Fetal hyperechoic kidneys: Diagnostic considerations and genetic testing strategies.

Isolated bilateral hyperechoic kidneys (HEK) on prenatal ultrasound presents diagnostic, prognostic, and counseling challenges. Prognosis ranges from normal outcome to lethal postnatally. Presence/absence of extra-renal malformations, gestational age at presentation, amniotic fluid volume, and renal size may distinguish underlying etiologies and thereby prognosis, as prognosis is highly dependent upon underlying etiology. An underlying genetic diagnosis, clearly impactful, is determined in only 55%-60% of cases. We conducted a literature review of chromosomal (aneuploidies, copy number variants [CNVs]) single genes and other etiologies of fetal bilateral HEK, summarized how this information informs prognosis and recurrence risk, and critically assessed laboratory testing strategies. The most commonly identified etiologies are autosomal recessive and autosomal dominant polycystic kidney disease and microdeletions at 17q12 involving HNF1b. With rapid gene discovery, alongside advances in prenatal imaging and fetal phenotyping, the growing list of single gene diagnoses includes ciliopathies, overgrowth syndromes, and renal tubular dysgenesis. At present, microarray and gene panels or whole exome sequencing (WES) are first line tests employed for diagnostic evaluation. Whole genome sequencing (WGS), with the ability to detect both single nucleotide variants (SNVs) and CNVs, would be expected to provide the highest diagnostic yield.

Serial lung mass volume ratios as prognostic indicators of neonatal respiratory morbidity in fetal pulmonary malformations.

BACKGROUND: Several studies have shown that the congenital pulmonary airway malformation volume ratio is a useful prognosticator of neonatal outcome in prenatally diagnosed lung lesions. However, there remains a lack of consensus on which congenital pulmonary airway malformation volume ratio values have the best predictive value because of operator dependence, inherent changes in lung lesion size throughout gestation, and the widespread use of maternal steroids. OBJECTIVE: This study sought to determine the association between serial congenital pulmonary airway malformation volume ratio measurements and neonatal outcomes among fetuses with lung malformations. STUDY DESIGN: This was a retrospective cohort study of fetuses with a prenatally diagnosed lung malformation managed at 2 major fetal centers from January 2010 to December 2021. Prenatal variables, including prospectively measured congenital pulmonary airway malformation volume ratio measurements (initial, maximum, and final), were analyzed. The results were correlated with 3 outcome measures, namely surgical resection before 30 days of life, a need for supplemental O2 at birth, and endotracheal intubation at birth. Statistical analyses were performed using receiver operating characteristic curve analyses, Welch 2 sample t tests, and multivariable logistic regressions (P<.05). RESULTS: There were 123 fetuses with isolated lung lesions identified. Eight (6.5%) had hydrops. The mean initial congenital pulmonary airway malformation volume ratio was 0.67±0.61 cm2 at 22.9±3.9 weeks' gestation. The mean maximum congenital pulmonary airway malformation volume ratio was 1.08 ± 0.94 cm2 at 27.0 ± 4.0 weeks' gestation. The mean final congenital pulmonary airway malformation volume ratio was 0.58±0.60 cm2 at 33.2±4.1 weeks' gestation. At a mean gestational age at delivery of 38.3±2.6 weeks, 15 (12.2%) underwent neonatal lung resection for symptomatic disease. In a multivariable regression, all 3 congenital pulmonary airway malformation volume ratio measurements showed a significant correlation with neonatal lung resection (P<.001). Optimal congenital pulmonary airway malformation volume ratio cutoffs were established based on an initial congenital pulmonary airway malformation volume ratio of ≥0.8 cm2, maximum congenital pulmonary airway malformation volume ratio of ≥1.5 cm2, and a final congenital pulmonary airway malformation volume ratio of ≥1.3 cm2 with associated areas under the curve of 0.89, 0.97, and 0.93, respectively. The final congenital pulmonary airway malformation volume ratio had the highest specificity for predicting surgical lung resection in the early postnatal period. CONCLUSION: Measuring congenital pulmonary airway malformation volume ratios throughout pregnancy in fetuses with pulmonary malformations has clinical value for prenatal counseling and planning care transition after delivery. Fetuses with a final congenital pulmonary airway malformation volume ratio of more than 1.3 cm2 are likely to require neonatal surgery and therefore should be delivered at tertiary care centers with a neonatal intensive care unit and pediatric surgical expertise.

