Prenatal Diagnosis Of Fetal Aneuploidies Research Articles

Noninvasive prenatal testing in megacity

Introduction. The article presents an analysis of the use of non-invasive prenatal testing for chromosomal abnormalities in the fetal extracellular DNA in the blood of pregnant women in Moscow. Materials and methods. When processing materials and research results, authors considered all available clinical data: findings of an ultrasound examination, medical history and results of additional laboratory tests. Results. The article presents results of invasive prenatal diagnostics and pregnancy outcomes in patients with high NIPT risks. Discussion. Authors analyzed diagnostic capabilities of NIPT, its limitations, false-positive and false- negative results, and described 3 cases of prenatal diagnosis of fetal aneuploidy identified in patients who are in the «gray zone» of risk based on the results of combined screening of the first trimester of pregnancy. Conclusion. Prenatal diagnosis of the described aneuploidy is difficult due to individual risk of developing chromosomal abnormalities of the fetus based on the results of combined first-trimester screening in the range of 1:101-1: 2500 and lack of indications for invasive prenatal diagnostics.

Quantitative fluorescent PCR (QF-PCR) for prenatal diagnosis of fetal aneuploidy: Indian experience

Introduction: Prenatal diagnosis of fetal chromosomal aneuploidies has traditionally relied on cytogenetics. In recent times QF-PCR, to detect the common aneuploidies has been reported. In view of the paucity of Indian experience regarding QF-PCR, we present prospective data from our centre. Materials and Methods: 572 AF samples were collected from Indian women with singleton pregnancy between 16-20 weeks gestation after counselling. The samples were collected over one year and followed up till delivery. AF was sent for QF-PCR for chromosomes 13, 18, 21 and 23. Results: There was no procedure related miscarriage, or IUFD. There were seventeen trisomy 21, two 47XXX and one 47XXY. All pregnancies with fetal aneuploidies underwent termination. All 552/572 women with normal report were followed up and none had IUFD or clinical features of trisomy 21 after term or preterm births. Discussion: The current study stresses the clinical importance of shorter TAT advantage and the slight cost advantage of QF-PCR over FISH. The current study shows QF-PCR is a satisfactory method for diagnosing chromosomal aneuploidy from amniotic fluid in screen positive population, has advantages and might be preferred more in near future in place of FISH, especially in the scenario of increasing awareness of biochemical screening for chromosomal aneuploidies in India. However, more such studies with increased numbers and in multiple pregnancies are required. The current study is ongoing and hopefully we will be able to present such data soon. Keywords: QF-PCR, Aneuploidy, Prenatal diagnosis, Segmental duplication.

To NIPT or not to NIPT

Introduction: Fetal chromosomal abnormalities, particularly aneuploidies such as Down's syndrome and other trisomies are common and their detection has been one of the main goals of fetal medicine. Prenatal diagnosis of fetal aneuploidies requires invasive procedures but these are risk-associated and expensive. Consequently strategies have focused on the development of effective methods of screening to define the group in need for such invasive testing.

Noninvasive prenatal diagnosis of fetal aneuploidy by circulating fetal nucleated red blood cells and extravillous trophoblasts using silicon-based nanostructured microfluidics

BackgroundNoninvasive prenatal testing (NIPT) based on cell-free DNA in maternal circulation has been accepted worldwide by the clinical community since 2011 but limitations, such as maternal malignancy and fetoplacental mosaicism, preclude its full replacement of invasive prenatal diagnosis. We present a novel silicon-based nanostructured microfluidics platform named as “Cell Reveal™” to demonstrate the feasibility of capturing circulating fetal nucleated red blood cells (fnRBC) and extravillous cytotrophoblasts (EVT) for cell-based noninvasive prenatal diagnosis (cbNIPD).MethodsThe “Cell Reveal™” system is a silicon-based, nanostructured microfluidics using immunoaffinity to capture the trophoblasts and the nucleated RBC (nRBC) with specific antibodies. The automated computer analysis software was used to identify the targeted cells through additional immunostaining of the corresponding antigens. The identified cells were retrieved for whole genome amplification for subsequent investigations by micromanipulation in one microchip, and left in situ for subsequent fluorescence in situ hybridization (FISH) in another microchip. When validation, bloods from pregnant women (n = 24) at gestational age 11–13+6 weeks were enrolled. When verification, bloods from pregnant women (n = 5) receiving chorionic villus sampling or amniocentesis at gestation age 11+4–21 weeks with an aneuploid or euploid fetus were enrolled, followed by genetic analyses using FISH, short tandem repeat (STR) analyses, array comparative genomic hybridization, and next generation sequencing, in which the laboratory is blind to the fetal genetic complement.ResultsThe numbers of captured targeted cells were 1–44 nRBC/2 ml and 1–32 EVT/2 ml in the validation group. The genetic investigations performed in the verification group confirmed the captured cells to be fetal origin. In every 8 ml of the maternal blood being blindly tested, both fnRBC and EVT were always captured. The numbers of captured fetal cells were 14–22 fnRBC/4 ml and 1–44 EVT/4 ml of maternal blood.ConclusionsThis report is one of the first few to verify the capture of fnRBC in addition to EVT. The scalability of our automated system made us one step closer toward the goal of in vitro diagnostics.

