Abnormal Fetal Ultrasound Findings Research Articles

High rate of abnormal findings in Prenatal Exome Trio in low risk pregnancies and apparently normal fetuses.

Data on the value of exome sequencing in fetuses with no structural anomalies are limited, especially in the early stages of pregnancy and in low risk pregnancies. We investigated the yield of targeted clinical prenatal trio exome sequencing (pES) in pregnancies with and without fetal structural anomalies. We performed pES in 353 pregnancies: Group 1 included 143 pregnancies with high clinical suspicion for a genetic disease: pregnancies with increased nuchal translucency, ultrasound structural defects, intrauterine growth restriction, polyhydramnios, or effusion/nuchal edema. Group 2 included 210 pregnancies with no notable abnormal fetal ultrasound findings. 2a. Low risk pregnancies with minor ultrasound findings, referred to the geneticist due to mildly increased risk for genetic disease (50); and 2b. Normal pregnancy surveillance (160). Overall, 26 (7.36%) fetal analyses had pathogenic (P)/likely pathogenic (LP) variants. In group 1, 20/143 (13.99%) cases had P/LP variants. In group 2, 6/210 (2.86%) cases were found to have P/LP variants [5/50 in (2a) and 1/160 in (2b)]. These results show a high rate of abnormal findings on pES even in apparently normal pregnancies.

Evaluation of Diagnostic Yield in Fetal Whole-Exome Sequencing: A Report on 45 Consecutive Families.

Prenatal ultrasound (US) abnormalities often pose a clinical dilemma and necessitate facilitated investigations in the search of diagnosis. The strategy of pursuing fetal whole-exome sequencing (WES) for pregnancies complicated by abnormal US findings is gaining attention, but the reported diagnostic yield is variable. In this study, we describe a tertiary center’s experience with fetal WES from both terminated and ongoing pregnancies, and examine the clinical factors affecting the diagnostic rate. A total of 45 consecutive families of Jewish descent were included in the analysis, for which clinical fetal WES was performed under either single (fetus only), trio (fetus and parents) or quatro (two fetuses and parents) design. Except one, all families were non-consanguineous. In 41 of the 45 families, WES was sought following abnormal fetal US findings, and 18 of them had positive relevant family history (two or more fetuses with US abnormalities, or single fetus with US abnormalities and an affected parent). The overall diagnostic yield was 28.9% (13/45 families), and 31.7% among families with fetal US abnormalities (13/41). It was significantly higher in families with prenatal US abnormalities and relevant family history (10/18, 55.6%), compared to families with prenatal US abnormal findings and lack of such history (3/23, 13%) (p = 0.004). WES yield was relatively high (42.9–60%) among families with involvement of brain, renal or musculoskeletal US findings. Taken together, our results in a real-world setting of genetic counseling demonstrates that fetal WES is especially indicated in families with positive family history, as well as in fetuses with specific types of congenital malformation.

The ethics of lethal congenital malformations. Is palliative therapy possible?

Aim: This study aims to show that palliative care can be offered to babies born with lethal malformations according to the Islamic Code of Ethics, which takes into account the well-being of the mother and her fetus. Methods: For our study, a lethal congenital malformation is defined as a condition that invariably leads to death in utero or the newborn period regardless of attempted supportive care. The cases were identified during weekly prenatal meetings, which discuss abnormal fetal ultrasound findings and genetic testing to provide plans for their management. In addition, cases that were not diagnosed antenatally but diagnosed at birth were also included. The management plans for those cases with lethal malformations were discussed before birth, and the families were counseled, and their consent was taken for nonmonitoring of the fetus during pregnancy and noninterference with the newborn baby except for palliative care. Families who requested full support during pregnancy and delivery were given that option. Results: Over a period of 16 years from 2001 to 2016, a total number of 92705 babies were born in our hospital. Antenatal ultrasounds were performed by the feto-maternal physician team. There were 1563 abnormal fetal ultrasounds (1.7%) with significant various organs malformations. Of these abnormal ultrasounds, 384 were diagnosed as possible lethal congenital malformations (24.6%). The remaining abnormal fetal ultrasounds were compatible with life and were managed according to the standard clinical practices. Fetuses diagnosed with lethal malformations were discussed at length and parents were informed about the lethal outcome and the plan of nonmonitoring of the mother at delivery and avoidance of cesarean section except for maternal indication and eventual palliative care for the live newborn. Parents' consent was obtained, and the decision and the plan of the management are documented clearly in the mother's medical record file. With this management plan, we were able to offer palliative care to the cases of lethal congenital malformations who eventually expired within a short time. Conclusion: Within the guidance of the Islamic Jurisprudence (Figh), it is possible to manage cases of congenital malformations, which are considered incompatible with life palliatively and avoid unnecessary cesarean sections in the mother. This practice has resulted in better utilization of the beds in our busy neonatal intensive care unit.