Prenatal Sonography in Suspected Proximal Gastrointestinal Obstructions: Diagnostic Accuracy and Neonatal Outcomes.

BACKGROUND: The purpose of this study was to assess diagnostic accuracy and neonatal outcomes in fetuses with a suspected proximal gastrointestinal obstruction (GIO). METHODS: After IRB approval, a retrospective chart review was conducted on prenatally suspected and/or postnatally confirmed cases of proximal GIO at a tertiary care facility (2012-2022). Maternal-fetal records were queried for presence of a double bubble ± polyhydramnios, and neonatal outcomes were assessed to calculate the diagnostic accuracy of fetal sonography. RESULTS: Among 56 confirmed cases, the median birthweight and gestational age at birth were 2550 g [interquartile range (IQR) 2028-3012] and 37 weeks (IQR 34-38), respectively. There was one (2%) false-positive and three (6%) false-negatives by ultrasound. Double bubble had a sensitivity, specificity, positive predictive value, and negative predictive value for proximal GIO of 85%, 98%, 98%, and 83%, respectively. Pathologies included 49 (88%) with duodenal obstruction/annular pancreas, three (5%) with malrotation, and three (5%) with jejunal atresia. The median postoperative length of stay was 27 days (IQR 19-42). Cardiac anomalies were associated with significantly higher complications (45% vs 17%, p = 0.030). CONCLUSIONS: In this contemporary series, fetal sonography has high diagnostic accuracy for detecting proximal gastrointestinal obstruction. These data are informative for pediatric surgeons in prenatal counseling and preoperative discussions with families. LEVEL OF EVIDENCE: Diagnostic Study, Level III.

Follow Your Nose: Repeat Nasal Bone Evaluation in First-Trimester Screening for Down Syndrome.

OBJECTIVE: Examine whether repeat nasal bone evaluation following an absent/uncertain nasal bone on first-trimester screening (FTS) improves Down syndrome (DS) screening specificity. METHODS: A retrospective chart review of FTS sonograms in one center from January 2015 to January 2018 was performed. Data was extracted for those with an absent/uncertain nasal bone. Repeat evaluations were offered. RESULTS: Of 6780 FTS sonograms, 589 (8.7%) had an absent/uncertain nasal bone. Upon repeat exam, 268/376 (71.3%) had a present nasal bone. Compared with Black patients, patients of other ethnicities were more likely to have a present nasal bone on exam 2 (P < .00001). Of 268 patients with a present nasal bone on exam 2, 37 (13.8%) had an abnormal DS risk following exam 1; 34/37 (91.9%) normalized following nasal bone visualization, dropping the screen positive rate to 1.1%. CONCLUSION: Repeat nasal bone examination is beneficial in refining DS risk assessment and improves the specificity of FTS.

Expanded carrier screening for reproductive risk assessment: An evidence-based practice guideline from the National Society of Genetic Counselors.

Expanded carrier screening (ECS) intends to broadly screen healthy individuals to determine their reproductive chance for autosomal recessive (AR) and X-linked (XL) conditions with infantile or early-childhood onset, which may impact reproductive management (Committee Opinion 690, Obstetrics and Gynecology, 2017, 129, e35). Compared to ethnicity-based screening, which requires accurate knowledge of ancestry for optimal test selection and appropriate risk assessment, ECS panels consist of tens to hundreds of AR and XL conditions that may be individually rare in various ancestries but offer a comprehensive approach to inherited disease screening. As such, the term "equitable carrier screening" may be preferable. This practice guideline provides evidence-based recommendations for ECS using the GRADE Evidence to Decision framework (Guyatt et al., BMJ, 2008, 336, 995; Guyatt et al., BMJ, 2008, 336, 924). We used evidence from a recent systematic evidence review (Ramdaney et al., Genetics in Medicine, 2022, 20, 374) and compiled data from peer-reviewed literature, scientific meetings, and clinical experience. We defined and prioritized the outcomes of informed consent, change in reproductive plans, yield in identification of at-risk carrier pairs/pregnancies, perceived barriers to ECS, amount of provider time spent, healthcare costs, frequency of severely/profoundly affected offspring, incidental findings, uncertain findings, patient satisfaction, and provider attitudes. Despite the recognized barriers to implementation and change in management strategies, this analysis supported implementation of ECS for these outcomes. Based upon the current level of evidence, we recommend ECS be made available for all individuals considering reproduction and all pregnant reproductive pairs, as ECS presents an ethnicity-based carrier screening alternative which does not rely on race-based medicine. The final decision to pursue carrier screening should be directed by shared decision-making, which takes into account specific features of patients as well as their preferences and values. As a periconceptional reproductive risk assessment tool, ECS is superior compared to ethnicity-based carrier screening in that it both identifies more carriers of AR and XL conditions as well as eliminates a single race-based medical practice. ECS should be offered to all who are currently pregnant, considering pregnancy, or might otherwise biologically contribute to pregnancy. Barriers to the broad implementation of and access to ECS should be identified and addressed so that test performance for carrier screening will not depend on social constructs such as race.