Obesity and Cell Free DNA Testing [24R

INTRODUCTION: Cell free fetal DNA is first detected in maternal serum at seven weeks gestation and the quantity increases during pregnancy. Non-invasive prenatal testing (NIPT) can be used as a screening test to aid in prenatal diagnosis of fetal aneuploidy. Recommendations for use are limited to women at “high risk.” There are no current guidelines for use in special populations including obese women, “low risk” women, or smokers. In obese women, the amount of maternal cfDNA is greater than in non-obese women. We hypothesize that obese women will have greater rates of “no result” than lean women. METHODS: A retrospective review was performed evaluating all pregnant women at our institution who had NIPT drawn From 1/1/11-1/1/15 (n=805). Women with BMI between 25.0-29.9 at initial prenatal visit were excluded. Categorical variables were compared using chi square or Fisher's exact test, continuous variables were assessed using a student t test. RESULTS: A total of 473 women met inclusion criteria (277 obese, 196 normal weight). A larger proportion of obese women had “no result” than lean women but this was not statistically significant (3.2% vs 1.5%, p=0.24). The mean BMI in those with “no result” was 36.2+/-13.0. One obese woman had a female result on NIPT and male genitalia on ultrasound and confirmed at birth to be 46, XY. CONCLUSION: There was a trend toward more “no result” in obese vs lean women. A larger study is needed to further elucidate the differences in performance of NIPT for lean vs obese women.

Quantitative fluorescent polymerase chain reaction for rapid prenatal diagnosis of fetal aneuploidies in chorionic villus sampling in a single institution.

ObjectiveTo validate quantitative fluorescent polymerase chain reaction (QF-PCR) via chorionic villus sampling (CVS) for the diagnosis of fetal aneuploidies.MethodsWe retrospectively reviewed the medical records of consecutive pregnant women who had undergone CVS at Cheil General Hospital between December 2009 and June 2014. Only cases with reported QF-PCR before long-term culture (LTC) for conventional cytogenetic analysis were included, and the results of these two methods were compared.ResultsA total of 383 pregnant women underwent QF-PCR and LTC via CVS during the study period and 403 CVS specimens were collected. The indications of CVS were as follows: abnormal first-trimester ultrasonographic findings, including increased fetal nuchal translucency (85.1%), advanced maternal age (6.8%), previous history of fetal anomalies (4.2%), and positive dual test results for trisomy 21 (3.9%). The results of QF-PCR via CVS were as follows: 76 (18.9%) cases were identified as trisomy 21 (36 cases), 18 (33 cases), or 13 (seven cases), and 4 (1.0%) cases were suspected to be mosaicism. All results of common autosomal trisomies by QF-PCR were consistent with those of LTC and there were no false-positive findings. Four cases suspected as mosaicism in QF-PCR were confirmed as non-mosaic trisomies of trisomy 21 (one case) or trisomy 18 (three cases) in LTC.ConclusionQF-PCR via CVS has the advantage of rapid prenatal screening at an earlier stage of pregnancy for common chromosomal trisomies and thus can reduce the anxiety of parents. In particular, it can be helpful for pregnant women with increased fetal nuchal translucency or abnormal first-trimester ultrasonographic findings.

Positive predictive value of non-invasive prenatal screening for fetal chromosome disorders using cell-free DNA in maternal serum: independent clinical experience of a tertiary referral center.

