Wearable technology for health monitoring during pregnancy: an observational cross-sectional survey study.

PURPOSE: To evaluate how women of child-bearing age perceive the use of remote fetal ECG monitoring technologies. Telemedicine has advanced to the forefront of healthcare delivery, including maternal-fetal medicine. Smart wearable electrocardiogram (ECG) devices can enable pregnant women to monitor their health and that of their fetuses. Such technology would be a logical extension of the telemedicine ecosystem. METHODS: We conducted an observational cross-sectional study via online surveying in the United States. Study participants were recruited using the SurveyMonkey Audience Polling system and responded virtually. In all, the sample consisted of 507 women, aged 18-45 from 45 states, who are expecting to become pregnant in the next five years. Women were asked to identify their willingness to use a wearable ECG device the size of a patch-sized large band-aid on their abdomen. Ten binary or multiple-choice questions were used to gauge population interest and related demographics toward the usage of a wearable ECG device. RESULTS: Of the 507 participants, 461 (91%) women expressed an acceptance of wearable ECG technology throughout the pregnancy as a mechanism for increased frequency of monitoring of maternal and fetal health outside the hospital. 395 (78%) women demonstrated a willingness to wear devices day and night or at least during sleep and 213 (42%) of the women would spend up to $200 on such a device. CONCLUSION: Even though conducted prior to the COVID-19 pandemic, this study clearly indicates a high degree of readiness of prospective pregnant women for telemedicine with continuous health monitoring of the mother-fetus dyad.

First evidence that intrinsic fetal heart rate variability exists and is affected by hypoxic pregnancy.

KEY POINTS: We introduce a technique to test whether intrinsic fetal heart rate variability (iFHRV) exists and we show the utility of the technique by testing the hypothesis that iFHRV is affected by chronic fetal hypoxia, one of the most common adverse outcomes of human pregnancy complicated by fetal growth restriction. Using an established late gestation ovine model of fetal development under chronic hypoxic conditions, we identify iFHRV in isolated fetal hearts and show that it is markedly affected by hypoxic pregnancy. Therefore, the isolated fetal heart has intrinsic variability and carries a memory of adverse intrauterine conditions experienced during the last third of pregnancy. ABSTRACT: Fetal heart rate variability (FHRV) emerges from influences of the autonomic nervous system, fetal body and breathing movements, and from baroreflex and circadian processes. We tested whether intrinsic heart rate variability (iHRV), devoid of any external influences, exists in the fetal period and whether it is affected by chronic fetal hypoxia. Chronically catheterized ewes carrying male singleton fetuses were exposed to normoxia (n = 6) or hypoxia (10% inspired O2 , n = 9) for the last third of gestation (105-138 days of gestation (dG); term ∼145 dG) in isobaric chambers. At 138 dG, isolated hearts were studied using a Langendorff preparation. We calculated basal intrinsic FHRV (iFHRV) indices reflecting iFHRV's variability, predictability, temporal symmetry, fractality and chaotic behaviour, from the systolic peaks within 15 min segments in each heart. Significance was assumed at P < 0.05. Hearts of fetuses isolated from hypoxic pregnancy showed approximately 4-fold increases in the Grid transformation as well as the AND similarity index (sgridAND) and a 4-fold reduction in the scale-dependent Lyapunov exponent slope. We also detected a 2-fold reduction in the Recurrence quantification analysis, percentage of laminarity (pL) and recurrences, maximum and average diagonal line (dlmax, dlmean) and the Multiscale time irreversibility asymmetry index. The iHRV measures dlmax, dlmean, pL and sgridAND correlated with left ventricular end-diastolic pressure across both groups (average R2  = 0.38 ± 0.03). This is the first evidence that iHRV originates in fetal life and that chronic fetal hypoxia significantly alters it. Isolated fetal hearts from hypoxic pregnancy exhibit a time scale-dependent higher complexity in iFHRV.

