A novel NONO nonsense variant in a fetus with renal abnormalities.

At 16 + 6-weeks a fetal scan performed in the second pregnancy of a 42 y.o. woman identified a right multicystic dysplastic kidney, left renal agenesis, absent urinary bladder, myocardial hypertrophy, increased nuchal fold, a single umbilical artery, and oligohydramnios.

Next-Generation Sequencing Gene Panels and "Solo" Clinical Exome Sequencing Applied in Structurally Abnormal Fetuses.

Objective: The aim of the study was to assess the diagnostic yield of 2 different next-generation sequencing (NGS) approaches: gene panel and "solo" clinical exome sequencing (solo-CES), in fetuses with structural anomalies and normal chromosomal microarray analysis (CMA), in the absence of a known familial mutation.

Methodology: Gene panels encompassing from 2 to 140 genes, were applied mainly in persistent nuchal fold/fetal hydrops and in large hyperechogenic kidneys. Solo-CES, which entails sequencing the fetus alone and only interpreting the Online Mendelian Inheritance in Man genes, was performed in multisystem or recurrent structural anomalies.

A New Stepwise Molecular Work-Up After Chorionic Villi Sampling in Women With an Early Pregnancy Loss.

To explore the use of a new molecular work-up based on the stepwise use of Quantitative Fluorescence PCR (QF-PCR) extended to eight chromosomes and single nucleotide polymorphism array (SNP-array) in chorionic villi obtained by chorionic villi sampling (CVS) offered to women experiencing an early pregnancy loss. During a 3-year period (January 2016-December 2018), CVS was offered to women experiencing an early pregnancy loss before the evacuation of the products of conception (POC) to retrieve chorionic villi, irrespective of the number of previous losses. A new molecular work-up was prospectively assayed encompassing a first QF-PCR round (with the 21, 18, 13, 7, X, and Y chromosomes), a second QF-PCR round (with the 15, 16, and 22 chromosomes), and a high resolution SNP-array in those cases with normal QF-PCR results.

Maternal plasma genome-wide cell-free DNA can detect fetal aneuploidy in early and recurrent pregnancy loss and can be used to direct further workup.

Study Question: Can maternal plasma cell-free DNA (cfDNA) detect chromosomal anomalies in early pregnancy loss (EPL) and recurrent pregnancy loss (RPL)?

Summary Answer: Genome-wide cfDNA testing can serve as an alternative to cytogenetic analysis in products of conception (POCs) in RPLs and can guide further management.

What Is Known Already: Random chromosomal anomalies are the single most common cause for EPL and RPL. Cytogenetic analysis in POCs may be used to direct management in RPL because the detection of random chromosomal anomalies can eliminate further unwarranted testing.

Is Cisterna Magna Width a Useful First-Trimester Marker of Aneuploidy?

Objective: To assess whether the cisterna magna (CM) width measured in first-trimester fetuses is a useful marker for aneuploidy detection.

Methods: This was a prospective study in 2 different cohorts in a tertiary referral center. The first cohort comprised 913 fetuses from the general pregnancy population during the period 2012-2016 and was used to construct the CM reference ranges applying the λ-μ-σ (LMS) method.

Should cell-free DNA testing be used in pregnancy with increased fetal nuchal translucency?

Objective: To assess the frequency of atypical chromosomal and submicroscopic anomalies, as well as fetal structural abnormalities, observed on first-trimester ultrasound scan in fetuses with nuchal translucency (NT) thickness > 99 centile, in order to evaluate the suitability of using standard cell-free DNA (cfDNA) testing as the sole screening test in these pregnancies.

Methods: This was a retrospective cohort study of 226 fetuses with NT > 99 centile at 11-14 weeks' gestation, between January 2013 and December 2017, in a clinical setting in which greater than 95% of pregnant women receive first-trimester combined screening. All patients underwent genetic testing by means of quantitative fluorescence polymerase chain reaction and chromosomal microarray analysis, mainly in chorionic villus samples.

Overview of Chromosome Abnormalities in First Trimester Miscarriages: A Series of 1,011 Consecutive Chorionic Villi Sample Karyotypes.

In order to contribute to the knowledge of type and frequency of chromosome abnormalities in early pregnancy losses, we analyzed the cytogenetic results from a large series of first trimester miscarriages, using a diagnostic approach with a high success rate and no maternal contamination. A total of 1,119 consecutive chorionic villi samples were obtained before evacuation, and karyotypes were prepared after short-term culture (STC). In 603 samples, a long-term culture (LTC) was also performed.

A 92,XXXY Miscarriage Consecutive to a Digynic Triploid Pregnancy.

