Obstetric imaging practice characteristics associated with prenatal detection of critical congenital heart disease in a rural US region over 20 years.

OBJECTIVE: To identify clinical practice characteristics associated with the frequency of prenatal critical congenital heart disease (CCHD) detection (i.e., the number of liveborn infants with postnatally confirmed CCHD identified on prenatal sonography) over 20 years in a rural setting comprised of 11 primarily low-volume obstetric hospitals and the single tertiary academic hospital to which they refer. METHODS: This was a retrospective cohort study of all patients in the referral region with an initial prenatal and/or postnatal diagnosis of CCHD from 01/01/2002 to 12/31/2021. The frequency of prenatal CCHD detection at the time of an obstetric ultrasound was reported, as was the change in detection over time. Critical congenital heart disease detection was assessed as a function of cardiac lesion type, practice setting, and practice characteristics. RESULTS: There were 271 cases with a confirmed postnatal CCHD diagnosis, of which 49% were identified prenatally. The majority of community practices each averaged <10 CCHD cases in total over the study period. Prenatal detection at the tertiary academic hospital's obstetric ultrasound unit was 64%, compared to 22% at the combined referring community practices (p < 0.001), though CCHD detection improved over time in both settings. Professional accreditation by the American Institute of Ultrasound in Medicine, image interpretation by radiology or Maternal Fetal Medicine, and use of video clips of ventricular outflow tracts were associated with improved prenatal CCHD detection. CONCLUSIONS: Our data demonstrate the infrequency of CCHD cases at small-volume, rural hospitals and the substantial variation in prenatal CCHD detection across practice settings. Our methods allowed for the identification of practice characteristics associated with prenatal CCHD detection.

Quality Initiative to Reduce Failed Trial of Labor after Cesarean Using Calculated VBAC Success Likelihood.

OBJECTIVE: Vaginal birth after cesarean can reduce morbidity associated with multiple cesarean deliveries. Failed vaginal birth after cesarean is associated with increased maternal and neonatal morbidity. The Maternal-Fetal Medicine Units Vaginal Birth After Cesarean calculator is a validated tool to predict the likelihood of successful trial of labor after cesarean. Predicted likelihood < 60% has been associated with increased maternal and neonatal morbidity. We sought to determine if formal incorporation of calculated vaginal birth after cesarean likelihood into patient-centered counseling would reduce failed vaginal birth after cesarean. STUDY DESIGN: This is a quality improvement intervention at a single tertiary-care academic medical center, in which standardized patient counseling was implemented, facilitated by an electronic medical record template featuring patient-specific likelihood of vaginal birth after cesarean success. Term singleton pregnancies with history of one to two cesareans were included; those with contraindication to labor were excluded. Historical controls (January 2016-December 2018, n = 693) were compared with a postimplementation cohort (January 2019-April 2020, n = 328). Primary outcome was failed vaginal birth after cesarean. RESULTS: Fewer patients in the postintervention cohort had a history of an arrest disorder (PRE: 48%, 330/693 vs. POST: 40%, 130/326, p = 0.03); demographics were otherwise similar, including the proportion of patients with <60% likelihood of success (PRE: 39%, 267/693, vs. POST: 38%, 125/326). Following implementation, induction of labor in patients with a <60% likelihood of successful vaginal birth after cesarean decreased from 17% (45/267) to 5% (6/125, p < 0.01). The proportion of failed vaginal birth after cesarean decreased from 33% (107/329) to 22% (32/143, p = 0.04). Overall vaginal birth after cesarean rate did not change (PRE: 32%, 222/693, vs. POST: 34%, 111/326, p = 0.52). CONCLUSION: An intervention targeting provider counseling that included a validated vaginal birth after cesarean success likelihood was associated with decreased risk of failed trial of labor after cesarean without affecting overall vaginal birth after cesarean rate. KEY POINTS: · Labored cesarean increases maternal morbidity.. · Application of the Maternal-Fetal Medicine Units (MFMU) calculator to antenatal counseling decreased labored cesarean.. · Application of the MFMU calculator to antenatal counseling did not decrease overall vaginal birth after cesarean rate..