Impact of ambient temperature on inflammation-induced encephalopathy in endotoxemic mice-role of phosphoinositide 3-kinase gamma.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is an early and frequent event of infection-induced systemic inflammatory response syndrome. Phosphoinositide 3-kinase γ (PI3Kγ) is linked to neuroinflammation and inflammation-related microglial activity. In homeotherms, variations in ambient temperature (Ta) outside the thermoneutral zone lead to thermoregulatory responses, mainly driven by a gradually increasing sympathetic activity, and may affect disease severity. We hypothesized that thermoregulatory response to hypothermia (reduced Ta) aggravates SAE in PI3Kγ-dependent manner. METHODS: Experiments were performed in wild-type, PI3Kγ knockout, and PI3Kγ kinase-dead mice, which were kept at neutral (30 ± 0.5 °C) or moderately lowered (26 ± 0.5 °C) Ta. Mice were exposed to lipopolysaccharide (LPS, 10 µg/g, from Escherichia coli serotype 055:B5, single intraperitoneal injection)-evoked systemic inflammatory response (SIR) and monitored 24 h for thermoregulatory response and blood-brain barrier integrity. Primary microglial cells and brain tissue derived from treated mice were analyzed for inflammatory responses and related cell functions. Comparisons between groups were made with one-way or two-way analysis of variance, as appropriate. Post hoc comparisons were made with the Holm-Sidak test or t tests with Bonferroni's correction for adjustments of multiple comparisons. Data not following normal distribution was tested with Kruskal-Wallis test followed by Dunn's multiple comparisons test. RESULTS: We show that a moderate reduction of ambient temperature triggers enhanced hypothermia of mice undergoing LPS-induced systemic inflammation by aggravated SAE. PI3Kγ deficiency enhances blood-brain barrier injury and upregulation of matrix metalloproteinases (MMPs) as well as an impaired microglial phagocytic activity. CONCLUSIONS: Thermoregulatory adaptation in response to ambient temperatures below the thermoneutral range exacerbates LPS-induced blood-brain barrier injury and neuroinflammation. PI3Kγ serves a protective role in suppressing release of MMPs, maintaining microglial motility and reinforcing phagocytosis leading to improved brain tissue integrity. Thus, preclinical research targeting severe brain inflammation responses is seriously biased when basic physiological prerequisites of mammal species such as preferred ambient temperature are ignored.

Computer-based intrapartum fetal monitoring and beyond: A review of the 2nd Workshop on Signal Processing and Monitoring in Labor (October 2017, Oxford, UK).

The second Signal Processing and Monitoring in Labor workshop gathered researchers who utilize promising new research strategies and initiatives to tackle the challenges of intrapartum fetal monitoring. The workshop included a series of lectures and discussions focusing on: new algorithms and techniques for cardiotocogoraphy (CTG) and electrocardiogram acquisition and analyses; the results of a CTG evaluation challenge comparing state-of-the-art computerized methods and visual interpretation for the detection of arterial cord pH <7.05 at birth; the lack of consensus about the role of intrapartum acidemia in the etiology of fetal brain injury; the differences between methods for CTG analysis "mimicking" expert clinicians and those derived from "data-driven" analyses; a critical review of the results from two randomized controlled trials testing the former in clinical practice; and relevant insights from modern physiology-based studies. We concluded that the automated algorithms performed comparably to each other and to clinical assessment of the CTG. However, the sensitivity and specificity urgently need to be improved (both computerized and visual assessment). Data-driven CTG evaluation requires further work with large multicenter datasets based on well-defined labor outcomes. And before first tests in the clinic, there are important lessons to be learnt from clinical trials that tested automated algorithms mimicking expert CTG interpretation. In addition, transabdominal fetal electrocardiogram monitoring provides reliable CTG traces and variability estimates; and fetal electrocardiogram waveform analysis is subject to promising new research. There is a clear need for close collaboration between computing and clinical experts. We believe that progress will be possible with multidisciplinary collaborative research.

Improving pregnancy outcomes in humans through studies in sheep.

Experimental studies that are relevant to human pregnancy rely on the selection of appropriate animal models as an important element in experimental design. Consideration of the strengths and weaknesses of any animal model of human disease is fundamental to effective and meaningful translation of preclinical research. Studies in sheep have made significant contributions to our understanding of the normal and abnormal development of the fetus. As a model of human pregnancy, studies in sheep have enabled scientists and clinicians to answer questions about the etiology and treatment of poor maternal, placental, and fetal health and to provide an evidence base for translation of interventions to the clinic. The aim of this review is to highlight the advances in perinatal human medicine that have been achieved following translation of research using the pregnant sheep and fetus.

