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. Trio exome sequencing analysis detected a novel pathogenic NONO variant. Postmortem examination after the termination of pregnancy confirmed the ultrasound findings and also revealed pulmonary hypoplasia, retrognathia and low-set ears. The variant was a novel de novo hemizygous pathogenic loss-of-function variant in NONO [NM_007363.5], associated with a rare X-linked recessive neurodevelopmental disorder, named intellectual developmental disorder, X-linked syndromic 34 (OMIM#300967). The postnatal characteristic features of this disorder include intellectual disability, developmental delay, macrocephaly, structural abnormalities involving the corpus callosum and/or cerebellum, left ventricular noncompaction and other congenital heart defects. In the prenatal setting, the phenotype has been poorly described, with all described cases presenting with heart defects. This case highlights the need of further clinical delineation to include renal abnormalities in the prenatal phenotype spectrum.

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. RESULTS: During the study period (2015-2020), 153 NGS studies were performed in 148 structurally abnormal fetuses with a normal CMA. The overall diagnostic yield accounted for 35% (53/153) of samples and 36% (53/148) of the fetuses. Diagnostic yield with the gene panels was 31% (15/49), similar to 37% (38/104) in solo-CES. CONCLUSIONS: A monogenic disease was established as the underlying cause in 35% of selected fetal structural anomalies by gene panels and solo-CES.

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. STUDY DESIGN, SIZE, DURATION: This was a prospective diagnostic test study from March 2018 to January 2019 of 109 patients experiencing pregnancy loss before 14 weeks gestation at a tertiary-care academic medical center. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood samples were drawn for genome-wide cfDNA testing prior to chorionic villous sampling for cytogenetic analysis of POCs with both short-term cultures (STCs) and long-term cultures (LTCs). Final analysis included 86 patients with non-mosaic cytogenetic results in POCs and available cfDNA results. Aneuploidy detection rates by cfDNA testing and POC cytogenetic analysis were compared. The first 50 samples served as the Training Set to establish pregnancy loss-specific log-likelihood ratio (LLR) thresholds using receiver-operator characteristic (ROC)-like analyses. These were then used for the entire cohort. MAIN RESULTS AND THE ROLE OF CHANCE: Seventy-eight samples (71.5%) had results available from both STC and LTC; 12 samples (11%) had a result from STC only, and 7 samples (6.4%) had a result from LTC only. A chromosomal anomaly was detected in 55/86 (64%). The rates of chromosomal anomalies were 61, 72, 73 and 44% in patients undergoing their first, second, third and ≥4th pregnancy losses, respectively. The median cfDNA fetal fraction was 5%. With standard LLR thresholds used for noninvasive prenatal screening, the sensitivity of cfDNA in detecting aneuploidy was 55% (30/55) and with a specificity of 100% (31/31). Using pregnancy loss-specific LLR thresholds, the sensitivity of cfDNA in detecting aneuploidy was 82% (45/55), with a specificity of 90% (28/31). The positive and negative likelihood ratios were 8.46 and 0.20, respectively. Fetal sex was correctly assigned in all cases. LIMITATIONS, REASONS FOR CAUTION: Cases with a false-positive result by cfDNA analysis would not receive the indicated RPL workup. Specificity could be improved by using a fetal fraction (FF) cutoff of 4%, but this would result in exclusion of more than a quarter of cases. WIDER IMPLICATIONS OF THE FINDINGS: cfDNA-based testing can serve as an alternative to POC cytogenetic analysis and can guide further RPL management: if cfDNA demonstrates aneuploidy, no further action is taken and if no abnormality is detected, the recommended RPL workup is performed. STUDY FUNDING/COMPETING INTEREST(S): Cell-free DNA testing was funded by Illumina, Inc., San Diego, CA. Y.Y. is a member of Illumina's Clinical Expert Panel and has received travel grants. A.B. has received travel grants from Illumina. All authors have no competing interest to declare.

