The Role of cfDNA Biomarkers and Patient Data in the Early Prediction of Preeclampsia: Artificial Intelligence Model.

OBJECTIVE: Accurate individualized assessment of preeclampsia risk enables the identification of patients most likely to benefit from initiation of low-dose aspirin at 12-16 weeks' gestation when there is evidence for its effectiveness, as well as guiding appropriate pregnancy care pathways and surveillance. The primary objective of this study was to evaluate the performance of artificial neural network models for the prediction of preterm preeclampsia (<37 weeks' gestation) using patient characteristics available at the first antenatal visit and data from prenatal cell-free DNA (cfDNA) screening. Secondary outcomes were prediction of early onset preeclampsia (<34 weeks' gestation) and term preeclampsia (≥37 weeks' gestation). METHODS: This secondary analysis of a prospective, multicenter, observational prenatal cfDNA screening study (SMART) included singleton pregnancies with known pregnancy outcomes. Thirteen patient characteristics that are routinely collected at the first prenatal visit and two characteristics of cfDNA, total cfDNA and fetal fraction (FF), were used to develop predictive models for early-onset (<34 weeks), preterm (<37 weeks), and term (≥37 weeks) preeclampsia. For the models, the 'reference' classifier was a shallow logistic regression (LR) model. We also explored several feedforward (non-linear) neural network (NN) architectures with one or more hidden layers and compared their performance with the LR model. We selected a simple NN model built with one hidden layer and made up of 15 units. RESULTS: Of 17,520 participants included in the final analysis, 72 (0.4%) developed early onset, 251 (1.4%) preterm, and 420 (2.4%) term preeclampsia. Median gestational age at cfDNA measurement was 12.6 weeks and 2,155 (12.3%) had their cfDNA measurement at 16 weeks' gestation or greater. Preeclampsia was associated with higher total cfDNA (median 362.3 versus 339.0 copies/ml cfDNA; p<0.001) and lower FF (median 7.5% versus 9.4%; p<0.001). The expected, cross-validated area under the curve (AUC) scores for early onset, preterm, and term preeclampsia were 0.782, 0.801, and 0.712, respectively for the LR model, and 0.797, 0.800, and 0.713, respectively for the NN model. At a screen-positive rate of 15%, sensitivity for preterm preeclampsia was 58.4% (95% CI 0.569, 0.599) for the LR model and 59.3% (95% CI 0.578, 0.608) for the NN model.The contribution of both total cfDNA and FF to the prediction of term and preterm preeclampsia was negligible. For early-onset preeclampsia, removal of the total cfDNA and FF features from the NN model was associated with a 6.9% decrease in sensitivity at a 15% screen positive rate, from 54.9% (95% CI 52.9-56.9) to 48.0% (95% CI 45.0-51.0). CONCLUSION: Routinely available patient characteristics and cfDNA markers can be used to predict preeclampsia with performance comparable to other patient characteristic models for the prediction of preterm preeclampsia. Both LR and NN models showed similar performance.

Impact of high-risk prenatal screening results for 22q11.2 deletion syndrome on obstetric and neonatal management: Secondary analysis from the SMART study.

OBJECTIVE: One goal of prenatal genetic screening is to optimize perinatal care and improve infant outcomes. We sought to determine whether high-risk cfDNA screening for 22q11.2 deletion syndrome (22q11.2DS) affected prenatal or neonatal management. METHODS: This was a secondary analysis from the SMART study. Patients with high-risk cfDNA results for 22q11.2DS were compared with the low-risk cohort for pregnancy characteristics and obstetrical management. To assess differences in neonatal care, we compared high-risk neonates without prenatal genetic confirmation with a 1:1 matched low-risk cohort. RESULTS: Of 18,020 eligible participants enrolled between 2015 and 2019, 38 (0.21%) were high-risk and 17,982 (99.79%) were low-risk for 22q11.2DS by cfDNA screening. High-risk participants had more prenatal diagnostic testing (55.3%; 21/38 vs. 2.0%; 352/17,982, p < 0.001) and fetal echocardiography (76.9%; 10/13 vs. 19.6%; 10/51, p < 0.001). High-risk newborns without prenatal diagnostic testing had higher rates of neonatal genetic testing (46.2%; 6/13 vs. 0%; 0/51, P < 0.001), echocardiography (30.8%; 4/13 vs. 4.0%; 2/50, p = 0.013), evaluation of calcium levels (46.2%; 6/13 vs. 4.1%; 2/49, P < 0.001) and lymphocyte count (53.8%; 7/13 vs. 15.7%; 8/51, p = 0.008). CONCLUSIONS: High-risk screening results for 22q11.2DS were associated with higher rates of prenatal and neonatal diagnostic genetic testing and other 22q11.2DS-specific evaluations. However, these interventions were not universally performed, and >50% of high-risk infants were discharged without genetic testing, representing possible missed opportunities to improve outcomes for affected individuals.

