Novel characterization of CASK variant c.1963 A>G (p.Asn655Asp) through whole-exome sequencing in a monochorionic diamniotic twin fetus with significant brain anomalies: A case report.

Whole-exome sequencing is an evolving technology in perinatal diagnosis which allows identification of genetic etiologies that would otherwise go undetermined. In this case report, a 38-year-old Hispanic woman, G5P3013, with a monochorionic diamniotic twin gestation with one fetus displaying significant cranial abnormalities on prenatal ultrasound and magnetic resonance imaging (MRI) of the brain is presented. Fetal anomalies included bilateral ventriculomegaly, absent cavum septum pellucidum, and absent corpus callosum. Diagnostic amniocentesis with chromosome analysis, chromosomal microarray, alpha-fetoprotein, cytomegalovirus, toxoplasmosis, and parvovirus had normal results. Whole-exome sequencing for the anomalous fetus detected a de novo mosaic variant of uncertain significance (VUS) in the calcium/calmodulin dependent serine protein kinase (CASK) gene: c.1963 A > G (p.Asn655Asp). This variant was absent in the normal twin fetus, the mother, and the father. Pathogenic CASK gene mutations are associated with three syndromes: FG syndrome 4, intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia (MICPCH), and intellectual developmental disorder with or without nystagmus. Whole-exome sequencing identified a potential etiology for the anomalies detected. The variant likely arose de novo and was the potential cause of the identified cranial abnormalities in one fetus of this monochorionic diamniotic twin gestation. Whole-exome sequencing may provide additional diagnostic utility when standard diagnostic testing is noncontributory.

Randomized control trial comparing hygroscopic cervical dilators to cervical ripening balloon for outpatient cervical ripening.

BACKGROUND: Outpatient term preinduction cervical ripening with mechanical agents has been associated with reduced length of stay, decreased cesarean delivery rates, low maternal and neonatal complications, and increased incidence of vaginal delivery within 24 hours. OBJECTIVE: This study aimed to demonstrate equivalent efficacy between synthetic hygroscopic dilators and the single-balloon catheter for outpatient cervical ripening. STUDY DESIGN: This randomized control equivalence trial compared synthetic hygroscopic dilators with the 30-mL silicone single-balloon catheter in primiparous and multiparous patients undergoing labor induction. The primary outcome was time from admission to delivery, with a prespecified 3-hour margin of equivalence. The secondary objectives were patient outcomes and perspectives. RESULTS: Between March 1, 2019, and May 31, 2021, 1605 patients met the screening criteria, and 174 patients completed the study. The mean admission-to-delivery time was equivalent at 18.01 hours for the dilator group vs 17.55 hours for the balloon group (P=.04). The cesarean delivery rate of primiparous patients was similar at 28.1% with dilators vs 29.7% with the balloon. The groups had similar median cervical dilation and pain scores on insertion and admission. Overall patient satisfaction was high, 92.8% with dilators vs 96.2% with the balloon. The balloon group had significantly higher rates of early admission and device expulsion. CONCLUSION: Although the enrollment goal was not met, our study suggests that synthetic hygroscopic dilators and the single-balloon catheter for outpatient cervical ripening are both efficacious with similar time from admission to delivery, pain scores, and patient satisfaction with the procedure.

Importance of the Third Trimester Complete Blood Count: A Case Report on Aplastic Anemia in Pregnancy.

Aplastic anemia (AA) poses a significant threat to maternal and fetal health throughout the perinatal period. Diagnosis is based on complete blood count (CBC) and bone marrow biopsy with treatment varying based on severity of disease. This report highlights a case of AA incidentally identified by the third trimester CBC drawn in the outpatient office. Patient was referred for inpatient management to mobilize a multidisciplinary team of healthcare professionals including obstetricians, hematologists, and anesthesiologists to optimize maternal and fetal outcome. The patient received blood and platelet transfusions prior to delivering a healthy liveborn infant by cesarean section. This case highlights the importance for routine third trimester CBC screening to identify potential complications and decrease maternal and fetal morbidity and mortality.

Identification of factors associated with delayed treatment of obstetric hypertensive emergencies.

