Cell-free DNA methylome analysis for early preeclampsia prediction.

Preeclampsia (PE) is a leading cause for peripartal morbidity, especially if developing early in gestation. To enable prophylaxis in the prevention of PE, pregnancies at risk of PE must be identified early-in the first trimester. To identify at-risk pregnancies we profiled methylomes of plasma-derived, cell-free DNA from 498 pregnant women, of whom about one-third developed early-onset PE. We detected DNA methylation differences between control and PE pregnancies that enabled risk stratification at PE diagnosis but also presymptomatically, at around 12 weeks of gestation (range 9-14 weeks). The first-trimester risk prediction model was validated in an external cohort collected from two centers (area under the curve (AUC) = 0.75) and integrated with routinely available maternal risk factors (AUC = 0.85). The combined risk score correctly predicted 72% of patients with early-onset PE at 80% specificity. These preliminary results suggest that cell-free DNA methylation profiling is a promising tool for presymptomatic PE risk assessment, and has the potential to improve treatment and follow-up in the obstetric clinic.

First-Trimester Normotension Is a Weak Indicator of Normal Maternal Cardiovascular Function.

BACKGROUND: As by definition, mean arterial pressure equals the product of cardiac output (CO) and total vascular resistance (TPR), we hypothesized that, irrespective of thresholds to define hypertension, a CO-TPR imbalance might exist in first-trimester normotensive pregnancies with altered risks for adverse gestational outcomes. METHODS: A standard protocol was used for automated blood pressure measurement combined with impedance cardiography assessment of CO and TPR (NICCOMO). First-trimester normotensive pregnant women were categorized into 3 groups relative to the reference 75th percentile (P75) of CO and TPR: (1) normal CO and TPR, (2) high CO, and (3) high TPR. These subgroups were compared at blood pressure thresholds 140/90, 130/85, and 130/80 mmHg. The gestational outcome was categorized after birth according to International Society for Studies of Hypertension in Pregnancy criteria. RESULTS: Compared with pregnancies with normal CO and TPR (≤P75), women with high TPR at blood pressure <140/90 mmHg are at risk for developing gestational hypertension (odds ratio, 3.795 [1.321-10.904]; P<0.010), late-onset preeclampsia (odds ratio, 3.137 [1.060-9.287]; P<0.050), and neonates small for gestational age (odds ratio, 1.780 [1.056-2.998]; P<0.050). CONCLUSIONS: Cardiovascular imbalance can present in normotensive women in the first trimester and is associated with increased risks for adverse gestational outcomes. This study illustrates the relevance of CO and TPR assessments as an adjunct to blood pressure measurement and invites for further exploring their value in screening algorithms for gestational hypertensive disorders and/or small for gestational age.

Information Resources Among Flemish Pregnant Women: Cross-sectional Study.

BACKGROUND: There has been an exponential growth in the availability of apps, resulting in increased use of pregnancy apps. However, information on resources and use of apps among pregnant women is relatively limited. OBJECTIVE: The aim of this study is to map the current information resources and the use of pregnancy apps among pregnant women in Flanders. METHODS: A cross-sectional study was conducted, using a semistructured survey (April-June 2019) consisting of four different domains: (1) demographics; (2) use of devices; (3) sources of information; and (4) use of pregnancy apps. Women were recruited by social media, flyers, and paper questionnaires at prenatal consultations. Statistical analysis was mainly focused on descriptive statistics. Differences in continuous and categorical variables were tested using independent Student t tests and chi-square tests. Correlations were investigated between maternal characteristics and the women's responses. RESULTS: In total, 311 women completed the entire questionnaire. Obstetricians were the primary source of information (268/311, 86.2%) for pregnant women, followed by websites/internet (267/311, 85.9%) and apps (233/311, 74.9%). The information that was most searched for was information about the development of the baby (275/311, 88.5%), discomfort/complaints (251/311, 80.7%) and health during pregnancy (248/311, 79.7%), administrative/practical issues (233/311, 74.9%), and breastfeeding (176/311, 56.6%). About half of the women (172/311, 55.3%) downloaded a pregnancy app, and primarily searched app stores (133/311, 43.0%). Pregnant women who are single asked their mothers (22/30, 73.3%) or other family members (13/30, 43.3%) for significantly more information than did married women (mother [in law]: 82/160, 51.3%, P=.02; family members: 35/160, 21.9%, P=.01). Pregnant women with lower education were significantly more likely to have a PC or laptop than those with higher education (72/73, 98.6% vs 203/237, 85.5%; P=.008), and to consult other family members for pregnancy information (30/73, 41.1% vs 55/237, 23.1%; P<.001), but were less likely to consult a gynecologist (70/73, 95.9% vs 198/237, 83.5%; P=.001). They also followed more prenatal sessions (59/73, 80.8% vs 77/237, 32.5%; P=.04) and were more likely to search for information regarding discomfort/complaints during pregnancy (65/73, 89% vs 188/237, 79.5%; P=.02). Compared to multigravida, primigravida were more likely to solicit advice about their pregnancy from other women in their social networks (family members: primigravida 44/109, 40.4% vs multigravida 40/199, 20.1%; P<.001; other pregnant women: primigravida 58/109, 53.2% vs multigravida 80/199, 40.2%; P<.03). CONCLUSIONS: Health care professionals need to be aware that apps are important and are a growing source of information for pregnant women. Concerns rise about the quality and safety of those apps, as only a limited number of apps are subjected to an external quality check. Therefore, it is important that health care providers refer to high-quality digital resources and take the opportunity to discuss digital information with pregnant women.

