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Fetal aneuploidies are among the most common causes of miscarriages, perinatal mortality and neurodevelopmental impairment. During the last 70 years, many efforts have been made in order to improve prenatal diagnosis and prenatal screening of these conditions. Recently, the use of cell-free fetal DNA (cff-DNA) testing has been increasingly used in different countries, representing an opportunity for non-invasive prenatal screening of pregnant women. The aim of this narrative review is to describe the state of the art and the main strengths and limitations of this test for prenatal screening of fetal aneuploidies.

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.

Non-invasive prenatal testing (NIPT) has the potential to screen for a wider range of genetic conditions than is currently possible at an early stage of pregnancy and with minimal risks. As such, there have been calls to apply a ‘threshold of seriousness’ to limit the scope of conditions being tested. This approach is based on concerns about society at large and the potential impact on specific groups within it. In this paper, we argue that limiting the scope of NIPT using the criterion of ‘seriousness’ is arbitrary, potentially stigmatises certain disabilities over others and fails to respect reproductive autonomy. We contend that concerns about expanded NIPT are more appropriately addressed by the provision of adequate information, counselling and consent procedures. We recommend a decision-making process that helps healthcare providers support prospective parents to make informed decisions about the nature and scope of NIPT screening based on their own values and social context. In addition to addressing concerns about expanded NIPT screening, this process would help clinicians to obtain legally valid consent and discharge their duty of care (including the duty to inform) in the prenatal context.

Evidence on the diagnostic yield of genome-wide non-invasive prenatal testing (GW-NIPT) is growing, but its comparative clinical and economic impact as a first-tier screening strategy for fetal chromosomal abnormalities remains unassessed. We compared GW-NIPT with targeted NIPT and first-trimester combined testing (FCT), in a Dutch setting where all pregnancies also undergo a routine second-trimester anomaly ultrasound scan (scan), to guide policymakers on optimal prenatal screening approaches. We developed a decision-analytic model for a cohort of 175,000 pregnancies, reflecting the Dutch obstetric population. All strategies screened for common trisomies 21 (Down syndrome), 18 (Edwards syndrome), and 13 (Patau syndrome); GW-NIPT additionally considered rare autosomal trisomies and structural aberrations. Model inputs were based on the TRIDENT-2 study data and historical FCT data. Base-case unit costs were €166 (scan), €191 (FCT), and €350 (NIPT). Sensitivity analyses were conducted to account for uncertainties in model parameters and potential country-specific variations. Outcomes included total screening costs, number of fetal chromosomal abnormalities diagnosed, number of invasive procedures, and expected procedure-related euploid fetal losses. We summarized economic results as cost per diagnosed case and incremental cost per additional diagnosis across strategies. GW-NIPT yielded the highest number of diagnoses (545) versus targeted NIPT (514) and FCT (452), and the lowest cost per diagnosed case (€152,785), compared with targeted NIPT (€159,852) and FCT (€170,050). Invasive tests required per diagnosis were lower for GW-NIPT and targeted NIPT (both 6) than for FCT (13), implying a lower risk of procedure-related miscarriage (iatrogenic miscarriage). Sensitivity analyses indicated that test uptake and unit costs strongly influenced outcomes. GW-NIPT remained the most favorable in terms of cost per diagnosis for NIPT prices up to €467. Key limitations include the use of a decision-analytic model without quality-of-life outcomes and the lack of comparisons against explicit cost-effectiveness thresholds. Therefore, the results should be interpreted as relative clinical and economic comparisons rather than cost-effectiveness judgements. