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As SARS-CoV-2 continues to spread and evolve, detecting emerging variants early is critical for public health interventions. Inferring lineage prevalence by clinical testing is infeasible at scale, especially in areas with limited resources, participation, or testing and/or sequencing capacity, which can also introduce biases1–3. SARS-CoV-2 RNA concentration in wastewater successfully tracks regional infection dynamics and provides less biased abundance estimates than clinical testing4,5. Tracking virus genomic sequences in wastewater would improve community prevalence estimates and detect emerging variants. However, two factors limit wastewater-based genomic surveillance: low-quality sequence data and inability to estimate relative lineage abundance in mixed samples. Here we resolve these critical issues to perform a high-resolution, 295-day wastewater and clinical sequencing effort, in the controlled environment of a large university campus and the broader context of the surrounding county. We developed and deployed improved virus concentration protocols and deconvolution software that fully resolve multiple virus strains from wastewater. We detected emerging variants of concern up to 14 days earlier in wastewater samples, and identified multiple instances of virus spread not captured by clinical genomic surveillance. Our study provides a scalable solution for wastewater genomic surveillance that allows early detection of SARS-CoV-2 variants and identification of cryptic transmission.

SummaryAs SARS-CoV-2 continues to spread and evolve, detecting emerging variants early is critical for public health interventions. Inferring lineage prevalence by clinical testing is infeasible at scale, especially in areas with limited resources, participation, or testing/sequencing capacity, which can also introduce biases. SARS-CoV-2 RNA concentration in wastewater successfully tracks regional infection dynamics and provides less biased abundance estimates than clinical testing. Tracking virus genomic sequences in wastewater would improve community prevalence estimates and detect emerging variants. However, two factors limit wastewater-based genomic surveillance: low-quality sequence data and inability to estimate relative lineage abundance in mixed samples. Here, we resolve these critical issues to perform a high-resolution, 295-day wastewater and clinical sequencing effort, in the controlled environment of a large university campus and the broader context of the surrounding county. We develop and deploy improved virus concentration protocols and deconvolution software that fully resolve multiple virus strains from wastewater. We detect emerging variants of concern up to 14 days earlier in wastewater samples, and identify multiple instances of virus spread not captured by clinical genomic surveillance. Our study provides a scalable solution for wastewater genomic surveillance that allows early detection of SARS-CoV-2 variants and identification of cryptic transmission.

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The incidence of placenta accreta has increased dramatically over the last three decades, in concert with the increase in the cesarean delivery rate. Optimal management requires accurate prenatal diagnosis. The purpose of this study was to determine the precision and reliability of ultrasonography and magnetic resonance imaging (MRI) in diagnosing placenta accreta.A historical cohort study was performed with information gathered from our obstetric, radiologic, and pathology databases. Records from January 2000 to June 2005 were reviewed to identify patients with a diagnosis of placenta previa, low-lying placenta with a prior cesarean delivery, or history of a myomectomy to determine the accuracy of pelvic ultrasonography in the diagnosis of placenta accreta. The records of those considered to be suspicious for placenta accreta and subsequently referred for additional confirmation by MRI were also analyzed. The sonographic and MRI diagnoses were compared with the final pathologic or operative findings or with both.Of the 453 women with placenta previa, previous cesarean delivery and low-lying anterior placenta, or previous myomectomy, 39 had placenta accreta confirmed by pathological examination. Ultrasonography accurately predicted placenta accreta in 30 of 39 of women and correctly ruled out placenta accreta in 398 of 414 without placenta accreta (sensitivity 0.77, specificity 0.96). Forty-two women underwent MRI evaluation because of findings suspicious or inconclusive of placenta accreta by ultrasonography. Magnetic resonance imaging accurately predicted placenta accreta in 23 of 26 cases with placenta accreta and correctly ruled out placenta accreta in 14 of 14 (sensitivity 0.88, specificity 1.0).A two-stage protocol for evaluating women at high risk for placenta accreta, which uses ultrasonography first, and then MRI for cases with inconclusive ultrasound features, will optimize diagnostic accuracy.