A multicentric validation study of a novel home sleep apnea test based on peripheral arterial tonometry.

STUDY OBJECTIVES: This paper reports on the multicentric validation of a novel FDA-cleared home sleep apnea test based on peripheral arterial tonometry (PAT HSAT). METHODS: One hundred sixty-seven participants suspected of having obstructive sleep apnea (OSA) were included in a multicentric cohort. All patients underwent simultaneous polysomnography (PSG) and PAT HSAT, and all PSG data were independently double scored using both the recommended 1A rule for hypopnea, requiring a 3% desaturation or arousal (3% Rule), and the acceptable 1B rule for hypopnea, requiring a 4% desaturation (4% Rule). The double-scoring of PSG enabled a comparison of the agreement between PAT HSAT and PSG to the inter-rater agreement of PSG. Clinical endpoint parameters were selected to evaluate the device's ability to determine the OSA severity category. Finally, a correction for near-boundary apnea-hypopnea index values was proposed to adequately handle the inter-rater variability of the PSG benchmark. RESULTS: For both the 3% and the 4% Rules, most endpoint parameters showed a close agreement with PSG. The 4-way OSA severity categorization accuracy of PAT HSAT was strong, but nevertheless lower than the inter-rater agreement of PSG (70% vs 77% for the 3% Rule and 78% vs 81% for the 4% Rule). CONCLUSIONS: This paper reported on a multitude of robust endpoint parameters, in particular OSA severity categorization accuracies, while also benchmarking clinical performances against double-scored PSG. This study demonstrated strong agreement of PAT HSAT with PSG. The results of this study also suggest that different brands of PAT HSAT may have distinct clinical performance characteristics.

Vital Signs Prediction for COVID-19 Patients in ICU.

This study introduces machine learning predictive models to predict the future values of the monitored vital signs of COVID-19 ICU patients. The main vital sign predictors include heart rate, respiration rate, and oxygen saturation. We investigated the performances of the developed predictive models by considering different approaches. The first predictive model was developed by considering the following vital signs: heart rate, blood pressure (systolic, diastolic and mean arterial, pulse pressure), respiration rate, and oxygen saturation. Similar to the first approach, the second model was developed using the same vital signs, but it was trained and tested based on a leave-one-subject-out approach. The third predictive model was developed by considering three vital signs: heart rate (HR), respiration rate (RR), and oxygen saturation (SpO2). The fourth model was a leave-one-subject-out model for the three vital signs. Finally, the fifth predictive model was developed based on the same three vital signs, but with a five-minute observation rate, in contrast with the aforementioned four models, where the observation rate was hourly to bi-hourly. For the five models, the predicted measurements were those of the three upcoming observations (on average, three hours ahead). Based on the obtained results, we observed that by limiting the number of vital sign predictors (i.e., three vital signs), the prediction performance was still acceptable, with the average mean absolute percentage error (MAPE) being 12%,5%, and 21.4% for heart rate, oxygen saturation, and respiration rate, respectively. Moreover, increasing the observation rate could enhance the prediction performance to be, on average, 8%,4.8%, and 17.8% for heart rate, oxygen saturation, and respiration rate, respectively. It is envisioned that such models could be integrated with monitoring systems that could, using a limited number of vital signs, predict the health conditions of COVID-19 ICU patients in real-time.

