BACKGROUND:Confined placental mosaicism can cause false-positive prenatal cell-free DNA (cfDNA) screening results, thereby reducing the positive predictive value (PPV) of the test. We sought to investigate how PPVs for the common fetal trisomies can be refined based on the presence or absence of chromosomal mosaicism in cfDNA sequencing data. METHODS:The study cohort included singleton pregnancies tested between March 2019 and December 2021. Outcome data were requested for high-risk results. Mosaic ratio (MR) generated by VeriSeq NIPT Solution v2 was used to classify high-risk cfDNA results as mosaic trisomy (MR < 0.7) or non-mosaic trisomy (MR ≥ 0.7) and the PPVs calculated. RESULTS:The cohort consisted of 821 high-risk results from 76 329 tests (1.08%). Prior to applying MR, PPVs for T21, T18 and T13 were 93.3% [95% CI 90.2-95.5], 81% [95% CI 73.1-87.0], and 55.3% [95% CI 44.7-65.4], respectively. After applying MR, PPVs for non-mosaic trisomy results were significantly higher (P < 0.001) than the PPVs for mosaic trisomy results; T21: 99.3% and 50%, T18: 97.6% and 22.7%, T13: 93.9% and 0%, respectively. CONCLUSIONS:Mosaic ratio can be used to calculate more specific PPVs for the common trisomies. There is currently limited guidance on the application of VeriSeq v2 MR. Our approach provides a framework for laboratories to consider using MRs to refine PPV estimates for the common trisomies. High-risk cfDNA screening results are distressing for tested individuals. A refined PPV incorporating the presence or absence of mosaicism provides patients with more accurate information on the likely outcome of the diagnostic testing result, helping guide genetic counseling, choice of prenatal procedure, and overall pregnancy management.

OBJECTIVE:To explore the experiences of people having cfDNA screening to detect unbalanced translocations, and to understand motivations for choosing this option. METHODS:We used a qualitative approach with in-depth semi-structured interviews with reciprocal translocation carriers and their partners. People who underwent cfDNA screening with translocation analysis through Victorian Clinical Genetics Services between 2015 and 2019 were invited to take part. Purposive sampling based on the participant's geographic location, requesting practitioner specialty and cfDNA screening result was used to capture a range of experiences. Interview transcripts were analysed using thematic analysis. RESULTS:Participants (n = 13) had complex reproductive journeys associated with the translocation and opted for cfDNA screening rather than prenatal diagnosis to avoid risk to their pregnancy. Participants benefited from having a result early in pregnancy and had sufficient confidence in the result to decline a diagnostic testing procedure. CONCLUSION:Participants' experiences with cfDNA screening were intertwined with the experience of being a carrier of a reciprocal translocation. cfDNA screening with translocation analysis was perceived as an acceptable alternative to prenatal diagnosis and should be made more accessible to balanced translocation carriers. Access to specialist genetic counselling services is needed to ensure couples are provided with information about all prenatal testing options, including the benefits and limitations associated with cfDNA screening with translocation analysis.

Abstract Background Non-invasive prenatal testing (NIPT) has been clinically available in Australia on a user-pays basis since 2012. There are numerous providers, with available tests ranging from targeted NIPT (only trisomies 21, 18, and 13 +/- sex chromosome aneuploidy) to genome-wide NIPT. While NIPT is being implemented in the public health care systems of other countries, in Australia, the implementation of NIPT has proceeded without public funding. The aim of this study was to investigate how NIPT has been integrated into antenatal care across Australia and reveal the successes and challenges in its implementation in this context. Methods An anonymous online survey was conducted from September to October 2022. Invitations to participate were sent to healthcare professionals (HCPs) involved in the provision of NIPT in Australia through professional society mailing lists and networks. Participants were asked questions on their knowledge of NIPT, delivery of NIPT, and post-test management of results. Results A total of 475 HCPs responded, comprising 232 (48.8%) obstetricians, 167 (35.2%) general practitioners, 32 (6.7%) midwives, and 44 (9.3%) genetic specialists. NIPT was most commonly offered as a first-tier test, with most HCPs (n = 279; 60.3%) offering it to patients as a choice between NIPT and combined first-trimester screening. Fifty-three percent (n = 245) of respondents always offered patients a choice between NIPT for the common autosomal trisomies and expanded (including genome-wide) NIPT. This choice was understood as supporting patient autonomy and informed consent. Cost was seen as a major barrier to access to NIPT, for both targeted and expanded tests. Equitable access, increasing time demands on HCPs, and staying up to date with advances were frequently reported as major challenges in delivering NIPT. Conclusions Our findings demonstrate substantial variation in the clinical implementation of NIPT in Australia, including in the offers of expanded screening options. After a decade of clinical use, Australian clinicians still report ongoing challenges in the clinical and equitable provision of NIPT.