Objective. To assess the impact of a sonographic diagnosis of marginal placental cord insertion on birth weight and duration of pregnancy. Methods. A retrospective chart review was performed for 100 singleton pregnancies with prospectively identified marginal placental cord insertion. Results. Birth weights below the 10th percentile occurred in 6.25% of pregnancies without preeclampsia. Spontaneous preterm delivery occurred in 7.3% of pregnancies without preeclampsia. Rates of birth weight below the 10th percentile and preterm delivery were not significantly different from those in the general population. Preeclampsia developed in 4 patients; all had elective preterm deliveries, and all gave birth to neonates with birth weights below the 10th percentile. Conclusions. A prenatal diagnosis of marginal placental cord insertion is not associated with increased risk of growth impairment or preterm delivery.

The finding of echogenic bowel on prenatal sonography is not infrequent, occurring in 0.6% to 1.4% of prenatal scans. 1-3 Originally described as a normal variant by Fakhry et al, 4 this finding has been shown subsequently to be associated with a variety of fetal abnormalities such as cystic fibrosis, chromosomal abnormalities, intrauterine growth restriction, congenital infection, intrauterine fetal death, intra-amniotic bleeding, and thalassemia. 1-3,5-9 We present a case of echogenic bowel in a fetus who subsequently had a diagnosis of familial microvillous atrophy.

The objective of this study was to determine the relative risk for aneuploidy in the presence of a cardiac intraventricular echogenic focus in a patient population at high risk for aneuploidy. A retrospective cohort study was conducted on patients referred to a fetal diagnostic center who were undergoing amniocentesis. Records and second trimester sonograms were reviewed. Approximately 5100 comprehensive prenatal sonograms were obtained over a 2 year study period. Karyotyping by amniocentesis was done in 2412 women; 84 of the karyotypes (3.5%) were abnormal. Fetuses with no ultrasonographic findings suggestive of aneuploidy had a 1.4% (28 of 1940) prevalence of significant chromosomal abnormalities. An intraventricular echogenic focus was found in 149 of the women with karyotype analysis; 15 had an abnormal karyotype. Fetuses with intraventricular echogenic foci had a relative risk of 3.30 of aneuploidy when compared to fetuses without echogenic cardiac foci. The presence of an isolated intraventricular echogenic focus carried a relative risk of 4.08 compared to those fetuses in which ultrasonography had no finding associated with aneuploidy. In conclusion, these preliminary data indicate that presence of an intraventricular echogenic cardiac focus carries an increased risk of fetal aneuploidy.

We report a female infant noted prenatally to have an umbilical cord mass. At birth, a labial strawberry haemangioma was noted. She subsequently developed an abdominal mass which was discovered to be a proliferating haemangioma, continuous with both the labial and the umbilical stump lesions.

Congenital anomalies are increasingly being identified in the first trimester, particularly when early screening sonography is performed for a previous abnormal pregnancy or diagnosis of a genetic disorder in the family. We present a case of first-trimester diagnosis of osteogenesis imperfecta (OI) type II in a woman with a previously affected pregnancy in which diagnosis was aided by the use of transvaginal three-dimensional (3D) sonography.

Congenital nephrosis of the Finnish type (CNF) is a rare, autosomal recessive disorder of glomerular filtration that results in massive proteinuria, edema, and ascites. Although previous studies describe the classic renal lesions characterizing this disorder, there are few documenting in detail the associated placental alterations. In this context, we present a case of CNF with emphasis on the placental pathology and compare our findings to what has been previously reported in the literature. A 36-year-old G2P1 with no significant medical history developed persistently elevated amniotic fluid alpha-fetoprotein in the absence of neural tube defects. Because of a clinical suspicion of CNF, she electively terminated the pregnancy at 19 weeks. Postmortem examination revealed characteristic renal changes, confirmed by electron microscopy, as well as significant placental villous edema. Although the placenta was not enlarged, the villi appeared profoundly hydropic. Extensive cystic vacuolar change was documented in both stem villi and tertiary villi, affecting 95% of the villi present. Since the fetus was not grossly edematous, the placental findings may represent the first sign of systemic hypoproteinemia.

