Exome sequencing for structurally normal fetuses-yields and ethical issues.

The yield of chromosomal microarray analysis (CMA) is well established in structurally normal fetuses (0.4-1.4%). We aimed to determine the incremental yield of exome sequencing (ES) in this population. From February 2017 to April 2022, 1,526 fetuses were subjected to ES; 482 of them were structurally normal (31.6%). Only pathogenic and likely pathogenic (P/LP) variants, per the American College of Medical Genetics and Genomics (ACMG) classification, were reported. Additionally, ACMG secondary findings relevant to childhood were reported. Four fetuses (4/482; 0.8%) had P/LP variants indicating a moderate to severe disease in ATP7B, NR2E3, SPRED1 and FGFR3, causing Wilson disease, Enhanced S-cone syndrome, Legius and Muenke syndromes, respectively. Two fetuses had secondary findings, in RET and DSP. Our data suggest that offering only CMA for structurally normal fetuses may provide false reassurance. Prenatal ES mandates restrictive analysis and careful management combined with pre and post-test genetic counseling.

The many etiologies of nonimmune hydrops fetalis diagnosed by exome sequencing.

OBJECTIVE: To explain the importance of identifying an etiology for the pathological finding of nonimmune hydrops fetalis (NIHF) and to explore the impact of exome sequencing in recurrent NIHF. In addition, we present two cases of pregnancies affected with recurrent NIHF, in which genetic investigation was advantageous. METHODS: Our study aimed to investigate the genetic background, if available, of all fetuses with NIHF referred to our tertiary medical center from January 2013 to August 2020. We summarized the etiology of NIHF if known, sonographic findings, genetic investigation and the pregnancies' outcomes. RESULTS: We encountered 144 families with NIHF. Genetic investigation was performed by chromosomal microarray analysis (CMA) in 63 (63/144. 44%) fetuses. Seventeen of 63 (27%) had a positive CMA result. In the negative CMA group, 15 (15/46, 33%) opted for exome sequencing, of which seven exomes were positive (47%). Among these, there were four couples with recurrent pregnancies affected by hydrops. Among the remaining 11 exome investigations for non-recurrent hydrops, another three were diagnostic. CONCLUSION: As identifying the etiology of the NIHF is an invaluable tool for the prognosis of the pregnancy, exome sequencing can provide further elucidation of the underlying pathogenesis of NIHF. Thus, genetic investigation should be recommended for cases of NIHF.

The Accuracy of Sonographic Assessment for Fetal Weight: Technicians versus Ultrasound-Certified Physicians.

BACKGROUND: Sonographic estimation of birth weight may differ among evaluators due to its operator-dependent nature. OBJECTIVES: To compare the accuracy of estimation of fetal birth weight by sonography between ultrasound-certified physicians and registered diagnostic medical technicians. METHODS: The authors reviewed ultrasound examinations that had been performed by either technicians or ultrasound-certified obstetricians between 2010 and 2017, and within 2 days of delivery. Inclusion criteria were: singleton viable pregnancy, details of four ultrasound measurements (abdominal circumference, bi-parietal diameter, head circumference, and femur length), and known birth weight. The estimated fetal weight (EFW) was calculated according to the Hadlock formula, incorporating the four ultrasound measurements. The mean percentage error (MPE) was calculated by the formula: (EFW-birth weight) x100 / birth weight. RESULTS: Technicians performed 9741examinations and physicians performed 352 examinations. The proportion of macrosomic neonates was similar in both groups. Technicians were more accurate than physicians in terms of the MPE, absolute MPE, proportion of estimates that fell within ± 10% of birth weight, and Euclidean distance (P < 0.0001 for all comparisons). They were also more accurate in terms of sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating curve. Furthermore, for fetuses weighing more than 4000 grams the technicians had a lower total false prediction rate. CONCLUSIONS: Medical technicians in our institute performed better than physicians in estimating fetal weight. Further studies are warranted to confirm our findings and better delineate the role of repeat physician's examination after an initial estimation by an experienced technician.