Guidelines discussed in article

Key points What is already known about this topic? In 2015, the International Society for Prenatal Diagnosis (ISPD) published its first position statement on the use of non‐invasive prenatal testing (NIPT) to screen for aneuploidy. Widespread uptake across the globe and subsequent published research has shed new light on test performance and implementation issues. What does this study add? This new position statement replaces the 2015 statement with updated information on the current technologies, clinical experience, and implementation practices. As an international organization, ISPD recognizes that there are important population‐specific considerations in the organization of prenatal screening and diagnosis. These opinions are designed to apply to high income settings where prenatal screening for aneuploidy is an established part of antenatal care. This position statement is not a clinical practice guideline but represents the consensus opinion of the current ISPD Board based on the current state of knowledge and clinical practice.

OBJECTIVES:To evaluate the performance of cell-free DNA (cfDNA) screening for common fetal aneuploidies, choice of prenatal procedure, and chromosome conditions identified during pregnancy after low-risk cfDNA screening. METHOD:A single-center prenatal cfDNA screening test was employed to detect trisomies 21, 18, and 13 (T21, T18, T13) and sex chromosome aneuploidies (SCAs). Test performance, choice of prenatal procedure, and cytogenetic results in pregnancies with low-risk cfDNA screening were reviewed. RESULTS:CfDNA screening of 38,289 consecutive samples identified 720 (1.9%) pregnancies at increased risk for aneuploidy. Positive predictive values (PPVs) for high-risk singleton pregnancies were 98.5% (T21), 92.5% (T18) and 55.2% (T13). PPVs for SCAs ranged from 30.6% to 95.2%. Most women elected chorionic villus sampling for prenatal diagnosis of T21, T18 and T13; amniocentesis and/or postnatal testing were commonly chosen for SCAs. Cytogenetic tests from 616 screen-negative pregnancies identified 64 cases (12.7%) with chromosome conditions not detected by cfDNA screening, including triploidy (n = 30) and pathogenic and likely pathogenic copy number variants (n = 34). A further 15 (0.04%) false-negative common aneuploidy results were identified. CONCLUSIONS:CfDNA screening was highly accurate for detecting fetal aneuploidy in this general-risk obstetric population. Fetal ultrasound and prenatal diagnostic testing were important in identifying chromosome conditions in pregnancies screened as low-risk.

Reciprocal translocation carriers are often diagnosed when they are experiencing difficulties conceiving or after a pregnancy affected by an unbalanced set of chromosomes inherited from the balanced carrier parent. Having a reciprocal translocation is not uncommon; carriers can benefit from reproductive options to achieve a healthy, chromosomally balanced, pregnancy. The aim of this study was to explore the lived experience of carriers and their partners. We conducted 13 semi-structured telephone interviews. Participants were recruited through Victorian Clinical Genetics Services and interviews took place between May and September 2020. Interview transcripts were analyzed using thematic analysis. Reciprocal translocation carriers and their partners described long term emotional and reproductive impacts, with carrier status identified at the time of prenatal diagnosis having marked emotional consequences. Couples facing reproductive challenges found the diagnosis created uncertainty for their future. When considering a pregnancy, couples worried about experiencing a miscarriage; during pregnancy, there was a reluctance to have an invasive diagnostic procedure due to fearing the risk of losing an unaffected pregnancy. Adaptation to their new reality involved having access to accurate information, peer support and maintaining hope. Couples valued having the option to know the carrier status of their children. The complex impacts of carrying a reciprocal translocation highlight the importance of access to specialist genetic counseling services to ensure couples are supported in understanding the implications of their translocation

Prenatal screening for sex chromosome aneuploidies (SCAs) is increasingly available through expanded non-invasive prenatal testing (NIPT). NIPT for SCAs raises complex ethical issues for clinical providers, prospective parents and future children. This paper discusses the ethical issues that arise around NIPT for SCAs and current guidelines and protocols for management. The first section outlines current practice and the limitations of NIPT for SCAs. It then outlines key guidelines before discussing the ethical issues raised by this use of NIPT. We conclude that while screening for SCAs should be made available for people seeking to use NIPT, its implementation requires careful consideration of what, when and how information is provided to users.