Performance of prenatal cfDNA screening for sex chromosomes.

PURPOSE: The aim of this study was to assess the performance of cell-free DNA (cfDNA) screening to detect sex chromosome aneuploidies (SCAs) in an unselected obstetrical population with genetic confirmation. METHODS: This was a planned secondary analysis of the multicenter, prospective SNP-based Microdeletion and Aneuploidy RegisTry (SMART) study. Patients receiving cfDNA results for autosomal aneuploidies and who had confirmatory genetic results for the relevant sex chromosomal aneuploidies were included. Screening performance for SCAs, including monosomy X (MX) and the sex chromosome trisomies (SCT: 47,XXX; 47,XXY; 47,XYY) was determined. Fetal sex concordance between cfDNA and genetic screening was also evaluated in euploid pregnancies. RESULTS: A total of 17,538 cases met inclusion criteria. Performance of cfDNA for MX, SCTs, and fetal sex was determined in 17,297, 10,333, and 14,486 pregnancies, respectively. Sensitivity, specificity, and positive predictive value (PPV) of cfDNA were 83.3%, 99.9%, and 22.7% for MX and 70.4%, 99.9%, and 82.6%, respectively, for the combined SCTs. The accuracy of fetal sex prediction by cfDNA was 100%. CONCLUSION: Screening performance of cfDNA for SCAs is comparable to that reported in other studies. The PPV for the SCTs was similar to the autosomal trisomies, whereas the PPV for MX was substantially lower. No discordance in fetal sex was observed between cfDNA and postnatal genetic screening in euploid pregnancies. These data will assist interpretation and counseling for cfDNA results for sex chromosomes.

Prenatal Weight Change Trajectories and Perinatal Outcomes among Twin Gestations.

OBJECTIVE: Despite an increase in twin pregnancies in recent decades, the Institute of Medicine twin weight gain recommendations remain provisional and provide no guidance for the pattern or timing of weight change. We sought to characterize gestational weight change trajectory patterns and examine associations with birth outcomes in a cohort of twin pregnancies. STUDY DESIGN: Prenatal and delivery records were examined for 320 twin pregnancies from a maternal-fetal medicine practice in Austin, TX 2011-2019. Prenatal weights for those with >1 measured weight in the first trimester and ≥3 prenatal weights were included in analyses. Trajectories were estimated to 32 weeks (mean delivery: 33.7 ± 3.3 weeks) using flexible latent class mixed models with low-rank thin-plate splines. Associations between trajectory classes and infant outcomes were analyzed using multivariable Poisson or linear regression. RESULTS: Weight change from prepregnancy to delivery was 15.4 ± 6.3 kg for people with an underweight body mass index, 15.4 ± 5.8 kg for healthy weight, 14.7 ± 6.9 kg for overweight, and 12.5 ± 6.4 kg for obesity. Three trajectory classes were identified: low (Class 1), moderate (Class 2), or high gain (Class 3). Class 1 (24.7%) maintained weight for 15 weeks and then gained an estimated 6.6 kg at 32 weeks. Class 2 (60.9%) exhibited steady gain with 13.5 kg predicted total gain, and Class 3 (14.4%) showed rapid gain across pregnancy with 21.3 kg predicted gain. Compared to Class 1, Class 3 was associated with higher birth weight z-score (ß = 0.63, 95% confidence interval [CI]: 0.31,0.96), increased risk for large for gestational age (IRR = 5.60, 95% CI: 1.59, 19.67), and birth <32 weeks (IRR = 2.44, 95%CI: 1.10, 5.4) that was attenuated in sensitivity analyses. Class 2 was associated with moderately elevated birth weight z-score (ß = 0.24, 95%CI: 0.00, 0.48, p = 0.050). CONCLUSION: Gestational weight change followed a low, moderate, or high trajectory; both moderate and high gain patterns were associated with increased infant size outcomes. Optimal patterns of weight change that balance risk during the prenatal, perinatal, and neonatal periods require further investigation, particularly in high-risk twin pregnancies. KEY POINTS: · A majority gained weight below IOM twin recommendations.. · Three patterns of GWC across pregnancy were identified.. · Moderate or high GWC was associated with infant size..

Obstetrical, perinatal, and genetic outcomes associated with nonreportable prenatal cell-free DNA screening results.

