Discovery and verification of extracellular microRNA biomarkers for diagnostic and prognostic assessment of preeclampsia at triage.

We report on the identification of extracellular miRNA (ex-miRNA) biomarkers for early diagnosis and prognosis of preeclampsia (PE). Small RNA sequencing of maternal serum prospectively collected from participants undergoing evaluation for suspected PE revealed distinct patterns of ex-miRNA expression among different categories of hypertensive disorders in pregnancy. Applying an iterative machine learning method identified three bivariate miRNA biomarkers (miR-522-3p/miR-4732-5p, miR-516a-5p/miR-144-3p, and miR-27b-3p/let-7b-5p) that, when applied serially, distinguished between PE cases of different severity and differentiated cases from controls with a sensitivity of 93%, specificity of 79%, positive predictive value (PPV) of 55%, and negative predictive value (NPV) of 89%. In a small independent validation cohort, these ex-miRNA biomarkers had a sensitivity of 91% and specificity of 57%. Combining these ex-miRNA biomarkers with the established sFlt1:PlGF protein biomarker ratio performed better than either set of biomarkers alone (sensitivity of 89.4%, specificity of 91.3%, PPV of 95.5%, and NPV of 80.8%).

Histopathologic and Transcriptomic Profiling Identifies Novel Trophoblast Defects in Patients With Preeclampsia and Maternal Vascular Malperfusion.

Preeclampsia (PE) is a heterogeneous disease for which the current clinical classification system is based on the presence or absence of specific clinical features. PE-associated placentas also show heterogeneous findings on pathologic examination, suggesting that further subclassification is possible. We combined clinical, pathologic, immunohistochemical, and transcriptomic profiling of placentas to develop integrated signatures for multiple subclasses of PE. In total, 303 PE and 1388 nonhypertensive control placentas were included. We found that maternal vascular malperfusion (MVM) in the placenta was associated with preterm PE with severe features and with small-for-gestational-age neonates. Interestingly, PE placentas with either MVM or no histologic pattern of injury showed a linear decrease in proliferative (p63+) cytotrophoblast per villous area with increasing gestational age, similar to placentas obtained from the nonhypertensive patient cohort; however, PE placentas with fetal vascular malperfusion or villitis of unknown etiology lost this phenotype. This is mainly because of cases of fetal vascular malperfusion in placentas of patients with preterm PE and villitis of unknown etiology in placentas of patients with term PE, which are associated with a decrease or increase, respectively, in the cytotrophoblast per villous area. Finally, a transcriptomic analysis identified pathways associated with hypoxia, inflammation, and reduced cell proliferation in PE-MVM placentas and further subclassified this group into extravillous trophoblast-high and extravillous trophoblast-low PE, confirmed using an immunohistochemical analysis of trophoblast lineage-specific markers. Our findings suggest that within specific histopathologic patterns of placental injury, PE can be subclassified based on specific cellular and molecular defects, allowing the identification of pathways that may be targeted for diagnostic and therapeutic purposes.

Retrospective identification of prenatal fetal anomalies associated with diagnostic neonatal genomic sequencing results.

OBJECTIVE: To determine which types of fetal anomalies are associated with postnatal diagnoses of genetic diseases by genomic sequencing and to assess how prenatal genomic sequencing could affect clinical management. METHOD: This was a secondary analysis of the second Newborn Sequencing in Genomic Medicine and Public Health study that compared fetal imaging results in critically ill infants who had actionable versus negative postnatal genomic sequencing results. RESULTS: Of 213 infants who received genomic sequencing, 80 had available prenatal ultrasounds. Twenty-one (26%) of these were found to have genetic diseases by genomic sequencing. Fourteen (67%) of the 21 with genetic diseases had suspected anomalies prenatally, compared with 33 (56%) of 59 with negative results. Among fetuses with suspected anomalies, genetic diseases were 4.5 times more common in those with multiple anomalies and 6.7 times more common in those with anomalies of the extremities compared to those with negative results. Had the genetic diseases been diagnosed prenatally, clinical management would have been altered in 13 of 14. CONCLUSION: Critically ill infants with diagnostic genomic sequencing were more likely to have multiple anomalies and anomalies of the extremities on fetal imaging. Among almost all infants with suspected fetal anomalies and diagnostic genomic sequencing results, prenatal diagnosis would have likely altered clinical management.

