Cell-free DNA in maternal blood and artificial intelligence: accurate prenatal detection of fetal congenital heart defects.

BACKGROUND: DNA cytosine nucleotide methylation (epigenomics and epigenetics) is an important mechanism for controlling gene expression in cardiac development. Combined artificial intelligence and whole-genome epigenomic analysis of circulating cell-free DNA in maternal blood has the potential for the detection of fetal congenital heart defects. OBJECTIVE: This study aimed to use genome-wide DNA cytosine methylation and artificial intelligence analyses of circulating cell-free DNA for the minimally invasive detection of fetal congenital heart defects. STUDY DESIGN: In this prospective study, whole-genome cytosine nucleotide methylation analysis was performed on circulating cell-free DNA using the Illumina Infinium MethylationEPIC BeadChip array. Multiple artificial intelligence approaches were evaluated for the detection of congenital hearts. The Ingenuity Pathway Analysis program was used to identify gene pathways that were epigenetically altered and important in congenital heart defect pathogenesis to further elucidate the pathogenesis of isolated congenital heart defects. RESULTS: There were 12 cases of isolated nonsyndromic congenital heart defects and 26 matched controls. A total of 5918 cytosine nucleotides involving 4976 genes had significantly altered methylation, that is, a P value of <.05 along with ≥5% whole-genome cytosine nucleotide methylation difference, in congenital heart defect cases vs controls. Artificial intelligence analysis of the methylation data achieved excellent congenital heart defect predictive accuracy (areas under the receiver operating characteristic curve, ≥0.92). For example, an artificial intelligence model using a combination of 5 whole-genome cytosine nucleotide markers achieved an area under the receiver operating characteristic curve of 0.97 (95% confidence interval, 0.87-1.0) with 98% sensitivity and 94% specificity. We found epigenetic changes in genes and gene pathways involved in the following important cardiac developmental processes: "cardiovascular system development and function," "cardiac hypertrophy," "congenital heart anomaly," and "cardiovascular disease." This lends biologic plausibility to our findings. CONCLUSION: This study reported the feasibility of minimally invasive detection of fetal congenital heart defect using artificial intelligence and DNA methylation analysis of circulating cell-free DNA for the prediction of fetal congenital heart defect. Furthermore, the findings supported an important role of epigenetic changes in congenital heart defect development.

Postpartum Hemorrhage-Epidemiology, Risk Factors, and Causes.

The incidence of postpartum hemorrhage (PPH) is increasing worldwide and in the United States. Coinciding, is the increased rate of severe maternal morbidity with blood transfusion in the United States over the past 2 decades. Consequences of PPH can be life-threatening and carry significant cost burden to the health care system. This review will discuss the current trends, distribution, and risk factors for PPH. Causes of PPH will be explored in detail.

Evaluation During Postpartum Hemorrhage.

Postpartum hemorrhage is an obstetric emergency that is the leading and the most preventable cause of maternal death that occurs on the day of birth. The treatment of postpartum hemorrhage in a timely fashion is crucial to prevent morbidity and mortality. The accurate assessment of blood loss during delivery and the postpartum period remains a major challenge. Hence, it is imperative to have a standardized evaluation strategy for accurate assessment of blood loss, adequate classification of hemorrhage, and timely initiated interventions. The multidisciplinary evaluation strategy should be in place regardless of the delivery route.

Establishment of fetal biometric charts using quantile regression analysis.

OBJECTIVES: Fetal growth evaluation is an essential component of pregnancy surveillance. There have been several methods used to construct growth charts. The conventional charts used in current daily practice are based on small numbers and traditional statistical methods. The purpose of this study was to improve fetal biometric charts based on a much larger number of observations with an alternative statistical method: quantile regression analysis. A comparison between the charts is presented. METHODS: During the 12 years of study, 17,708 sonographic examinations of pregnant women from the north of Israel, between 12 and 42 weeks of pregnancy, were performed. Fetal measurements were obtained by several operators using various equipment and included head circumference, abdominal circumference, and femur length. RESULTS: Growth charts were established based on these measurements. CONCLUSIONS: In this study, we constructed biometric growth charts using a large cohort of pregnant women. These charts offer the advantages of specific estimated regression parameters for each specified percentile, thus better defining the normal range. We suggest using these new charts in routine daily obstetric practice.

Urine metabolomic biomarkers for prediction of isolated fetal congenital heart defect.