BACKGROUND: The clinical implications of nonreportable cell-free DNA screening results are uncertain, but such results may indicate poor placental implantation in some cases and be associated with adverse obstetrical and perinatal outcomes. OBJECTIVE: This study aimed to assess the outcomes of pregnancies with nonreportable cell-free DNA screening in a cohort of patients with complete genetic and obstetrical outcomes. STUDY DESIGN: This was a prespecified secondary analysis of a multicenter prospective observational study of prenatal cell-free DNA screening for fetal aneuploidy and 22q11.2 deletion syndrome. Participants who underwent cell-free DNA screening from April 2015 through January 2019 were offered participation. Obstetrical outcomes and neonatal genetic testing results were collected from 21 primary-care and referral centers in the United States, Europe, and Australia. The primary outcome was risk for adverse obstetrical and perinatal outcomes (aneuploidy, preterm birth at <28, <34, and <37 weeks' gestation, preeclampsia, small for gestational age or birthweight <10th percentile for gestational week, and a composite outcome that included preterm birth at <37 weeks, preeclampsia, small for gestational age, and stillbirth at >20 weeks) after nonreportable cell-free DNA screening because of low fetal fraction or other causes. Multivariable analyses were performed, adjusting for variables known to be associated with obstetrical and perinatal outcomes, nonreportable results, or fetal fraction. RESULTS: In total, 25,199 pregnant individuals were screened, and 20,194 were enrolled. Genetic confirmation was missing in 1165 (5.8%), 1085 (5.4%) were lost to follow-up, and 93 (0.5%) withdrew; the final study cohort included 17,851 (88.4%) participants who had cell-free DNA, fetal or newborn genetic confirmatory testing, and obstetrical and perinatal outcomes collected. Results were nonreportable in 602 (3.4%) participants. A sample was redrawn and testing attempted again in 427; in 112 (26.2%) participants, results were again nonreportable. Nonreportable results were associated with higher body mass index, chronic hypertension, later gestational age, lower fetal fraction, and Black race. Trisomy 13, 18, or 21 was confirmed in 1.6% with nonreportable tests vs 0.7% with reported results (P=.013). Rates of preterm birth at <28, 34, and 37 weeks, preeclampsia, and the composite outcome were higher among participants with nonreportable results, and further increased among those with a second nonreportable test, whereas the rate of small for gestational age infants was not increased. After adjustment for confounders, the adjusted odds ratios were 2.2 (95% confidence interval, 1.1-4.4) and 2.6 (95% confidence interval, 0.6-10.8) for aneuploidy, and 1.5 (95% confidence interval, 1.2-1.8) and 2.1 (95% confidence interval, 1.4-3.2) for the composite outcome after a first and second nonreportable test, respectively. Of the patients with nonreportable tests, 94.9% had a live birth, as opposed to 98.8% of those with reported test results (adjusted odds ratio for livebirth, 0.20 [95% confidence interval, 0.13-0.30]). CONCLUSION: Patients with nonreportable cell-free DNA results are at increased risk for a number of adverse outcomes, including aneuploidy, preeclampsia, and preterm birth. They should be offered diagnostic genetic testing, and clinicians should be aware of the increased risk of pregnancy complications.

Performance of a Multianalyte 'Rule-Out' Assay in Pregnant Individuals With Suspected Preeclampsia.

BACKGROUND: The ability to diagnose preeclampsia clinically is suboptimal. Our objective was to validate a novel multianalyte assay and characterize its performance, when intended for use as an aid to rule-out preeclampsia. METHODS: Prospective, multicenter cohort study of pregnant individuals presenting between 280/7 and 366/7 weeks' with preeclampsia-associated signs and symptoms. Individuals not diagnosed with preeclampsia after baseline evaluation were enrolled in the study cohort, with those who later developed preeclampsia, classified as cases and compared with a negative control group who did not develop preeclampsia. Individuals with assay values at time of enrollment ≥0.0325, determined using a previously developed algorithm, considered at risk. The primary analysis was the time to develop preeclampsia assessed using a multivariate Cox regression model. RESULTS: One thousand thirty-six pregnant individuals were enrolled in the study cohort with an incidence of preeclampsia of 30.3% (27.6%-33.2%). The time to develop preeclampsia was shorter for those with an at-risk compared with negative assay result (log-rank P<0.0001; adjusted hazard ratio of 4.81 [3.69-6.27, P<0.0001]). The performance metrics for the assay to rule-out preeclampsia within 7 days of enrollment showed a sensitivity 76.4% (67.5%-83.5%), negative predictive value 95.0% (92.8%-96.6%), and negative likelihood ratio 0.46 (0.32-0.65). Assay performance improved if delivery occurred <37 weeks and for individuals enrolled between 28 and 35 weeks. CONCLUSIONS: We confirmed that a novel multianalyte assay was associated with the time to develop preeclampsia and has a moderate sensitivity and negative likelihood ratio but high negative predictive value when assessed as an aid to rule out preeclampsia within 7 days of enrollment. REGISTRATION: The study was registered on Clinicaltrials.gov (Identifier NCT02780414).

Cell-free DNA screening for trisomies 21, 18, and 13 in pregnancies at low and high risk for aneuploidy with genetic confirmation.