FundAl Retroflexion (FAR) Angle is a Novel Sonographic Marker Associated With Cesarean Scar Pregnancies in the First Trimester: A Case-Control Study.

OBJECTIVES: Early diagnosis of Cesarean scar pregnancies (CSP) remains difficult. This study describes a novel sonographic marker, the FundAl Retroflexion (FAR) angle, that may be used in the first trimester. The objective of the study is to compare the FAR angle between CSP and normal pregnancies. METHODS: For this case-control study, we reviewed images from our institution's database that were acquired from January 2016 to December 2019. All cases of CSP and randomly selected controls, defined as patients with history of Cesarean delivery and normal implantation, that underwent ultrasound evaluation at <14 weeks were included. The FAR angle, defined as the acute angle created between the endometrial echo and cervical canal, was measured. The mean FAR angle was then compared between the two groups and a receiver operating characteristic (ROC) curve was generated. RESULTS: We identified 15 cases of CSP during the study period and were able to measure the FAR angle in 14 of the cases. The mean FAR angle was larger in CSP than in normal control pregnancies (45° versus 27°, respectively, P < 0.001). Using an ROC curve, a FAR angle cut off of 40° maximizes the ability to distinguish between CSP from normal pregnancies. CONCLUSIONS: The FAR angle provides an easily obtainable and numerical measurement. CSP have larger FAR angle compared to normal controls with a distinguishing cut off of 40°. Larger studies are needed to determine if using the FAR angle can improve first trimester diagnosis for CSP.

Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization: the PASTIME protocol.

BACKGROUND: Multidisciplinary care of placenta accreta spectrum cases improves pregnancy outcomes, but the specific components of such a multidisciplinary collaboration varies between institutions. As experience with placenta accreta spectrum increases, it is crucial to assess new surgical techniques and protocols to help improve maternal outcomes and to advocate for hospital resources. OBJECTIVE: This study aimed to assess a novel multidisciplinary protocol for the treatment of placenta accreta spectrum that comprises cesarean delivery, multivessel uterine embolization, and hysterectomy in a single procedure within a hybrid operative suite. STUDY DESIGN: This was a matched prepost study of placenta accreta spectrum cases managed before (2010-2017) and after implementation of the Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization protocol (2018-2021) at a tertiary medical center. Historical cases were managed with internal iliac artery balloon placement in selected cases with the decision to inflate the balloons intraoperatively at the discretion of the primary surgeon. Intraoperative Embolization cases were compared with historical cases in a 1:2 ratio matched on the basis of placenta accreta spectrum severity and surgical urgency. The primary outcome was a requirement for transfusion with packed red blood cells. Secondary outcomes included estimated surgical blood loss, operative and postoperative complications, procedural time, length of stay, and neonatal outcomes. RESULTS: A total of 15 Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization cases and 30 matched historical cases were included in the analysis. There were no demographic differences noted between the groups. A median (interquartile range) of 0 units (0-2 units) of packed red blood cells were transfused in the Intraoperative Embolization group compared with 2 units (0-4.5 units) in the historical group (P=.045); 5 of 15 (33.3%) Intraoperative Embolization cases required blood transfusions compared with 19 of 30 (63.3%) cases in the historical group (P=.11). The estimated blood loss was significantly less in the Intraoperative Embolization group with a median (interquartile range) of 750 mL (450-1050 mL) compared with 1750 mL (1050-2500 mL) in the historical group (P=.003). There were no cases requiring massive transfusion (≥10 red blood cell units in 24 hours) in the Intraoperative Embolization group compared with 5 of 30 (16.7%) cases in the historical group (P=.15). There were no intraoperative deaths from hemorrhagic shock using the Intraoperative Embolization protocol, whereas this occurred in 2 of the historical cases. The mean duration of the interventional radiology procedure was longer in the Intraoperative Embolization group (67.8 vs 34.1 minutes; P=.002). Intensive care unit admission and postpartum length of stay were similar, and surgical and postoperative complications were not significantly different between the groups. The gestational age and neonatal birthweights were similar; however, the neonatal length of stay was longer in the Intraoperative Embolization group (median duration, 32 days vs 15 days; P=.02) with a trend toward low Apgar scores. Incidence of arterial umbilical cord blood pH <7.2 and respiratory distress syndrome and intubation rates were not statistically different between the groups. CONCLUSION: A multidisciplinary pathway including a single-surgery protocol with multivessel uterine embolization is associated with a decrease in blood transfusion requirements and estimated blood loss with no increase in operative complications. The Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization protocol provides a definitive surgical method that warrants consideration by other centers specializing in placenta accreta spectrum treatment.