OBJECTIVE: To identify maternal second and third trimester urine metabolomic biomarkers for the detection of fetal congenital heart defects (CHDs). STUDY DESIGN: This was a prospective study. Metabolomic analysis of randomly collected maternal urine was performed, comparing pregnancies with isolated, non-syndromic CHDs versus unaffected controls. Mass spectrometry (liquid chromatography and direct injection and tandem mass spectrometry, LC-MS-MS) as well as nuclear magnetic resonance spectrometry, 1H NMR, were used to perform the analyses between 14 0/7 and 37 0/7 weeks gestation. A total of 36 CHD cases and 41 controls were compared. Predictive algorithms using urine markers alone or combined with, clinical and ultrasound (US) (four-chamber view) predictors were developed and compared. RESULTS: A total of 222 metabolites were identified, of which 16 were overlapping between the two platforms. Twenty-three metabolite concentrations were found in significantly altered in CHD gestations on univariate analysis. The concentration of methionine was most significantly altered. A predictive algorithm combining metabolites (histamine, choline, glucose, formate, methionine, and carnitine) plus US four-chamber view achieved an AUC = 0.894; 95% CI, 0814-0.973 with a sensitivity of 83.8% and specificity of 87.8%. Enrichment pathway analysis identified several lipid related pathways that are dysregulated in CHD, including phospholipid biosynthesis, phosphatidylcholine biosynthesis, phosphatidylethanolamine biosynthesis, and fatty acid metabolism. This could be consistent with the increased risk of CHD in diabetic pregnancies. CONCLUSIONS: We report a novel, noninvasive approach, based on the analysis of maternal urine for isolated CHD detection. Further, the dysregulation of lipid- and folate metabolism appears to support prior data on the mechanism of CHD.

Temporal and quantitative associations of electronic fetal heart rate monitoring patterns and neonatal outcomes†.

Objective: The objective of this study is to evaluate the associations of electronic fetal heart rate monitoring (EFM) patterns and adverse neonatal outcomes Study design: From 2013 to 2016; 12,067 term, singleton deliveries in labor ≥2 h with abnormal EFM defined as absent accelerations, variable, late or prolonged decelerations, tachycardia, bradycardia, or minimal variability were analyzed as any documentation during labor, in first hour and last hour of labor. Outcomes were composite neonatal adverse outcomes, neonatal intensive care unit (NICU) admission, neonatal hypoxia, neonatal hypoglycemia, umbilical artery pH, and base excess. Independent associations were ascertained using regression analysis. Results: Significant independent associations occurred between any abnormal EFM during the last hour and five adverse neonatal outcomes; between abnormal EFM at any time and one adverse neonatal outcome while there was none with the first hour of labor. In the last hour, accelerations had significant negative associations with three adverse neonatal outcomes, while prolonged decelerations, late decelerations, tachycardia, and bradycardia had significant positive associations with three adverse neonatal outcomes. Throughout labor, increasing accelerations events were significantly negatively correlated with all adverse neonatal outcomes, while increasing frequency of late, variable, and prolonged decelerations were positively associated with five adverse neonatal outcomes. Hierarchical analysis showed that bradycardia/tachycardia contributed only 0.8%, while all EFM periodic changes contributed 1%; the addition of the frequencies of abnormal EFM events contributed 0.6% to the variance in umbilical artery pH and base excess. Conclusions: Terminal EFM patterns are independently associated with neonatal outcomes. Accelerations are protective of adverse neonatal outcomes. Increasing frequency of EFM patterns overtime contributes to neonatal outcome.

A Multidisciplinary Model for Reviewing Severe Maternal Morbidity Cases and Teaching Residents Patient Safety Principles.