Not just a carrier: Clinical presentation and management of patients with heterozygous disease-causing alkaline phosphatase (ALPL) variants identified through expanded carrier screening.

Hypophosphatasia (HPP) is an underrecognized, complex bone mineralization disorder with variable manifestations caused by one or two deleterious variants in the alkaline phosphatase (ALPL) gene. Expanded carrier screening (ECS), inclusive of ALPL, intends to inform reproductive risk but may incidentally reveal an HPP diagnosis with 50% familial risks. We sought to investigate at-risk individuals and develop a multidisciplinary referral and evaluation protocol for ECS-identified ALPL heterozygosity. A retrospective database query of ECS results from 8 years to 1 month for heterozygous pathogenic/likely pathogenic ALPL variants was completed. We implemented a clinical protocol for diagnostic testing and imaging, counseling, and interdisciplinary care management for identified patients, and outcomes were documented. Heterozygous ALPL variants were identified in 12/2248 unrelated patients undergoing ECS (0.53%; heterozygote frequency 1/187). Of 10 individuals successfully contacted, all demonstrated symptomatology and/or alkaline phosphatase values consistent with HPP. ECS may reveal incidental health risks, including recognition of missed HPP diagnoses in ALPL heterozygotes. In our cohort, all ECS-identified ALPL heterozygotes with clinical and/or biochemical data available demonstrated features of HPP. Referral to a genetics professional familiar with HPP is indicated for family history assessment, genetic counseling, cascade testing, and long-term bone health management.

Outcomes of both complex and isolated cases of infants with large stomach on fetal ultrasound.

BACKGROUND: A sonographically large fetal stomach has been associated with gastrointestinal obstruction, per case reports, and is often followed up with serial ultrasound examinations. The frequency of this phenomenon has not been systematically studied, resulting in challenges in counseling parents about the prognosis and making cost-benefit analysis of serial ultrasound follow-up difficult to assess. OBJECTIVE: This study aimed to determine the frequency at which an enlarged fetal stomach as the sole abnormality on fetal ultrasound reflects a bowel obstruction to aid in parental counseling and determine the best practice for follow-up. STUDY DESIGN: We performed a retrospective cohort study of all prenatal sonographic cases in which a large fetal stomach was visualized between January 1, 2002, and June 1, 2016. The inclusion criteria required a fetal diagnosis of a large stomach, defined as an increased measurement in ≥2 dimensions based on a nomogram, that resulted in a liveborn delivery within the Johns Hopkins Health System. We excluded pregnancy loss, pregnancy termination, and cases delivered outside of the Johns Hopkins Health System. Cases were subclassified as isolated or complex based on the absence or presence of additional ultrasound findings at initial presentation of the enlarged stomach. The perinatal outcomes and maternal demographics were determined and compared between isolated and complex cases. RESULTS: Of 57,346 total cases with ultrasound examinations in the Johns Hopkins Health System within the study time frame, 348 fetuses had enlarged stomachs, with 241 (69.3%) who met the inclusion criteria as follows: 161 (66.8%) isolated and 80 (33.2%) complex. Of the 161 isolated cases, 1 resulted in neonatal small bowel obstruction (0.62%). Of note, 158 of the isolated large stomach cases (98.1%) had no postnatal abnormalities of any kind. Of the 80 complex cases, 18 (22.5%) resulted in neonatal gastrointestinal obstruction (14 cases of duodenal atresia and 4 cases of jejunal atresia). Those with isolated findings were significantly less likely to deliver preterm (n=24 [14.9%] vs n=35 [43.8%]; P<.001), be complicated by polyhydramnios (n=18 [11.2%] vs n=23 [28.8%]; P<.001), have a neonatal intensive care unit admission (n=31 [19.3%] vs n=76 [95.0%]; P<.01), or have a major surgical procedure (n=2 [1.2%] vs n=66 [82.5]; P<.001) compared with complex cases. CONCLUSION: We found that 0.62% of isolated large fetal stomachs (1 of 161) were associated with neonatal intestinal obstruction. Of the complex cases with an enlarged stomach, 18 of 80 (22.5%) were found to have a gastrointestinal obstruction; by definition, none of these complex cases began as an isolated large stomach as their initial ultrasound finding, but rather had other concurrent sonographic abnormalities, including a double bubble sign and intestinal dilation. With a prevalence of <1% resulting in the development of a small bowel obstruction, our results suggest that, when isolated, a large stomach does not seem to warrant serial prenatal ultrasound follow-up or postnatal imaging and is likely to reflect an incidental finding.