Accelerated acidosis in response to variable fetal heart rate decelerations in chronically hypoxic ovine fetuses.

BACKGROUND: Due to limitations of technology, clinicians are typically unable to determine if human fetuses are normoxic or moderately, chronically hypoxic. Risk factors for chronic hypoxia include fetal growth restriction, which is associated with an increased incidence of oligohydramnios and thus a risk for umbilical cord occlusion (UCO) and variable fetal heart rate (FHR) decelerations. At delivery, fetal growth restriction infants (<3rd percentile) have nearly twice the incidence of low Apgar scores and umbilical pH <7.0. Despite the risks of oligohydramnios and intermittent UCO, there is little understanding of the acid/base responses rates of chronically hypoxic fetuses to variable FHR decelerations as might occur during human labor. OBJECTIVE: We sought to compare the increase in base deficit (BD) among chronically hypoxic as compared to normoxic ovine fetuses in response to simulated mild, moderate, and severe variable FHR decelerations. STUDY DESIGN: Near-term ovine fetuses were chronically prepared with brachial artery catheters and an inflatable umbilical cuff occluder. Following a recovery period, normoxic (n = 9) and spontaneously hypoxic (n = 5) fetuses were identified (arterial O2 saturation ≤55%). Both animal groups underwent graded, 1-minute occlusions every 2.5 minutes with 1 hour of mild (∼30 beats/min [bpm] decrease from baseline), 1 hour of moderate (∼60 bpm decrease from baseline), and up to 2 hours of severe (∼90 bpm decrease from baseline) variable FHR decelerations until fetal arterial pH reached 7.00, when occlusions were stopped. RESULTS: Repetitive UCO resulted in development of acidosis (pH <7.0) in both groups. Hypoxic and normoxic fetuses demonstrated similar BD increases in response to both mild (0.39, interquartile range [IQR] 0.28-0.45 vs 0.26, IQR 0.01-0.30 mEq/L/10 min, P = .25) and severe (1.97, IQR 1.50-2.43 vs 1.51, IQR 0.97-2.45 mEq/L/10 min, P = .63) variable decelerations. However, moderate variable decelerations increased BD in hypoxic fetuses at 2.5 times the rate of normoxic fetuses (0.97, IQR 0.52-1.72 vs 0.39, IQR 0.23-0.47 mEq/L/10 min, P = .03). During the recovery period, hypoxic fetuses cleared BD slower than normoxic fetuses (0.08 ± 0.02 vs 0.12 ± 0.03 mEq/L/min, P = .02). CONCLUSION: In comparison to normoxic fetuses, hypoxic fetuses can more rapidly progress to significant metabolic acidosis in response to moderate FHR variable decelerations, and more slowly recover with in utero resuscitation, likely a consequence of impaired placental function and fetal physiologic responses.

Can Monitoring Fetal Intestinal Inflammation Using Heart Rate Variability Analysis Signal Incipient Necrotizing Enterocolitis of the Neonate?