[ADVANCES IN FETAL THERAPY IN COMPLICATED MONOCHORIONIC PREGNANCIES AND IN SEVERE CONGENITAL DIAPHRAGMATIC HERNIA: FIVE YEARS EXPERIENCE].

INTRODUCTION: : Minimally invasive fetal therapeutic procedures reduce the morbidity and mortality in monochorionic (MC) twins and in fetuses with congenital diaphragmatic hernia (CDH). MC pregnancies share their blood systems due to communicating vessels over their single placenta and may develop specific complications: Twin-to-Twin transfusion syndrome (TTTS), Selective intrauterine growth restriction (sIUGR), Twin Anemia-Polycythemia Sequence (TAPS), Twin Reverse Arterial Perfusion Syndrome (TRAP) or anomalies in one. Half of complicated MC require intrauterine interventions. Severe CDH is linked to a high rate of neonatal death due to pulmonary hypoplasia. Fetoscopic tracheal occlusion (FETO) with a balloon improves postnatal outcome. AIMS: A fetal therapy center was established in the Hadassah Medical Centers, Jerusalem in 2011 for intrauterine interventions. We report our 5 years' experience. METHODS: This prospective cohort follows the outcome of MC pregnancies and cases of severe CDH which underwent therapeutic fetal procedures in Hadassah between the years 2011-16. RESULTS: Out of 114 procedures, 95 were in MC: 84 monochorionic diamniotic twins, 7 monochorionic monoamniotic twins, 2 dichorionic triamniotic triplets and 2 monochorionic triplets. We treated 65 TTTS cases with fetoscopy and laser ablation of communicating vessels. The survival rate of both twins was 58.5% and at least one survived in 81.5% of the cases. In 2nd/3rd trimesters selective termination of 15 cases the survival rate of the remaining twin was 87%. In 11 cases of TRAP sequence treated with laser ablation of the feeding vessel the survival of the remaining twin was 91%. In 19 fetoscopies in severe CDH, 12 were for balloon insertion and 7 for removal. Endotracheal balloon was successfully placed in 11 of 12 cases (10 left-sided, 1 right-sided CDH). Balloon removal was prenatally performed by elective fetoscopy (n=7) or by intrapartum urgent puncture. There were no intrauterine fetal deaths. In isolated left-sided CDH the survival was 57%, whereas none survived in non-isolated left-sided CDH and right sided CDH. CONCLUSIONS: In-utero procedures are safe for the mother and increase newborn survival in MC pregnancies, thus specialized clinics are life-saving. FETO is a therapeutic option for severe CDH. Our results meet similar achievements reported by other leading world centers.

Ultrasound findings provide clues to investigate founder mutations expressed as runs of homozygosity in chromosomal microarray studies.

OBJECTIVES: Chromosomal microarray analysis is effectively applied prenatally to detect copy number changes. Single nucleotide polymorphism (SNP) probes included in the microarray platform can detect regions of excessive homozygosity and identical-by-descent genomic stretches. The utility of the latter as part of prenatal diagnosis is not well established. Recessive founder mutations are well recognized within distinct ethnic groups. Combining these data with prenatal sonography provides accurate focused molecular diagnoses quickly. We aimed to evaluate the application of this approach in expectant families presenting to our unit. METHODS: Three unrelated gravidae presenting with specific fetal sonographic findings: (1) ventriculomegaly with encephalocele; (2) severe polyhydramnion; and (3) enlarged echogenic kidneys, underwent amniocentesis for chromosomal microarray analysis, and genome-wide human SNP array was used to analyze DNA from amniocytes. The Genomic Oligoarray and SNP array evaluation tool v3.0© was used to detect recessive loci associated with the reported clinical findings. Candidate genes were further interrogated using the Israeli National Genetic Database (INGD) and specifically searching and identifying a corresponding founder mutation within the defined ethnic group. RESULTS: Three fetuses from 3 distinct nuclear families in which the parents shared a similar ethnicity (either Ashkenazi or Bukharan Jews) albeit no reported consanguinity were assessed. We found no copy number changes; however, by evaluating regions of homozygosity, we were able to reveal relevant candidate gene for the specific phenotype for each fetus. Using the INGD led to targeted testing of a specific homozygous fetal mutation for which parents were found to be carriers. In the fetus with ventriculomegaly with encephalocele c.1167dupA mutation in the FKTN gene, in the fetus with severe polyhydramnion c.167ins6[TTTCCC] mutation in the BSND gene, and in the fetus with enlarged echogenic kidneys, c.3761_3762delCCinsG in the PKHD1 gene were identified. CONCLUSIONS: A tripartite approach integrating sonographic pathology with regions of excessive homozygosity data and INGD-based founder mutation repository yields a comprehensive streamlined approach to provide accurate genetic diagnosis and counselling within the time constraints of an ongoing pregnancy.