Ultrasound imaging for identification of cerebral damage in congenital Zika virus syndrome: a case series

Zika virus is a novel teratogenic agent associated with cerebral anomalies. Because of the challenges associated with assessment of antenatal diagnosis and prognosis in fetuses, screening for other congenital infections mostly relies on ultrasound. We aimed to assess whether a similar approach might be adequate for Zika virus congenital syndrome provided that early markers of infection and adequate timing for screening are established. For this case series we reviewed all pregnant women who had a laboratory-confirmed Zika virus infection in their first trimester or early second trimester and abnormal fetal ultrasound findings who were managed at the Pluridisciplinary Center for Prenatal Diagnosis of Martinique during the Zika virus epidemic (Jan 1, 2016, to Nov 10, 2016) in Martinique, a French Caribbean island. Ultrasound imaging was done with GE Healthcare Voluson E10 and E8 machines with abdominal and vaginal probes. We analysed 14 cases of pregnant women with confirmed Zika virus infection and fetal abnormalities of the brain, and 31 ultrasound imaging results. Between 16 and 20 weeks of gestation, four (33%) of 12 fetuses had an abnormal ultrasound examination. Anomalies were detected in nine (90%) of the ten fetuses from whom ultrasound images were obtained between 20 and 24 weeks of gestation. All five remaining fetuses at 24-28 weeks of gestation, and all four after 28 weeks, had severe anomalies. Major anomalies identified were ventriculomegaly (12 fetuses, 86%), cortical atrophy (11, 79%), calcifications (ten, 71%; particularly located at the corticosubcortical junction), and anomalies of the corpus callosum (ten, 71%). Prenatal assessment of head circumference measurement by imaging was not an effective screening tool for congenital Zika virus infection, with microcephaly only identified in nine (64%) fetuses. Ultrasound monitoring appears to be a good screening strategy to monitor Zika virus-exposed pregnancies. Public health efforts should focus on scanning at 22-26 weeks of gestation. Identification of ventriculomegaly, cortical atrophy, calcifications, and anomalies of the corpus callosum should prompt laboratory screening for Zika virus. None.

Abnormal Fetal Findings Associated With a Global Sphericity Index of the 4-Chamber View Below the 5th Centile.

The purpose of this study was to evaluate the global sphericity index (GSI) of the 4-chamber view and correlate the results with abnormal ultrasound findings. The epicardial end-diastolic basal-apical length (BAL) and transverse length (TL) of the 4-chamber view were measured to compute the GSI (BAL/TL) in 200 control fetuses between 20 and 40 weeks' gestation. Three hundred study fetuses were prospectively examined between 17 and 39 weeks' gestation. The GSI, Z score, and centile were computed for each of the fetuses. The GSI (1.233; SD, 0.0953) in the control fetuses was independent of gestational age. Eighteen percent of the study fetuses (55 of 300) had a GSI below the 5th centile (<1.08), of whom 96% (53 of 55) had additional abnormal ultrasound findings. Fetuses with an estimated fetal weight below the 10th centile had a significantly (P < .05) higher rate of an umbilical artery Doppler pulsatility index above the 95th centile (27% versus 17.7%), a middle cerebral artery Doppler pulsatility index below the 5th centile (27% versus 0%), an abnormal cerebroplacental ratio (27% versus 4.5%), and an amniotic fluid index of less than 5 cm (36% versus 9%). The TL was significantly increased compared with the BAL in fetuses with cardiac dysfunction, irrespective of the estimated fetal weight. An abnormal GSI below the 5th centile is associated with abnormal fetal ultrasound findings.