BackgroundNon-invasive prenatal screening (NIPS) for fetal chromosome abnormalities using cell-free deoxyribonucleic acid (cfDNA) in maternal serum has significantly influenced prenatal diagnosis of fetal aneuploidies since becoming clinically available in the fall of 2011. High sensitivity and specificity have been reported in multiple publications, nearly all of which have been sponsored by the commercial performing laboratories. Once results are returned, positive and negative predictive values (PPVs, NPVs) are the performance metrics most relevant to clinical management. The purpose of this report is to present independent data on the PPVs of NIPS in actual clinical practice.MethodsCharts were retrospectively reviewed for patients who had NIPS and were seen March 2012 to December 2013 in a tertiary academic referral center. NIPS results were compared to diagnostic genetic test results, fetal ultrasound results, and clinical phenotype/outcomes. The PPV was calculated using standard epidemiological methods. Correlation between screen results and both maternal age at delivery and gestational age at time of screening was assessed using Wilcoxon’s rank sum test.ResultsOf 632 patients undergoing NIPS, 92 % of tests were performed in one of the four major commercial laboratories offering testing. However, all four laboratories are represented in both the normal and abnormal results groups. There were 55 abnormal NIPS results. Forty-one of 55 abnormal NIPS results were concordant with abnormal fetal outcomes, 12 were discordant, and 2 were undetermined. The PPV for all conditions included in the screen was 77.4 % (95 % CI, 63.4 – 87.3). Of 578 patients with normal NIPS results, normal pregnancy outcome was confirmed for 156 (27 %) patients. This incomplete follow-up of normal NIPS results does not affect PPV calculations, but it did preclude calculations of sensitivity, specificity, and NPV. Maternal age at delivery was significantly lower for patients with abnormal discordant results, compared to patients with abnormal concordant results (P = 0.034). Gestational age at time of screening was not associated with concordance of screen results (P = 0.722).ConclusionsThe experience of using NIPS in clinical practice confirms that abnormal results cannot be considered diagnostic. Pre-test counseling should emphasize this. Diagnostic genetic testing should always be offered following abnormal NIPS results.

Amplification-free sequencing of cell-free DNA for prenatal non-invasive diagnosis of chromosomal aberrations

Cell-free DNA has been used for fetal rhesus factor and sex determination, fetal aneuploidy screening, cancer diagnostics and monitoring, and other applications. However current methods of using cell free DNA require amplification, which leads to allelic dropout and bias especially when starting with small amounts of DNA. Here we describe an amplification-free method for sequencing of cell-free DNA, even from low levels of starting material. We evaluated this method in the context of prenatal diagnosis of fetal aneuploidy and compared it with a PCR-based library preparation method as well as a recently described method using unique molecular identifiers (UMI). All methods performed well, however coverage was increased by the amplification-free method and GC-induced bias was reduced by both the amplification-free method and the UMI method. Future diagnostic applications including whole genome sequencing of cell-free DNA will benefit from amplification-free sequencing.

Comparison of the performance of Ion Torrent chips in noninvasive prenatal trisomy detection.

Semiconductor high-throughput sequencing, represented by Ion Torrent PGM/Proton, proves to be feasible in the noninvasive prenatal diagnosis of fetal aneuploidies. It is commendable that, with less data and relevant cost also, an accurate result can be achieved owing to the high sensitivity and specificity of such kind of technology. We conducted a comparative analysis of the performance of four different Ion chips in detecting fetal chromosomal aneuploidies. Eight maternal plasma DNA samples, including four pregnancies with normal fetuses and four with trisomy 21 fetuses, were sequenced on Ion Torrent 314/316/318/PI chips, respectively. Results such as read mapped ratio, correlation coefficient and phred quality score were calculated and parallelly compared. All samples were correctly classified even with low-throughput chip, and, among the four chips, the 316 chip had the highest read mapped ratio, correlation coefficient, mean read length and phred quality score. All chips were well consistent with each other. Our results showed that all Ion chips are applicable in noninvasive prenatal fetal aneuploidy diagnosis. We recommend researchers or clinicians to use the appropriate chip with barcoding technology on the basis of the sample number.