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. The second cohort included 714 high-risk fetuses undergoing chorionic villus sampling during the period 2012-2016. Mean detection rates using the 95th percentile for CM width observed in chromosomal anomaly groups were compared with those obtained in chromosomally normal fetuses. RESULTS: The 50th percentile for CM ranged from 1.66 to 2.75 mm when crown-rump length (CRL) increased from 45 to 84 mm. Among high-risk fetuses, the following chromosomal anomalies were diagnosed in 125 (17%) fetuses: trisomy 21 (n = 63), trisomy 18 or 13 (n = 21), monosomy X (n = 9), submicroscopic anomalies (n = 11), and other anomalies (n = 22). The mean CM width for euploid fetuses was 2.4 mm (1.13 multiples of the median, MoM). While CM width was significantly increased in trisomy 21 (mean 2.7 mm; 1.23 MoM; p > 0.05), no differences were found in the other anomaly groups. Among the 63 fetuses with trisomy 21, a CM width above the 99th percentile was observed in 23 fetuses (37%). CONCLUSIONS: The new reference range for CM width at 11-13 weeks of gestation did not differ from previous studies. In first-trimester fetuses with trisomy 21, CM width appears to be increased, although its value as an ultrasound marker is limited, because of its detection rate of 37%.

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. The overall and individual frequencies of the different types of chromosome abnormalities were established, including placental mosaicisms, and their relationship with maternal age and gestational weeks was assessed. An abnormal karyotype was detected in 70.3% of the samples. Single autosomal trisomy was the most frequent abnormality (64.6% of the abnormal cases), followed by triploidy (13.1%) and monosomy X (10.4%). Chromosome rearrangements were found in 5.2%, combined abnormalities in 8.9%, and placental mosaicism in 3.5% of the cases with STC and LTC performed. Individual trisomies behaved differently with respect to maternal age and intrauterine survival. Due to the combination of STC and LTC, our study offers reliable information on the incidence and type of chromosome abnormalities and placental mosaicism in miscarriages and contributes to define the cytogenetic implication in their etiology.

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. Macroscopic examination of the villi sample did not reveal molar vesicular appearance. QF-PCR and cytogenetic analyses were performed on amniotic fluid (first pregnancy) and chorionic villi samples (second pregnancy). A 69,XXY and 92,XXXY karyotype was found, respectively. QF-PCR results disclosed 2 maternal and 1 paternal alleles in the first pregnancy (digynic triploidy), and double maternal and double paternal contribution to the tetraploid pregnancy. Among the few reported cases of 92,XXXY tetraploidy, those associated with partial moles show a PPPM genotype (3 paternal and 1 maternal alleles), and the only case with a PPMM genotype was found in a spontaneously aborted fetus similar to our case. We are not aware of other cases with combination of a digynic triploid pregnancy and a tetraploid pregnancy with a PPMM contribution. Our case adds evidence to the influence of the balance between paternal and maternal genomic doses on the phenotype.

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). The screening performance was assessed using three different approaches: received operator curve; detection rate and false positive rates for a fixed 1/250 threshold; and detection rates for a fixed 3% false positive rate. A non-significant trend was shown for AMH-derived age for both an increased area under the curve (0.986 versus 0.979) and an increased detection rate (from 83% to 100%) for a 1/250 risk threshold. For a 3% false-positive rate, a non-significant trend for increased detection with the use of both AMH- and AFC-derived ovarian ages was observed (from 67% to 83%). These results indicate that, although ovarian derived ages seem to potentially reflect a more precise background risk for fetal trisomies, the improvement in screening performance is only residual.