Increased Intra-Abdominal Pressure During Laparoscopic Pneumoperitoneum Enhances Albuminuria via Renal Venous Congestion, Illustrating Pathophysiological Aspects of High Output Preeclampsia.

Intra-abdominal hypertension (IAH) causes severe organ dysfunction. Our aim is to evaluate the effect of increased intra-abdominal pressure (IAP) on renal function, hypothesizing that venous congestion may increase proteinuria and fluid retention without endothelial dysfunction. Three urine samples were collected from 32 non-pregnant women undergoing laparoscopic-assisted vaginal hysterectomy (LAVH) and from 10 controls placed in Trendelenburg position for 60 min. Urine sampling was done before (PRE), during or immediately after (PER), and two hours after (POST) the procedure. Urinary albumin, protein and creatinine concentrations were measured in each sample, and ratios were calculated and compared within and between groups. During LAVH, the albumin/creatinine ratio (ACR) increased and persisted POST-procedure, which was not observed in controls. A positive correlation existed between the LAVH duration and the relative change in both ACR and protein/creatinine ratio (PCR) PER- and POST-procedure. Iatrogenic IAH increases urinary ACR and PCR in non-pregnant women via a process of venous congestion. This mechanism might explain the presentation of one specific subtype of late-onset preeclampsia, where no drop of maternal cardiac output is observed.

Portable Detection of Apnea and Hypopnea Events Using Bio-Impedance of the Chest and Deep Learning.

Sleep apnea is one of the most common sleep-related breathing disorders. It is diagnosed through an overnight sleep study in a specialized sleep clinic. This setup is expensive and the number of beds and staff are limited, leading to a long waiting time. To enable more patients to be tested, and repeated monitoring for diagnosed patients, portable sleep monitoring devices are being developed. These devices automatically detect sleep apnea events in one or more respiration-related signals. There are multiple methods to measure respiration, with varying levels of signal quality and comfort for the patient. In this study, the potential of using the bio-impedance (bioZ) of the chest as a respiratory surrogate is analyzed. A novel portable device is presented, combined with a two-phase Long Short-Term Memory (LSTM) deep learning algorithm for automated event detection. The setup is benchmarked using simultaneous recordings of the device and the traditional polysomnography in 25 patients. The results demonstrate that using only the bioZ, an area under the precision-recall curve of 46.9% can be achieved, which is on par with automatic scoring using a polysomnography respiration channel. The sensitivity, specificity and accuracy are 58.4%, 76.2% and 72.8% respectively. This confirms the potential of using the bioZ device and deep learning algorithm for automatically detecting sleep respiration events during the night, in a portable and comfortable setup.

Low Volume Circulation in Normotensive Women Pregnant with Neonates Small for Gestational Age.

BACKGROUND: Pregnancies complicated with small for gestational age (SGA) neonates are reported with maternal circulatory maladaptations. OBJECTIVES: We aimed to understand the pathophysiology of the maternal circulation in normotensive SGA pregnancies and to point out the trimestral differences from those with appropriate-to-large (non-SGA [NGA]) neonates. METHODS: An observational study was conducted in 3 trimestral cohorts of normotensive pregnancies, categorized after birth according to neonatal birth weight percentile (BW%) as SGA (BW% ≤10, n = 158) or NGA (BW% > 10, n = 1,038). Standardized electrocardiogram-Doppler ultrasound, impedance cardiography, and bio-impedance were used to assess the maternal heart, arteries, veins, and fluid. RESULTS: Diastolic blood pressure and mean arterial pressure were not significantly different, unless in the third trimester. In SGA compared to NGA pregnancies, total peripheral resistance (TPR) was higher and total arterial compliance, cardiac output (CO), and total body water (TBW) were lower throughout pregnancy. Venous return-enhancing functions were activated. In NGA but not SGA pregnancies, a positive correlation was found between BW% and CO + TBW and a negative correlation between BW% and TPR. CONCLUSIONS: SGA pregnancies are characterized by lower maternal body fluid volume and CO, while normal blood pressures are maintained via increased TPR already from the first trimester onwards. Pregnancy-induced hemodynamic changes are superimposed on these characteristics.