OBJECTIVE: Necrotizing enterocolitis of the neonate is an acute inflammatory intestinal disease that can cause necrosis and sepsis. Chorioamnionitis is a risk factor of necrotizing enterocolitis. The gut represents the biggest vagus-innervated organ. Vagal activity can be measured via fetal heart rate variability. We hypothesized that fetal heart rate variability can detect fetuses with incipient gut inflammation. DESIGN: Prospective animal study. SETTING: University research laboratory. SUBJECTS: Chronically instrumented near-term fetal sheep (n = 21). MEASUREMENTS AND MAIN RESULTS: Animals were surgically instrumented with vascular catheters and electrocardiogram to allow manipulation and recording from nonanesthetized animals. In 14 fetal sheep, inflammation was induced with lipopolysaccharide (IV) to mimic chorioamnionitis. Fetal arterial blood samples were drawn at selected time points over 54 hours post lipopolysaccharide for blood gas and cytokines (interleukin-6 and tumor necrosis factor-α enzymelinked immunosorbent assay). Fetal heart rateV was quantified throughout the experiment. The time-matched fetal heart rate variability measures were correlated to the levels of interleukin-6 and tumor necrosis factor-α. Upon necropsy, ionized calcium binding adaptor molecule 1+ (Iba1+), CD11c+ (M1), CD206+ (M2 macrophages), and occludin (leakiness marker) immunofluorescence in the terminal ileum was quantified along with regional Iba1+ signal in the brain (microglia). Interleukin-6 peaked at 3 hours post lipopolysaccharide accompanied by mild cardiovascular signs of sepsis. At 54 hours, we identified an increase in Iba1+ and, specifically, M1 macrophages in the ileum accompanied by increased leakiness, with no change in Iba1 signal in the brain. Preceding this change on tissue level, at 24 hours, a subset of nine fetal heart rate variability measures correlated exclusively to the Iba+ markers of ileal, but not brain, inflammation. An additional fetal heart rate variability measure, mean of the differences of R-R intervals, correlated uniquely to M1 ileum macrophages increasing due to lipopolysaccharide. CONCLUSIONS: We identified a unique subset of fetal heart rate variability measures reflecting 1.5 days ahead of time the levels of macrophage activation and increased leakiness in terminal ileum. We propose that such subset of fetal heart rate variability measures reflects brain-gut communication via the vagus nerve. Detecting such noninvasively obtainable organ-specific fetal heart rate variability signature of inflammation would alarm neonatologists about neonates at risk of developing necrotizing enterocolitis and sepsis. Clinical validation studies are required.

Ex Vivo Biomechanical Comparison of 4 Suture Materials for Laparoscopic Bladder Closure in the Horse.

OBJECTIVE: To compare a knotless, barbed suture to standard suture using laparoscopic suturing methods in an ex vivo model of equine bladder repair. STUDY DESIGN: Cadaveric study. SAMPLE POPULATION: Equine cadaver bladders (n=42). METHODS: A 5-cm incision was created and repaired in a laparoscopic training box with 4 different suture materials. Groups 1 and 2 used 2-0 poliglecaprone and 2-0 glycomer knotless, barbed suture, respectively, placed using laparoscopic instruments. Groups 3 and 4 used 0 and 2-0 polyglyconate knotless, barbed suture, respectively, placed using an automated laparoscopic suturing device. All groups used a double-layer inverting pattern. Time for suture placement was recorded. Bladders were inflated with water and bursting strength pressures recorded, including a control group of intact bladders. Statistical analysis using a linear model and taking into account the unequal variances was followed by a post-hoc Tukey's test. Significance was set at P<.05. RESULTS: Bursting strength did not vary significantly between treatment groups, but was significantly decreased compared to the control group (P<.001). Time to place the sutures with the 2 automated suture device groups (groups 3 and 4) was significantly faster than those in which the suture was placed using laparoscopic needle holders and forceps (groups 1 and 2; P=.001). CONCLUSION: Knotless, barbed suture may be a viable alternative to standard suture material for laparoscopic closure of the urinary bladder in horses. Further cyclic and in vivo testing should be performed before use in clinical cases.

Mathematical Model of Cardiovascular and Metabolic Responses to Umbilical Cord Occlusions in Fetal Sheep.

Fetal acidemia during labor is associated with an increased risk of brain injury and lasting neurological deficits. This is in part due to the repetitive occlusions of the umbilical cord (UCO) induced by uterine contractions. Whereas fetal heart rate (FHR) monitoring is widely used clinically, it fails to detect fetal acidemia. Hence, new approaches are needed for early detection of fetal acidemia during labor. We built a mathematical model of the UCO effects on FHR, mean arterial blood pressure (MABP), oxygenation and metabolism. Mimicking fetal experiments, our in silico model reproduces salient features of experimentally observed fetal cardiovascular and metabolic behavior including FHR overshoot, gradual MABP decrease and mixed metabolic and respiratory acidemia during UCO. Combined with statistical analysis, our model provides valuable insight into the labor-like fetal distress and guidance for refining FHR monitoring algorithms to improve detection of fetal acidemia and cardiovascular decompensation.

Effect of maternal ketoacidosis on the ovine fetus.