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. STUDY DESIGN, SIZE, DURATION: Our study comprised a prospective cohort including 1239 singleton pregnancies scanned before 14 weeks in our center during a 14-month period. PARTICIPANTS/MATERIALS, SETTING, METHODS: Reference ranges for AFC were constructed using 812 spontaneously conceived, chromosomally normal singleton ongoing pregnancies using the Lambda-Mu-Sigma method. The study population (n = 934) included 19 pregnancies with viable autosomal trisomies (trisomies 21, 18 and 13), 17 non-viable autosomal trisomies (other than 21, 18 or 13), 7 monosomies X, 1 sex trisomy and 3 triploidies (total n = 47 with chromosomal abnormalities). AFC in chromosomally abnormal pregnancies was plotted against the reference ranges. AFC multiple of the median was calculated according to the median AFC obtained by each year of age. MAIN RESULTS AND THE ROLE OF CHANCE: Sixty-eight percent of women carrying a pregnancy with viable trisomies and 65% with non-viable trisomies presented an AFC below the 50th percentile. The median ovarian age in viable trisomies and non-viable trisomies was estimated to be 3 and 6 years above than median maternal age, respectively. However, the median ovarian age in monosomies X and triploidies was not higher than median maternal age. LIMITATIONS, REASONS FOR CAUTION: We did not assess the intra- and inter-observer reliability, or use specific three-dimensional analysis which may have advantages over our two-dimensional study. In clinical practice, a drawback for assessing AFC during pregnancy is that transvaginal ultrasound is needed at the 11- to 13-week scan, when the transabdominal approach is used most commonly. Furthermore identifying ovaries by ultrasound during pregnancy could be challenging. WIDER IMPLICATIONS OF THE FINDINGS: Considering that AFC reflects ovarian aging, this 'ovarian biological age' could potentially reflect a more precise background risk of fetal aneuploidy. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by PI 11/00685. Instituto de Salud Carlos III. Fondo de Investigación Sanitaria. No competing interests declared.

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 [1.72 mm, 95% confidence interval (CI): 1.49-1.96; 1.14 MoM; 95% CI: 1.01-1.26], the 38 fetuses with balanced translocations (1.78 mm, 95% CI: 1.44-2.12; 1.22 MoM; 95% CI: 1.01-1.43) and the 7 fetuses with unbalanced translocations (2.21 mm, 95% CI: 1.33-3.09; 1.59 MoM; 95% CI: 0.72-2.45). The proportions of fetuses with NT above 95th centile in the three groups were 9.1% in fetuses with normal karyotype, 18.4% in balanced translocations and 28.6% in unbalanced translocations, not significantly different. CONCLUSION: Although a trend to an increased NT was observed in fetuses with unbalanced translocation, no significant differences were reached. According to our results, a normal NT evaluation should not preclude the performance of CVS in pregnancies of balanced translocation parents.

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. Likelihood ratios were multiplied to the combined test risk either to the entire population or to the intermediate risk group (expanded and sequential strategies, respectively). RESULTS: Down syndrome was diagnosed in 101 pregnancies. Feasibility for marker assessment ranged from 71 to 97%, DRs for isolated markers from 20 to 54% and FPRs from 1.3 to 5.3%. PLR ranged from 10 to 15, NLR from 0.5 to 0.8 and iLR from 3.9 to 5.6. When ultrasound markers were added to both strategies, a significant FPR reduction was observed. CONCLUSION: The application of NB, DV and TF likelihood ratios to the combined test risk, either in an expanded or contingent strategy, result in a FPR reduction.

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. PARTICIPANTS/MATERIALS, SETTING, METHODS: Among the 353 women, 153 were below 35 years (73 with sporadic, 48 with two and 32 with recurrent miscarriage) and 200 were 35 years or more (81 with sporadic, 55 with two and 64 with recurrent miscarriage). The chromosomal anomaly rate and the anomaly spectrum were compared between sporadic and recurrent miscarriage, within the two maternal age groups, using the chi-square test and the Bonferroni correction for all the P-values. Risk of chromosomal anomaly was estimated for maternal age, number of miscarriages and previous live births by multivariate binary logistic regression analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Sporadic and recurrent miscarriage did not show significantly different chromosomal anomaly rates (68 versus 60%) and maternal age was the only statistically significant predictor of the chromosomal anomaly risk we identified. Some trends were observed in the chromosomal anomaly spectrum when sporadic was compared with recurrent miscarriage: recurrent miscarriage exhibited a decrease in viable trisomies (37 versus 11%) and an increase in non-viable trisomies (38 versus 57%) in women >35 years, together with an increase in unbalanced structural anomalies (4.9 versus 29%) in younger women. LIMITATION, REASONS FOR CAUTION: The mixed origin of our study population, and the limited number of recurrent miscarriages, particularly in the younger group, limits statistical power to detect differences. WIDER IMPLICATIONS OF THE FINDINGS: The most commonly observed chromosomal anomaly type in recurrent miscarriage depends on maternal age: non-viable autosomal trisomies in older women and unbalanced structural anomalies in younger women. When a chromosomal anomaly is identified as the cause of miscarriage, additional maternal evaluation may be avoided. STUDY FUNDING/COMPETING INTERESTS: No competing interests declared.