Placental Maternal Vascular Malperfusion is Associated with Prepregnancy and Early Pregnancy Maternal Cardiovascular and Thrombotic Profiles.

Characteristics of maternal vascular malperfusion (MVM) are frequently observed in placentas from pregnancies impacted by preeclampsia, intrauterine growth restriction, preterm labor, and intrauterine fetal demise. We sought to evaluate the associations of features of MVM with subclinical measures of cardiovascular health and coagulation potential in healthy young women. Sixty-three healthy young women were recruited and assessed prior to pregnancy on cycle day 9 ± 4, at gestational age 90 ± 6 of early pregnancy, and gestational age 216 ± 5 of late pregnancy. Women were assessed for plasma volume, blood pressure, response to volume loading, cardiac output, and uterine hemodynamics. Platelet-poor plasma was collected to assess thrombin generation on a subset of 33 women at all time points. Following delivery, placentas were collected and analyzed for evidence of MVM. Thrombin generation (TG) was evaluated in the presence of tissue factor (TF) with and without recombinant soluble thrombomodulin (TM). For each, we compared TG lagtime, peak level, and endogenous thrombin potential (ETP). Comparisons were made between dichotomized presence and absence of each individual feature of MVM and cardiovascular and coagulation features. Mean ± standard deviation are presented. Women were 31 ± 4 years of age, body mass index of 24 ± 5 kg/m2, 86% white race, and 80% nulliparous. MVM occurred in 70% of placentas, with infarcts and agglutination (44%), decidual arteriopathy (40%), accelerated villous maturation (32%), placental hypoplasia (29%), and distal villous hypoplasia (17%) documented. Decidual arteriopathy and distal villous hypoplasia were associated with prepregnancy maternal physiology, including decreased plasma volume and subclinical cardiovascular variations. All assessed MVM characteristics had identifiable early pregnancy physiologic characteristics consistent with altered cardiovascular function and decreased uterine response to pregnancy when compared with women who did and did not develop MVM. Accelerated villous maturation was the only MVM feature to differ by thrombin generation parameters in early pregnancy. Thrombin generation potential and blood pressure were elevated in late pregnancy in women who developed decidual arteriopathy. Prepregnancy health status and adaptation to pregnancy play important roles in pregnancy outcomes. Both cardiovascular health and thrombin generation potential may influence early placentation. Longitudinal assessment of subclinical maternal factors may allow for better understanding of the etiologies of MVM lesions, as well as allow for identification of a timeline of the origins of placental pathologies.

Provider group type and Tdap coverage in pregnancy.

INTRODUCTION: The Advisory Committee on Immunization Practices (ACIP) has focused on maternal Tdap immunization as an important means to protect neonates from pertussis infections. There is little published data on provider and/or clinic characteristics as predictors of maternal Tdap uptake. This study examined differences in maternal Tdap coverage in women delivering at a single academic institution, but cared for prenatally in different clinical settings, in 2013, 2014, and 2015. Additionally, the accuracy and utilization of Vermont's immunization information system (IIS) was assessed. METHODS: This was a retrospective, multiple time-point cross-sectional analysis of annual maternal Tdap coverage in women delivering at a single academic institution in the 3 years following a fundamental change in national maternal Tdap vaccination guidelines. Tdap administration was examined across different obstetric groups using chart review and data from the state's IIS. RESULTS: All obstetric care groups except the resident-staffed clinic significantly increased maternal Tdap coverage in 2014, compared to 2013 coverage, with no further increase in 2015. In contrast, there was no increase in maternal Tdap coverage in 2014 in the resident-staffed clinics, but then a statistically significant increase in 2015. Overall Tdap coverage in 2014 was 80.4%, with variation in Tdap coverage between clinics types. In the subset of women who were cared for by the University-based groups, there was significant variation in Tdap coverage between clinics, despite racial homogeneity, which persisted after adjustment for maternal age and insurance type. The state's IIS was found to be highly accurate, using individual chart review as the "gold standard." DISCUSSION: While we demonstrated high maternal Tdap coverage in women delivering at our institution, differences in clinic type and provider training appeared to impact immunization rates, as well as how quickly evolving national recommendations were adopted. Additionally, the fidelity of the state's IIS data was verified.