BACKGROUND: Cell-free DNA noninvasive prenatal screening for trisomies 21, 18, and 13 has been rapidly adopted into clinical practice. However, previous studies are limited by a lack of follow-up genetic testing to confirm the outcomes and accurately assess test performance, particularly in women at a low risk for aneuploidy. OBJECTIVE: To measure and compare the performance of cell-free DNA screening for trisomies 21, 18, and 13 between women at a low and high risk for aneuploidy in a large, prospective cohort with genetic confirmation of results STUDY DESIGN: This was a multicenter prospective observational study at 21 centers in 6 countries. Women who had single-nucleotide-polymorphism-based cell-free DNA screening for trisomies 21, 18, and 13 were enrolled. Genetic confirmation was obtained from prenatal or newborn DNA samples. The test performance and test failure (no-call) rates were assessed for the cohort, and women with low and high previous risks for aneuploidy were compared. An updated cell-free DNA algorithm blinded to the pregnancy outcome was also assessed. RESULTS: A total of 20,194 women were enrolled at a median gestational age of 12.6 weeks (interquartile range, 11.6-13.9). The genetic outcomes were confirmed in 17,851 cases (88.4%): 13,043 (73.1%) low-risk and 4808 (26.9%) high-risk cases for aneuploidy. Overall, 133 trisomies were diagnosed (100 trisomy 21; 18 trisomy 18; 15 trisomy 13). The cell-free DNA screen positive rate was lower in the low-risk vs the high-risk group (0.27% vs 2.2%; P<.0001). The sensitivity and specificity were similar between the groups. The positive predictive value for the low- and high-risk groups was 85.7% vs 97.5%; P=.058 for trisomy 21; 50.0% vs 81.3%; P=.283 for trisomy 18; and 62.5% vs 83.3; P=.58 for trisomy 13, respectively. Overall, 602 (3.4%) patients had no-call result after the first draw and 287 (1.61%) after including cases with a second draw. The trisomy rate was higher in the 287 cases with no-call results than patients with a result on a first draw (2.8% vs 0.7%; P=.001). The updated algorithm showed similar sensitivity and specificity to the study algorithm with a lower no-call rate. CONCLUSION: In women at a low risk for aneuploidy, single-nucleotide-polymorphism-based cell-free DNA has high sensitivity and specificity, positive predictive value of 85.7% for trisomy 21 and 74.3% for the 3 common trisomies. Patients who receive a no-call result are at an increased risk of aneuploidy and require additional investigation.

Cell-free DNA screening for prenatal detection of 22q11.2 deletion syndrome.

BACKGROUND: Historically, prenatal screening has focused primarily on the detection of fetal aneuploidies. Cell-free DNA now enables noninvasive screening for subchromosomal copy number variants, including 22q11.2 deletion syndrome (or DiGeorge syndrome), which is the most common microdeletion and a leading cause of congenital heart defects and neurodevelopmental delay. Although smaller studies have demonstrated the feasibility of screening for 22q11.2 deletion syndrome, large cohort studies with confirmatory postnatal testing to assess test performance have not been reported. OBJECTIVE: This study aimed to assess the performance of single-nucleotide polymorphism-based, prenatal cell-free DNA screening for detection of 22q11.2 deletion syndrome. STUDY DESIGN: Patients who underwent single-nucleotide polymorphism-based prenatal cell-free DNA screening for 22q11.2 deletion syndrome were prospectively enrolled at 21 centers in 6 countries. Prenatal or newborn DNA samples were requested in all cases for genetic confirmation using chromosomal microarrays. The primary outcome was sensitivity, specificity, positive predictive value, and negative predictive value of cell-free DNA screening for the detection of all deletions, including the classical deletion and nested deletions that are ≥500 kb, in the 22q11.2 low-copy repeat A-D region. Secondary outcomes included the prevalence of 22q11.2 deletion syndrome and performance of an updated cell-free DNA algorithm that was evaluated with blinding to the pregnancy outcome. RESULTS: Of the 20,887 women enrolled, a genetic outcome was available for 18,289 (87.6%). A total of 12 22q11.2 deletion syndrome cases were confirmed in the cohort, including 5 (41.7%) nested deletions, yielding a prevalence of 1 in 1524. In the total cohort, cell-free DNA screening identified 17,976 (98.3%) cases as low risk for 22q11.2 deletion syndrome and 38 (0.2%) cases as high risk; 275 (1.5%) cases were nonreportable. Overall, 9 of 12 cases of 22q11.2 were detected, yielding a sensitivity of 75.0% (95% confidence interval, 42.8-94.5); specificity of 99.84% (95% confidence interval, 99.77-99.89); positive predictive value of 23.7% (95% confidence interval, 11.44-40.24), and negative predictive value of 99.98% (95% confidence interval, 99.95-100). None of the cases with a nonreportable result was diagnosed with 22q11.2 deletion syndrome. The updated algorithm detected 10 of 12 cases (83.3%; 95% confidence interval, 51.6-97.9) with a lower false positive rate (0.05% vs 0.16%; P<.001) and a positive predictive value of 52.6% (10/19; 95% confidence interval, 28.9-75.6). CONCLUSION: Noninvasive cell-free DNA prenatal screening for 22q11.2 deletion syndrome can detect most affected cases, including smaller nested deletions, with a low false positive rate.