PF.51 Expectant Management of Prenatally Diagnosed Fetal Aneuploidy

It is essential to counsel patients about all options following the prenatal diagnosis of fetal aneuploidy (FA). We sought to ascertain the prenatal course and pregnancy outcomes in those with...

Cell-free nucleic acid based non-invasive prenatal diagnosis of fetal aneuploidies

Prenatal detection of fetal aneuploidies is one of the main goals of the prenatal diagnostic approach. As a benefit of the development of advanced ultrasound equipment and advances in molecular biology in the last decade, there is a significant progress in screening methods for fetal aneuploidies, although invasive methods remain the gold standard for aneuploidy detection. Non-invasive prenatal diagnosis has substantial medical impact as it targets the development of safer and more effective methods to avoid the risk of fetal loss associated with currently used invasive methods. Identification of fetal-specific messenger ribonucleic acids, digital polymerase chain reaction and next-generation sequencing give the real chance for non-invasive prenatal diagnosis of fetal aneuploidies. Although all these methods have both advantages and limitations, some of them are moving closer to clinical implementation. In this review the authors highlight the most recent advances in methods for non-invasive prenatal diagnosis of aneuploidies.

Non-invasive prenatal diagnosis of fetal aneuploidies using massively parallel sequencing-by-ligation and evidence that cell-free fetal DNA in the maternal plasma originates from cytotrophoblastic cells

Blood plasma of pregnant women contains circulating cell-free fetal DNA (ccffDNA), originating from the placenta. The use of this DNA for non-invasive detection of fetal aneuploidies using massively parallel sequencing (MPS)-by-synthesis has been proven previously. Sequence performance may, however, depend on the MPS platform and therefore we have explored the possibility for multiplex MPS-by-ligation, using the Applied Biosystems SOLiD™ 4 system. DNA isolated from plasma samples from 52 pregnant women, carrying normal or aneuploid fetuses, was sequenced in multiplex runs of 4, 8 or 16 samples simultaneously. The sequence reads were mapped to the human reference genome and quantified according to their genomic location. In case of a fetal aneuploidy, the number of reads of the aberrant chromosome is expected to be higher or lower than in normal reference samples. To statistically determine this, Z-scores per chromosome were calculated as described previously, with thresholds for aneuploidies set at > +3.0 and < -3.0 for chromosomal over- or underrepresentation, respectively. All samples from fetal aneuploidies yielded Z-scores outside the thresholds for the aberrant chromosomes, with no false negative or positive results. Full-blown fetal aneuploidies can thus be reliably detected in maternal plasma using a multiplex MPS-by-ligation approach. Furthermore, the results obtained with a sample from a pregnancy with 45,X in the cytotrophoblastic cell layer and 46,XX in the mesenchymal core cells show that ccffDNA originates from the cytotrophoblastic cell layer. Discrepancies between the genetic constitution of this cell layer and the fetus itself are well known, and therefore, care should be taken when translating results to the fetus itself.

QF-PCR as a Rapid Technique for Routine Prenatal Diagnosis of Fetal Aneuploidies

Background: The most common chromosomal abnormalities are aneuploidies of chromosome 21, 18, 13, X and Y. Prenatal diagnosis of fetal aneuploidies is routinely done by traditional cytogenetic culture, a major drawback of this technique is the long period required to reach a diagnosis. In this study we evaluated the QF-PCR as a rapid technique for prenatal diagnosis of common aneuploidies Method: This work was carried out on Sixty amniotic fluid samples taken from patients with one or more of the following indications: Advanced maternal age (3 case), abnormal biochemical markers (6 cases), abnormal ultrasound (12 cases) or previous history of abnormal child (39 cases). Each sample was tested by QF-PCR and traditional cytogenetic. Aneuploidy screenings were performed amplifying four STRs on chromosomes 21, 18, 13, two pseudoautosomal,one X linked, as well as the AMXY and SRY; markers were distributed in two multiplex QFPCR assays (S1 and S2) in order to reduce the risk of sample mishandling. Results: All the QF-PCR results were successful, while there was two culture failures, only one of them was repeated. No discrepancy was seen between the results of both techniques. Fifty six samples showed normal patterns, three sample showed trisomy 21, successfully detected by both techniques and one sample showed normal pattern by QF-PCR but could not be compared to the cytogenetics due to culture failure, the pregnancy outcome of this case was a normal baby. Conclusion: Our study concluded that QF-PCR is a reliable technique for prenatal diagnosis of the common chromosomal aneuploidies.