Objective. To determine whether fetal echocardiography is warranted in cases of single umbilical artery in a population at risk for aneuploidy. Methods. All cases of fetal single umbilical artery identified over a 2-year period were reviewed for other sonographically detected abnormalities, fetal echocardiographic results, and karyotype. Results. Sixty-five cases of single umbilical artery were diagnosed on the basis of initial sonograms. Five were subsequently shown to have 3-vessel cords (8% false-positive diagnosis; incidence, 1.2 %). Excluding 3 from twin gestations, 57 cases formed the study population. Thirty-one fetuses (54%) were initially thought to have isolated single umbilical arteries, and 26 (46%) had nonisolated single umbilical arteries. Fetal echocardiography was performed in 29 cases (51%), 24 (83%) with normal findings and 5 (17%) with abnormal findings. Four (50%) of 8 nonisolated single umbilical arteries had abnormal echocardiographic findings versus 1 (5%) of 21 apparently isolated single umbilical arteries (P

Objective: This study was undertaken to assess the value of minor ultrasonographic markers in predicting significant karyotypic abnormalities. Study Design: A total of 2743 fetuses (14-24 weeks' gestation) prospectively underwent a detailed ultrasonographic survey before genetic amniocentesis. Criteria for 8 minor ultrasonographic markers were established. Odds ratios for significant karyotypic abnormalities in the presence of minor ultrasonographic markers were calculated with the χ 2 and Fisher exact tests. Results: Of the fetuses, 14.6% had a single minor ultrasonographic marker, 2.1% had ≥2 minor ultrasonographic markers, and 2.7% had ≥1 major ultrasonographic abnormality. One hundred four fetuses (3.8%) had an abnormal karyotype. Compared with a normal ultrasonographic examination result a single minor ultrasonographic marker increased the risk of karyotypic abnormality 5.7-fold (95% confidence interval, 3.5-9.3), whereas multiple minor markers increased the risk of an abnormal karyotype 12-fold (95% confidence interval, 5.5-26.5). When they were identified ultrasonographically in isolation, echogenic bowel, 2-vessel umbilical cord, echogenic intracardiac foci, choroidal separation, and choroid plexus cysts were statistically associated with an abnormal karyotype. When minor markers were identified in clusters of ≥2, echogenic bowel, short femur, 2-vessel umbilical cord, echogenic intracardiac foci, and mild ventriculomegaly were significantly predictive of karyotypic abnormality. With respect to the a priori aneuploidy risk of 1:26 and the a priori Down syndrome risk of 1:50, a normal ultrasonographic examination result reduced the risks to 1:67 and 1:120, respectively. The use of minor ultrasonographic markers in addition to major ultrasonographic abnormalities increased the detection of karyotypic abnormality from 27.9% to 68.3%. For trisomy 21 the sensitivity rose from 16.4% to 67.3%. Conclusions: Significant karyotypic abnormality risk assessment by ultrasonography was greatly enhanced by the addition of minor ultrasonographic markers. Further, clusters of minor ultrasonographic markers greatly increased the likelihood of karyotypic abnormality compared with a single minor marker. A completely normal ultrasonographic examination result reduced the risk of an abnormal karyotype by 62%. Inclusion of minor ultrasonographic markers in the genetic sonogram in a high-risk population will allow the detection of 68% of fetuses with karyotypic abnormalities with a false-positive rate of 17%. (Am J Obstet Gynecol 1999;181:898-903.)