BACKGROUND: The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recently recommended offering genetic counseling and diagnostic testing for enlarged nuchal translucency at >= 3.0 mm, regardless of previous negative screening with noninvasive prenatal testing. OBJECTIVE: This study aimed to perform a population-based, individual record linkage study to determine the optimal definition of an enlarged nuchal translucency for the detection of atypical chromosome abnormalities. STUDY DESIGN: This was a retrospective study of women resident in Victoria, Australia, undergoing combined first-trimester screening during the 24-month period from January 2015 to December 2016. Linkages between statewide results for combined first-trimester screening, prenatal diagnostic procedures, and postnatal cytogenetic results from products of conception and infants up to 12 months of age were used to ascertain the frequency and type of chromosome abnormality by gestation and nuchal translucency measurement. An atypical chromosome abnormality was defined as any major chromosome abnormality other than whole chromosome aneuploidy involving chromosomes 21, 18, 13, X, and Y. RESULTS: Of the 81,244 singleton pregnancies undergoing combined first-trimester screening, 491 (0.60%) had a nuchal translucency of >= 3.5 mm, 534 (0.66%) had a nuchal translucency of 3.0 to 3.4 mm, and 80,219 (98.74%) had a nuchal translucency of < 3.0 mm. When grouped by nuchal translucency multiples of the median (MoM), 192 (0.24%) had a nuchal translucency of >= 3.0 MoM, 513 (0.63%) had a nuchal translucency of 1.9 to 2.9 MoM, and 80,539 (99.13%) had a nuchal translucency of <1.9 MoM. A total of 1779 pregnancies underwent prenatal or postnatal diagnostic testing, of which 89.60% were performed by whole-genome single-nucleotide polymorphism chromosomal microarray. The frequency of total major chromosome abnormalities was significantly higher in the group with a nuchal translucency of >= 3.5 mm (147 of 491, 29.94%) than the group with a nuchal translucency of 3.0 to 3.4 mm(21 of 534, 3.93%) or a nuchal translucency of<3.0 mm (71 of 80,219, 0.09%) (P<.001). There were 93 atypical chromosome abnormalities in the total screened cohort. The frequency of an atypical chromosome abnormality was 4.07% (95% confidence interval, 2.51-6.22), 0.37% (95% confidence interval, 0.05-1.35), and 0.09% (95% confidence interval, 0.07-0.11) in the groups with a nuchal translucency of >= 3.5 mm, 3.0 to 3.4 mm, and <3.0 mm, respectively. The frequency of atypical chromosome abnormalities was 4.69% (95% confidence interval, 2.17-8.71), 2.53% (95% confidence interval, 1.36-4.29), and 0.09% (95% confidence interval, 0.07-0.11) in the groups with a nuchal translucency of >= 3.0 MoM, 1.9 to 2.9 MoM, and<1.9 MoM, respectively. When defining thresholds for offering diagnosis with chromosomal microarray at 11 to 13 weeks, both a nuchal translucency threshold of 1.9 MoM and a fixed threshold of 3.0 mm captured 22 of 93 fetuses (23.7%) with an atypical chromosome abnormality. Of these, 50.0% had a coexisting fetal abnormality on ultrasound. However, the gestation-specific threshold of 1.9 MoM had a better specificity than 3.0 mm. The positive predictive value of an enlarged nuchal translucency for any atypical chromosome abnormality was 1 in 47 for nuchal translucency of>3.0 mm and 1 in 32 for nuchal translucency of >1.9 MoM. Our nuchal translucency threshold of 1.9 MoM captured 0.87% of fetuses, thus approximating the 99th centile. CONCLUSION: A gestational age-adjusted nuchal translucency threshold of 1.9 MoM or 99th centile is superior to the fixed cutoff of 3.0 mm for the identification of atypical chromosome abnormalities. The risk of an atypical chromosome abnormality in a fetus with an enlarged nuchal translucency is more than tripled in the presence of an additional ultrasound abnormality.

Noninvasive prenatal testing (NIPT) is a screening test for fetal chromosomal aneuploidy using cell-free DNA derived from maternal blood. It has been rapidly accepted into obstetric practice because of its application from 10-weeks' gestation, and its high sensitivity and specificity. NIPT results can be influenced by several factors including placental or maternal mosaicism and co-twin demise; cell-free DNA from a maternal origin can also complicate interpretation, with evidence that NIPT can detect previously unsuspected malignancies. This study aimed to develop management guidelines for women with NIPT results suspicious of maternal malignancy. The Peter MacCallum Cancer Center's experience of seven cases where abnormal NIPT results led to investigation for maternal malignancy between 2016 and 2019 were reviewed, along with the published literature. Six of the seven women (86%) referred for investigation were diagnosed with advanced malignancies, including colorectal cancer, breast cancer, melanoma, and Hodgkin lymphoma. Based on our single-center experience, as well as the available literature, guidelines for the investigation of women with NIPT results suspicious of malignancy are proposed, including utilization of fluorodeoxyglucose positron emission tomography-computed tomography, which had a high concordance with other investigations and diagnoses. These guidelines include maternal and fetal investigations, as well as consideration of the complex medical, psychologic, social, and ethical needs of these patients and their families.

BACKGROUND Noninvasive prenatal tests (NIPTs) detect fetal chromosomal anomalies with high clinical sensitivity and specificity. We examined the performance of a paired-end sequencing-based NIPT in the detection of genome-wide fetal chromosomal anomalies including common trisomies, sex chromosomal aneuploidies (SCA), rare autosomal aneuploidies (RAAs), and partial deletions/duplications ≥7 Mb. METHODS Frozen plasma samples from pregnant women were tested using the VeriSeq NIPT Solution v2 assay. All samples were previously tested with a laboratory-developed NIPT and had known clinical outcomes. Individuals performing the sequencing were blinded to clinical outcome data. Clinical sensitivity and specificity were determined for basic (chromosomes 21, 18, 13, X, and Y) and genome-wide screening modes. RESULTS Of 2335 samples that underwent genome-wide analysis, 28 did not meet QC requirements, resulting in a first-pass assay failure rate of 1.2%. Basic screening analysis, excluding known mosaics, correctly classified 130/130 trisomy 21 samples (sensitivity >99.9%, 95% confidence interval [CI] 97.1%-100%), 41/41 trisomy 18 samples (sensitivity >99.9%, 95% CI 91.4%-100%), and 26/26 trisomy 13 samples (sensitivity >99.9%, 95% CI 87.1%-100%) with 6 false-positive results; specificities ≥99.90% were reported for all 3 trisomies. Concordance for SCAs ranged from 90.5%-100%. Genome-wide screening analysis including known mosaics correctly classified 27/28 RAAs and 20/27 partial deletions/duplications with a specificity of 99.80% for both anomalies, and an overall genome-wide specificity for all anomalies of 99.34%. CONCLUSIONS The VeriSeq NIPT Solution v2 assay enables accurate identification of fetal aneuploidy, allowing detection of genome-wide fetal chromosomal anomalies with high clinical sensitivities and specificities and a low assay failure rate.Clinical Trial Notification [CTN] identification number [ID]: CT-2018-CTN-01585-1 v1, Protocol: NIPT T05 002.

Purpose Balanced reciprocal translocation carriers are at increased risk of producing gametes with unbalanced forms of the translocation leading to miscarriage, fetal anomalies, and birth defects. We sought to determine if genome-wide cell-free DNA based noninvasive prenatal screening (gw-NIPS) could provide an alternative to prenatal diagnosis for carriers of these chromosomal rearrangements. Methods This pilot series comprises a retrospective analysis of gw-NIPS and clinical outcome data from 42 singleton pregnancies where one parent carried a balanced reciprocal translocation. Gw-NIPS was performed between August 2015 and March 2018. Inclusion criteria required at least one translocation segment to be ≥15 Mb in size. Results Forty samples (95%) returned an informative result; 7 pregnancies (17.5%) were high risk for an unbalanced translocation and confirmed after diagnostic testing. The remaining 33 informative samples were low risk and confirmed after diagnostic testing or normal newborn physical exam. Test sensitivity of 100% (95% confidence interval [CI]: 64.6–100%) and specificity of 100% (95% CI: 89.6–100%) were observed for this pilot series. Conclusion We demonstrate that gw-NIPS is a potential option for a majority of reciprocal translocation carriers. Further confirmation of this methodology could lead to adoption of this noninvasive alternative.