Examining ultrasound diagnostic performance improvement with utilization of maternal-fetal medicine tele-interpretation.

BACKGROUND: Telemedicine can extend essential health services to under-resourced settings and improve the quality of obstetrical care. Specifically, the evaluation and management of fetal anomalies require perinatal subspecialists, rendering prenatal diagnosis essential, and may benefit from telemedicine platforms to improve access to care. OBJECTIVE: This study aimed to evaluate the impact of a maternal-fetal medicine telemedicine ultrasound program on the diagnostic accuracy of fetal anomalies when used within practices where ultrasounds are interpreted by general obstetricians or family medicine physicians. STUDY DESIGN: This was a cross-sectional study of all patients receiving care at 11 private obstetrical practices and imaging centers who had obstetrical ultrasounds performed from January 1, 2020, to July 6, 2020. All ultrasounds were performed by sonographers remotely trained under a standardized protocol and interpreted by maternal-fetal medicine physicians via telemedicine. Ultrasound characteristics and interpretation were extracted from ultrasound reports. Before the introduction of maternal-fetal medicine telemedicine, all ultrasound interpretations were reviewed by general obstetricians and family medicine physicians with reliance predominantly on the sonographer's impression. The primary outcome was potential missed diagnosis of a fetal anomaly, defined as an ultrasound designated as normal by a sonographer but diagnosed with an anomaly by a maternal-fetal medicine physician via telemedicine. This outcome serves as a proxy measure for anomaly diagnoses that would likely be missed without the supervision of a maternal-fetal medicine physician. The characteristics of the potential missed diagnoses were compared by type of scan and fetal organ system in univariable analysis. Moreover, a survey was conducted for sonographers and obstetrical providers to assess their perceptions of ultrasound interpretation via telemedicine. RESULTS: Overall, 6403 ultrasound examinations were evaluated, 310 of which had a diagnosis of fetal anomaly by a maternal-fetal medicine physician (4.8%). Of the fetal anomalies, 43 were diagnosed on an anatomic survey (13.9%), and 89 were diagnosed as cardiac anomalies (28.7%). The overall rate of the potential missed diagnoses was 34.5% and varied significantly by type of ultrasound (anatomy scans vs other first-, second-, and third-trimester ultrasounds) (P<.01). Moreover, there were significant differences in the rate of the potential missed diagnoses by organ system, with the highest rate for cardiac anomalies (P<.01). CONCLUSION: Expertise in maternal-fetal medicine telemedicine improves the diagnostic performance of antenatal ultrasound throughout pregnancy. However, there are implications for improving the quality of antenatal care, such as ensuring appropriate referrals and site of delivery, particularly for cardiac anomalies.

Physical examination-indicated cerclage in twin pregnancy: a randomized controlled trial.

BACKGROUND: Women with twin pregnancies and a dilated cervix in the second trimester are at increased risk of pregnancy loss and early preterm birth; there is currently no proven therapy to prevent preterm birth in this group of women. OBJECTIVE: This study aimed to determine whether physical examination-indicated cerclage reduces the incidence of preterm birth in women with a diagnosis of twin pregnancies and asymptomatic cervical dilation before 24 weeks of gestation. STUDY DESIGN: Multicenter, parallel group, open-label, randomized controlled trial of women with twin pregnancies and asymptomatic cervical dilation of 1 to 5 cm between 16 weeks 0/7 days of gestation and 23 weeks 6/7 days of gestation were enrolled from July 2015 to July 2019 in 8 centers. Eligible women were randomized in a 1:1 ratio into either cerclage or no cerclage groups. We excluded women with monochorionic-monoamniotic twin pregnancy, selective fetal growth restriction, twin-twin transfusion syndrome, major fetal malformation, known genetic anomaly, placenta previa, signs of labor, or clinical chorioamnionitis. The primary outcome was the incidence of preterm birth at <34 weeks of gestation. Secondary outcomes were preterm births at <32, <28, and <24 weeks of gestation, interval from diagnosis to delivery, and perinatal mortality. Data were analyzed by intention-to-treat methods. RESULTS: After an interim analysis was performed, the Data and Safety Monitoring Board recommended stopping the trial because of a significant decrease in perinatal mortality in the cerclage group. We randomized 34 women, with 4 women being excluded because of expired informed consent. A total of 17 women were randomized to physical examination-indicated cerclage and 13 women to no cerclage. Whereas 4 women randomized to cerclage did not receive the surgical procedure, no women in the no cerclage group received cerclage. Maternal demographics were not significantly different. All women in the cerclage group also received indomethacin and antibiotics. When comparing the cerclage group vs the no cerclage group, the incidence of preterm birth was significantly decreased as follows: preterm birth at <34 weeks of gestation, 12 of 17 women (70%) vs 13 of 13 women (100%) (risk ratio, 0.71; 95% confidence interval, 0.52-0.96); preterm birth at <32 weeks of gestation, 11 of 17 women (64.7%) vs 13 of 13 women (100%) (risk ratio, 0.65; 95% confidence interval, 0.46-0.92); preterm birth at <28 weeks of gestation, 7 of 17 women (41%) vs 11 of 13 women (84%) (risk ratio, 0.49; 95% confidence interval, 0.26-0.89); and preterm birth at <24 weeks of gestation, 5 of 17 women (30%) vs 11 of 13 women (84%) (risk ratio, 0.35; 95% confidence interval, 0.16-0.75). The mean gestational age at delivery was 29.05±1.7 vs 22.5±3.9 weeks (P<.01), respectively; the mean interval from diagnosis of cervical dilation to delivery was 8.3±5.8 vs 2.9±3.0 weeks (P=.02), respectively. Perinatal mortality was also significantly reduced in the cerclage group compared with the no cerclage group as follows: 6 of 34 women (17.6%) vs 20 of 26 women (77%) (risk ratio, 0.22; 95% confidence interval, 0.1-0.5), respectively. CONCLUSION: In women with twin pregnancies and asymptomatic cervical dilation before 24 weeks of gestation, a combination of physical examination-indicated cerclage, indomethacin, and antibiotics significantly decreased preterm birth at all evaluated gestational ages. Most importantly, cerclage in this population was associated with a 50% decrease in early preterm birth at <28 weeks of gestation and with a 78% decrease in perinatal mortality.