We correlated sonographic findings with fetal outcomes in women with unsuspected twin pregnancies who had sonography in the second trimester as part of a screening program for maternal serum alpha-fetoprotein (MSAFP) level and history of neural tube defect.The study group consisted of 97 women with twin pregnancies who participated in a screening program for MSAFP level and history of neural tube defect. Seventy-three had normal MSAFP levels, 21 had elevated MSAFP levels, and two had low MSAFP levels. One patient had a family history of anencephaly. All 97 patients had sonography during their second trimester of pregnancy. Sonographic findings were reviewed retrospectively for information on gestational age, fetal anomalies, sex of the fetus, location of the placenta, presence and thickness of a dividing membrane, and interpretation of amnionicity and chorionicity. Information on fetal outcome included gestational age at delivery, survival, birth weight, sex, congenital anomalies, obstetric complications, amnionicity, chorionicity, and placental abnormalities.Amnionicity and chorionicity were correctly detected on sonograms in 44 (90%) of 49 diamniotic-dichorionic gestations, 23 (72%) of 32 diamniotic-monochorionic gestations, and two (50%) of four monoamniotic-monochorionic gestations. Fetal anomalies were present at delivery in five neonates and had been correctly detected at sonography in one (hemivertebra); one fetus with duodenal atresia had abnormal sonographic findings in the third trimester. Missed anomalies included absent forearm, cleft lip and palate, and imperforate anus. Sex of the fetuses was correctly predicted on the basis of sonographic findings in 40 of 43 pairs. Nine twin pairs had possible twin-twin transfusion syndrome suspected sonographically on the basis of abnormal fluid volumes, discrepant growth measurements, and abnormal findings on Doppler studies. Outcomes included two confirmed cases of the syndrome (two survivors, two deaths) and three probable cases (six deaths); four pregnancies resulted in eight survivors who were delivered after 34.4 weeks' gestation and had birth weights in the 25th percentile or higher. Survival rates for diamniotic-dichorionic, diamniotic-monochorionic, and monoamniotic-monochorionic gestations were 90%, 91%, and 50%, respectively. Fetuses in women with MSAFP levels greater than 4.5 multiples of the median and with monochorionic placentation had lower survival rates than fetuses in women with normal MSAFP levels and monochorionic placentation (67% vs 96%). Half the fetuses delivered after 20 weeks' gestation had birth-weight discordance of less than 10%. Premature deliveries occurred in 56% of pregnancies.The results suggest that (1) sonography is useful in predicting placentation, (2) placentation may be helpful in predicting fetal outcome, (3) increased MSAFP levels correlate with increased perinatal mortality in diamniotic-monochorionic pregnancies, and (4) caution should be taken in diagnosing and determining prognosis for suspected twin-twin transfusion syndrome in the second trimester.

PURPOSE: To determine fetal outcomes and the capability of sonography to help predict these outcomes in patients with maternal serum alpha-fetoprotein (MSAFP) levels of 5.0 multiples of the median or greater. MATERIALS AND METHODS: Real-time sonography was performed in patients with singleton and multiple gestations. After sonography, the pregnancy was monitored. RESULTS: Inaccurate historical dating caused elevated MSAFP levels in 14 patients. In the remaining 72 singleton gestations, 42 fetuses (58%) had anomalies, 13 (18%) died in utero or after birth, three (4%) had intrauterine growth retardation or were premature, and 14 (19%) were normal, with no complications. A poor outcome occurred in 58 (80%) of the singleton pregnancies, and sonography depicted an abnormality in 49 (84%) of these patients. CONCLUSION: Most pregnant patients with MSAFP levels of 5.0 MOM or greater have an unfavorable outcome. Sonography depicts most of these abnormal pregnancies.

OBJECTIVE: Our objective was to examine the outcomes of pregnancies in which echogenic bowel was detected in the second trimester. STUDY DESIGN: Twenty-two cases with a prospective diagnosis of echogenic bowel were reviewed. Karyotypic studies were performed in 19 cases, and 17 families had deoxyribonucleic acid-based risk assessment for cystic fibrosis. The echogenicity of the bowel was retrospectively reviewed and graded as mild or bright. RESULTS: Five cases of trisomy 21 and one case of trisomy 18 were detected; four of these had other ultrasonographic abnormalities. Twenty-seven percent of fetuses with echogenic bowel were aneuploid. Risk was greatest for cases with brightly echogenic bowel. No cystic fibrosis mutations were detected. The diagnosis of echogenic bowel was reproducible. CONCLUSION: Brightly echogenic bowel in the second trimester was found to be associated with asignificant risk of fetal aneuploidy. (Am J Obstet Gynecol 1992;167:889–94.)

