTRICTION

Detection of fetal hypoxia with Doppler flow studies of Umbilical Artery (UA) &amp; Middle Cerebral Artery (MCA), to reduce perinatal morbidity and mortality by timely intervention. Evaluation of foetal health in cases of severe PIH &amp; IUGR by Doppler flow studies of UA and MCA flow velocimetry. Gestational age and mode of delivery, Evaluation of the perinatal outcome &amp; Cut-off values of RI, PI and S/D ratio of UA and MCA to identify IUGR.&#x0D; IUGR was higher in patients with PIH (76.6%) in comparison to the control group (50.0%). Only 76.7% patients with PIH had an apgar of &gt; 7, while all control group patients had apgar of &gt; 7. 28 (46.6%) neonates needed NICU support and 1 neonate expired, while 100% of control group neonates were shifted to mother.&#x0D; In both control and study groups weight of IUGR babies was significantly lower in comparison to their non-IUGR counterparts (by USG and actual)&#x0D; Keywords: Fetal, USG Color Doppler, PIH &amp; Outcome.

In Vivo Imaging of Hypoxia Associated with Inflammatory Bowel Disease by a Cytoplasmic Protein-Powered Fluorescence Cascade Amplifier.

Accurate and sensitive imaging of hypoxia associated with inflammatory bowel disease (IBD) is significant for the precise diagnosis and treatment of this disease, but it remains a challenge for traditional hypoxia-activatable fluorescence probes because of a more moderate hypoxic state during IBD than under other pathological conditions. To address this issue, herein, we designed a hypoxia-activatable and cytoplasmic protein-powered fluorescence cascade amplifier, named HCFA, to image hypoxia associated with IBD in vivo. In our design, a 4-aminobenzoic acid (azo)-modified mesoporous silica nanoparticle (MSN) was used as a container to load black hole quencher 2 (BHQ2) and cytoplasmic protein-binding squarylium dye (SQ); then, the β-cyclodextrin polymer (β-CDP) combined with azo through a host-guest interaction to form HCFA. Upon passive stagnation in the inflamed tissue of IBD, the azo band would be cleaved under a hypoxic microenvironment, and SQ was released to activate the fluorescence of HCFA. Moreover, the unconstrained SQ can bind with cytoplasmic protein to exhibit drastic fluorescence intensity enhancement, realizing the fluorescence signal amplification for imaging of hypoxia. When one takes advantage of the large load capacity of MSN and the unique property of SQ, HCFA can sense oxygen levels in the range of 0% to 10%. Meanwhile, the fluorescence imaging results demonstrate that HCFA can sensitively distinguish different levels of cellular hypoxia and monitor the variations of hypoxia in vivo, highlighting HCFA as a promising tool for the detection of hypoxia associated with IBD.

Novel Strategy for Validating the Existence and Mechanism of the "Gut-Liver Axis" in Vivo by a Hypoxia-Sensitive NIR Fluorescent Probe.

Liver fibrosis is a major stage in the development of liver disease, and it is important to investigate its pathogenesis for early intervention or even reversal. Recent studies have found that intestinal disease can aggravate liver fibrosis through the role of the "gut-liver axis". Hypoxia is considered to be a typical characteristic of many diseases including ulcerative colitis and liver fibrosis. However, there is no fluorescent probe for hypoxia detection to investigate the "gut-liver axis". Herein we design and synthesize a turn-on fluorescent probe termed Cy-AP, which displays high sensitivity and selectivity to hypoxia given by sodium dithionite (Na2S2O4) in vitro with near-infrared (NIR) emission (725 nm). The possible response mechanism of Cy-AP toward hypoxia is given and proved though HPLC, MS, and theory calculation. Moreover, on the basis of low cell cytotoxicity, the probe is used in visualizing hypoxia in four cell lines (HepG2, HCT116, HeLa, and MCF-7 cells) by fluorescence imaging, flow cytometry, and 3D imaging. Furthermore, due to its NIR emission, Cy-AP can monitor the hypoxia condition in vivo such as in liver fibrosis mice and ulcerative colitis mice models. In particular, the probe can validate the existence and mechanism of the "gut-liver axis" in vivo by monitoring hypoxia. To the best of our knowledge, this is the first work to give a strategy for studying the "gut-liver axis" by a NIR hypoxia-sensitive fluorescent probe, which will provide some powerful support for delaying the progression of liver fibrosis and thus promoting the treatment of liver disease.

Protocol for a prospective, controlled, cross-sectional, diagnostic accuracy study to evaluate the specificity and sensitivity of ambulatory monitoring systems in the prompt detection of hypoxia and during movement

IntroductionAutomated continuous ambulatory monitoring may provide an alternative to intermittent manual vital signs monitoring. This has the potential to improve frequency of measurements, timely escalation of care and patient safety....

Responsive fluorinated nanoemulsions for 19F magnetic resonance detection of cellular hypoxia.