Use of a DNA Method, QF-PCR, in the Prenatal Diagnosis of Fetal Aneuploidies

ObjectiveTo provide Canadian health care providers with current information on the use of quantitative fluorescent polymerase chain reaction (QF-PCR) or equivalent technology in the prenatal diagnosis of fetal chromosomal abnormalities. OptionsOver the last few decades, prenatal diagnosis of fetal chromosomal abnormalities has relied on conventional cytogenetic analysis of cultured amniocytes, chorionic villi, or fetal blood. In the last few years, the clinical validity of a newer technique, QF-PCR, to detect the common aneuploidies has been reported by a number of investigators. This technique has the advantage of providing rapid results for the diagnosis or exclusion of aneuploidy in chromosomes 13, 18, 21, X or Y. It is now possible to choose standard chromosome analysis or QF-PCR for the prenatal diagnosis of chromosomal abnormalities, or to perform both tests, depending on the clinical indication for testing. This document reviews the clinical utility of QF-PCR and makes recommendations for its use in the care of Canadian patients. EvidenceMedline and PubMed were searched for articles published in English between January 2000 and December 2010 that presented data on the use of QF-PCR versus standard cytogenetic analysis of prenatal samples. A second search was done to identify publications in English that provided results of cytogenetic analysis performed on prenatal samples for women at an increased risk of fetal aneuploidy because of maternal age, abnormal prenatal screening results, or fetal soft ultrasound markers suggestive of an increased risk of aneuploidy. Publications were included if they provided detailed information on the abnormalities detected, regardless of whether or not rapid aneuploidy screening was undertaken.Results were restricted to systematic reviews, randomized controlled trials, and relevant observational studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. ValuesThe quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Benefits, harms, and costsThis guideline promotes the use of a rapid aneuploidy DNA test for women at increased risk of having a pregnancy affected by a common aneuploidy. This will have the benefit of providing rapid and accurate results to women at increased risk of fetal Down syndrome, trisomy 13, trisomy 18, sex chromosome aneuploidy or triploidy. It will also promote better use of laboratory resources and reduce the cost of prenatal diagnosis. However, a small percentage of pregnancies with a potentially clinically significant chromosomal abnormality will remain undetected by QF-PCR but detectable by conventional cytogenetics. Recommendations1. QF-PCR is a reliable method to detect trisomies and should replace conventional cytogenetic analysis whenever prenatal testing is performed solely because of an increased risk of aneuploidy in chromosomes 13, 18, 21, X or Y. As with all tests, pretest counselling should include a discussion of the benefits and limitations of the test. In the initial period of use, education for health care providers will be required. (II-2A)2. Both conventional cytogenetics and QF-PCR should be performed in all cases of prenatal diagnosis referred for a fetal ultrasound abnormality (including an increased nuchal translucency measurement > 3.5 mm) or a familial chromosomal rearrangement. (II-2A)3. Cytogenetic follow-up of QF-PCR findings of trisomy 13 and 21 is recommended to rule out inherited Robertsonian translocations. However, the decision to set up a back-up culture for all cases that would allow for traditional cytogenetic testing if indicated by additional clinical or laboratory information should be made by each centre offering the testing according to the local clinical and laboratory experience and resources. (III-A)4. Other technologies for the rapid detection of aneuploidy may replace QF-PCR if they offer a similar or improved performance for the detection of trisomy 13, 18, 21, and sex chromosome aneuploidy. (III-A)

Biomarker development for non-invasive prenatal diagnosis of fetal aneuploidies: predictive reliability and potential clinical application

Current non-invasive prenatal diagnosis for fetal aneuploidies is based on biochemical and ultrasound markers and needs to be improved in order to reduce the number of pregnant women subjected to invasive diagnostic procedures. Proteomic technologies allow for new strategies for discovering biomarkers in complex biological fluids in a high-throughput and sensitive manner. Application of advance proteomic tools to profile pathology-specific proteins in maternal plasma obtained from pregnancies with aneuploid fetuses revealed biomarker-candidates that can potentially revolutionize the diagnostic and treatment procedure in favor of better prediction and improved individual outcomes. The current review focuses on studies of maternal peripheral blood using proteomic technologies, describes alterations noted in the presence of fetal aneuploidies and discuss their potential use as biomarkers for non-invasive prenatal diagnosis.