AB109. Noninvasive prenatal testing (NIPT): differences in testing indications between the US and Southeast Asia

Background and objective Cell-free DNA-based noninvasive prenatal testing (NIPT) has been validated as a screening test for certain fetal aneuploidy in high-risk women. High-risk indications include advanced maternal age (AMA), positive serum screen result, abnormal fetal ultrasound findings, and a previous affected pregnancy. However, recent studies show the effectiveness of NIPT in all pregnant women, regardless of risk. Determine if there are global differences in NIPT implementation between centers in Southeast Asia and the United States (US).

Whole-Genome Array CGH Evaluation for Replacing Prenatal Karyotyping in Hong Kong

ObjectiveTo evaluate the effectiveness of whole-genome array comparative genomic hybridization (aCGH) in prenatal diagnosis in Hong Kong.MethodsArray CGH was performed on 220 samples recruited prospectively as the first-tier test study. In addition 150 prenatal samples with abnormal fetal ultrasound findings found to have normal karyotypes were analyzed as a ‘further-test’ study using NimbleGen CGX-135K oligonucleotide arrays.ResultsArray CGH findings were concordant with conventional cytogenetic results with the exception of one case of triploidy. It was found in the first-tier test study that aCGH detected 20% (44/220) clinically significant copy number variants (CNV), of which 21 were common aneuploidies and 23 had other chromosomal imbalances. There were 3.2% (7/220) samples with CNVs detected by aCGH but not by conventional cytogenetics. In the ‘further-test’ study, the additional diagnostic yield of detecting chromosome imbalance was 6% (9/150). The overall detection for CNVs of unclear clinical significance was 2.7% (10/370) with 0.9% found to be de novo. Eleven loci of common CNVs were found in the local population.ConclusionWhole-genome aCGH offered a higher resolution diagnostic capacity than conventional karyotyping for prenatal diagnosis either as a first-tier test or as a ‘further-test’ for pregnancies with fetal ultrasound anomalies. We propose replacing conventional cytogenetics with aCGH for all pregnancies undergoing invasive diagnostic procedures after excluding common aneuploidies and triploidies by quantitative fluorescent PCR. Conventional cytogenetics can be reserved for visualization of clinically significant CNVs.

711: Adverse perinatal outcomes in euploid pregnancies with double-positive first trimester prenatal screening for Trisomy 18 and 21

were selected for testing because they are not easily detectable by karyotype, their cumulative frequency is substantial, and they are not usually associated with abnormal ultrasound (US) findings. STUDY DESIGN: Clinical prenatal samples (n 80) were referred to our laboratory for testing with this assay using specimens derived from amniotic fluid and chorionic villi. All samples tested were also karyotyped. Indications for study included AMA (30/80), AMA with a positive family history (4/80), AMA with an abnormal maternal serum screen (MSS) (13/80), abnormal fetal US findings with AMA, family history, and/or abnormal MSS (12/80), abnormal fetal US findings only (11/80), family history alone (2/80), abnormal MSS alone (6/80) and anxiety non-AMA (2/80). RESULTS: For our first 80 prospective specimens, the assay detected abnormalities in 7 cases: 2 Tri-18, 3 Tri-21, 1 each of deletion 1p36 and 5p15. One case with a normal result had 69,XXX by karyotyping. One case with an ambiguous result due to maternal cell contamination had 45,X in 18/19 cells by karyotyping. The mean turnaround time was 1.85 days. Overall, our detection rate of abnormal findings utilizing this assay and karyotyping is 12.5% and a 2.5% detection rate for microdeletions that would have been missed by karyotyping. CONCLUSION: Our results suggest that this new rapid assay, which is designed to avoid detection of results of unclear clinical significance, is a viable alternative to the FISH aneuploidy screening and microarray testing in low-risk pregnancies.