We report two highly fluorinated Cu-based imaging agents, CuL1 and CuL2, for detecting cellular hypoxia as nanoemulsion formulations. Both complexes retained their initial quenched 19F MR signals due to paramagnetic Cu2+; however, both complexes displayed a large signal increase when the complex was reduced. DLS studies showed that the CuL1 nanoemulsion (NECuL1) had a hydrodiameter of approximately 100 nm and that it was stable for four weeks post-preparation. Hypoxic cells incubated with NECuL1 showed that 40% of the Cu2+ taken up was reduced in low oxygen environments.

Histopathological significance of microRNA-210 expression in acute peripheral ischemia in a murine femoral artery ligation model.

Under hypoxic conditions, microRNA-210 is upregulated and plays multiple physiological roles including in cell growth arrest, stem cell survival, repression of mitochondrial respiration, angiogenesis, and arrest of DNA repair. In this study, we investigated the histopathological expression of microRNA-210 under hypoxic conditions using a femoral artery ligation model established in C57BL/6J mice to determine the pathological significance of microRNA-210. Following femoral artery ligation, ischemia was represented by decreased blood flow compared to the control, in which a sham operation was performed. On histopathology, degeneration/necrosis of the muscle fibers, inflammatory cell infiltration, and regeneration of the muscle fibers were sequentially observed from 3 h to 3 d after ligation of the artery. The degree of these effects was more severe in the area in which type I muscular fibers are dominant. The histological expression of hypoxia-inducible factor 1α, a well-known biomarker of hypoxia, and microRNA-210 was observed in a few necrotic muscle fibers, macrophages, and myoblasts, a distribution consistent with the histopathological lesions, and their signal increased over time. The expression of microRNA-210 in macrophages and myoblasts under ischemia might be indicative of a significant role in the recovery from ischemic lesions. In addition, the in situ hybridization of microRNA-210 could potentially be used for the detection of hypoxia as a histological marker in addition to the immunohistochemistry of hypoxia-inducible factor 1α.

A Conformationally Restricted Aza-BODIPY Platform for Stimulus-Responsive Probes with Enhanced Photoacoustic Properties.

Photoacoustic (PA) dyes, which absorb near-infrared (NIR) light to generate an ultrasonic signal, can be detected at centimeter depths in tissues with significantly higher resolution than dyes imaged with fluorescence-based methods. As such, PA agents show great promise as research tools for the study of live-animal disease models. However, the development of activatable PA probes has been hampered by the relative scarcity of appropriate PA-active molecular platforms with properties that can be manipulated in a rational manner. Herein we synthesized and evaluated six modifications to the aza-BODIPY dye platform with respect to their absorbance, fluorescence, and PA properties. We identified a promising conformationally restricted aza-BODIPY (CRaB) scaffold that prioritizes three criteria necessary for the design of stimulus-responsive dyes with optimal ratiometric PA response: absorbance at NIR wavelengths, strong PA intensity, and large Δλ upon interaction with the desired stimulus. Using this scaffold, we synthesized three chemically diverse stimulus-responsive PA probes and demonstrated between 2- and 8-fold improvements in theoretical ratiometric response in vitro. This suggests that improvements in PA parameters are generalizable. Finally, we validated the in vitro turnover of each CRaB PA probe and demonstrated the in vivo potential of the CRaB scaffold by direct comparison to an established hypoxia-responsive probe for the detection of tumor hypoxia.

Oxygen-Sensing Probes and Bandage for Optical Detection of Inflammation.

Small-molecular and macromolecular optical probes based on an iridium complex chromophore were designed for detecting hypoxic inflammation in this work. The optical probes had a large conjugated ligand that could extend its phosphorescence emission to the red-wavelength region, thus increasing the tissue penetration depth of the optical signal. Due to good water solubility, the macromolecular optical probe could image both monolayer cells and three-dimensional multicellular spheroids. Moreover, this macromolecular probe was able to effectively image inflammation and distinguish healthy and inflammatory regions in a mouse model of lipopolysaccharide (LPS)-induced inflammation with low background interference. Furthermore, we integrated the hydrophobic small-molecular probe into the polyurethane thin film, and the resulting film successfully monitored the inflammation of chronic wounds in a mouse model. This work demonstrated the great potential of the iridium complex in optical imaging hypoxia and hypoxia-associated inflammation and will have significant impact on the design of high-sensitivity sensors for the detection of hypoxia.

Feeding the Data Monster: Data Science in Head and Neck Cancer for Personalized Therapy

ObjectiveHead and neck carcinomas are clinically challenging malignancies because of tumor heterogeneities and resilient tumor subvolumes that require individualized treatment planning and delivery for an improved outcome. Although current approaches to diagnosis and therapy have boosted locoregional control, the long-term survival in this patient group remains unchanged over the last decades. A new approach to head and neck cancer management is therefore needed to better identify patient subgroups that are responsive to specific therapies. The aim of this article is to review the current status of knowledge and practice utilizing big data toward personalized therapy in head and neck cancers based on CT and PET imaging modalities. MethodsLiterature published in English since 2000 was searched using Medline. Additional articles were retrieved via pearling of identified literature. Publications were reviewed and summarized in tabulated format. ResultsStudies based on big data in head and neck cancer are limited; however, the field of radiomics is under continuous development and provides valuable input for personalized treatment. Using PET/PET CT biomarkers for patient treatment individualization and response prediction seems promising, especially in regard to detection of hypoxia and clonogenic cancer stem cells. Literature shows that macroscopic changes in medical images (whether structural or functional) are correlated with biologic and biochemical changes within a tumor. ConclusionCurrent trends in data science suggest that the ideal model for decision support in head and neck cancers should be based on human-machine collaboration, namely, on (1) software-based algorithms, (2) physician innovation collaboratives, and (3) clinician mix optimization.

