Euploid Fetuses Research Articles

Further insights into diastolic dysfunction in first‐trimester trisomy‐21 fetuses

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. 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. Cardiac parameters among study groups were compared with the use of 95% CIs. The study population comprised 28 fetuses with trisomy 21, 25 with other aneuploidies, 94 euploid fetuses with abnormal findings (27 with cardiac defects, 31 with other structural anomalies and 36 with isolated increased NT) and 271 controls. Trisomy-21 fetuses showed signs of diastolic dysfunction such as increased DV pulsatility index and E/A ratios together with a higher prevalence of tricuspid regurgitation. However, no differences were found in euploid fetuses with cardiac defects or isolated increased NT. No signs of cardiac dysfunction were observed in euploid fetuses with increased NT or cardiac defects, while in trisomy-21 fetuses signs of diastolic dysfunction could be potentially attributed to volume overload.

Nasal bone length, prenasal thickness, prenasal thickness-to-nasal bone length ratio and prefrontal space ratio in second- and third-trimester fetuses with Down syndrome.

To evaluate nasal bone length (NBL), prenasal thickness (PT), prenasal thickness-to-nasal bone length (PT-NBL) ratio and prefrontal space ratio (PFSR) as markers for Down syndrome in the second and third trimesters. NBL, PT, PT-NBL ratio and PFSR were measured retrospectively in stored two-dimensional images or three-dimensional volumes (corrected to the mid-sagittal plane) of fetuses with Down syndrome, which were retrieved from the digital databases of participating units. Measurements were performed on the stored images and volumes by two experienced operators, and the values obtained were compared to our previously reported normal ranges for euploid fetuses in order to assess the detection rates for Down syndrome. A total of 159 fetuses with Down syndrome were included in the analysis, six of which were excluded because of inadequate available images. Median maternal age was 36.0 years and median gestational age was 23 + 1 weeks. NBL and PT were correlated with gestational age (P < 0.001), but the PT-NBL ratio and PFSR were not. Mean NBL, PT, PT-NBL ratio and PFSR were 4.42 mm, 5.56 mm, 1.26 and 0.34, respectively. The nasal bone was absent in 23 (15.4%) cases. As a marker for Down syndrome, the PT-NBL ratio yielded the highest detection rate (86.2%), followed by PFSR (79.7%), PT (63.4%) and NBL (61.9%). All markers were abnormal in 33.6% of cases, whilst all were normal in 4.7%. At least one of the four markers was abnormal in 95.3%, and either the PT-NBL ratio or PFSR was abnormal in 93.8%. Detection rates were not related to gestational age. The PT-NBL ratio and PFSR are robust second- and third-trimester markers for Down syndrome. Both provide high detection rates and are easy to use, as the cut-off for normality is constant throughout gestation. Ltd.

Nasal Bone Length Normogram of Mid-second Trimester Euploid Fetuses of an Indian Population

ABSTRACTIntroductionDown syndrome (DS) is the most common chromosomal aneuploidy to result in a live birth. Absent nasal bone has been consistently observed in fetuses with ds. Multiple studies have been conducted to measure and compare the nasal bone length (NBL) in different races and ethnicity and is found to vary in size. In countries, such as India where often only the second trimester scan is performed for screening of aneuploidies, NBL could be regarded as a useful marker.Aims and objectivesTo estimate the NBL of fetuses at 18 to 22 + 6 weeks gestational age in an Indian population, establish a normogram and compare it with that of the Caucasian population.Materials and methodsProspective observational study in a tertiary care hospital with 500 antenatal subjects after considering the inclusion and exclusion criteria.ResultsThe normogram was established and found to be comparable to previously established ones for Indian subjects. The 5th centiles for 18-18.6, 19-19.6, 20-20.6, 21-21.6 and 22- 22.6 weeks of gestations were 3.4, 3. 5, 4.2, 4.3 and 5.4 mm respectively. The NBL increased with gestational age (GA), and the mean NBL was 5.48 mm. No correlation was noted with maternal age, sex of fetus or religion. The NBLs were significantly shorter than those of the Caucasian population.ConclusionMean NBL values of Indian population are less than the mean NBL of Caucasian population. This along with the GA needs to be considered in counseling patients and decisions regarding further invasive and noninvasive tests.How to cite this articleVikraman SK, Chandra V, Balakrishanan B, Gudi A, Batra M, Kannoli G. Nasal Bone Length Normogram of Mid-second Trimester Euploid Fetuses of an Indian Population. Int J Infertil Fetal Med 2015;6(1):25-29.