ARRAY CGH AND ITS APPLICATIONS IN PRENTAL DIAGNOSIS

In prenatal diagnosis, array CGH has several advantages more than traditional chromosomal analysis. It can detect all of aneuploidies, deletions, duplications and unbalanced structural rearrangements of chromosomes with higher resolution, avoidance of culturing amniocytes or chorionic villi, automation, and faster turnaround times. But array CGH has high cost, inability to detect balanced inversions or translocations as well as polyploidy and mosaicism below 20%. Array CGH can identify marker chromosomes and copy number variants (CNVs) of chromosomes but many of them have uncertain clinical significance. So that in prenatal diagnosis array CGH is indicated in the following cases : (1) abnormal fetal ultrasound findings; (2) suspected chromosome imbalances; (3) had children with abnormal chromosomes (4) parents with chromosome balances; (5) advanced maternal age.

Prenatal Diagnosis of Chromosomal Abnormalities through Amniocentesis

The incidence of major chromosome abnormalities in newborns is about 0.7 percent and increases with maternal age. Amniocentesis is the most common invasive prenatal procedure for the detection of fetal chromosomal abnormalities. Amniocentesis is a relatively safe procedure and fetal loss related to amniocentesis is about 0.5%. An advanced maternal age is the most common reason for using amniocentesis. The use of amniocentesis because of abnormal fetal ultrasound findings has increased recently. Fluorescence in situ hybridization (FISH) is currently a powerful tool in the area of prenatal cytogenetics. The number of amniocentesis procedures in Japan is about ten thousand per year and it is generally recognized to be a great benefit for pregnant women who have a risk of fetal chromosomal abnormalities.

Atypical case of Smith-Lemli-Opitz syndrome: Implications for diagnosis

Smith-Lemli-Opitz (SLO) syndrome is an autosomal recessive disorder comprised of recognizable facial abnormalities, growth retardation, and multiple congenital anomalies, commonly involving genitalia, second and third toe syndactyly, and cleft palate. The condition is associated with hypocholesterolemia and elevated levels of 7-dehydrocholesterol (7DHC) resulting from deficient activity of the enzyme 7-dehydrocholesterol reductase. The clinical spectrum of SLO ranges from individuals with mental retardation and minor anomalies to those with major structural defects and early or even prenatal lethality. Low maternal serum unconjugated estriol (uE3) levels and a variety of fetal ultrasound anomalies have been identified in affected pregnancies, and prenatal diagnosis is possible by measurement of amniotic fluid 7DHC levels in pregnancies known to be at risk because of a previously affected child. We report on a pregnancy with low maternal uE3 level, abnormal antenatal ultrasound findings including limb deformities, ventriculomegaly, and hydrops fetalis, and a normal 46,XY karyotype. The infant died at birth. At autopsy the infant had hydrops, unusual face, cleft palate, genital abnormalities, Dandy-Walker malformation, and absence of toe syndactyly. Tests performed on cultured skin fibroblasts showed elevated levels of 7DHC and abnormalities of cholesterol biosynthesis characteristic of the metabolic defect that causes SLO. The atypical findings of hydrops, uncharacteristic facial appearance, and absence of toe syndactyly in this case additionally illustrates the wide phenotypic spectrum of SLO and the need for a high index of suspicion for a disorder with great clinical variability. Identification of another affected pregnancy with a low maternal uE3 level and abnormal fetal ultrasound findings in the presence of a normal karyotype lends additional support for consideration of prenatal biochemical testing for SLO in pregnancies with these findings, including pregnancies not previously known to be at risk.