BACKGROUND: Obstetric hypertensive emergency is defined as having systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥110 mm Hg, confirmed 15 minutes apart. The American College of Obstetricians and Gynecologists recommends that acute-onset, severe hypertension be treated with first line-therapy (intravenous labetalol, intravenous hydralazine or oral nifedipine) within 60 minutes to reduce risk of maternal morbidity and death. OBJECTIVE: Our objective was to identify barriers that lead to delayed treatment of obstetric hypertensive emergency. STUDY DESIGN: A retrospective cohort study was performed that compared women who were treated appropriately within 60 minutes vs those with delay in first-line therapy. We identified 604 patients with discharge diagnoses of chronic hypertension, gestational hypertension, or preeclampsia using International Classification of Diseases-10 codes and obstetric antihypertensive usage in a pharmacy database at 1 academic institution from January 2017 through June 2018. Of these, 267 women (44.2%) experienced obstetric hypertensive emergency in the intrapartum period or within 2 days of delivery; the results from 213 women were used for analysis. We evaluated maternal characteristics, presenting symptoms and circumstances, timing of hypertensive emergency, gestational age at presentation, and administered medications. Chi square, Fisher's exact, Wilcoxon rank-sum, and sample t-tests were used to compare the 2 groups. Univariable logistic regression was applied to determine predictors of delayed treatment. Multivariable regression model was also performed; C-statistic and Hosmer and Lemeshow goodness-of-fit test were used to assess the model fit. A result was considered statistically significant at P<.05. RESULTS: Of the 213 women, 110 (51.6%) had delayed treatment vs 103 (48.4%) who were treated within 60 minutes. Patients who had delayed treatment were 3.2 times more likely to have an initial blood pressure in the nonsevere range vs those who had timely treatment (odds ratio, 3.24; 95% confidence interval, 1.85-5.68). Timeliness of treatment was associated with presence or absence of preeclampsia symptoms; patients without preeclampsia symptoms were 2.7 times more likely to have delayed treatment (odds ratio, 2.68; 95% confidence interval, 1.50-4.80). Patients with hypertensive emergencies that occurred overnight between 10 pm and 6 am were 2.7 times more likely to have delayed treatment vs those emergencies that occurred between 6 am and 10 pm (odds ratio, 2.72; 95% confidence interval, 1.27-5.83). Delayed treatment also had an association with race, with white patients being 1.8 times more likely to have delayed treatment (odds ratio, 1.79; 95% confidence interval, 1.04-3.08). Patients who were treated at <60 minutes had a lower gestational age at presentation vs those with delayed treatment (34.6±5 vs 36.6±4 weeks, respectively; P<.001). For every 1-week increase in gestational age at presentation, there was a 9% increase in the likelihood of delayed treatment (odds ratio, 1.11; 95% confidence interval, 1.04-1.19). Another factor that was associated with delay of treatment was having a complaint of labor symptoms, which made patients 2.2 times as likely to experience treatment delay (odds ratio, 2.17; 95% confidence interval, 1.07-4.41). CONCLUSION: Initial blood pressure in the nonsevere range, absence of preeclampsia symptoms, presentation overnight, white race, having complaint of labor symptoms, and increasing gestational age at presentation are barriers that lead to a delay in the treatment of obstetric hypertensive emergency. Quality improvement initiatives that target these barriers should be instituted to improve timely treatment.

Second trimester marginal cord insertion is associated with adverse perinatal outcomes.

Objectives: To determine the feasibility in visualizing placental cord insertion (PCI) during second-trimester fetal anatomical survey and the association between marginal cord insertion (MCI) and preterm delivery (PTD) and low birth weight (LBW). Our secondary objectives were to evaluate the association of MCI with adverse composite obstetrical and neonatal outcomes. Methods: A prospective cohort study was performed over a 28-month period. Women with singleton pregnancies presenting for routine anatomical survey between 18 and 22 weeks' gestation were included. PCI site was visualized on 2D grayscale and color Doppler and the shortest distance from the sagittal and transverse planes to the placental edge were recorded. MCI was diagnosed when any of measured distances was ≤2 cm. Correlations were assessed via bivariate chi-squared, independent t-test analyses and Fisher's exact tests. Regression models evaluated associations between MCI and adverse composite outcomes. Results: Three hundred one women were included and PCI was feasible in all cases. The incidence of MCI was 11.3% (n = 34). Baseline characteristics between those with and without MCI were similar, except for story of prior PTD, which was greater among those with MCI (17.65 versus 7.17%, p = .04). MCI was associated with increased likelihood of LBW (RR four; 95%CI, 1.46-10.99) and PTD (RR 3.2; 95%CI, 1.53-6.68); in multivariate analysis, we found associations between MCI and composite adverse obstetrical (RR 2.33; 95%CI, 1.30-4.19) and neonatal (RR 2.46; 95%CI, 1.26-4.81) outcomes. Conclusions: Evaluation of PCI is feasible in all cases. Second-trimester MCI is associated with increased likelihood for LBW, PTD, and composite adverse obstetrical and neonatal outcomes.