Fetal lower urinary tract obstruction: What should we tell the prospective parents?

Fetal lower urinary tract obstruction (LUTO), which often results in marked perinatal morbidity and mortality, is caused by a heterogeneous group of anatomical defects that lead to blockage of the urethra. The classic prenatal presentation of LUTO includes megacystis with hydronephrosis. While mild forms of the disease can be associated with favorable outcomes, more severe disease commonly leads to dysplastic changes in the fetal kidneys, and ultimately oligohydramnios, which can result in secondary pulmonary hypoplasia and renal failure at birth. The aim of this review is to provide practitioners with a general overview of the diagnosis and treatment of LUTO based on disease severity, along with some points to consider when counseling prospective parents of fetuses with this condition.

Vasa previa: a multicenter retrospective cohort study.

OBJECTIVE: The objective of the study was to describe the characteristics and outcomes of patients with antenatal diagnosis of vasa previa and evaluate the predictive factors of resolution in a contemporary large, multicenter data set. STUDY DESIGN: This was a retrospective multicenter cohort study of all antenatally diagnosed cases of vasa previa, identified via ultrasound and electronic medical record, between January 2011 and July 2018 in 5 US centers. Records were abstracted to obtain variables at diagnosis, throughout pregnancy, and outcomes, including maternal and neonatal variables. Data were reported as median [range] or n (percentage). Descriptive statistics, receiver-operating characteristics, and logistic regression analysis were used as appropriate. RESULTS: One hundred thirty-six cases of vasa previa were identified in 5 centers during the study period, 19 (14%) of which resolved spontaneously at median estimated gestational age of 27 weeks [19-34]. All subjects with unresolved vasa previa underwent cesarean delivery at a median estimated gestational age of 34 weeks [27-39] with the median estimated blood loss of 800 mL [250-2000]. Rates for vaginal bleeding, preterm labor, premature rupture of membrane, and need for blood product transfusion were not different between the resolved and unresolved group (P = NS). The odds ratio for resolution in those with the estimated gestational age of less than 24 weeks at the time of diagnosis was 7.9 (95% confidence interval, 2.1-29.4) after adjustment for confounding variables. CONCLUSION: Our data suggest that outcomes in antenatally diagnosed cases of vasa previa are excellent. Furthermore, our data report a higher chance of resolution when the condition is diagnosed before 24 weeks of gestation.

Treatment of Morbidly Adherent Placentation Utilizing a Standardized Multidisciplinary Approach in the Community Hospital-Private Practice Setting.

Objective Morbidly adherent placentation is associated with increased maternal morbidity and mortality. Recently, there has been mounting evidence supporting the benefits of a standardized multidisciplinary approach at tertiary teaching hospitals. Our objective was to estimate the impact of the implementation of a similar program at a high-volume private community hospital. Study Design In this retrospective cohort study, we evaluated maternal outcomes in all cases of histopathologically confirmed morbidly adherent placentation since the initiation of our multidisciplinary program (2012-2016). Our data were compared with the previously published outcomes of two large cohorts from tertiary teaching hospitals in Utah and Texas. Results In the 28 cases included for evaluation, our group's median estimated blood loss, median packed red blood cells transfused, median anesthesia time, median length of stay, or rates of maternal morbidity did not statistically differ from the published data in Utah or Texas. Conclusion Our data demonstrate the feasibility and utility of a multidisciplinary morbidly adherent placentation program in the private practice/community hospital setting with outcomes similar to those at tertiary teaching hospitals. Implementation of such program may prove beneficial in remote centers, where various factors may prohibit patient travel to a larger center.