Ketoacidosis during pregnancy carries significant risk of intrauterine fetal demise, but little is known about the impact of ketoacids on the ovine fetus. We report a case series of maternal ketoacidosis in ewes. Maternal ketoacidosis may result in biochemical and acid-base fetal abnormalities associated with changes in feto-placental unit perfusion.

Effet de l'acidocétose maternelle sur un fœtus ovin. L'acidocétose durant la gestation comporte un risque important de mortalité intra-utérine du fœtus, mais on connaît peu de choses à propos de l'impact des acides cétoniques sur le fœtus ovin. Nous signalons une série de cas d'acidocétose maternelle chez les brebis. L'acidocétose maternelle peut provoquer des anomalies biochimiques et acides avec des changements dans la perfusion de l'unité fœto-placentaire.(Traduit par Isabelle Vallières).

The Vagus Nerve Regulates Immunometabolic Homeostasis in the Ovine Fetus near Term: The Impact on Terminal Ileum.

BACKGROUND: Glucosensing elements are widely distributed throughout the body and relay information about circulating glucose levels to the brain via the vagus nerve. However, while anatomical wiring has been established, little is known about the physiological role of the vagus nerve in glucosensing. The contribution of the vagus nerve to inflammation in the fetus is poorly understood. Increased glucose levels and inflammation act synergistically when causing organ injury, but their interplay remains incompletely understood. We hypothesized that vagotomy (Vx) will trigger a rise in systemic glucose levels and this will be enhanced during systemic and organ-specific inflammation. Efferent vagus nerve stimulation (VNS) should reverse this phenotype. METHODS: Near-term fetal sheep (n = 57) were surgically prepared using vascular catheters and ECG electrodes as the control and treatment groups (lipopolysaccharide (LPS), Vx + LPS, Vx + LPS + selective efferent VNS). The experiment was started 72 h postoperatively to allow for post-surgical recovery. Inflammation was induced with LPS bolus intravenously (LPS group, 400 ng/fetus/day for 2 days; n = 23). For the Vx + LPS group (n = 11), a bilateral cervical vagotomy was performed during surgery; of these n = 5 received double the LPS dose, LPS800. The Vx + LPS + efferent VNS group (n = 8) received cervical VNS probes bilaterally distal from Vx in eight animals. Efferent VNS was administered for 20 min on days 1 and 2 +/10 min around the LPS bolus. Fetal arterial blood samples were drawn on each postoperative day of recovery (-72 h, -48 h, and -24 h) as well as at the baseline and seven selected time points (3-54 h) to profile inflammation (ELISA IL-6, pg/mL), insulin (ELISA), blood gas, and metabolism (glucose). At 54 h post-LPS, a necropsy was performed, and the terminal ileum macrophages' CD11c (M1 phenotype) immunofluorescence was quantified to detect inflammation. The results are reported for p < 0.05 and for Spearman R2 > 0.1. The results are presented as the median (IQR). RESULTS: Across the treatment groups, blood gas and cardiovascular changes indicated mild septicemia. At 3 h in the LPS group, IL-6 peaked. That peak was decreased in the Vx + LPS400 group and doubled in the Vx + LPS800 group. The efferent VNS sped up the reduction in the inflammatory response profile over 54 h. The M1 macrophage activity was increased in the LPS and Vx + LPS800 groups only. The glucose and insulin concentrations in the Vx + LPS group were, respectively, 1.3-fold (throughout the experiment) and 2.3-fold higher vs. control (at 3 h). The efferent VNS normalized the glucose concentrations. CONCLUSIONS: The complete withdrawal of vagal innervation resulted in a 72-h delayed onset of a sustained increase in glucose for at least 54 h and intermittent hyperinsulinemia. Under the conditions of moderate fetal inflammation, this was related to higher levels of gut inflammation. The efferent VNS reduced the systemic inflammatory response as well as restored both the concentrations of glucose and the degree of terminal ileum inflammation, but not the insulin concentrations. Supporting our hypothesis, these findings revealed a novel regulatory, hormetic, role of the vagus nerve in the immunometabolic response to endotoxin in near-term fetuses.

Correlation of arterial fetal base deficit and lactate changes with severity of variable heart rate decelerations in the near-term ovine fetus.