Endocytosed factor V is trafficked to CD42b+ proplatelet extensions during differentiation of human umbilical cord blood-derived megakaryocytes.

Plasma- and platelet-derived factor Va are essential for thrombin generation catalyzed by the prothrombinase complex; however, several observations demonstrate that the platelet-derived cofactor, which is formed following megakaryocyte endocytosis and modification of the plasma procofactor, factor V, is more hemostatically relevant. Factor V endocytosis, as a function of megakaryocyte differentiation and proplatelet formation, was assessed by flow cytometry and microscopy in CD34+ hematopoietic progenitor cells isolated from human umbilical cord blood and cultured for 12 days in the presence of cytokines to induce ex vivo differentiation into megakaryocytes. Expression of an early marker of megakaryocyte differentiation, CD41, endocytosis of factor V, and the percentage of CD41+ cells that endocytosed factor V increased from days 6 to 12 of differentiation. In contrast, statistically significant decreases in expression of the stem cell marker, CD34, and in the percentage of CD34+ cells that endocytosed factor V were observed. A statistically significant increase in the expression of CD42b, a late marker of megakaryocyte differentiation, was also observed over time, such that by Day 12, all CD42b+ cells endocytosed factor V and expressed CD41. This endocytosed factor V was trafficked to proplatelet extensions and was localized in a punctate pattern in the cytoplasm consistent with its storage in α-granules. In conclusion, loss of CD34 and expression of CD42b define cells capable of factor V endocytosis and trafficking to proplatelet extensions during differentiation of megakaryocytes ex vivo from progenitor cells isolated from umbilical cord blood.

Diagnosis and Management of VTE in Pregnancy.

Venous thromboembolism is a leading cause of maternal death. Because of the low absolute frequency of events, however, outcome-based clinical data are limited. Consequently, clinicians must additionally rely both on published guidelines and on extrapolation of data from studies focused on nonpregnant individuals. The diagnosis and treatment of deep vein thrombosis, pulmonary embolism, and cerebral vein and dural sinus thrombosis are complicated by pregnancy, and often require modifications to standard diagnostic and treatment algorithms outside of pregnancy. Treatment of VTE in pregnant women is in particular need of future research.

Venous thromboembolism and stroke in pregnancy.

Pregnancy and the postpartum period substantially increase the risk for thrombotic events. Although the absolute risk for thrombosis is low, these events comprise a significant portion of maternal morbidity and mortality. The vast majority of such events are venous, although the risk for ischemic stroke also appears to be increased in pregnancy. This review will explore the overlapping and unique risk factors for venous and arterial thrombosis in pregnancy. Diagnosis and prevention will be discussed, and treatment will be briefly touched on. The benefit of using a multidisciplinary model in caring for pregnant women who have had a thrombotic event or who are at increased risk for thrombosis is a major focus of the review. Using the experience of our own Hematology and Obstetrics/Maternal Fetal Medicine shared care model, we discuss specific examples of when the use of such an approach is particularly valuable.

From principle to practice: bridging the gap in patient profiling.

The standard clinical coagulation assays, activated partial thromboplastin time (aPTT) and prothrombin time (PT) cannot predict thrombotic or bleeding risk. Since thrombin generation is central to haemorrhage control and when unregulated, is the likely cause of thrombosis, thrombin generation assays (TGA) have gained acceptance as "global assays" of haemostasis. These assays generate an enormous amount of data including four key thrombin parameters (lag time, maximum rate, peak and total thrombin) that may change to varying degrees over time in longitudinal studies. Currently, each thrombin parameter is averaged and presented individually in a table, bar graph or box plot; no method exists to visualize comprehensive thrombin generation data over time. To address this need, we have created a method that visualizes all four thrombin parameters simultaneously and can be animated to evaluate how thrombin generation changes over time. This method uses all thrombin parameters to intrinsically rank individuals based on their haemostatic status. The thrombin generation parameters can be derived empirically using TGA or simulated using computational models (CM). To establish the utility and diverse applicability of our method we demonstrate how warfarin therapy (CM), factor VIII prophylaxis for haemophilia A (CM), and pregnancy (TGA) affects thrombin generation over time. The method is especially suited to evaluate an individual's thrombotic and bleeding risk during "normal" processes (e.g pregnancy or aging) or during therapeutic challenges to the haemostatic system. Ultimately, our method is designed to visualize individualized patient profiles which are becoming evermore important as personalized medicine strategies become routine clinical practice.