Software-guided insulin dosing improves intrapartum glycemic management in women with diabetes mellitus.

BACKGROUND: During labor, maintenance of maternal euglycemia is critical to decrease the risk of neonatal hypoglycemia and associated morbidities. When continuous intravenous insulin infusion is needed, standardized insulin dosing charts have been used for titration of insulin to maintain glucose in target range. The GlucoStabilizer software program (Indiana University Health Inc, Indianapolis, IN) is a software-guided insulin dosing system that calculates the dose of intravenous insulin that is needed based on metabolic parameters, target glucose concentration, and an individual's response to insulin. Although this tool has been validated and shown to reduce both hypoglycemia and errors in critical care settings, the utility of this software has not been examined in obstetrics. OBJECTIVE: The purpose of this study was to determine whether the use of intravenous insulin dosing software in women with pregestational or gestational diabetes mellitus that requires intrapartum insulin infusion can improve the rate of glucose concentration in target range (70-100 mg/dL; 3.9-5.5 mmol/L) at the time delivery. STUDY DESIGN: We performed a retrospective cohort study comparing laboring patients with diabetes mellitus that required insulin infusion who were dosed by standard insulin dosing chart vs the GlucoStabilizer software program from January 2012 to December 2017. The GlucoStabilizer software program, which was implemented in May 2016, replaced the standard intravenous insulin dosing chart. Inclusion criteria were women with pregestational or gestational diabetes mellitus who were treated with an intravenous insulin infusion intrapartum for at least 2 hours. Maternal characteristics, glucose values in labor, and neonatal outcomes were extracted from delivery and neonatal records. The primary outcome was the percentage of women who achieved the target glucose range (defined as a blood glucose between 70-100 mg/dL; 3.9-5.5 mmol/L) before delivery. Parametric and nonparametric statistics were used to compare both groups; a probability value of <.05 was considered statistically significant. RESULTS: We identified 22 patients who were dosed by a standard insulin dosing chart and 11 patients who were dosed by the GlucoStabilizer software program during intrapartum management. The GlucoStabilizer software program was superior in achieving glucose values in target range at delivery (81.8% vs 9.1%; P<.001) compared with standard insulin dosing without increasing maternal hypoglycemia (0% vs 4.3%; P=.99). Patients whose insulin dosing was managed by the GlucoStabilizer software program also had lower mean capillary blood glucose values compared with the standard insulin infusion (102.9±5.9 mg/dL [5.7±0.33 mmol/L] vs 121.7±5.9 mg/dL [6.8±0.33 mmol/L]; P=.02). Before the initiation of the infusion, both groups demonstrated mean capillary blood glucose values outside of target range (122.6±8.8 mg/dL [6.7±0.49 mmol/L] for the GlucoStabilizer software program vs 131.9±10.1 mg/dL [7.3±0.56 mmol/L] for standard insulin treatment group; P=not significant). There were no significant differences in baseline maternal characteristics between the groups or neonatal outcomes. CONCLUSION: This study is the first to demonstrate that the use of software-guided intravenous insulin dosing in obstetrics can improve intrapartum glycemic management without increasing hypoglycemia in women with both pregestational and gestational diabetes mellitus that is treated with an insulin infusion.

Effectiveness and short-term safety of modified sodium hyaluronic acid-carboxymethylcellulose at cesarean delivery: a randomized trial.