Acceleration and plateau: two patterns and outcomes of isolated severe fetal cerebral ventricular dilation.

OBJECTIVES: We sought to characterize patterns of in utero dilation in isolated severe fetal ventriculomegaly (ISVM) and investigate their value in predicting obstetrical and postnatal outcomes. METHODS: This is a retrospective cohort study. ISVM was defined as a sonographic cerebral ventricle atrial with width ≥15 mm in the absence of additional cerebral or other anatomic anomalies. The aim of this study was to characterize two ISVM groups using a receiver operator curve to evaluate the rate of ventricular progression versus need for ventriculoperitoneal (VP) shunt postnatally. Outcomes were compared between the groups using Pearson's chi-squared test, Student t-test, and descriptive statistics. RESULTS: Based on the ROC analysis, ventricular growth of ≥3 mm/week versus <3 mm/week distinguished fetuses likely to require a postnatal VP shunt. Fetuses were characterized as accelerators if ventricle growth was ≥3 mm/week at any point and plateaus if <3 mm/week. Accelerators showed a greater average rate of ventricle progression than plateaus (4.1 vs. 1.0 mm/week, respectively, p = .031) and were more likely to be delivered at earlier gestational ages (34.7 vs. 37.1 weeks respectively, p = .02). Ninety percent of accelerators demonstrated a need for shunt placement compared with 18.8% of plateaus (p < .001). Significantly more plateaus (87.5%) underwent a trial of labor while accelerators were more likely to have planned cesareans (70%, p = .009). CONCLUSIONS: This study characterizes ISVM into two distinct populations based upon the rate of ventricle expansion, differentiated by the need for postnatal shunting. Once a ventricular growth pattern is determined, these distinctions should prove useful in prenatal management and delivery planning.

Sacral protuberance with cleft lip and palate: Prenatal presentation of 3MC syndrome.

3MC syndromes are rare heterogeneous autosomal recessive conditions previously designated as Mingarelli, Malpuech, Michels, and Carnevale syndromes, characterized by dysmorphic facial features, facial clefts, growth restriction, and intellectual disability. 3MC is secondary to mutations in the MASP1, MASP3, COLEC11, and COLEC10 genes. The number of patients with 3MC syndrome with known mutations in the COLEC11 or MASP1 is, to date, less than 50. At the time this case presented (2015), the only gene identified in Online Mendelian Inheritance in Man to be associated with 3MC syndrome was MASP1. We present, to the best of our knowledge, the first prenatal report of 3MC syndrome, secondary to a homozygous variant in MASP1. Fetal findings included bilateral cleft lip and palate, abnormality of the sacral spine, a right echogenic pelvic kidney, and brachycephaly. 3MC syndrome should be considered as part of the differential diagnosis when fetal ultrasound detects facial clefts and spinal defects, as the risk of recurrence is significant and a molecularly confirmed diagnosis allows for alternate reproductive options.

Single-Center Outcome of Fetoscopic Tracheal Balloon Occlusion for Severe Congenital Diaphragmatic Hernia.