Performance of screening for aneuploidies by cell-free DNA analysis of maternal blood in twin pregnancies.

To report clinical implementation of cell-free DNA (cfDNA) analysis of maternal blood in screening for trisomies 21, 18 and 13 in twin pregnancies and examine variables that could influence the failure rate of the test. cfDNA testing was performed in 515 twin pregnancies at 10-28 weeks' gestation. The failure rate of the test to provide results was compared with that in 1847 singleton pregnancies, and logistic regression analysis was used to determine which factors among maternal and pregnancy characteristics were significant predictors of test failure. Failure rate of the cfDNA test at first sampling was 1.7% in singletons and 5.6% in twins. Of those with a test result, the median fetal fraction in twins was 8.7% (range, 4.1-30.0%), which was lower than that in singletons (11.7% (range, 4.0-38.9%)). Multivariable regression analysis demonstrated that twin pregnancy, higher maternal weight and conception by in-vitro fertilization provided significant independent prediction of test failure. Follow-up was available in 351 (68.2%) of the twin pregnancies and comprised 334 with euploid fetuses, 12 discordant for trisomy 21 and five discordant for trisomy 18. In all 323 euploid cases with a result, the risk score for each trisomy was < 1:10 000. In 11 of the 12 cases with trisomy 21 and in the five with trisomy 18, the cfDNA test gave a high-risk result, but in one case of trisomy 21, the score was < 1:10 000. In twin pregnancies screening by cfDNA testing is feasible, but the failure rate is higher and detection rate may be lower than in singletons.

OP35.05: Influence of first trimester screening on the prenatal detection of structural malformations in euploid fetuses

<scp>OP</scp>35.05: Influence of first trimester screening on the prenatal detection of structural malformations in euploid fetuses

Frontomaxillary Facial Angle Measurement in Trisomy 21 and Euploid Fetuses: Two- and Three-Dimensional Assessment during Routine First Trimester Screening

Objective: To assess 2D and 3D frontomaxillary facial angle (FMFA) measurements in euploid and trisomy 21 fetuses. Materials and Methods: Over a 2-year period, women with singleton pregnancies attending a private prenatal screening and diagnosis practice in Sydney, Australia, were invited to participate in this study where 2D images and 3D volumes of the fetal face were collected during routine first trimester screening. In pregnancies where trisomy 21 was confirmed, FMFA measurements were performed in 2D and 3D and compared with those from a euploid cohort. Results: Overall, 250 women carrying euploid and 22 women carrying trisomy 21 fetuses participated. Trisomy 21 fetuses had significantly larger FMFA measurements than euploid fetuses in both 2D and 3D assessments. 95% of 3D and 100% of 2D FMFA measurements for the trisomy 21 fetuses were above the mean FMFA measurement of the euploid fetuses. There was no relationship between increasing crown-rump length and FMFA measurement. Conclusion: 2D and 3D FMFA measurements in trisomy 21 fetuses are statistically greater (p < 0.001) than those in euploid fetuses. This supports FMFA as a possible additional marker for trisomy 21 for first trimester screening.

Prenatal management, pregnancy and pediatric outcomes in fetuses with septated cystic hygroma.