The patient was referred for prenatal diagnosis due to the sonographic finding of a polymalformed male fetus, and an amniocentesis was performed before termination of pregnancy. The pathological study of the placenta did not show morphological alterations. In her next pregnancy, sonographic examination disclosed a missed abortion with a visible embryo, and a chorionic villi sample was obtained for cytogenetic analysis before evacuation.

Heterotrisomy recurrence risk: a practical maternal age-dependent approach for excess trisomy 21 risk calculation after a previous autosomal trisomy.

A new maternal age-dependent method to estimate absolute excess risks of trisomy 21, either after a previous trisomy 21 (homotrisomy) or after another trisomy (heterotrisomy), is proposed to be added to the estimated risk by conventional screening methods. Excess risk at term for a subsequent trisomy 21 was calculated from midtrimester risks reported by Morris et al., decreasing from 0.

Effectiveness of ovarian age as the background risk for aneuploidy screening in an unselected pregnant population.

The aim of this study was to assess the performance of first-trimester combined screening when replacing the chronological maternal age by Anti-Müllerian hormone (AMH) and antral follicle count (AFC)-derived ovarian ages, as the background risk in trisomy risk estimation. A total of 639 pregnant women who completed first-trimester combined screening together with AMH and AFC determination were included. Trisomy risks were estimated based on three distinct 'maternal ages' as a-priori risk (chronological age, AMH- and AFC-derived ovarian age).

Transcervical chorionic villus sampling: a practical guide.

First trimester screening for fetal aneuploidies has made the implementation of diagnostic techniques essential. Chorionic villus sampling (CVS) is the method of choice for obtaining chorionic villi for molecular and cytogenetic analysis in the first trimester. Two techniques have been developed, a transcervical and a transabdominal.

Role of ovarian reserve markers, antimüllerian hormone and antral follicle count, as aneuploidy markers in ongoing pregnancies and miscarriages.

Objective: To assess the role of two ovarian reserve markers, antimüllerian hormone (AMH) and antral follicle count (AFC), as markers of the background risk for fetal trisomy.

Design: Prospective study.

Setting: Tertiary referral hospital.

Nuchal translucency thickness in the prediction of unbalanced translocations.

Objective: The aim of this study was to assess the role of nuchal translucency (NT) in the prediction of unbalanced translocation in offspring of couples in which one of the parents is a balanced translocation carrier.

Material And Methods: From January 1996 to December 2012, fetal NT was measured before chorionic villus sampling in 86 pregnancies referred because of parental balanced translocation.

Results: No significant differences in pregnancy characteristics and in NT expressed in millimetres or in multiples of the median (MoMs) were observed between the 41 fetuses with a normal karyotype [1.

Further insights into diastolic dysfunction in first-trimester trisomy-21 fetuses.

Objective: To assess fetal cardiac function in first-trimester trisomy-21 fetuses as compared with fetuses with other aneuploidies, euploid fetuses with cardiac defects or isolated increased nuchal translucency (NT) and controls.

Methods: During a 2.5-year period, NT, ductus venosus (DV) blood flow, diastolic filling time, early filling time, tricuspid flow, tricuspid and mitral valve E/A velocity ratios, left ventricle shortening fraction, left myocardial performance index and fetal heart rate were assessed in fetuses with a crown-rump length between 45 and 84 mm undergoing chorionic villus sampling at our center.

Antral follicle count as a marker of ovarian biological age to reflect the background risk of fetal aneuploidy.

Study Question: Can antral follicle count (AFC) measured during pregnancy be used as a marker of ovarian age to assess the background risk of fetal aneuploidy?

Summary Answer: AFC was lower than expected according to maternal chronological age in trisomic pregnancies; therefore ovarian age could potentially reflect a more precise background risk of fetal aneuploidy screening.

What Is Known Already: The decline in a woman's reproductive function is determined by a decline in the ovarian follicle pool and the quality of oocytes. The quantitative status of ovarian reserve can be indirectly assessed by AFC, but the role of AFC as an aneuploidy risk marker in pregnant women has not been assessed yet.

Is nuchal translucency a useful aneuploidy marker in fetuses with crown-rump length of 28-44 mm?

Objective: To investigate whether increased nuchal translucency (NT) in fetuses with a crown-rump length (CRL) below 45 mm needs to be re-evaluated at a later stage, or whether the early NT measurement can be used effectively as an aneuploidy marker.

Methods: This was a prospective cohort study including all singleton fetuses with a CRL between 28 and 44 mm, scanned in our center during 2002-2012. The CRL, NT, fetal karyotype (when available) and pregnancy outcome were recorded.