OBJECTIVE: To assess feasibility and maternal and infant outcome after fetoscopic tracheal balloon occlusion in patients with severe congenital diaphragmatic hernia. METHODS: We conducted a prospective cohort study of fetuses with congenital diaphragmatic hernia and observed/expected lung/head ratio less than 30%. Eligible women had planned fetoscopic tracheal balloon occlusion at 26 0/7-29 6/7 weeks of gestation and balloon removal 4-6 weeks later. Standardized prenatal and postnatal care was at a single institution. Fetoscopic tracheal balloon occlusion details, lung growth, obstetric complications, birth outcome, and infant outcome details until discharge were evaluated. RESULTS: Of 57 women screened, 14 (25%) were enrolled between 2015 and 2019. The congenital diaphragmatic hernia was left in 12 (86%); the pre-fetoscopic tracheal balloon occlusion observed/expected lung/head ratio was 23.2% (range 15.8-29.0%). At a median gestational age of 28 5/7 weeks (range 27 3/7-29 6/7), fetoscopic tracheal balloon occlusion was successful in all cases, and balloons remained in situ. Removal was elective in 10 (71%) patients, by ultrasound-guided needle puncture in eight (57%), and occurred at a median of 33 4/7 weeks of gestation (range 32 1/7-34 4/7; median occlusion 34 days, range 17-44). The post-fetoscopic tracheal balloon occlusion observed/expected lung/head ratio increased to a median of 62.8% (44.0-108) and fell to a median of 46.6% (range 30-92) after balloon removal (all Mann Whitney U, P<.003). For prevention of preterm birth, all patients received vaginal progesterone; 11 (79%) required additional tocolytics, three (21%) had vaginal pessary placement for cervical shortening, and five (36%) had amnioreduction for polyhydramnios. Median gestational age at birth was 39 2/7 weeks (range 33 6/7-39 4/7), with term birth in eight (57%) patients. Twelve (86%) neonates required high-frequency ventilation, and seven (50%) required extracorporeal membrane oxygenation for a median of 7 days (range 3-19). All neonates needed patch repair. Neonatal survival was 93% (n=13, 95% CI 49-100%), and survival to hospital discharge was 86% (n=12, 95% CI 44-100%). CONCLUSION: Fetoscopic tracheal balloon occlusion for severe congenital diaphragmatic hernia was feasible in our single-center setting, with few obstetric complications and favorable infant outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02710968.

Prenatal diagnosis of Desbuquois dysplasia Type 1: Utilization of high-density SNP array to map homozygosity and identify the gene.

Desbuquois dysplasia (DBQD1 [MIM 251450]) is an autosomal recessive chondrodysplasia with micromelia, severe joint laxity and dislocations, and a characteristic radiographic "monkey wrench" appearance at the proximal femur. Type 1 Desbuquois dysplasia is caused by mutations in CANT1 and is distinct from Type 2, caused by mutations in XYLT1, in that the former has unique hand anomalies including accessory phalangeal ossification centers, advanced carpal bone maturation, and/or axial phalangeal deviation. Severe prenatal presentations have been rarely reported. We report a Pakistani female in a consanguineous relationship with a diagnosis of Type 1 Desbuquois dysplasia in three consecutive pregnancies. Multiple similar severe fetal limb anomalies were detected by ultrasound in Pregnancy 1 and 2. Regions of homozygosity within the single nucleotide polymorphism (SNP)-microarray from both terminated fetuses were compared, revealing CANT1 as a likely disease-causing candidate gene. Insufficient fetal DNA precluded confirmatory testing, therefore parents were tested; both had a previously reported heterozygous CANT1 mutation (c.643G>T; Glu215Term). The patient presented with a third pregnancy revealing similarly abnormal limb position and probable polysyndactyly by ultrasound. Targeted testing of CANT1 revealed homozygous c.643G>T CANT1 mutations and this pregnancy was terminated. In clinical situations in which ample DNA is not available or more expensive testing (e.g., whole exome sequencing) with a longer turnaround time is not feasible, utilization of SNP-microarray in consanguineous families at risk for rare autosomal recessive disorders may dramatically narrow the list of candidate genes.

Preoperative Ultrasound Prediction of Essential Landmarks for Successful Fetoscopic Laser Treatment of Twin-Twin Transfusion Syndrome.

INTRODUCTION: The insertion site of the fetoscope for laser occlusion (FLOC) treatment of twin-twin transfusion syndrome (TTTS) determines the likelihood of treatment success. We assessed a standardized preoperative ultrasound approach for its ability to identify critical landmarks for successful FLOC. METHODS: Three surgeons independently performed preoperative ultrasound and deduced the likely orientation of the intertwin membrane (ITM) and vascular equator (VE) based on the sites of the cord insertion, the lie of the donor, and the size discordance between twins. At FLOC, these landmarks were visually verified and compared to preoperative assessments. RESULTS: Fifty consecutive FLOC surgeries had 127 preoperative assessments. Basic ITM and VE orientation were accurately predicted in 115 (90.6%), 109 (85.8%), and 105 (82.7%) assessments. Predictions were anatomically correct in 96 (75.6%), 70 (55.1%), and 58 (45.7%) assessments with no differences in accuracy between operators of different training level. The ITM/VE relationship was most poorly predicted in stage-3 TTTS (χ2, p = 0.016). CONCLUSION: In TTTS, preoperative ultrasound identification of placental cord insertion sites, lie of the donor twin, and size discordance enables preoperative prediction of key landmarks for successful FLOC.