It has been reported that, compared with simple increased nuchal translucency, fetal cases with septated cystic hygroma (CH) are more likely to face perinatal handicaps. However, pediatric outcomes and proper prenatal counseling for this anomaly have not yet been truly defined. We performed this study to determine pregnancy and pediatric outcomes of fetuses with septated CH. We searched records for cases with septated CH and collected data for structural abnormalities, karyotype analysis, and pregnancy outcomes. Fetuses born with septated CH were also evaluated for their pediatric outcomes. Sixty-nine fetuses with septated CH were enrolled in the study. Results showed that chromosomal abnormalities were present in 28 fetuses (40.6%), and the most common aneuploidy was Turner syndrome (n=14, 20.3%); 16 (23.2%) of the remaining cases, in which aneuploidy was not found, had coexistent structural malformations; 25 (36.2%) cases had normal karyotype and morphology. The total number of live births and infants with unfavorable neurologic follow-up were 13 (18.8%) and 2 (2.9%), respectively. Septated CH is associated with poor perinatal outcomes; therefore, karyotype analysis and ultrasonographic anomaly screening should be performed as initial steps, and expectant management should be offered to couples with euploid fetuses that have normal morphology.

Prenatal diagnosis versus first-trimester screening of trisomy 21 among pregnant women aged 35 or more

Objective: To compare the policy of prenatal diagnosis versus first trimester screening of trisomy 21 among pregnant women of advanced age.Methods: A retrospective study was conducted on patients aged ≥35 divided in two groups: patients who requested first trimester combined test and only in case of screen-positive result underwent invasive testing (group A); patients undergoing chorionic villous sampling or amniocentesis as first investigation (group B). The following outcome variables were compared: antenatal detection of trisomy 21, occurrence of trisomy 21 at birth, miscarriage rate, hospitals' costs.Results: 4527 women were included. Of these, 534 (11.80%) underwent T21 screening whereas 3993 (88.20%) requested primary invasive testing. In group A, 64 combined test were positive (11.99%) and 8 trisomy 21 cases were diagnosed (1.50%); the loss of euploid fetuses after invasive procedure was 4.55% (2/44). No false-negative case was observed. In group B 57 cases of trisomy 21 were diagnosed (1.43%), and pregnancy loss rate of chromosomally normal fetuses was 0.45% (17/3806). The estimated cost was, respectively, 67.720€ for the primary screening versus 1.996.500€ for direct prenatal diagnosis.Conclusion: First trimester screening of trisomy 21 is highly accurate and cost saving among women ≥35.

Prenatal diagnosis of Down syndrome using cell-free fetal DNA in amniotic fluid by quantitative fluorescent polymersase chain reaction

Backgroud Amniotic fluid (AF) supernatant contains cell-free fetal DNA (cffDNA) fragments. This study attempted to take advantage of cffDNA as a new material for prenatal diagnosis, which could be combined with simple quantitative fluorescent polymerase chain reaction (QF-PCR) to provide an ancillary method for the prenatal diagnosis of trisomy 21 syndrome. Methods AF supernatant samples were obtained from 27 women carrying euploid fetuses and 28 women carrying aneuploid fetuses with known cytogenetic karyotypes. Peripheral blood samples of the parents were collected at the same time. Short tandem repeat (STR) fragments on chromosome 21 were amplified by QF-PCR. Fetal condition and the parental source of the extra chromosome could be determined by the STR peaks. Results The sensitivity of the assay for the aneuploid was 93% (26/28; confidence interval, CI: 77%-98%) and the specificity was 100% (26/26; CI: 88%-100%). The determination rate of the origin of the extra chromosome was 69%. The sensitivity and the specificity of the assay in the euploid were 100% (27/27). Conclusions Trisomy 21 can be prenatally diagnosed by the QF-PCR method in AF supernatant. This karyotype analysis method greatly reduces the requirement for the specimen size. It will be a benefit for early amniocentesis and could avoid pregnancy complications. The method may become an ancillary method for prenatal diagnosis of trisomy 21.

First trimester tricuspid regurgitation and fetal abnormalities.