Gestational hypertensive disorders show unique patterns of circulatory deterioration with ongoing pregnancy.

A combined assessment of heart, arteries, veins, and body fluid content throughout pregnancy has not yet been reported. We hypothesized that a gradual aggravation of circulatory dysfunction exists from the latent to the clinical phase of gestational hypertensive disease (GHD), and that pathways are unique for preeclampsia with early onset < 34 wk (EPE) and late onset ≥ 34 wk (LPE), and gestational hypertension (GH). Women with singleton pregnancy and no known diseases were invited for a prospective, observational study and had standardized sphygmomanometric blood pressure measurement, bioimpedance body water spectrum analysis, impedance cardiography for cardiac and arterial assessment, and combined Doppler-ECG of hepatic and renal interlobar veins and uterine arteries. Outcome was categorized as uncomplicated (UP, n = 1,700), EPE ( n = 87), LPE ( n = 218), or GH ( n = 188). A linear mixed model for repeated measurements, corrected for age, parity, and body mass index, was employed in SAS 9.4 to analyze trimestral changes within and between groups. From the first to the third trimester, body water increased in all groups, and an increasing number of abnormal parameters relative to UP occurred in all GHD. First-trimester blood pressure and peripheral resistance were higher in GHD than UP, together with increased uterine flow resistance and extracellular water in EPE, and with lower heart rate and aorta flow velocity in LPE. An overall gestational rise of body water volumes coexists with a gradual worsening of cardiovascular dysfunction in GHD, of which pathophysiological pathways are unique for EPE, LPE, and GH, respectively.

Systematic Comparison of Respiratory Signals for the Automated Detection of Sleep Apnea.

Sleep apnea is one of the most common sleep disorders. It is characterized by the cessation of breathing during sleep due to airway blockages (obstructive sleep apnea) or disturbances in the signals from the brain (central sleep apnea). The gold standard for diagnosing sleep apnea is performing an overnight polysomnography recording which contains, among others, a wide array of respiratory signals. Respiration information can also be extracted from other physiological signals such as an electrocardiogram or from a bio-impedance measurement on the chest. Studies have shown that algorithms can be developed for automated sleep apnea detection using one of these many respiratory signals. In this work, the predictive power of these different respiratory signals is analyzed and compared. The results provide useful insights into the comparative predictive power of the different respiratory signals in a realistic setting for automated sleep apnea detection and provide a basis for the development of less obtrusive measurement techniques.

Body fluid volume homeostasis is abnormal in pregnancies complicated with hypertension and/or poor fetal growth.

OBJECTIVES: To evaluate body water volumes and cardiac output in each trimester of pregnancies complicated with hypertension and/or poor fetal growth, relative to uncomplicated pregnancy. METHODS: In this semi-longitudinal cohort study, a standardised non-invasive maternal hemodynamics assessment in first, second or third trimester was performed in 1068 women with uncomplicated pregnancy (UP), 75 with early onset (EPE) and 117 with late onset preeclampsia (LPE), 139 with gestational hypertension (GH), 129 with small for gestational age (SGA) neonates and 43 with essential hypertension (EH). Women with hypertension or SGA were included prior to onset of symptoms or at diagnosis of disease; 46% of women (758/1631) were assessed in ≥ 2 trimesters. Impedance cardiography and spectrum analysis were used to measure cardiac output, total body water (TBW), extracellular (ECW) and intracellular water (ICW). A linear mixed model was used for inter-trimestrial comparison of parity-, age- and BMI-corrected values within and between groups. RESULTS: For all pregnancies, TBW is higher in each consecutive trimester, mainly due to increasing fraction of ECW (ECW%). Compared to first trimester UP, ECW and ECW% are higher in EPE whereas TBW, ECW and ICW are lower in SGA. Compared to inter-trimestrial differences in UP, abnormal changes for body water volumes are observed in GH, EPE and LPE and for CO in EPE and LPE. Changes in EH are not different from UP. CONCLUSIONS: This study is the first to show that concomitant gestational changes of ECW and CO are different from UP already in preclinical stages of pregnancies complicated with hypertension and/or poor fetal growth, except EH. This finding highlights the relevance of early gestational assessment of maternal body fluid status in pregnancies at risk for hypertension or poor fetal growth.