Placental Alpha Microglobulin-1 Compared With Fetal Fibronectin to Predict Preterm Delivery in Symptomatic Women.

OBJECTIVE: To compare the rapid bedside test for placental α microglobulin-1 with the instrumented fetal fibronectin test for prediction of imminent spontaneous preterm delivery among women with symptoms of preterm labor. METHODS: We conducted a prospective observational study on pregnant women with signs or symptoms suggestive of preterm labor between 24 and 35 weeks of gestation with intact membranes and cervical dilatation less than 3 cm. Participants were prospectively enrolled at 15 U.S. academic and community centers. Placental α microglobulin-1 samples did not require a speculum examination. Health care providers were blinded to placental α microglobulin-1 results. Fetal fibronectin samples were collected through speculum examination per manufacturer requirements and sent to a certified laboratory for testing using a cutoff of 50 ng/mL. The coprimary endpoints were positive predictive value (PPV) superiority and negative predictive value (NPV) noninferiority of placental α microglobulin-1 compared with fetal fibronectin for the prediction of spontaneous preterm birth within 7 days and within 14 days. RESULTS: Of 796 women included in the study cohort, 711 (89.3%) had both placental α microglobulin-1 and fetal fibronectin results and valid delivery outcomes available for analysis. The overall rate of preterm birth was 2.4% (17/711) within 7 days of testing and 4.2% (30/711) within 14 days of testing with respective rates of spontaneous preterm birth of 1.3% (9/703) and 2.9% (20/701). Fetal fibronectin was detected in 15.5% (110/711), and placental α microglobulin-1 was detected in 2.4% (17/711). The PPVs for spontaneous preterm delivery within 7 days or less among singleton gestations (n=13) for placental α microglobulin-1 and fetal fibronectin were 23.1% (3/13) and 4.3% (4/94), respectively (P<.025 for superiority). The NPVs were 99.5% (619/622) and 99.6% (539/541) for placental α microglobulin-1 and fetal fibronectin, respectively (P<.001 for noninferiority). CONCLUSION: Although placental α microglobulin-1 performed the same as fetal fibronectin in ruling out spontaneous preterm delivery among symptomatic women, it demonstrated statistical superiority in predicting it.

The Value of Implementing Multidisciplinary Perinatal Care Conference in the Private Practice Setting.

Objective The objective of this study was to estimate the impact of multidisciplinary (Multi-D) perinatal care conference (PCC) implementation in the private practice setting. Methods After the initial 12-month period following implementation of the monthly PCC by private maternal-fetal medicine and neonatology practitioners, conference attendees were asked to completed a modified version of the Attitudes Toward Health Care Teams Scale, involving 19 questions assessing their attitudes and opinions toward Multi-D team care on a five-point Likert's scale. Results Of the 51 average attendees to the PCC, 82.3% completed the survey. A majority of respondents agreed that Multi-D team care resulted in improved care for patients and family, was not overly complex to coordinate, and resulted in significant job satisfaction and improved medical knowledge. Conclusion Multi-D care is an effective approach to the complicated needs of maternal-fetal medicine patients which may lead to improved patient and family outcomes, high provider satisfaction, and can easily be implemented and utilized within a private practice or community hospital setting.

Postmortem Whole Exome Sequencing Identifies Novel EIF2B3 Mutation With Prenatal Phenotype in 2 Siblings.

OBJECTIVE: We describe 2 male siblings with a severe, prenatal phenotype of vanishing white matter disease and the impact of whole exome sequencing on their diagnosis and clinical care. METHODS: The 2 children underwent detailed clinical characterization, through clinical and laboratory testing, as well as prenatal and postnatal imaging. Biobanked blood from the 2 siblings was submitted for whole exome sequencing at Baylor Laboratories. RESULTS: Both male children had abnormal prenatal neuroimaging and suffered precipitous, fatal neurologic decline. Neuropathologic findings included subependymal pseudocysts, microcalcifications, and profound lack of brain myelin and sparing of peripheral nerve myelin. A novel homozygous mutation in the EIF2B3 gene (c.97A>G [p.Lys33Glu]) was found in both children; both parents were heterozygous carriers. The family subsequently conceived a healthy child via in vitro fertilization with preimplantation mutation screening. CONCLUSION: These histories expand the prenatal phenotype of eIF2b-related disorders and poignantly illustrate the impact that unbiased genomic sequencing can have on the diagnosis and medical decision making for families affected by childhood neurodegenerative disorders.