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

Objective: 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. Methods: 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. A control group in which POC were collected after surgical uterine evacuation was used to be compared with the intervention group. Results: Around 459 women were enrolled in the intervention group (CVS) and 185 in the control group (POC after uterine evacuation). The QF-PCR testing success rates were significantly higher in the intervention group (98.5%: 452/459) as compared to the control group (74%: 109/147; p < 0.001), while the chromosomal anomaly rate at the two QF-PCR rounds was similar between the two groups: 52% (234/452) in the intervention and 42% (46/109) in the control group (p = 0.073). The SNP-array was performed in 202 QF-PCR normal samples of the intervention group and revealed 67 (33%) atypical chromosomal anomalies (>10 Mb), 5 (2.5%) submicroscopic pathogenic copy number variants, and 2 (1%) variant of uncertain significance (VOUS). Conclusion: Eighty-two percent of women experiencing an early pregnancy loss opted for a CVS. The testing success rates were higher in the intervention group (CVS; 98%) as compared to the control group (POC; 74%). The overall yields were 52% by QF-PCR (including three complete hydatiform moles), and 16% by SNP-array, including 15% atypical chromosomal anomalies and 1.1% submicroscopic pathogenic copy number variants.

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. Samples were obtained by transcervical CVS from women with a diagnosis of missed abortion, most of them referred for cytogenetic prenatal diagnosis. Cytogenetic analysis was performed using semi-direct technique. A karyotype was obtained in 103 cases. Eighty-two abnormal karyotypes were found (80%), including 12 triploidies, 10 monosomies, 61 trisomies, and 9 structural abnormalities; a double abnormality being present in 10 cases. Between 10% and 50% of our abnormal results would have been missed using the most common molecular cytogenetic techniques. Semi-direct analysis of CVS may still be considered as a comprehensive, reasonably rapid, cost-effective and reliable method for detecting the broadest spectrum of chromosome abnormalities in missed abortions.

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 0.49% at 20 years to 0.01% at 46 years at the index pregnancy. Excess risk after a previous uncommon trisomy was derived from data reported by Warburton et al., decreasing from 0.37% at 20 years to 0.01% at 50 years.

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. The selection criteria have been based historically on factors, such as placental location, parity, maternal weight and preference of the operator. In our institution, we developed an elevated level of expertise in the field of transcervical approach, resulting in good quality of samples and comparable fetal loss rate to other approaches. Despite three decades of transcervical CVS performance, little consensus in terms of its technique and clinical guidelines exists. Considering the expertise and the volume of procedures performed at our center, we suggest a practical clinical guideline for transcervical CVS.

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. PATIENT(S): Assessment was carried out either in ongoing pregnancies or miscarriages in our center. INTERVENTION(S): AFC was assessed transvaginally during a routine (11-13 weeks) or referral scan. AMH was determined either during the first-trimester maternal serum markers assessment or in cases referred for chorionic villi sampling after the invasive procedure. MAIN OUTCOME MEASURE(S): AMH reference ranges were constructed according to maternal age, and AMH- and AFC-derived ovarian ages were compared among three different cytogenetic groups (normal karyotype, autosomal trisomies, and other chromosomal anomalies) in both ongoing pregnancies and miscarriages. RESULT(S): In autosomal trisomies, the median AFC-derived ovarian age was 3-5 years above the median maternal age. No differences were observed between AMH-derived ovarian age and maternal age. CONCLUSION(S): AFC-derived ovarian biologic age reflects a more precise background risk for fetal aneuploidy that is not observed for AMH-derived age.

False positives in the prenatal ultrasound screening of fetal structural anomalies.