Tricuspid regurgitation (TR) is a common sonographic finding during the fetal life. It has been reported in 7% of normal fetuses. It may be associated with aneuploidy and with both cardiac and extracardiac defects. In this study, we have looked at the characteristics of fetuses with and without TR at 11+0 to 13+6 weeks' gestation. Groups were compared with respect to the following variables: prevalence of chromosomal defects; other markers of aneuploidy; fetal cardiac; and extracardiac anomalies. The study group included women, who underwent an ultrasound examination at 11-13+6 weeks' gestation between 2009 and 2012. The inclusion criteria were singleton pregnancies with crown-rump length measurements of 45-84 mm where the pregnancy outcome was known. Some 1075 patients met our inclusion criteria including 979 fetuses without TR and 96 with TR. There were 72 cases of aneuploidy diagnosed (6.7%). Isolated TR was found in 53 euploid fetuses (5.2%). All of the TR(+) aneuploid fetuses (n=40) had additional ultrasound markers present. Extracardiac anatomy showed a higher prevalence of abnormalities in the group of TR positives (12.5%) vs. TR negatives (1.6%). Abnormal cardiac findings were more frequent in the TR-positive group independently of chromosomal status and were found in 18.8% of fetuses with TR and in 1.9% with a normal tricuspid flow. TR in combination with other markers is the strongest predictor for aneuploidy. TR, as an isolated parameter, is a poor screening tool both for all and for each individual chromosomal abnormality and congenital cardiac defects.

Assessment of Fetal Sex Chromosome Aneuploidy Using Directed Cell-Free DNA Analysis

Objective: To examine the performance of chromosome-selective sequencing of cell-free (cf) DNA in maternal blood for assessment of fetal sex chromosome aneuploidies. Methods: This was a case-control study of 177 stored maternal plasma samples, obtained before fetal karyotyping at 11-13 weeks of gestation, from 59 singleton pregnancies with fetal sex chromosome aneuploidies (45,X, n = 49; 47,XXX, n = 6; 47,XXY, n = 1; 47,XYY, n = 3) and 118 with euploid fetuses (46,XY, n = 59; 46,XX, n = 59). Digital analysis of selected regions (DANSR™) on chromosomes 21, 18, 13, X and Y was performed and the fetal-fraction optimized risk of trisomy evaluation (FORTE™) algorithm was used to estimate the risk for non-disomic genotypes. Performance was calculated at a risk cut-off of 1:100. Results: Analysis of cfDNA provided risk scores for 172 (97.2%) samples; 4 samples (45,X, n = 2; 46,XY, n = 1; 46,XX, n = 1) had an insufficient fetal cfDNA fraction for reliable testing and 1 case (47,XXX) failed laboratory quality control metrics. The classification was correct in 43 (91.5%) of 47 cases of 45,X, all 5 of 47,XXX, 1 of 47,XXY and 3 of 47,XYY. There were no false-positive results for monosomy X. Discussion: Analysis of cfDNA by chromosome-selective sequencing can correctly classify fetal sex chromosome aneuploidy with reasonably high sensitivity.

Fetal right ventricular contraction and relaxation times at 11–13 weeks' gestation on speckle tracking imaging

To examine the contraction time and relaxation time of the right ventricle at 11-13 weeks' gestation in trisomy 21 and euploid fetuses by speckle tracking ultrasound imaging. Measurement of fetal nuchal translucency (NT) thickness, Doppler assessment for tricuspid regurgitation and reversed A-wave in the ductus venosus (DV) and fetal echocardiography were performed immediately before chorionic villus sampling for fetal karyotyping at 11-13 weeks' gestation. Digital videoclips of the four-chamber view of the fetal heart were recorded and analyzed offline using speckle tracking imaging software. The contraction time, which is the time between the highest and lowest peaks in the right ventricular area, and relaxation time, which is the time between the lowest and the subsequent highest area peak, were measured and expressed as a percentage of the duration of the cardiac cycle. Values in trisomy 21 and euploid fetuses were compared. Mean contraction time and relaxation time in 119 euploid fetuses were 52.1% (95% CI, 51.6-52.8%) and 47.8% (95% CI, 47.2-48.4%), respectively. In 21 trisomy 21 fetuses, mean contraction time was significantly higher (57.0% (95% CI, 55.2-58.9%); P<0.01) and relaxation time lower (42.9% (95% CI, 41.1-44.8%); P<0.01) than in euploid fetuses. Multiple regression analysis showed that significant contributions to contraction time and relaxation time were provided by fetal karyotype, NT and tricuspid regurgitation, but not by reversed A-wave in the DV or the presence of a cardiac defect. In first-trimester fetuses with trisomy 21 and in euploid fetuses with increased NT and tricuspid regurgitation there is evidence of increased right ventricular contraction time and shortening of the relaxation time.