Atypical case of Smith‐Lemli‐Opitz syndrome: Implications for diagnosis

Smith-Lemli-Opitz (SLO) syndrome is an autosomal recessive disorder comprised of recognizable facial abnormalities, growth retardation, and multiple congenital anomalies, commonly involving genitalia, second and third toe syndactyly, and cleft palate. The condition is associated with hypocholesterolemia and elevated levels of 7-dehydrocholesterol (7DHC) resulting from deficient activity of the enzyme 7-dehydrocholesterol reductase. The clinical spectrum of SLO ranges from individuals with mental retardation and minor anomalies to those with major structural defects and early or even prenatal lethality. Low maternal serum unconjugated estriol (uE3) levels and a variety of fetal ultrasound anomalies have been identified in affected pregnancies, and prenatal diagnosis is possible by measurement of amniotic fluid 7DHC levels in pregnancies known to be at risk because of a previously affected child. We report on a pregnancy with low maternal uE3 level, abnormal antenatal ultrasound findings including limb deformities, ventriculomegaly, and hydrops fetalis, and a normal 46,XY karyotype. The infant died at birth. At autopsy the infant had hydrops, unusual face, cleft palate, genital abnormalities, Dandy-Walker malformation, and absence of toe syndactyly. Tests performed on cultured skin fibroblasts showed elevated levels of 7DHC and abnormalities of cholesterol biosynthesis characteristic of the metabolic defect that causes SLO. The atypical findings of hydrops, uncharacteristic facial appearance, and absence of toe syndactyly in this case additionally illustrates the wide phenotypic spectrum of SLO and the need for a high index of suspicion for a disorder with great clinical variability. Identification of another affected pregnancy with a low maternal uE3 level and abnormal fetal ultrasound findings in the presence of a normal karyotype lends additional support for consideration of prenatal biochemical testing for SLO in pregnancies with these findings, including pregnancies not previously known to be at risk. Am. J. Med. Genet. 80:322–326, 1998. © 1998 Wiley-Liss, Inc.

Pathological pregnancies. Results of amniotic fluid studies and fetal outcome.

Late amniocenteses (greater than 20 weeks' gestation) were performed in 114 pregnancies with no a priori genetic risk, but referred because of abnormal clinical and/or ultrasound findings suggesting fetal malformations. Reasons for referral included polyhydramnios (51 cases), oligohydramnios (15 cases), fetal growth retardation (FGR) (16 cases) and abnormal fetal ultrasound findings excluding anencephaly (32 cases). In 42 of these cases, referral was motivated by a combination of the above abnormal findings. When polyhydramnios was the sole anomaly (25 cases), 5 fetuses were malformed (20%), abnormal fetal karyotype and/or elevated amniotic fluid alphafetoprotein (AFP) were demonstrated in 2 cases. Oligohydramnios was the sole anomaly in one case; the infant died of prematurity. Fetal growth retardation was the sole anomaly in 14 cases, 11 otherwise normal newborns were small for date, 2 died at birth and 1 was malformed (1/14, 7%). In this group all fetal karyotypes were normal and in 2 cases amniotic fluid AFP were increased. In the 32 pregnancies without abnormal amniotic fluid volume and/or FGR and with fetal malformation(s) suggested by ultrasound, all malformations except one (ovarian cyst possibly ruptured during birth) were confirmed at birth, amniotic fluid AFP was elevated, and/or karyotype was abnormal in 6 cases. In 42 pregnancies where more than one alarm sign was present, abnormal karyotype and/or elevated amniotic fluid AFP level were recorded in 21 of the 39 cases where amniocentesis was performed, 33 fetuses were malformed (79%) and 13 died in the perinatal period (31%). The high incidence of abnormal results of amniocentesis found in this survey of pathological pregnancies, particularly in those with multiple alarm signs, emphasizes the need for amniocentesis in these situations.