Abstract Circulating cell-free DNA (cfDNA) is rapidly transitioning from discovery research to an important tool in clinical decision making. However, the lack of harmonization of preanalytic practices across institutions may compromise the reproducibility of cfDNA-derived data and hamper advancements in cfDNA testing in the clinic. Differences in cellular genomic contamination, cfDNA yield, integrity, and fragment length have been attributed to different collection tube types and anticoagulants, processing delays and temperatures, tube agitation, centrifugation protocols and speeds, plasma storage duration and temperature, the number of freeze-thaw events, and cfDNA extraction and quantification methods, all of which can also ultimately impact subsequent downstream analysis. Thus, there is a pressing need for widely applicable standards tailored for cfDNA analysis that include all preanalytic steps from blood draw to analysis. The NCI's Biorepositories and Biospecimen Research Branch has developed cfDNA-specific guidelines that are based upon published evidence and have been vetted by a panel of internationally recognized experts in the field. The guidelines include optimal procedures as well as acceptable alternatives to facilitate the generation of evidence-based protocols by individual laboratories and institutions. The aim of the document, which is entitled “Biospecimen Evidence-based Best Practices for Cell-free DNA: Biospecimen Collection and Processing,” is to improve the accuracy of cfDNA analysis in both basic research and the clinic by improving and harmonizing practices across institutions.

STUDY QUESTION What is the frequency of major chromosome abnormalities in a population-based diagnostic data set of genomic tests performed on miscarriage, fetal and infant samples in a state with >73 000 annual births? SUMMARY ANSWER The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826), with a significant decrease in the detection of major chromosome abnormalities with later developmental stage, from 50.9% to 21.3% to 15.6% of tests in the miscarriage, prenatal and postnatal cohorts, respectively. WHAT IS KNOWN ALREADY Over the past decade, technological advances have revolutionized genomic testing at every stage of reproduction. Chromosomal microarrays (CMAs) are now the gold standard of chromosome assessment in prenatal diagnosis and pediatrics. STUDY DESIGN, SIZE, DURATION A population-based cohort study including all chromosome analysis was performed in the Australian state of Victoria during a 24-month period from January 2015 to December 2016. All samples obtained via invasive prenatal diagnosis and postnatal samples from pregnancy tissue and infants ≤12 months of age were included. PARTICIPANTS/MATERIALS, SETTING, METHODS A research collaboration of screening and diagnostic units in the Australian state of Victoria was formed (the Perinatal Record Linkage collaboration), capturing all instances of prenatal and postnatal chromosome testing performed in the state. Victoria has over 73 000 births per annum and a median maternal age of 31.5 years. We analyzed our population-based diagnostic data set for (i) chromosome assessment of miscarriage, prenatal diagnosis and postnatal samples; (ii) testing indications and diagnostic yields for each of these cohorts; (iii) and the combined prenatal/infant prevalence of 22q11.2 deletion syndrome (DS) as a proportion of all births ≥20 weeks gestation. MAIN RESULTS AND THE ROLE OF CHANCE During the 24-month study period, a total of 8826 chromosomal analyses were performed on prenatal and postnatal specimens in Victoria. The vast majority (91.2%) of all chromosome analyses were performed with CMA.The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826). There was a significant decreasing trend in the percentage of chromosome abnormalities with later developmental stage from 50.9% to 21.3% to 15.6% in the miscarriage, prenatal and postnatal cohorts, respectively (χ2 trend = 790.0, P < 0.0001). The total frequency of abnormalities in the live infant subgroup was 13.4% (244/1816). The frequencies of pathogenic copy number variants (CNVs) detected via CMA for the miscarriage, prenatal and postnatal cohorts were 1.9% (50/2573), 2.2% (82/3661) and 4.9% (127/2592), respectively. There was a significant increasing trend in the frequency of pathogenic CNVs with later developmental stage (χ2 trend = 39.72, P < 0.0001). For the subgroup of live infants, the pathogenic CNV frequency on CMA analysis was 6.0% (109/1816). There were 38 diagnoses of 22q11.2 DS, including 1 miscarriage, 15 prenatal and 22 postnatal cases. After excluding the miscarriage case and accounting for duplicate testing, the estimated prevalence of 22q11 DS was 1 in 4558 Victorian births. LIMITATIONS, REASONS FOR CAUTION Clinical information was missing on 11.6% of postnatal samples, and gestational age was rarely provided on the miscarriage specimens. We were unable to obtain rates of termination of pregnancy and stillbirth in our cohort due to incomplete data provided by clinical referrers. We therefore cannot make conclusions on pregnancy or infant outcome following diagnostic testing. Childhood and adult diagnoses of 22q11 DS were not collected. WIDER IMPLICATIONS OF THE FINDINGS Our study marks a complete transition in genomic testing from the G-banded karyotype era, with CMA now established as the first line investigation for pregnancy losses, fetal diagnosis and newborn/infant assessment in a high-income setting. Integration of prenatal and postnatal diagnostic data sets provides important opportunities for estimating the prevalence of clinically important congenital syndromes, such as 22q11 DS. STUDY FUNDING/COMPETING INTEREST(S) L.H. is funded by a National Health and Medical Research Council Early Career Fellowship (1105603); A.L. was funded by a Mercy Perinatal Research Fellowship; J.H. was funded by a National Health and Medical Research Council Senior Research Fellowship (10121252). The funding bodies had no role in the conduct of the research or the manuscript. Discretionary funding from the Murdoch Children's Research Institute has supported the prenatal diagnosis data collection and reporting over the years.Dr Ricardo Palma-Dias reports a commercial relationship with Roche Diagnostics, personal fees from Philips Ultrasound, outside the submitted work. Debbie Nisbet reports a commercial relationship with Roche Diagnostics, outside the submitted work. TRIAL REGISTRATION NUMBER NA.