An Evaluation of the NightOwl Home Sleep Apnea Testing System.

STUDY OBJECTIVES: The objective of this study was to evaluate the performance of a miniaturized home sleep apnea test, called NightOwl. The system consists of a sensor placed on the fingertip and a cloud-based analytics software. The sensor acquires accelerometer and photoplethysmographic data. The software derives actigraphy from the former, and blood oxygen saturation and peripheral arterial tone, among other features, from the latter. METHODS: Data of 101 participants who underwent an in-laboratory polysomnography (PSG), while wearing the NightOwl sensor, were collected. In order to establish an external benchmark, all PSG tests were edited by a somnologist of Younes Medical Technologies Ltd. (YMT) after analysis by the Michele Sleep Scoring System (MSSS). The respiratory event index (REI) derived by NightOwl (NightOwl-REI), the apnea-hypopnea index (AHI) derived by Ziekenhuis Oost-Limburg (ZOL-AHI), and the AHI derived by YMT (MSSS-AHI) were compared. RESULTS: The NightOwl-REI had a high correlation with the MSSS-AHI (ρ = .87, P < .001), which was close to the correlation between the ZOL-AHI and MSSS-AHI (ρ = .84, P < .001). The NightOwl-REI and ZOL-AHI had a correlation of .77 (P < .001). After categorization of the AHI, the agreement between the NightOwl-REI and the MSSS-AHI was .812 and the agreement between the ZOL-AHI and MSSS-AHI was .743, after double-labeling near-boundary participants. CONCLUSIONS: The NightOwl-REI achieved a close correlation and REI-categorization with the MSSS-AHI, especially in light of the significant inter-scorer variability of the analysis of the PSG.

A Novel Intelligent Two-Way Communication System for Remote Heart Failure Medication Uptitration (the CardioCoach Study): Randomized Controlled Feasibility Trial.

BACKGROUND: European Society of Cardiology guidelines for the treatment of heart failure (HF) prescribe uptitration of angiotensin-converting enzyme inhibitors (ACE-I) and ß-blockers to the maximum-tolerated, evidence-based dose. Although HF prognosis can drastically improve when correctly implementing these guidelines, studies have shown that they are insufficiently implemented in clinical practice. OBJECTIVE: The aim of this study was to verify whether supplementing the usual care with the CardioCoach follow-up tool is feasible and safe, and whether the tool is more efficient in implementing the guideline recommendations for ß-blocker and ACE-I. METHODS: A total of 25 HF patients were randomly assigned to either the usual care control group (n=10) or CardioCoach intervention group (n=15), and observed for 6 months. The CardioCoach follow-up tool is a two-way communication platform with decision support algorithms for semiautomatic remote medication uptitration. Remote monitoring sensors automatically transmit patient's blood pressure, heart rate, and weight on a daily basis. RESULTS: Patients' satisfaction and adherence for medication intake (10,018/10,825, 92.55%) and vital sign measurements (4504/4758, 94.66%) were excellent. However, the number of technical issues that arose was large, with 831 phone contacts (median 41, IQR 32-65) in total. The semiautomatic remote uptitration was safe, as there were no adverse events and no false positive uptitration proposals. Although no significant differences were found between both groups, a higher number of patients were on guideline-recommended medication dose in both groups compared with previous reports. CONCLUSIONS: The CardioCoach follow-up tool for remote uptitration is feasible and safe and was found to be efficient in facilitating information exchange between care providers, with high patient satisfaction and adherence. TRIAL REGISTRATION: ClinicalTrials.gov NCT03294811; https://clinicaltrials.gov/ct2/show/NCT03294811 (Archived by WebCite at http://www.webcitation.org/6xLiWVsgM).