A New Strategy toward “Simple” Water‐Soluble AIE Probes for Hypoxia Detection

AbstractHypoxia‐responsive fluorescent probes have emerged as a novel scaffold for tumor diagnosis. However, dilemma often exists between simple synthesis and high water solubility in traditional probes. Owing to the intrinsic property of N‐oxides, herein, a new strategy is proposed to design and synthesize probes for in vitro hypoxia imaging. Equipped with tetraphenylethene (TPE), the N‐oxides exhibit aggregation‐induced emission characteristics and emit no light in aqueous solutions. Interestingly, the N‐oxides can be reduced by ferrous ions in different rates. The aggregation of the resulting hydrophobic TPE residues restricts the intramolecular motions of the molecules, which “turns‐on” their fluorescence. The NO covalent bond of one molecule can be specifically cleaved by cellular reductase overexpressed under hypoxic conditions, and thus turn‐on hypoxia imaging in vitro is achieved. The new strategy to design hypoxia imaging probes is extremely valuable and has great potential for application in tumor diagnosis.

Detection of cellular hypoxia by pimonidazole adduct immunohistochemistry in kidney disease: methodological pitfalls and their solution.

Pimonidazole adduct immunohistochemistry is one of the few available methods for assessing renal tissue hypoxia at the cellular level. It appears to be prone to artifactual false positive staining under some circumstances. Here, we assessed the nature of this false positive staining and, having determined how to avoid it, reexamined the nature of cellular hypoxia in rat models of kidney disease. When a mouse-derived anti-pimonidazole primary antibody was used, two types of staining were observed. First, there was diffuse staining of the cytoplasm of tubular epithelial cells, which was largely absent when the primary antibody was omitted from the incubation protocol or in tissues known not to contain pimonidazole adducts. Second, there was staining of the apical membranes of tubular epithelial cells, debris within the lumen of renal tubules, including tubular casts, and the interstitium; this latter staining was present even when the primary antibody was omitted from the incubation protocol. Such false positive staining was particularly prominent in acutely injured kidneys. It could not be avoided by preincubation of sections with a mouse IgG blocking reagent. Furthermore, preadsorption of the secondary antibody against rat Ig abolished all staining; however, when a rabbit-derived polyclonal anti-pimonidazole primary antibody was used, the false positive staining was largely avoided. Using this method, we confirmed the presence of hypoxia, localized mainly to the tubular epithelium, in the acute phase of severe renal ischemia-reperfusion injury, adenine-induced chronic kidney disease, and polycystic kidney disease. We conclude that this new method provides improved detection of renal cellular hypoxia.

Perinatal losses in anamnesis as a factor of fetus adaptation damage

In literature there are many works about prediction of chronic hypoxia of fetus, based on the assessment of the mother-placenta-fetus system, such as ultrasound, doppler velocimetry, cardiotocography, placental hormones and proteins tests; separate immunological, biochemical, hemostasiological and functional markers were introduced. However, the prognostic value most of these methods is insufficient by the standards of evidence-based medicine; they do not have a complex pathogenetically based approach. In this regard, the search for new methods for timely prediction and preclinical detection of fetal hypoxia continues to be a priority for obstetrics and perinatology. Cardiointervalography can be a promising method to study the relationship of the mother-placenta-fetus system; it allows simultaneous registration and assessment of the functional systems of mother and fetus. The high probability of such interrelations is evidenced by previous studies.Study aim was to assess the adaptation disorders of the fetus and newborn, to determine perinatal outcomes with a burdened obstetric history.A total of 200 pregnant women with perinatal losses in history (main group) and 100 pregnant women without perinatal losses in history (control group) were examined. Accordingto the results of fetal cardiointervalography in women with perinatal losses in history, the state of regulation of the fetal autonomic nervous system is characterized by a tendency to hypersympathicotonia, stress adaptation systems in the fetus in 66.0% of women. In 10.0% of women, hypertension of the regulatory systems of the fetus enters the stage of exhaustion and breakdown of adaptation, which is confirmed by the diagnosis of fetal distress. Assessing the condition of the fetus with an automatic analysis of the cardiotogram by the Dawes-Redman criteria showed an STV value of &lt;4 in 89.6% of women with fetal distress. The total assessment of the biophysical profile of the fetus was 4.43 ± 0.31 points. The results of the Gausknecht test were less than 15 s, and in severe cases they dropped to 5–7 s. 76.1% of children after intrauterine distress are born in a state of asphyxia, which causes a high frequency of disadaptation syndromes: most often central nervous system disorders (73.9%) and cardiovascular disadaptation (41.3%) was occured.