OBJECTIVE: Recent guidelines classify variable decelerations without detail as to degree of depth. We hypothesized that variable deceleration severity is highly correlated with fetal base deficit accumulation. STUDY DESIGN: Seven near-term fetal sheep underwent a series of graded umbilical cord occlusions resulting in mild (30 bpm decrease), moderate (60 bpm decrease), or severe (decrease of 90 bpm to baseline <70 bpm) variable decelerations at 2.5 minute intervals. RESULTS: Mild, moderate, and severe variable decelerations increased fetal base deficit (0.21 ± 0.03, 0.27 ± 0.03, and 0.54 ± 0.09 mEq/L per minute) in direct proportion to severity. During recovery, fetal base deficit cleared at 0.12 mEq/L per minute. CONCLUSION: In this model, ovine fetuses can tolerate repetitive mild and moderate variable decelerations with minimal change in base deficit and lactate. In contrast, repetitive severe variable decelerations may result in significant base deficit increases, dependent on frequency. Modified guideline differentiation of mild/moderate vs severe variable decelerations may aid in the interpretation of fetal heart rate tracings and optimization of clinical management paradigms.

Psychosocial stress in pregnancy and preterm birth: associations and mechanisms.

AIMS: Psychosocial stress during pregnancy (PSP) is a risk factor of growing interest in the etiology of preterm birth (PTB). This literature review assesses the published evidence concerning the association between PSP and PTB, highlighting established and hypothesized physiological pathways mediating this association. METHOD: The PubMed and Web of Science databases were searched using the keywords "psychosocial stress", "pregnancy", "pregnancy stress", "preterm", "preterm birth", "gestational age", "anxiety", and "social support". After applying the exclusion criteria, the search produced 107 articles. RESULTS: The association of PSP with PTB varied according to the dimensions and timing of PSP. Stronger associations were generally found in early pregnancy, and most studies demonstrating positive results found moderate effect sizes, with risk ratios between 1.2 and 2.1. Subjective perception of stress and pregnancy-related anxiety appeared to be the stress measures most closely associated with PTB. Potential physiological pathways identified included behavioral, infectious, neuroinflammatory, and neuroendocrine mechanisms. CONCLUSIONS: Future research should examine the biological pathways of these different psychosocial stress dimensions and at multiple time points across pregnancy. Culture-independent characterization of the vaginal microbiome and noninvasive monitoring of cholinergic activity represent two exciting frontiers in this research.

Predicting Patients Requiring Treatment for Depression in the Postpartum Period Using Common Electronic Medical Record Data Available Antepartum.

Introduction: Depression requiring treatment in the postpartum period significantly impacts maternal and neonatal health. Although preventive management of depression in pregnancy has been shown to decrease the negative impacts, current methods for identifying at-risk patients are insufficient. Given the complexity of the diagnosis and interplay of clinical/demographic factors, we tested whether machine learning techniques can accurately identify at-risk patients in the postpartum period. Methods: This is a retrospective cohort study of the NIH Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be, which enrolled 10,038 nulliparous people. The primary outcome was depression in the postpartum period. We constructed and optimized 4 machine learning models using distributed random forest modeling and 1 logistic regression model on the basis of the NIH Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be dataset. Model 1 utilized only readily obtainable sociodemographic data. Model 2 added maternal prepregnancy mental health data. Model 3 utilized recursive feature elimination to construct a parsimonious model. Model 4 further titrated the input data to simplify prepregnancy mental health variables. The logistic regression model used the same input data as Model 3 as a proof of concept. Results: Of 8,454 births, 338 (4%) were complicated by depression in the postpartum period. Model 3 was the highest performing, showing the area under the receiver operating characteristics curve of 0.91 (±0.02). Models 1-3 identified the 9 variables most predictive of depression hierarchically, ranging from depression history (highest), history of mental health condition, recent psychiatric medication use, BMI, income, age, anxiety history, education, and preparedness for pregnancy (lowest). In Model 4, the area under the receiver operating characteristics curve remained at 0.79 (±0.05). Conclusions: Postpartum depression can be predicted with high accuracy for individual patients using antepartum information commonly found in electronic medical records. In addition, baseline mental health status and sociodemographic factors have a larger role in the postpartum period than previously understood.