Gestational Alloimmune Liver Disease: A Devastating Condition Preventable With Maternal Intravenous Immunoglobulin.

BACKGROUND: Gestational alloimmune liver disease, a form of profound liver failure in the newborn, is the main underlying cause of the entity formerly known as neonatal hemochromatosis. Antepartum maternal intravenous immunoglobulin (IVIG) has been shown to prevent gestational alloimmune liver disease, which otherwise has a recurrence risk above 90% in subsequent pregnancies. CASE: A 30-year-old woman, gravida 3 para 0120, presented early in gestation. Her previous pregnancy had been complicated by fetal growth restriction, oligohydramnios, and ultimately fatal fulminant neonatal liver failure. With gestational alloimmune liver disease recognized as the primary diagnosis for the liver failure, we began maternal weekly IVIG therapy. She delivered a healthy newborn at term without evidence of hepatic dysfunction. CONCLUSION: Recognition of gestational alloimmune liver disease enables antepartum treatment that dramatically alters the course of disease.

Placental α-Microglobulin-1 in Vaginal Secretions of Women with Evidence of Preterm Labor.

OBJECTIVE: To evaluate the presence of placental α-microglobulin-1 (PAMG-1) in vaginal secretions in women with symptoms of preterm labor and assess its use as a predictor of preterm birth. STUDY DESIGN: A prospective cohort study of women between 16 and 34 weeks of gestation with symptoms of preterm labor and intact membranes was conducted. The presence of PAMG-1 was determined using a commercially available kit (AmniSure, AmniSure International LLC, Boston, MA). RESULTS: A total of 100 women were enrolled, of which 86 had outcome data available. PAMG-1 was detected in 19/86 (22.1%) subjects. These women were more likely to deliver within 7 days than those without PAMG-1 detected (6/19 [31.6%] vs. 5/67 [7.5%]; odds ratio 5.6; 95% confidence interval 1.5-21.6). These findings persisted after adjusting for potential confounders. The sensitivity was 54.6%, specificity was 82.7%, positive predictive value was 31.6%, and the negative predictive was 92.5%. CONCLUSION: The presence of PAMG-1 is associated with an increased likelihood of delivery within 7 days.

Vaginal electrohysterography: the design and preliminary evaluation of a novel device for uterine contraction monitoring in an ovine model (.).

OBJECTIVE: Tocodynamometry is the most common method of labor evaluation but most clinicians would agree it has limited utility before 26 weeks of gestation. The obesity epidemic has further reduced our ability to accurately detect uterine contractions using the tocodynamometer at any gestational age. We sought to design and test a novel contraction monitor that bypasses the maternal abdomen. METHODS: An optimized version of an intravaginal electrohysterographic ring device was tested in an ovine model. The device and its methodology as well as the tocodynamometer were validated against the current gold standard uterine activity monitor, the intrauterine pressure catheter in six sheep at varying gestational ages. RESULTS: Both the intravaginal ring device and the tocodynamometer correlated well with IUPC, r = 0.69 and 0.73, respectively (p < 0.001). The number of contractions detected by each monitor remained similar even after accounting for confounders. CONCLUSIONS: These results suggest that uterine activity can be monitored from the vaginal interface in an ovine model and offers an alternative clinical tool for the detection of contractions in situations, in which tocodynamometry would be ineffective or intrauterine monitoring inappropriate.

Vein of galen aneurysmal malformation: prognostic markers depicted on fetal MRI.

Fetal magnetic resonance imaging (MRI) serves a dual role in the prenatal diagnostic work up of a vein of Galen aneurysmal malformation (VGAM). First, it may confirm the prenatal ultrasound findings and secondly it may identify prognostically important secondary complications of the VGAM. Progressive heart failure with development of fetal hydrops and hemispheric white matter injuries are associated with a poor outcome in children with a VGAM. We present the prenatal findings using both ultrasound and MRI of a fetus with VGAM including bilateral injury of the cerebral hemispheres, severe dilatation of the jugular veins, cardiomegaly, and hydrops fetalis. The neonate died within 30 minutes after delivery. Moreover, fetal MRI revealed complete placenta praevia, uterine fibroids, and wrapping of the umbilical cord around the fetal neck. This additional information is unrelated to the fetal pathology, but could have been of importance to plan the delivery.