Serial amnioinfusions for fetal pulmonary palliation in fetuses with renal failure.

Fetal lower urinary tract obstruction (LUTO) encompasses a heterogeneous group of congenital pathologies and generally results in oligohydramnios. Fetal intervention (e.g. vesicoamniotic shunting, fetal cystoscopy) has traditionally been reserved for cases with a favorable renal profile, while those with unfavorable renal function have been offered termination or expectant management with the latter leading to high incidence of marked pulmonary hypoplasia, neonatal morbidity and mortality. Here, we describe two cases, which were not candidates for traditional intervention based on abnormal fetal renal function, who elected to proceed with serial amnioinfusions for fetal pulmonary palliation to attenuate the risk of pulmonary hypoplasia.

Changes in cerebral autoregulation in the second half of pregnancy and compared to non-pregnant controls.

OBJECTIVE: The mechanism by which pregnancy affects the cerebral circulation is unknown, but it has a central role in the development of neurological complications in preeclampsia, which is believed to be related to impaired autoregulation. We evaluated the cerebral autoregulation in the second half of pregnancy, and compared this with a control group of healthy, fertile non-pregnant women. METHODS: In a prospective cohort analysis, cerebral blood flow velocity of the middle cerebral artery (determined by transcranial Doppler), blood pressure (noninvasive arterial volume clamping), and end-tidal carbon dioxide (EtCO2) were simultaneously collected for 7min. The autoregulation index (ARI) was calculated. ARI values of 0 and 9 indicated absent and perfect autoregulation, respectively. ANOVA and Pearson's correlation coefficient were used, with p<0.05 considered significant. RESULTS: A total of 76 pregnant and 18 non-pregnant women were included. The ARI did not change during pregnancy, but pregnant women had a significantly higher ARI than non-pregnant controls (ARI 6.7±0.9 vs. 5.3±1.4, p<0.001). This remained significant after adjusting for EtCO2 (p<0.001). CONCLUSION: Cerebral autoregulation functionality is enhanced in the second half of pregnancy, when compared to non-pregnant fertile women, even after controlling for EtCO2. The autoregulation does not change with advancing gestational age.

Oligohydramnios and growth restriction do not portend worse prognosis in gastroschisis pregnancies.

OBJECTIVES: Gastroschisis is a common abdominal wall defect. While most neonates have an excellent prognosis, complications do occur. Several risk factors for adverse neonatal outcomes have been identified, however, the impact of intrauterine growth restriction (IUGR) and oligohydramnios on neonatal morbidity and mortality has not been fully elucidated. METHODS: In this retrospective cohort study of pregnancies complicated by gastroschisis at two tertiary-care centers during an eight-year period, maternal, fetal and neonatal data were analyzed to estimate the impact of IUGR and oligohydramnios upon neonatal outcomes. Adverse outcomes were defined as five-minute Apgar score <7, umbilical cord pH <7.12, neonatal sepsis, prolonged ventilator support, prolonged total parenteral nutrition, extended NICU stay, death and a composite of the above. RESULTS: Among the 179 cases of gastroschisis, there were no differences in maternal demographics between cases with and without IUGR or oligohydramnios. Fetuses with oligohydramnios demonstrated a trend toward lower birthweight (p = 0.06). Small for gestational age infants showed a trend toward prolonged ventilator support (p = 0.06). Oligohydramnios and IUGR were otherwise not associated with adverse neonatal outcomes. CONCLUSIONS: While risk factors for adverse neonatal outcomes have been identified in pregnancies complicated by gastroschisis, IUGR and oligohydramnios do not appear to be among them.

Intrahepatic Persistent Right Umbilical Vein and Associated Outcomes: A Systematic Review of the Literature.

The aim of this study was to provide a comprehensive review of the current data surrounding an intrahepatic persistent right umbilical vein in the fetus, including associated anomalies and outcomes, and to assist practitioners in counseling and management of affected pregnancies. We performed a MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Northern Light database search for articles reporting outcomes on prenatally diagnosed cases of a persistent right umbilical vein. Each article was independently reviewed for eligibility by the investigators. Thereafter, the data were extracted and validated independently by 3 investigators. A total of 322 articles were retrieved, and 16 were included in this systematic review. The overall prevalence of an intrahepatic persistent right umbilical vein was found to be 212 per 166,548 (0.13%). Of the 240 cases of an intrahepatic persistent right umbilical vein identified, 183 (76.3%) were isolated. The remaining cases had a coexisting abnormality, including 19 (7.9%) cardiac, 9 (3.8%) central nervous system, 15 (6.3%) genitourinary, 3 (1.3%) genetic, and 17 (7%) placental/cord (predominantly a single umbilical artery). In summary, a persistent right umbilical vein is commonly an isolated finding but may be associated with a coexisting cardiac defect in 8% of cases. Therefore, consideration should be given to fetal echocardiography in cases of a persistent right umbilical vein.