OBJECTIVE: To describe the false-positive diagnoses of prenatal ultrasound screening of fetal structural anomalies. METHODS: Pregnancies with fetal structural anomalies either detected prenatally in our center or referred to us, were registered, evaluated, and followed-up prospectively by a multidisciplinary Congenital Defects Committee. After postnatal follow-up was completed, cases were assigned as true positives, false positives or false negatives and categorized by anatomical systems. Pregnancies referred with a nonconfirmed suspicion of anomaly were not included. The false-positive diagnoses were analyzed. RESULTS: From 1994 to 2004, 903 new registry entries of fetuses structurally abnormal at ultrasound with a complete follow-up were included in the Committee database. There were 76 false positives, accounting for 9.3% of all the prenatally established diagnoses. The urinary tract anomalies were the most frequent false-positive diagnoses found (n = 25; accounting for 8.7% of the urinary tract defects), but the genital anomalies showed the higher rate of no confirmation (n = 5; 15.2%). The specific anomalies most commonly not confirmed were renal pyelectasis (n = 9), cerebral ventriculomegaly (n = 9), abdominal cysts (n = 7) and short limbs (n = 7). CONCLUSION: Several prenatally diagnosed anomalies would benefit from prudent counseling, because they may be normal variants or transient findings.

First-trimester screening for Down syndrome with ductus venosus Doppler studies in addition to nuchal translucency and serum markers.

OBJECTIVE: To estimate the improvement in screening efficiency when fetal ductus venosus Doppler studies are added to existing first-trimester Down syndrome screening protocols. METHODS: Statistical modelling was used with parameters derived from prospective ductus venosus studies and from the published literature. The pulsatility index for veins (PIV), was determined in the fetal ductus venosus for 3706 unaffected and 25 Down syndrome pregnancies at 10-14 weeks' gestation. Concurrent nuchal translucency measurement and maternal serum pregnancy associated plasma protein A and free-beta human chorionic gonadotrophin were also measured. RESULTS: The median PIV in Down syndrome was 1.70 times higher than in unaffected pregnancies (95% confidence interval 1.36-2.12). PIV levels followed an approximately log Gaussian distribution with log(10) standard deviations of 0.193 and 0.076 in Down syndrome and unaffected pregnancies. There were no statistically significant correlations between PIV and the other markers. Modelling predicts that for a fixed 5% false-positive rate, the addition of PIV to nuchal translucency alone will increase the detection rate from 76 to 85%, and combined with serum markers, from 88 to 92%. For a fixed 85% detection rate, the false-positive rate reduced from 15 to 4.8% and from 3.2 to 1.2% respectively. CONCLUSION: Ductus venosus Doppler studies can substantially improve Down syndrome screening efficiency.

Ductus venosus assessment at the time of nuchal translucency measurement in the detection of fetal aneuploidy.

OBJECTIVE: To assess the potential value of ductus venosus Doppler studies in the detection of fetal aneuploidy on measurement of nuchal translucency. METHODS: The pulsatility index for veins (PIV) and the lowest velocity during atrial contraction (A-wave) were determined in the fetal ductus venosus in 3382 consecutive pregnancies at 10 to 14 weeks and studied from December 1996 to December 2001. Nuchal translucency was also measured. The population studied included 1664 pregnancies at high risk and 1718 at low risk for fetal aneuploidy. RESULTS: In relation to the prenatal detection of trisomy 21, the ductus venosus PIV was increased in 75% (36/48), the A-wave was decreased in 58% (28/48), and nuchal translucency was enlarged in 81% (39/48) of the trisomy 21 fetuses [71% (22/31) when nuchal translucency referrals were excluded]. The corresponding figures for trisomies 18 and 13 were 71, 58 and 83%, respectively, being 33, 33 and 33% for other unbalanced anomalies. CONCLUSION: There is a high proportion of fetuses with trisomies 21, 18 and 13 (around 75%) in which the ductus venosus PIV is increased (above the 95th percentile) at 10 to 14 weeks, this proportion being similar to that observed for increased nuchal translucency measurement.