A historical and practical review of first trimester aneuploidy screening.

There have been tremendous advancements over the past three decades in prenatal screening for aneuploidy and we have changed our practice from screening by maternal age alone to 'combined' first trimester screening and circulating cell-free fetal DNA. We currently use the nuchal translucency and biochemical markers of free ß-hCG and PAPP-A to determine the risk of fetal aneuploidy. The primary goal is to identify higher risk women for fetal aneuploidy early in pregnancy and give them the option to pursue invasive testing in a timely manner if desired.

First trimester diagnosis of holoprosencephaly secondary to a ring chromosome 7.

Holoprosencephaly (HPE) is a developmental defect in humans in which the forebrain fails to completely separate into two hemispheres. We describe a 12 3/7-week-old fetus found on ultrasound evaluation to have features consistent with HPE, including a single anterior ventricle, fused thalami, and a flattened profile. Cytogenetic analysis of chorionic villi revealed a ring chromosome 7 [r(7)]. This uncommon finding has been associated with growth delay, microcephaly, and dermatologic abnormalities. However, both the clinical features and the extent of cytogenetic imbalance of chromosome 7 are variable, and few reported cases of r(7) have been molecularly studied. To our knowledge, this is the first report of a prenatally identified r(7), molecularly characterized using array comparative genomic hybridization.

In utero hematopoietic stem cell transplantation in canines: exploring the gestational age window of opportunity to maximize engraftment.

OBJECTIVE: In utero hematopoietic stem cell transplantation (IUHSCT) is a promising therapy for a variety of congenital disorders. Our objective was to determine the optimal time in gestation for IUHSCT in a canine model. METHODS: IUHSCT was performed in day 31-50 (term 63) fetal canines with CD34+ cells isolated from paternal bone marrow at doses of 0.09-3.4 × 109 CD34+ cells/kg and T cells (CD3+/CD5+) from paternal blood at 0.11-1.1 × 109 cells/kg. Engraftment was assayed using PCR-based chimerism analysis (SRY gene detection for female recipients, and unique microsatellite loci for both sexes). RESULTS: Microchimerism and chimerism were present in multiple recipients across most gestational ages at transplant. Maximal engraftment was obtained in hematopoietic tissues in transplants performed at 42 days. At extremes of recipient gestational age, minimal to no engraftment was seen. CONCLUSION: Fetal age at the time of IUHSCT plays an important role in achieving engraftment in our canine model.

Atrial natriuretic peptide production and natriuretic peptide receptors in the human uterus and their effect on myometrial relaxation.

OBJECTIVE: The objective of the study was to identify the effect of atrial natriuretic peptide (ANP) on uterine contractility, production of ANP, and natriuretic peptide receptor (NPR) expression in human myometrial tissue. STUDY DESIGN: In an institutional review board-approved study, gravid human myometrium was obtained from patients undergoing cesarean section. Uterine contractility was examined using isometric force tension studies. After regular uterine contractions were obtained with oxytocin, ANP was added in increasing concentrations. ANP concentration was measured from myometrial tissue using radioimmunoassay (RIA). Primary myometrial cell culture was performed and treated with nifedipine vs oxytocin. RIA was performed on these cells and the cell culture media. Western blot analysis was performed on uterine tissue samples for natriuretic peptide receptors. RESULTS: With increasing concentration of ANP (starting at 3 pM), myometrial contraction frequency decreased. ANP was identified in primary cultured myometrial cells and cell culture media. Myometrial ANP concentration increased with advancing gestational age. The concentration of ANP decreased within myometrial cells treated with oxytocin. The amount of ANP in the cell culture media increased from cells treated with nifedipine. Western blot identified NPR-A, -B, and -C in myometrial tissue. NPR-A expression was significantly increased in preterm samples. CONCLUSION: ANP has a dose dependent effect on uterine relaxation. ANP is present in human myometrial cells and appears to be secreted by myometrial cells. The concentration of ANP may vary with gestational age and modulators of uterine contractility. NPR-A, -B, and -C receptor proteins are present in myometrial tissue. NPR-A levels may correlate with gestational age.