BACKGROUND: The rising cesarean birth rate has drawn attention to risks associated with repeat cesarean birth. Prevention of adhesions with adhesion barriers has been promoted as a way to decrease operative difficulty. However, robust data demonstrating effectiveness of such interventions are lacking. OBJECTIVE: We report data from a multicenter trial designed to evaluate the short-term safety and effectiveness of a modified sodium hyaluronic acid (HA)-carboxymethylcellulose (CMC) absorbable adhesion barrier for reduction of adhesions following cesarean delivery. STUDY DESIGN: Patients who underwent primary or repeat cesarean delivery were included in this multicenter, single-blinded (patient), randomized controlled trial. Patients were randomized into either HA-CMC (N = 380) or no treatment (N = 373). No other modifications to their treatment were part of the protocol. Short-term safety data were collected following randomization. The location and density of adhesions (primary outcome) were assessed at their subsequent delivery using a validated tool, which can also be used to derive an adhesion score that ranges from 0-12. RESULTS: No differences in baseline characteristics, postoperative course, or incidence of complications between the groups following randomization were noted. Eighty patients from the HA-CMC group and 92 controls returned for subsequent deliveries. Adhesions in any location were reported in 75.6% of the HA-CMC group and 75.9% of the controls (P = .99). There was no significant difference in the median adhesion score; 2 (range 0-10) for the HA-CMC group vs 2 (range 0-8) for the control group (P = .65). One third of the HA-CMC patients met the definition for severe adhesions (adhesion score >4) compared to 15.5% in the control group (P = .052). There were no significant differences in the time from incision to delivery (P = .56). Uterine dehiscence in the next pregnancy was reported in 2 patients in HA-CMC group vs 1 in the control group (P = .60). CONCLUSION: Although we did not identify any short-term safety concerns, HA-CMC adhesion barrier applied at cesarean delivery did not reduce adhesion formation at the subsequent cesarean delivery.

Down-regulation of placental neuropilin-1 in fetal growth restriction.

BACKGROUND: Fetal growth restriction (FGR) is associated with adverse outcomes extending from fetal to adult life, and thus, constitutes a major health care challenge. Fetuses with progressive growth restriction show increasing impedance in the umbilical artery flow, which may become absent during end-diastole. Absent end-diastolic flow (AEDF) is associated with adverse perinatal outcomes including stillbirths and perinatal asphyxia. Placentas from such pregnancies demonstrate deficient fetoplacental vascular branching. Current evidence, moreover, indicates an antiangiogenic state in maternal circulation in several pregnancy complications including preeclampsia, small-for-gestational-age births, fetal death, and preterm labor. The angiogenic mediators in maternal circulation are predominantly of placental origin. Information, however, on the role of specific proangiogenic and antiangiogenic mechanisms operating at the placental level remains limited. Elucidation of these placenta-specific angiogenic mechanisms will not only extend our understanding of the causal pathway for restricted fetal growth but may also lead to the development of biomarkers that may allow early recognition of FGR. OBJECTIVE: We sought to test the hypothesis that fetoplacental angiogenic gene expression is altered in pregnancies complicated with FGR and umbilical artery Doppler AEDF. STUDY DESIGN: Placental samples were collected from FGR pregnancies complicated with umbilical artery Doppler AEDF (study group, n = 7), and from uncomplicated pregnancies (control group, n = 7), all delivered by cesarean during the last trimester of pregnancy. Angiogenic oligonucleotide microarray analysis was performed and was corroborated by quantitative real-time polymerase chain reaction, Western blot analysis, and immunohistochemistry. The Student t test with Bonferroni correction was used with P < .05 considered statistically significant. Independent groups t test was used to analyze the immunostain intensity scores with a P < .05 considered statistically significant. RESULTS: Our microarray results showed that among several differentially expressed angiogenic genes in the growth-restricted group, only the down-regulation of neuropilin (NRP)-1 was most significant (P < .0007). Quantitative real-time polymerase chain reaction confirmed a significantly lower NRP-1 gene expression in the FGR group than in the control group (mean ± SD (ˆ)cycle threshold: 0.624 ± 0.55 and 1.325 ± 0.84, respectively, P = .04). Western blot validated significantly lower NRP-1 protein expression in the FGR group than in the control group (mean ± SD NRP-1/ß-actin ratio: 0.13 ± 0.04 and 0.34 ± 0.05, respectively, P < .001). Finally, immunohistochemistry of placental villi further corroborated a significantly decreased expression of NRP-1 in the FGR group (P = .006). CONCLUSION: The study demonstrated significant down-regulation of placental NRP-1 expression in FGR pregnancies complicated with AEDF in umbilical artery. As NRP-1 is known to promote sprouting angiogenesis, its down-regulation may be involved in the deficient vascular branching observed in FGR placentas suggesting the presence of an antiangiogenic state. Further studies may elucidate such a causal role and may lead to the development of novel diagnostic and therapeutic tools.

A novel approach to teaching placement of a B-lynch suture: description of technique and validation of teaching model.