A "See and Treat" Office Procedure for Retained Products of Conception Removal After Normal Vaginal Delivery Using Manual Vacuum Aspiration: Preliminary Efficacy and Reproductive Outcomes.

STUDY OBJECTIVE: To compare the efficacy and reproductive outcomes of an ultrasound-guided manual vacuum aspiration (MVA) procedure with the widely accepted operative hysteroscopic (OH) procedure in the removal of retained products of conception (RPOCs) after normal vaginal delivery. DESIGN: A retrospective cohort study (Canadian Task Force classification II-2). SETTING: A university-affiliated tertiary medical center. PATIENTS: Eighty-six patients after normal vaginal delivery diagnosed with RPOCs from 2005 through 2015. This study was approved by the local institutional review board. INTERVENTIONS: Treatment with either MVA or OH for patients diagnosed with RPOCs. MEASUREMENTS AND MAIN RESULTS: Of 86 patients, 23 underwent remnant removal by ultrasound-guided MVA using a 6- to 7-mm catheter in a "see and treat" office procedure. Sixty-three patients underwent remnant removal using the OH procedure. Follow-up included sonographic examination 3 to 5 weeks after the procedure and long-term follow-up on complications and reproductive outcomes. Successful remnant evacuation and the overall complications rates were similar when comparing the MVA group and the OH group (95.7% vs 96.8% and 4.3% vs 4.7%, respectively). Conception rates and miscarriage rates were comparable in the MVA and OH groups (78.6% vs 72.2% and 9.1% vs 14.8%, respectively). CONCLUSION: Preliminary results from 23 patients suggest that MVA is an efficient procedure with low complication rates and satisfactory reproductive outcomes. It does not require anesthesia or operating room facilities, allowing an immediate and inexpensive "see and treat" option for RPOCs. Further larger controlled trials are required.

Application of 3-dimensional ultrasonography to imaging the fetal anal canal.

OBJECTIVE: Ultrasonography has been applied previously to the assessment of the fetal anal canal. We aimed to examine the potential of 3-dimensional ultrasonography (3DUS) in the evaluation of the fetal anal canal and to obtain normal fetal anal canal measurements. METHODS: Patients were recruited from an unselected population of gravidas with known gestational age (by dates or first-trimester ultrasonography) and without known fetal anomalies presenting for fetal evaluation in the ultrasound units of 2 tertiary care centers between 16 and 39 gestational weeks. In addition to the ordered scan, 3DUS imaging of the fetal anal canal was performed. Transverse and sagittal views and volumes were obtained. Measurements of the fetal anal canal anteroposterior diameter, lateral diameter, and length were performed in transverse and sagittal planes, respectively, and scatterplots of these dimensions were created. Measurements were performed and repeated on raw data sets by 2 independent observers, and the results were analyzed to estimate interobserver and intraobserver reliability. RESULTS: A total of 186 patients were examined for this study at 16 to 39 weeks' gestation (mean, 27.4 weeks). The anteroposterior diameter of the fetal anal canal in this study group ranged from 4 to 21 mm (mean, 11.2 mm; SD, +/-3.5 mm), whereas the lateral diameter ranged from 7 to 18 mm (mean, 9.1 mm; SD, +/-3.0 mm). The length of the fetal anal canal in this study group ranged from 3 to 24 mm (mean, 14.3 mm; SD, +/-3.8 mm). CONCLUSIONS: Ultrasonographic assessment of the fetal anal canal with 3DUS is feasible. Scatterplots were created for internal anal sphincter width and length measurements from 16 to 39 weeks' gestation. Larger studies are necessary to establish nomograms of these measurements and their application to the evaluation of pathologic cases. We speculate that 3DUS assessment of the fetal anal canal may improve detection rates of disorders involving this system.