Interval growth across gestation in pregnancies with fetal gastroschisis.

BACKGROUND: Gastroschisis is often complicated by fetal growth restriction, preterm delivery, and prolonged neonatal hospitalization. Prenatal management and delivery decisions are often based on estimated fetal weight and interval growth; however, appropriate interval growth from week to week across gestation for these fetuses is poorly understood. OBJECTIVE: This study aimed to determine the median increase in overall estimated fetal weight and individual biometric measurements across each week of gestation in pregnancies with fetal gastroschisis and to assess whether lower in utero fetal weight gain is predictive of postnatal growth or adverse neonatal outcomes. STUDY DESIGN: This was a retrospective cohort study of pregnancies with gastroschisis evaluated at 5 institutions of the University of California Fetal-Maternal Consortium from December 2014 to December 2019. The inclusion criteria were prenatally diagnosed gastroschisis with at least 1 ultrasound performed at a University of California Fetal-Maternal Consortium institution. Estimated fetal weight and individual biometric measurements were recorded for each ultrasound performed at a University of California Fetal-Maternal Consortium institution from the time of gastroschisis diagnosis to delivery. Median estimated fetal weight and biometric measurements were calculated for each gestational age in 1-week increments. Neonatal outcomes collected were birthweight, length of stay, complications of gastroschisis (bowel atresia, bowel stricture, ischemic bowel before closure, or severe pulmonary hypoplasia), and growth failure at discharge. RESULTS: We identified 95 pregnancies with fetal gastroschisis who, in aggregate, had 360 growth ultrasounds at a University of California Fetal-Maternal Consortium institution. The median interval growth was 130 g/wk. The median estimated fetal weight and abdominal circumference in fetal gastroschisis cases were approximately the tenth percentile on the Hadlock growth curve across gestation. Moreover, the median biparietal diameter, head circumference, and femur length measurements remained below the 50th percentile on the Hadlock growth curve across gestation. The median birthweight for neonates with less than the median weekly prenatal weight gain was less than for those with greater than the median weekly prenatal weight gain (2185 g vs 2780 g; P<.01). There was no difference in prenatal weight gain trajectory when comparing neonates who had or did not have bowel complications of gastroschisis. CONCLUSION: In this multicenter cohort of pregnancies with fetal gastroschisis, the median interval growth was 130 g/wk, and overall, in utero growth closely followed the tenth percentile on the Hadlock curve. Poor prenatal growth in cases of fetal gastroschisis correlates with lower neonatal weights but did not predict a more complicated course.

Significance and Outcomes of Fetal Growth Restriction Below the 5th Percentile Compared to the 5th to 10th Percentiles on Midgestation Growth Ultrasonography.

OBJECTIVE: To determine whether there are differences in neonatal and pregnancy outcomes in pregnancies complicated by severe fetal growth restriction, defined as estimated fetal weight below the 5th percentile, compared with estimated fetal weight in the 5th to 10th percentiles at midgestation. METHODS: We conducted a retrospective review of singleton nonanomalous gestations with estimated fetal weight at or below the 10th percentile (Hadlock et al. Radiology 1991; 181:129-133) at 18 to 24 weeks' gestation. The cohort was divided into fetuses with estimated fetal weight below the 5th percentile and estimated fetal weight in the 5th to 10th percentiles. Antenatal and neonatal outcomes were compared across the groups. RESULTS: Of the 254 growth-restricted fetuses, 91 had estimated fetal weight below the 5th percentile, and 163 were in the 5th to 10th percentiles. Fetuses below the 5th percentile were 2.82 times more likely to be born small for gestational age compared to fetuses at the 5th to 10th percentiles (P = .001). Fetuses with estimated fetal weight below the 5th percentile had higher rates of hypertensive disorders of pregnancy (relative risk [RR], 1.79; P = .04), abnormal umbilical artery Doppler waveforms (RR, 6.27; P = .01), labor induction (RR, 1.45; P = .002), neonatal intensive care unit admission (RR, 1.73; P = .02), and Apgar scores of less than 7 at 1 minute (RR, 2.05; P = .04). CONCLUSIONS: Severely growth-restricted fetuses with an estimated fetal weight below the 5th percentile at 18 to 24 weeks are born smaller and have worse antepartum and neonatal outcomes than those with an estimated fetal weight in the 5th to 10th percentiles. These findings suggest that severely growth-restricted fetuses at midgestation should be treated and counseled differently than those in the 5th to 10th percentiles.