Non-invasive prenatal diagnosis using massively parallel sequencing - first experience in Germany.

Non-invasive prenatal diagnosis (NIPD) of aneuploidies by cell free fetal DNA (cff-DNA) from maternal plasma has reached the reliability to be applied in a clinical setting. It started with an observation that fetal DNA fragments are present in the blood of pregnant women. One main obstacle to be resolved had been the low concentration of cff-DNA among maternal DNA fragments, in general 2 – 10 % at 10th week of pregnancy. This problem was resolved by the technical development of next generation sequencing applying massively parallel sequencing of millions of DNA fragments out of a single blood sample of 10 ml followed by bioinformatic processing of the data. Algorithms for calculations of z-scores were validated to allow a highly accurate distinction of pregnancies with an euploid fetus from those with a fetus carrying certain aneuploidies. With focus on the reliability of results it should be in mind that the cff-DNA is derived from the cytotrophoblast, e.g. from the placental tissue which is analyzed in CVS short term culture. Hitherto collected clinical data show sensitivity and specificity in agreement with a diagnostic test. In Germany, aneuploidy testing by NIPD started in 2012. Initially, the approach allowed the detection of trisomy 21. However, meanwhile probing for trisomy 13, trisomy 18 and the sex chromosome constitution is feasible. At the moment, the test is indicated for women with singleton pregnancies at an increased risk for aneuploidies. Blood samples should not be taken before 9+0 week of pregnancy. However, it is suggested to perform NIPD only in conjunction with a first trimester ultrasonographic examination for a profound judging of the fetal situation. For the time being, testing time is reduced to 10 working days or even less. In Germany, by now more than 4000 tests had been performed. In Berlin, data exceeding 250 cases had been collected by BG Berlin Genetics. The data of NIPD will be discussed in comparison to invasive prenatal diagnosis.

Circulating Fetal Cell-Free DNA Fractions Differ in Autosomal Aneuploidies and Monosomy X

Noninvasive prenatal testing based on massively parallel sequencing (MPS) of cell-free DNA in maternal plasma has become rapidly integrated into clinical practice for detecting fetal chromosomal aneuploidy. We directly determined the fetal fraction (FF) from results obtained with MPS tag counting and examined the relationships of FF to such biological parameters as fetal karyotype and maternal demographics. FF was determined from samples previously collected for the MELISSA (Maternal Blood Is Source to Accurately Diagnose Fetal Aneuploidy) study. Samples were resequenced, analyzed blindly, and aligned to the human genome (assembly hg19). FF was calculated in pregnancies with male or aneuploid fetuses by means of an equation that incorporated the ratio of the tags in these samples to those of a euploid training set. The mean (SD) FF from euploid male pregnancies was 0.126 (0.052) (n = 160). Weak but statistically significant correlations were found between FF and the maternal body mass index (r(2) = 0.18; P = 2.3 × 10(-8)) and between FF and gestational age (r(2) = 0.02; P = 0.047). No relationship with maternal ethnicity or age was observed. Mean FF values for trisomies 21 (n = 90), 18 (n = 38), and 13 (n = 16) and for monosomy X (n = 20) were 0.135 (0.051), 0.089 (0.039), 0.090 (0.062), and 0.106 (0.045), respectively. MPS tag-count data can be used to determine FF directly and accurately. Compared with male euploid fetuses, the FF is higher in maternal plasma when the fetus has trisomy 21 and is lower when the fetus has trisomy 18, 13, or monosomy X. The different biologies of these aneuploidies have practical implications for the determination of cutoff values, which in turn will affect the diagnostic sensitivity and specificity of the test.