Likelihood ratios to apply for nasal bone, ductus venosus and tricuspid flow at the 11-13 weeks' scan in down syndrome screening.

Objective: To assess the feasibility of nasal bone (NB), ductus venosus (DV) and tricuspid flow (TF) at the 11-13 weeks' scan, calculate likelihood ratios for each of the markers and evaluate their efficacy in expanded and contingent screening strategies for Down syndrome.

Material And Methods: NB, DV and TF were assessed in 11,261 singleton fetuses undergoing first trimester combined screening. For each marker, Down syndrome detection rate (DR), false positive rate (FPR), positive, negative and isolated likelihood ratios (PLR, NLR and iLR) were calculated.

First-trimester detection of major cardiac defects with the use of ductus venosus blood flow.

Objective: To assess the best method of combining fetal nuchal translucency (NT) and ductus venosus (DV) blood flow measurements in the detection of major cardiac defects in chromosomally normal fetuses during the first-trimester scan.

Methods: During an 8-year period NT and DV blood flow were routinely assessed at 11-14 weeks' gestation. Only chromosomally normal singleton pregnancies were included in the study.

The effect of maternal age on chromosomal anomaly rate and spectrum in recurrent miscarriage.

Study Question: Is there any effect of maternal age on chromosomal anomaly rate and spectrum in recurrent miscarriage?

Summary Answer: There was no significant difference in the chromosome abnormality rate between sporadic and recurrent miscarriage but the chromosome abnormality rate increased significantly with maternal age.

What Is Known Already: About 50-70% of non-recurrent miscarriages occur because of a chromosomal anomaly, but no agreement about the effect of either maternal age or the number of previous miscarriages on the chromosomal anomaly rate has been reached.

Study Design, Size, Duration: A retrospective cohort of 353 miscarriages successfully karyotyped in the same center between 2002 and 2011, grouped according to the number of miscarriages and maternal age.

First-trimester detection of structural abnormalities and the role of aneuploidy markers.

Objectives: To determine the sensitivity of first-trimester ultrasound for diagnosing different structural anomalies in chromosomally normal pregnancies, and to establish the role of aneuploidy markers in the detection of abnormalities.

Methods: This was a retrospective study of chromosomally normal singleton pregnancies with an 11-14-week scan performed in our center during 2002-2009. The ultrasound examination included an early fetal anatomy survey and assessment of nuchal translucency, ductus venosus blood flow and nasal bone.

Contingent screening for Down syndrome completed in the first trimester: a multicenter study.

Objective: To assess a new contingent screening strategy for Down syndrome completed in the first trimester.

Methods: First-trimester screening combining nuchal translucency thickness measurement and assessment of serum analytes (combined test) was offered to pregnant women who presented for prenatal care during the first trimester to nine health centers and community hospitals in the area served by the Catalan Public Health Service. If an intermediate risk (1/101-1/1000) for Down syndrome was identified, women were referred to the Hospital Clinic Barcelona for risk reassessment that included the use of secondary ultrasound markers (nasal bone, ductus venosus blood flow and tricuspid flow).

Ductus venosus pulsatility index as an antenatal screening marker for Down's syndrome: use with the Combined and Integrated tests.

Objectives: To assess the value of ductus venosus blood flow (expressed as pulsatility index, DVPI) in antenatal Down's syndrome screening when used with the Combined and Integrated tests.

Methods: DVPI measurements between 10 and 13 weeks' gestation in 66 Down's syndrome and 7184 unaffected pregnancies were collected from women attending the Hospital Clinic, Barcelona, for antenatal care from 1999 to 2007 and combined with the Serum Urine and Ultrasound Screening Study (SURUSS) data to model screening performance, safety and cost-effectiveness of the screening tests with and without DVPI.

Results: The median DVPI multiple of the normal median in Down's syndrome pregnancies was 1.

Cytogenetic study of spontaneous abortions using semi-direct analysis of chorionic villi samples detects the broadest spectrum of chromosome abnormalities.

Conventional tissue culturing and karyotyping of spontaneous abortions has limitations such as culture failure, external contamination and selective growth of maternal cells. Molecular cytogenetic techniques such as FISH, QF-PCR, and CGH allow diagnosis on uncultured cells but are also limited as to the spectrum of cytogenetic abnormalities detected. We describe the cytogenetic findings in a series of 116 first trimester arrested pregnancies, obtained through chorionic villi sampling (CVS) and semi-direct analysis that avoids some of the long-culture pitfalls such as maternal contamination, and compare our results with those that would have been obtained theoretically using molecular cytogenetic techniques.