Tissue factor-dependent thrombin generation across pregnancy.

OBJECTIVE: Normal pregnancy results in a prothrombotic state. Studies that have investigated the capacity of pregnant women to generate thrombin are limited. Our aim was to evaluate thrombin generation longitudinally from the preconception period, through pregnancy, and after pregnancy. STUDY DESIGN: We evaluated young, healthy nulligravid women (n = 20) at 4 time points and compared the data with 10 control women at 2 time points. Coagulation was initiated with tissue factor in contact pathway inhibited plasma, and thrombin generation was determined in the presence of a fluorogenic substrate. RESULTS: The maximum level and rate of thrombin generation increased during pregnancy; the highest level and rate occurred in late pregnancy compared with prepregnancy (P < .001). Subsequently, thrombin generation decreased in the postpregnancy samples that included maximum level, rate, and area under the curve (P < .001). CONCLUSION: Our data provide evidence for an increase in tissue factor-dependent thrombin generation with pregnancy progression, followed by a return to prepregnancy thrombin levels.

Phospholipid scramblase expression in the pregnant mouse uterus in LPS-induced preterm delivery.

Phospholipid scramblases (PLSCR), stimulated by proinflammatory cytokines, are thought to mediate the loss of lipid asymmetry in cell membranes, allowing for specific reactions in the coagulation cascade. The PLSCR may therefore provide a link between inflammation, coagulation, and, because thrombin is a uterotonic, preterm birth (PTB). To explore the relationship between PLSCR expression and inflammation-related PTB, we utilized reverse transcriptase-polymerase chain reaction and Western blot studies to quantify messenger RNA (mRNA) and protein expression for the 4 PLSCR homologues (PLSCR 1-4). Uteri from day 15 pregnant mice were harvested at several time points after intrauterine lipopolysaccharide (LPS) injection (or normal saline, for controls). Expression of mRNA in all 4 Plscr isoforms was demonstrated. Lipopolysaccharide treatment resulted in increased expression of PLSCR-1 and a decrease in Plscr4 mRNA, thereby demonstrating modulation of PLSCR-1 and PLSCR-4 in LPS-induced PTB. Additionally, protein expression was confirmed for all except PLSCR-4, with increased expression of PLSCR-1 after LPS treatment.

Proteomics of human breast ductal carcinoma in situ.

We report the first proteomic analysis of matched normal ductal/lobular units and ductal carcinoma in situ (DCIS) of the human breast. An understanding of the transition from normal epithelium to the first definable stage of cancer at the functional level of protein expression is hypothesized to contribute to improved detection, prevention, and treatment. Ten sets of two-dimensional gels were evaluated, containing either matched normal ductal/lobular units or DCIS from either whole tissue sections or up to 100,000 laser capture microdissected epithelial cells. Differential protein expression was confirmed by image analysis. Protein spots (315) were excised and subjected to mass spectrometry sequencing. Fifty-seven proteins were differentially expressed between normal ductal/lobular units and DCIS. Differences in overall protein expression levels and posttranslational processing were evident. Ten differentially expressed proteins were validated in independent DCIS specimens, and 14 of 15 proteomic trends from two-dimensional gel analyses were confirmed by standard immunohistochemical analysis using a limited independent tumor cohort. Many of the proteins identified were previously unconnected with breast cancer, including proteins regulating the intracellular trafficking of membranes, vesicles, cancer preventative agents, proteins, ions, and fatty acids. Other proteomic identifications related to cytoskeletal architecture, chaperone function, the microenvironment, apoptosis, and genomic instability. Proteomic analysis of DCIS revealed differential expression patterns distinct from previous nucleic acid-based studies and identified new facets of the earliest stage of breast cancer progression.