DIAGNOSIS OF PLACENTA ACCRETA AND PERCRETA CARRI WARSHAK (F), RAMEZ ESKANDER, ANDREW HULL, ANGELA SCIOSCIA, ROBERT MATTREY, KURT BENIRSCHKE, ROBERT RESNIK, University of California, San Diego, Reproductive Medicine, San Diego, California, University of California, San Diego, Radiology, San Diego, California, UCSD Medical Center, Reproductive Medicine, San Diego, California, University of California, San Diego, La Jolla, California OBJECTIVE: The incidence of placenta accreta and percreta (PA) has increased dramatically over the last three decades. Optimal management requires accurate prenatal diagnosis. The purpose of this study was to determine the precision and reliability of ultrasound and MRI to accurately diagnose PA. STUDY DESIGN: A retrospective review of our perinatal database from 1/ 2000 to 6/2005 yielded 433 patients with placenta previa. Ultrasound records were reviewed for findings considered to be positive for PA including obliteration of the bladder wall-uterine interface, loss of hypoechoic area between the placenta and the uterine wall, and adjacent placental sonolucent spaces with increased vascularity by color or power Doppler. We also reviewed 58 patients who underwent MRI from 1/1992 to 6/2005 for suspected PA on ultrasound. MRI findings considered to be positive included bulge of the outer margin of the uterus at the footprint of the placenta, a dark nodular band at the outer margin of the uterus and heterogenous placental signal with dark internal bands/vessels. RESULTS: Of the 433 women with placenta previa, 32 had PA confirmed by pathologic examination. Ultrasound accurately predicted PA in 25/32 women and correctly ruled out PA in 396/401 patients (sensitivity 0.78; specificity 0.99). Of the 58 women referred for MRI, 39 patients had PA. MRI accurately predicted 35/39 PA cases and ruled out 19/19 patients without disease (sensitivity 0.90; specificity 1.00). CONCLUSION: Pelvic ultrasound was highly accurate for ruling out PA, and should be the primary modality for screening women at high risk for PA. However, MRI should be considered as part of the evaluation of all suspected cases.

The rapid diagnosis of intra-amniotic infection in patients with premature rupture of the membranes (PROM) and preterm labor is of utmost importance. The Gram's stain examination of amniotic fluid can only detect half of these infections. The acridine orange (AO) stain has been claimed to be superior to the Gram's stain in the detection of bacteria in biologic fluids. Therefore, we undertook the present study to examine the value of AO in the detection of bacteria in amniotic fluid. One hundred and thirty-eight patients with a culture-documented prevalence of intra-amniotic infection of 23.2% were studied. The diagnostic indices of the AO were: sensitivity, 43.8%, specificity, 97.2%, positive predictive value, 82.8%, and negative predictive value, 85.1%; the diagnostic indices for the Gram's stain were: sensitivity, 46.8%, specificity, 98.1%, positive predictive value, 88.2%, and negative predictive value, 85.9%. There was no difference in the diagnostic values of the tests. The agreement between the two techniques was substantial, as indicated by a kappa index of 0.72 (SE = 0.17, p less than 0.001). The AO offered no significant advantage over the Gram's stain examination of amniotic fluid in the detection of intra-amniotic infection. However, the AO stain was able to identify mycoplasma infections that escaped detection by the Gram's stain. Therefore, the AO is presently the only microscopic technique capable of detecting mycoplasma in amniotic fluid.

Current management of isoimmunization in pregnancy is predicted on the assumption that all sensitized women carry antigen-positive fetuses. In addition, management is based on indirect predictors of the magnitude of the fetal hemolytic disease. We present a preliminary report using a new approach of direct fetal blood sampling for the diagnosis and treatment of these patients. This form of evaluation provides specific information about fetal red blood cell antigen status and the degree of fetal anemia at an earlier gestational age than that validated by the Liley curves and eliminates empiricism from both the diagnosis and treatment of the isoimmunized pregnancy. The use of such a management protocol reduces the need for multiple invasive procedures in fetuses at little risk for disease and provides specific information about the status of those fetuses truly at risk.