An Initiative to Reduce the Episiotomy Rate: Association of Feedback and the Hawthorne Effect With Leapfrog Goals.

OBJECTIVE: To assess the association of education, performance feedback, and the Hawthorne effect with a reduction in the episiotomy rate in a large academic institution. METHODS: We describe a prospective observational study of a project conducted between March 2012 and February 2017 to assist clinicians in meeting the Leapfrog Group (www.leapfroggroup.org) target rates for episiotomy. Phases of this project included preintervention (phase 1, March 2012 to April 2014), education and provision of collective department episiotomy rates (phase 2, May 2014 to December 2014), ongoing education with emphasis on a revised Leapfrog target rate (phase 3, January 2015 to February 2016), and provision of individual episiotomy rates to practitioners on a monthly basis (phase 4, March 2016 to February 2017). We analyzed the department episiotomy rates before, during, and after these efforts. Cases of shoulder dystocia were excluded from this analysis. Statistical analysis was performed using a two-tailed Student t test and χ test with P<.05 considered significant. RESULTS: During the study period 1,176 episiotomies were performed in 16,441 vaginal deliveries (7.2%). In phase 2 (2,352 vaginal deliveries), there was a nonsignificant drop in the episiotomy rate with education alone (9.0-8.2%, P=.21). In phase 3 (4,379 vaginal deliveries), the episiotomy rate demonstrated an additional, significant drop to 5.9% (P<.001), but this reduction did not reach the new Leapfrog goal of 5%. In phase 4 (3,160 vaginal deliveries), the hospital episiotomy rate again dropped significantly from 5.9% to 4.37% (P=.007) and met the target rate of 5%. This reduction was sustained over a 12-month time period. During this same time period, the rate of operative vaginal delivery among vaginal births increased (4.5-5.4%, P=.003) and there was no significant change in the rates of third- and fourth-degree perineal laceration (3.8-3.3%, P=.19). CONCLUSION: Education, performance feedback, and the Hawthorne effect were associated with a reduction in the episiotomy rate in a large academic institution without a reduction in the rate of operative vaginal delivery or an increase in the rate of third- and fourth-degree lacerations.

A history of low birth weight alters recovery following a future head injury: a case series.

OBJECTIVE: Low birth weight (LBW; below 2500 grams) is a general risk factor for a variety of neurodevelopmental difficulties. However, these children may remain more vulnerable to neurologic and environmental insults occurring years later. This prospective case series reports on children who sustained a mild, moderate, or severe traumatic brain injury (TBI) in middle childhood but who had also been born with birth weights below 2500 grams. PARTICIPANTS: PARTICIPANTS were 14 children with mild, moderate, or severe traumatic brain injury (TBI), 5 of whom had birth weights under 2500 grams (LBW) and 9 children with normal birth weight (NBW). All participants were drawn from a larger study on the long-term cognitive and behavioral impact of pediatric TBI and were matched on age, estimated socioeconomic status (SES), and severity of TBI (with NBW children actually having a slightly worse overall injury severity). RESULTS: At baseline, both groups exhibited similar scores on WJ-R Letter Word Identification and Calculations, Tower of London number solved, and CVLT-C total correct. Baseline group differences were observed on the CELF-III Formulated Sentences (NBW > LBW) and on the VABS Adaptive Behavior Composite and Socialization subdomain (LBW > NBW). Over 2 years, relative to the NBW group, the LBW group evidenced declines on both WJ-R subtests, CVLT-C total correct, CELF-III Formulated Sentences, and VABS Adaptive Behavior Composite and Socialization. CONCLUSIONS: Although preliminary in nature due to small sample size, findings suggest a history of LBW influences the recovery trajectory following childhood TBI. Academic and adaptive functioning and verbal memory appeared particularly affected.