Diagnosis, surveillance, and treatment of the anemic fetus using middle cerebral artery peak systolic velocity measurement.

The in utero course of the anemic fetus has improved dramatically, owing to early diagnosis and cordocentesis transfusion. In utero invasive procedures such as amnio- and cordocentesis have become important modalities in the evaluation and treatment of anemic fetuses. However, they carry risks for both the mother and fetus. A valid and sensitive noninvasive means of following the anemic fetus is the evaluation of changes in the middle cerebral artery peak systolic flow velocity (MCA-PSV). This is a sensitive tool for both the evaluation of fetal anemia and response to treatment. Intracerebral vessels respond earliest to the fetal anemic state, and are readily accessible for ultrasound examination. We describe the methodology and evolving clinical applications of MCA-PSV measurement in the fetus, through an overview of the literature describing the development and application of MCA-PSV measurement in fetuses at risk of fetal anemia of various immune and nonimmune etiologies, illustrated by index cases from our center. MCA-PSV measurement is essential in the diagnosis, evaluation, and management of cases of fetal anemia. The use of this modality lessens the need for invasive procedures. The method is readily accessible and should be integrated into the repertoire of all obstetric ultrasound centers.

The role of magnetic resonance imaging in the evaluation of isolated mild ventriculomegaly.

OBJECTIVE: Isolated mild ventriculomegaly is defined as dilatation of the lateral ventricle from 10 to 15 mm, with no other structural abnormalities observed at the time of diagnosis. Its reported frequency is between 1 per 50 and 1 per 700 deliveries. There are no universal recommendations for evaluation of isolated mild ventriculomegaly. Targeted sonography, karyotype analysis, and viral antigen testing, particularly for cytomegalovirus, are most often used for further investigation of this finding. We studied the role of magnetic resonance imaging as part of the prenatal evaluation of isolated mild ventriculomegaly. METHODS: Thirty-six pregnant women were referred to 2 Hadassah hospitals between 1999 and 2002 for evaluation of isolated mild ventriculomegaly. They underwent targeted sonography to exclude other anomalies, genetic amniocentesis for fetal karyotype, and serologic cytomegalovirus tests. Mild ventriculomegaly was the only pathologic finding diagnosed. Fetal brain magnetic resonance imaging was performed to evaluate the correlation between sonographic and magnetic resonance imaging findings and the additional contribution of magnetic resonance imaging in evaluating isolated mild ventriculomegaly. RESULTS: Thirty-six magnetic resonance imaging studies were performed. All tests were adequate for evaluation. In 3 (8.3%) of 36 cases, magnetic resonance imaging showed additional findings: in a severely obese woman, ventricular dilatation up to 18 mm and periventricular cystic lesions with abnormal sulcation suggestive of diffuse parenchymal abnormality were diagnosed, and in 2 cases, bleeding in germinal centers was found. On subsequent sonographic examination, no other finding but isolated mild ventriculomegaly was diagnosed. In the remaining 33 women (91.7%), magnetic resonance imaging studies correlated well with sonographic findings. Further sonographic follow-up in this subgroup failed to reveal any other pathologic findings. CONCLUSIONS: Our study supports the view that magnetic resonance imaging should be considered as part of the evaluation of isolated mild ventriculomegaly, especially when objective difficulties preclude detailed sonographic examination.