The Joint Commission recommends that severe maternal morbidity (SMM) cases involving peripartum ICU admissions and blood transfusion > 4 units undergo systematic reviews to determine opportunities for improvement in care. This article describes a retrospective study of an SMM multidisciplinary committee review using a published template. METHODS: Residents attend a patient safety and quality improvement (PSQI) course at orientation, learn in serial PSQI educational sessions, and receive individual training on the SMM review. The multidisciplinary SMM review process determines contributory factors, identifies best practices, recognizes care improvement opportunities, and facilitates adoption of appropriate interventions. How the process educated residents on the Clinical Learning Environment Review (CLER) focus areas was explored. RESULTS: From January 2015 to June 2017, 45 SMM cases were reviewed. Reviewers were primarily residents/fellows (64.4% of cases), nurses (11.1%), and maternal-fetal medicine faculty (24.4%). Transfusion > 4 units occurred in 44.4% of cases, and ICU admission in 68.9%. Causes of SMM included obstetric bleeding (57.8%), hypertensive crisis (42.2%), and cardiac disease (24.4%). Preterm delivery occurred in 60.0% of cases; 71.1% were postpartum, and 80.0% had cesarean deliveries. Contributory provider factors included diagnostic delays (55.6%) and treatment delays or errors (44.4%). Contributory patient factors included psychiatric/behavioral health (20.0%) and health care barriers (22.2%). Morbidity could have been prevented by provider factors in 53.3% of cases and by patient factors in 37.8%. Interventions initiated included recruiting a safety nurse, TeamSTEPPS® training, and adoption of hypertension and postpartum hemorrhage safety bundles. CONCLUSION: SMM reviews can be successfully implemented and provide training on safety and quality.

The Contribution of Untreated and Treated Anxiety and Depression to Prenatal, Intrapartum, and Neonatal Outcomes.

Objective To determine independent perinatal associations of anxiety and depression in women who were and were not treated with psychotropic drugs in comparison to unaffected pregnancies. Study Design From 2013 to 2014, 978 (6.3%) cases of anxiety/depression, of which 35% used psychotropic drugs, were compared with 14,514 (93.7%) unaffected pregnancies using logistic regression. Results Subjects were more likely to be Non-Hispanic Whites, use tobacco and illegal substances, be unmarried, use public insurance, and have medical complications of pregnancy. For independent maternal outcomes, untreated anxiety/depression was associated with labor induction (adjusted odds ratio [aOR] = 2.02), cesarean deliveries (aOR = 1.69), longer length of stay (aOR = 1.96), readmission (aOR = 2.40), fever (aOR = 2.03), magnesium exposure (aOR = 1.82), and postpartum hemorrhage (aOR = 2.57), whereas treated cases were associated with increased blood transfusion (aOR = 4.81), severe perineal lacerations (aOR = 2.93), and postpartum hemorrhage (aOR = 3.85), but decreased risk of cesarean deliveries (aOR = 0.59). Independent neonatal outcomes included small for gestational age (aOR = 3.04), meconium-stained fluid (aOR = 1.85; 2.61), respiratory failure (aOR = 5.84), neonatal adaptation syndrome (aOR = 11; 10.2), and neonatal seizures (aOR = 12.3) in treated cases, whereas untreated cases were associated with hypoxia (aOR = 2.83), low Apgar score (aOR = 3.82), and encephalopathy (aOR = 18.3). Exposure to multiple psychotropic medications independently increased the risk of neonatal adaptation syndrome, neonatal length of stay, and hypoglycemia. Conclusion Untreated cases were associated with increased maternal adverse outcomes, whereas treated cases were associated with more adverse neonatal outcomes when compared with unaffected pregnancies.

Carbon Monoxide Exposure During Pregnancy.

IMPORTANCE: Carbon monoxide (CO) is the leading cause of poisoning in the United States and is associated with high maternal and fetal mortality rates. Given the nonspecific signs and symptoms of toxicity, cases may go unsuspected or attributed to other etiologies. As CO adversely affects both mother and fetus, it is important for practitioners to recognize and treat poisoning in a timely manner. OBJECTIVE: We seek to assist practitioners with understanding the physiology and recognizing the presentations of both acute and chronic CO poisoning, as well as provide information on diagnosis and treatment options. We also conducted a review of cases described in the literature during the past half century to show varying presentations and treatment methodologies. EVIDENCE ACQUISITION: A qualitative literature search was conducted using PubMed and Google Scholar for articles published between 1970 and 2014 that assessed cases of CO poisoning during pregnancy. Excluded studies were not in English or contained nonhuman subjects. RESULTS: Nineteen published reports of CO poisoning during pregnancy described in varying levels of detail were found in the literature from 1971 to 2010. CONCLUSIONS AND RELEVANCE: Carbon monoxide poisoning requires a high degree of suspicion. Diagnosis is made based on initial history and physical evaluation and assessment of environmental CO levels; presenting carboxyhemoglobin levels may be poor indicators of severity of disease. Oxygen therapy should be initiated promptly in all possible cases with consideration of hyperbaric oxygen therapy in cases of significant maternal exposure. Treatment requires a longer duration for fetal CO elimination than in the nonpregnant patients. Importantly, practitioners should educate pregnant patients on prevention.