Cell free DNA (cfDNA) based non-invasive prenatal testing (NIPT) has revolutionised prenatal care. CfDNA NIPT assays are often NGS based, but also include microarray and single nucleotide polymorphism (SNP) based methods. The NGS based methods can be targeted capturing chromosomes 21, 18, 13, X and Y only, or genome wide. NGS based genome wide NIPT was utilised to analyse chromosomal aneuploidy for a 40-year-old woman who presented to Victorian Clinical Genetics Services for prenatal screening due to advanced maternal age. NIPT results identified a female fetus with an increased risk for trisomy 14. Amniocentesis was recommended following normal fetal ultrasound. SNP molecular karyotype analysis confirmed a genotyping profile consistent with mosaic trisomy 14. Genotype evidence for a cell line with uniparental disomy (UPD) 14 was also observed, and a maternal origin was subsequently determined (UPD14mat; Temple syndrome). A conventional G-banding karyotype on cultured amniotic fluid cells also demonstrated true fetal mosaicism for trisomy 14. The combination of UPD(14)mat and mosaic trisomy 14 is rare with approximately 8 live-born cases reported. This case study demonstrates the additional clinical utility of using an NGS based genome wide NIPT assay and represents the first report of UDP(14) ascertained using NIPT.

Department of Pathology and Laboratory Medicine, Women & Infants Hospital and the Alpert Medical School at Brown University, Providence, Rhode Island Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China Victorian Clinical Genetics Services (VCGS), Murdoch Children's Research Institute, Melbourne, Victoria, Australia Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands Prenatal Genetic Diagnosis Unit, Genetic Institute, Tel Aviv Medical Center, Faculty of Medicine Tel Aviv University, Tel Aviv, Israel Department of Human Genetics, KU Leuven, Leuven, Belgium Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina University of South Carolina SOM Greenville, Greenville, South Carolina Division of Maternal Fetal Medicine and Reproductive Genetics, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts

Occult maternal malignancies presenting with copy-number gains and losses across multiple chromosomes at NIPT have been reported.1,2 We present a 37-year-old pregnant woman with a history of breast cancer, diagnosed 15 years prior. NIPT was performed at 15/40. Genome-wide analysis of cell-free DNA from consecutive samples showed multiple copy-number gains (1q, 7, 8q and 20) and losses (3q and 12). Localised amplification within chromosome region 17q12 (containing ERBB2) was noted. The copy-number changes were considered likely to be maternal in origin and acquired. The patient had no clinical symptoms and further investigations failed to identify a malignancy. Microarray analysis of amniotic fluid confirmed a normal fetal karyotype. The pregnancy continued and a healthy baby was delivered by caesarean at full term. Repeat NIPT collected 7 weeks post-delivery demonstrated a decrease in the intensity of the copy-number changes observed during pregnancy, however amplification of 17q12 was still noted. PET-CT and subsequent MRI demonstrated an anterior mediastinal mass which was resected and diagnosed as HER2 positive metastatic breast cancer in two lymph nodes. While pre-symptomatic primary malignancies detected at NIPT have been described, this is the first report of a pre-symptomatic re-occurrence of a previous malignancy detected by an aberrant NIPT result. References1.Bianchi DW, Chudova D, Sehnert AJ, et al. Noninvasive prenatal testing and incidental detection of occult maternal malignancies. JAMA 2015; 314: 162–9.2.Amant F, Verheecke M, Wlodarska I, et al. Presymptomatic identification of cancers in pregnant women during noninvasive prenatal testing. JAMA Oncol 2015; 1: 814–9.