INTRODUCTION: Postpartum hemorrhage is a major cause of maternal morbidity and mortality throughout the world and uterine atony is the leading cause of postpartum hemorrhage. The B-Lynch brace suture is a fertility-sparing approach to treating intractable uterine atony at the time of cesarean delivery. However, many obstetricians lack confidence to perform this procedure, which they may not have performed during residency. In order to train all residents to perform the B-Lynch brace suture, we developed a realistic model by using a flank steak to imitate a gravid uterus. METHODS: A convenience sample of obstetrics-gynecology faculty and residents at different levels of training at a single large hospital participated in this pilot project. Each physician reported self-perceived understanding of and confidence in performing the B-Lynch procedure before and immediately after practicing the technique using the flank-steak model, via a Likert-type survey (scale 1  =  low, 5  =  high). A Wilcoxon matched-pairs signed rank test was used to compare the before and after responses. RESULTS: Thirty-four participants completed the flank-steak model training and pretraining/posttraining surveys. The median score (range) for self-perceived understanding was 4 (2-5) and increased to 5 (4-5) (P < .01) after exposure to the training model. The confidence scores rose from 3 (1-5) to 5 (4-5) (P < .01) after training. CONCLUSION: The flank-steak model for teaching the B-Lynch suture significantly improved resident and faculty self-perceived understanding of and confidence in performing this procedure, which is otherwise rarely practiced in residency.

Safety of local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions.

To help define the safety profile of the use of adenovirus (Ad) gene transfer vectors in humans, this report summarizes our experience since April 1993 of the local administration of E1(-)/E3(-) Ad vectors to humans using low (<10(9) particle units) or intermediate (10(9)-10(11) particle units) doses. Included in the study are 90 individuals and 12 controls, with diverse comorbid conditions, including cystic fibrosis, colon cancer metastatic to liver, severe coronary artery disease, and peripheral vascular disease, as well as normals. These individuals received 140 different administrations of vector, with up to seven administrations to a single individual. The vectors used include three different transgenes (human cystic fibrosis transmembrane conductance regulator cDNA, E. coli cytosine deaminase gene, and the human vascular endothelial growth factor 121 cDNA) administered by six different routes (nasal epithelium, bronchial epithelium, percutaneous to solid tumor, intradermal, epicardial injection of the myocardium, and skeletal muscle). The total population was followed for 130.4 patient-years. The study assesses adverse events, common laboratory tests, and long-term follow-up, including incidence of death or development of malignancy. The total group incidence of major adverse events linked to an Ad vector was 0.7%. There were no deaths attributable to the Ad vectors per se, and the incidence of malignancy was within that expected for the population. Overall, the observations are consistent with the concept that local administration of low and intermediate doses of Ad vectors appears to be well tolerated.

Analysis of risk factors for local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of comorbid conditions.

In this study we analyze the adverse events and abnormal laboratory parameters following local administration of low (<10(9) particle units) and intermediate (10(9)-10(11) particle units) single and repetitive doses (140 total) of E1(-)E3(-) adenovirus (Ad) gene transfer vectors administered to the respiratory epithelium, solid tumors, skin, myocardium, and skeletal muscle in eight gene transfer trials since April 1993. In the accompanying paper by Harvey et al., (Hum. Gene Ther. 2002; 13:15-63), we conclude that for the total group, no deaths were attributable to the Ad vectors per se, and the incidence of major adverse events likely caused by an Ad vector was 0.7%. The present study analyzes the trials as a group to evaluate risk factors for the adverse events, abnormal values among laboratory parameters, and known deaths. Ten putative risk factors were assessed, including "patient-related" (age, sex, comorbid index and pretherapy anti-Ad antibodies), "vector-related" (dose, route, transgene, and number of vector administrations), and "trial-related" (trial in which the individual was enrolled, and whether surgery was part of the trial). While assessment of each factor individually suggested several possible associations with adverse events, abnormal laboratory parameters, or deaths, multivariate analysis identified only age, comorbid index, and surgery (comorbid index for death; age and surgery for non-death adverse events) as variables significantly associated with increased risk for a major (severity scale 3-4 of 4) adverse event for individuals enrolled in these gene transfer trials. Importantly, multivariate analysis suggested that vector-related parameters, including dose, route, transgene, or number of vector administrations at the doses and routes evaluated in these studies, do not appear to be significant risk factors for a major adverse event. With the caveat that these are phase I, uncontrolled trials, we conclude that (1) there is no definitive risk factor that will clearly predict a major adverse outcome resulting from local administration of low and intermediate doses of Ad gene transfer vectors; and (2) major adverse events in these gene transfer trials are associated primarily with the study population and/or trial procedures, not the Ad vectors themselves. This assessment is consistent with the concept that local administration of low and intermediate doses of Ad gene transfer vectors appears to be well tolerated.