Application of multiplex SNaPshot assay in measurement of PLAC4 RNA-SNP allelic ratio for noninvasive prenatal detection of trisomy 21

For the samples in which the fetus was heterozygous for the placenta-specific 4 (PLAC4) single-nucleotide polymorphism (SNP), our research is to develop a rapid, accurate, and cost-effective assay for the noninvasive prenatal detection of fetal trisomy 21 (T21). Maternal plasma samples were prepared from 60 euploid pregnancies (range: 15-23 weeks) to 17 T21 pregnancies (range: 19-26 weeks). With the application of the SNaPshot assay in measuring the PLAC4 RNA-SNP allelic ratio, we can achieve noninvasive prenatal detection of T21. Also we detected the genotypes of SNP located in gene PLAC4 in samples collected in Southeast China of 216 volunteers. Of all 77 singleton pregnancies, 21 gravidas were found heterozygous for the PLAC4 SNP. Among them, four pregnancies with a T21 fetus and 17 pregnancies with a euploid fetus were detected. The SNPs with higher heterozygosity rates on gene PLAC4 were Rs8130833 and Rs4818219, which were estimated to be 0.278 and 0.343, respectively. For samples with heterozygous SNPs, the PLAC4 RNA-SNP allelic ratio approach can be used for noninvasive prenatal detection of T21 by the multiplex SNaPshot assay. The two SNPs with higher frequency of heterozygosity on gene PLAC4 were Rs8130833 and Rs4818219 in population of Southeast China.

Assessment of Fetal Sex Chromosome Aneuploidy Using Directed Cell-Free DNA Analysis

Objective: To examine the performance of chromosome-selective sequencing of cell-free (cf) DNA in maternal blood for assessment of fetal sex chromosome aneuploidies. Methods: This was a case-control study of 177 stored maternal plasma samples, obtained before fetal karyotyping at 11-13 weeks of gestation, from 59 singleton pregnancies with fetal sex chromosome aneuploidies (45,X, n = 49; 47,XXX, n = 6; 47,XXY, n = 1; 47,XYY, n = 3) and 118 with euploid fetuses (46,XY, n = 59; 46,XX, n = 59). Digital analysis of selected regions (DANSR™) on chromosomes 21, 18, 13, X and Y was performed and the fetal-fraction optimized risk of trisomy evaluation (FORTE™) algorithm was used to estimate the risk for non-disomic genotypes. Performance was calculated at a risk cut-off of 1:100. Results: Analysis of cfDNA provided risk scores for 172 (97.2%) samples; 4 samples (45,X, n = 2; 46,XY, n = 1; 46,XX, n = 1) had an insufficient fetal cfDNA fraction for reliable testing and 1 case (47,XXX) failed laboratory quality control metrics. The classification was correct in 43 (91.5%) of 47 cases of 45,X, all 5 of 47,XXX, 1 of 47,XXY and 3 of 47,XYY. There were no false-positive results for monosomy X. Discussion: Analysis of cfDNA by chromosome-selective sequencing can correctly classify fetal sex chromosome aneuploidy with reasonably high sensitivity.

Comparison of right ventricular measurements and SFRV in fetuses with and without tricuspid regurgitation at 11+0 and 13+6 weeks’ gestation

Objectives: To compare right ventricular dimensions and systolic shortening fraction of the right ventricle (SFRV) in fetuses with tricuspid regurgitation (TR [+]) to those without tricuspid regurgitation (TR [−]).Methods: Unselected patients presenting for first trimester screening between 11 + 0 and 13 + 6 weeks’ gestation were examined for the presence or absence of fetal tricuspid regurgitation using a standard approach. Only euploid fetuses without structural anomalies were included in the study. The heart was examined with the aid of M-mode using a previously described method. The right ventricular diastolic diameter (RVDD) and right ventricular systolic diameter (RVSD) were measured on stored M-mode images and the SFRV was calculated using the following formula [(RVDD−RVSD)/RVDD] × 100.Results: A total of 69 fetuses (n = 44 (TR [−]); n = 25 (TR [+])) were examined. The two groups were similar in maternal age, gestational age and nuchal translucency (NT) measurements. The SFRV was noted not to change with gestational age and there was no statistical difference between the two groups. Both the RVDD and the RVSD increased with gestational age. The calculated delta RVDD was statistically larger in the TR [+] group (mean: 0.29, CI 95%: 0.054–0.532) than the TR [−] group (mean: 0.013, CI 95%: −0.128 to 0.154) (p < 0.05). This was not true for the delta RVSD: TR [+] (mean: 0.17, CI 95%: 0.015–0.325) versus TR [−] group (mean: 0.035, CI 95%: −0.061 to 0.131). However, there was a trend towards larger RVSD in the TR [+] group (p = 0.13).Conclusions: The presence of TR appears to be associated with an increased RVDD in normal fetuses between 11 + 0 and 13 + 6 weeks’ gestation.