Systematic Identification of Placental Epigenetic Signatures for the Noninvasive Prenatal Detection of Edwards Syndrome

BackgroundNoninvasive prenatal diagnosis of fetal aneuploidy by maternal plasma analysis is challenging owing to the low fractional and absolute concentrations of fetal DNA in maternal plasma. Previously, we demonstrated for the first time that fetal DNA in maternal plasma could be specifically targeted by epigenetic (DNA methylation) signatures in the placenta. By comparing one such methylated fetal epigenetic marker located on chromosome 21 with another fetal genetic marker located on a reference chromosome in maternal plasma, we could infer the relative dosage of fetal chromosome 21 and noninvasively detect fetal trisomy 21. Here we apply this epigenetic-genetic (EGG) chromosome dosage approach to detect Edwards syndrome (trisomy 18) in the fetus noninvasively.Principal FindingsWe have systematically identified methylated fetal epigenetic markers on chromosome 18 by methylated DNA immunoprecipitation (MeDIP) and tiling array analysis with confirmation using quantitative DNA methylation assays. Methylated DNA sequences from an intergenic region between the VAPA and APCDD1 genes (the VAPA-APCDD1 DNA) were detected in pre-delivery, but not post-delivery, maternal plasma samples. The concentrations correlated positively with those of an established fetal genetic marker, ZFY, in pre-delivery maternal plasma. The ratios of methylated VAPA-APCDD1(chr18) to ZFY(chrY) were higher in maternal plasma samples of 9 male trisomy 18 fetuses than those of 27 male euploid fetuses (Mann-Whitney test, P = 0.029). We defined the cutoff value for detecting trisomy 18 fetuses as mean+1.96 SD of the EGG ratios of the euploid cases. Eight of 9 trisomy 18 and 1 of 27 euploid cases showed EGG ratios higher than the cutoff value, giving a sensitivity of 88.9% and a specificity of 96.3%.ConclusionsOur data have shown that the methylated VAPA-APCDD1 DNA in maternal plasma is predominantly derived from the fetus. We have demonstrated that this novel fetal epigenetic marker in maternal plasma is useful for the noninvasive detection of fetal trisomy 18.

Prenatal diagnosis of fetal aneuploidies: post-genomic developments

Prenatal diagnosis of fetal aneuploidies and chromosomal anomalies is likely to undergo a profound change in the near future. On the one hand this is mediated by new technical developments, such as chromosomal microarrays, which allow a much more precise delineation of minute sub-microscopic chromosomal aberrancies than the classical G-band karyotype. This will be of particular interest when investigating pregnancies at risk of unexplained development delay, intellectual disability or certain forms of autism. On the other hand, great strides have been made in the non-invasive determination of fetal genetic traits, largely through the analysis of cell-free fetal nucleic acids. It is hoped that, with the assistance of cutting-edge tools such as digital PCR or next generation sequencing, the long elusive goal of non-invasive prenatal diagnosis for fetal aneuploidies can finally be attained.

Noninvasive prenatal diagnosis of fetal aneuploidies and Mendelian disorders: new innovative strategies

The application of recent technical developments, such as digital PCR or shot-gun sequencing, for the analysis of cell-free fetal DNA, have indicated that the long-sought goal of the noninvasive detection of Down syndrome may finally be attained. Although these methods are still cumbersome and not high throughput, they provide a paradigm shift in prenatal diagnosis, as they could effectively pronounce the end of invasive procedures, such as amniocentesis or chorionic villous sampling for the detection of such fetal anomalies. However, it remains to be determined how suitable these approaches are for the detection of more subtle fetal genetic alterations, such as those involved in hereditary Mendelian disorders (e.g., thalassemia and cystic fibrosis). New technical developments, such as microfluidics and reliable automated scanning microscopes, have indicated that it may be possible to efficiently retrieve and examine circulating fetal cells. As these contain the entire genomic complement of the fetus, future developments may include the noninvasive determination of the fetal karyotype.

Women’s health—what’s new worldwide

Women’s health—what’s new worldwide

Non-invasive prenatal diagnosis of fetal aneuploidies

Non-invasive prenatal diagnosis of fetal aneuploidies