Seventy-two intrauterine intravascular transfusions were performed on 26 patients with severe erythroblastosis fetalis. Twenty of the 26 fetuses were hydropic at the time of referral. Of the 20 hydropic fetuses, 16 (80%) survived. Hydrops was completely reversed in 13 of the 16 fetuses (81%). Total protein of less than 3 gm/dl, albumin less than 2 gm/dl, and a hematocrit level of less than 15% were associated with hydrops fetalis. After hydrops was reversed, total protein greater than 3 gm/dl, albumin greater than 2 gm/dl, along with a sustained hematocrit level of greater than 15%, were found. Only three neonates were born with minimal ascites, two of whom had had intraperitoneal transfusions before intravascular treatments. There were 21 survivors of the total group, giving an overall survival rate of 82%. There was one neonatal death from severe respiratory distress syndrome. Thirty-eight percent of the neonates did not require exchange transfusions in the newborn period. Intrauterine intravascular transfusions appear to be an effective mode of therapy in severe erythroblastosis fetalis and not only increase survival rates but also decrease neonatal morbidity and mortality.

The successful eradication of bacterial colonization of the amniotic fluid with parenteral maternal antibiotic therapy in a preterm gestation with premature rupture of membranes is reported. Amniotic fluid, obtained by amniocentesis, of a pregnancy complicated by premature rupture of membranes at 29 weeks was found to have three different bacterial species (Bacteroides bivius, Veillonella parvula, and Peptococcus). Because of prematurity and clinical quiescence, parenteral antibiotics were administered to the mother. Repeat amniocentesis was performed during treatment and 48 hours after the cessation of antibiotics failed to demonstrate bacterial growth in the amniotic fluid. Fetal lung maturity was attained, and an induction of labor was performed when antepartum heart rate testing was equivocal. This was accomplished without maternal or fetal/neonatal mishap.

One hundred thirty-one uncomplicated, singleton pregnancies between 7 and 12 weeks of gestation were ultrasonically examined. Evaluation included confirmation of cardiac activity and measurements of fetal crown-rump length and trunk circumference. Both crown-rump length and trunk circumference were curvilinearly correlated with gestational age. A second- and third-degree polynomial equation best described this curvilinear relationship between trunk circumference and gestational age and between crown-rump length and gestational age. The crown-rump length and trunk circumference were similar in their prediction of gestational age, but the combination of the two parameters did not improve the prediction of gestational age. A nomogram of gestational age as predicted by trunk circumference was generated. These data provide an additional measurement for the estimation of gestational age in the first trimester of pregnancy.

As the use of Rhesus immune globulin has decreased the incidence of Rh sensitization, other red blood cell antigen systems have become relatively more common. The most common of these is the Kell antigen, which often produces unexpectedly severe fetal disease. High-resolution ultrasound was used to guide in the sampling of fetal blood directly from the umbilical cord as an aid in the management of these patients.

Maternal immune thrombocytopenic purpura has been associated with profound fetal and neonatal thrombocytopenia. Percutaneous umbilical blood sampling offers a reliable method of determining the fetal platelet count antenatally and optimizing obstetric management. We present our experience with this technique in 19 gestations.

The sonographic characteristics of six viable triploid fetuses, with gestational ages ranging from 16 to 33 weeks, are presented. Each pregnancy was associated with decreased amniotic fluid volume, a significant lag in biparietal diameter and femur length, and severe head-to-body disproportion. No placental abnormalities were noted on ultrasound and only one placenta demonstrated hydropic change (15% to 20% of villi) on pathologic examination. Since the nonmolar triploid fetus often presents with unexplained intrauterine growth retardation, identification of its characteristic sonographic features allows for karyotype confirmation and the avoidance of inappropriate obstetric management.