Absent Fetal Nasal Bone

Our purpose was to review the outcomes of singleton pregnancies in which an absent nasal bone was noted on first- or second-trimester sonography and aneuploidy was not present. We identified singleton pregnancies from 2005 to 2011 in which an absent nasal bone was noted on sonography, aneuploidy was excluded, and newborn examinations were available for review. Sonographic reports were reviewed for anomalies, growth, and amniotic fluid volume. Newborn records were reviewed for physical examinations, complications, and radiologic or genetic tests. We identified 142 fetuses with a sonographic appearance of an absent nasal bone. We excluded 52 cases with aneuploidy and 33 in which newborn examination information was unavailable. Fifty-seven cases met inclusion criteria. For 3 euploid fetuses with an absent nasal bone on sonography, the presence of additional anomalies on second-trimester sonography ultimately signaled an adverse outcome: the presence of multiple congenital anomalies, a microdeletion syndrome, and a specific genetic diagnosis. All cases with adverse outcomes had additional prenatal sonographic findings. For the remainder, normal newborn examination findings provide some reassurance, especially in the setting of otherwise normal second-trimester sonographic findings. A microarray as a test for microdeletion and duplication syndromes in this situation could be considered.

Evaluation of the role of first-trimester obstetric ultrasound in the detection of major anomalies: a systematic review

To perform a systematic review to assess the accuracy of first-trimester ultrasound (US) in the diagnoses of major structural malformations in chromosomally normal fetuses. References were obtained from the MEDLINE database, without time range limitations. For each, the risk of bias was evaluated and the important data were extracted. Only studies that used first-trimester US to diagnose major structural malformations were included. We evaluated the sensitivity of US over a low-risk unselected population of pregnant women carrying euploid fetuses. A total of 19 studies were included, contributing to 126,937 fetuses and 1399 major malformations. The prevalence of lethal and severe malformations obtained was 1.2% [95% confidence interval (CI), 1.0-1.4]. Both averaged and pooled sensitivity, 50.0% (95% CI 44.1-55.9) and 45.2%, respectively, presented a moderate value for first-trimester US in the detection of structural malformations. Based on our analysis of the data, the average sensitivity of first-trimester US to detect structural malformations was 50%. It is our conviction that US has the potential to evolve in this role by exploiting the natural history of malformations and the development of US techniques.

Prenatal Detection of Fetal Triploidy from Cell-Free DNA Testing in Maternal Blood

Objective: To investigate potential performance of cell-free DNA (cfDNA) testing in maternal blood in detecting fetal triploidy. Methods: Plasma and buffy coat samples obtained at 11-13 weeks' gestation from singleton pregnancies with diandric triploidy (n = 4), digynic triploidy (n = 4), euploid fetuses (n = 48) were sent to Natera, Inc. (San Carlos, Calif., USA) for cfDNA testing. Multiplex polymerase chain reaction amplification of cfDNA followed by sequencing of single nucleotide polymorphic loci covering chromosomes 13, 18, 21, X, and Y was performed. Sequencing data were analyzed using the NATUS algorithm which identifies copy number for each of the five chromosomes. Results: cfDNA testing provided a result in 44 (91.7%) of the 48 euploid cases and correctly predicted the fetal sex and the presence of two copies each of chromosome 21, 18 and 13. In diandric triploidy, cfDNA testing identified multiple paternal haplotypes (indicating fetal trisomy 21, trisomy 18 and trisomy 13) suggesting the presence of either triploidy or dizygotic twins. In digynic triploidy the fetal fraction corrected for maternal weight and gestational age was below the 0.5th percentile. Conclusions: cfDNA testing by targeted sequencing and allelic ratio analysis of single nucleotide polymorphisms covering chromosomes 21, 18, 13, X, and Y can detect diandric triploidy and raise the suspicion of digynic triploidy.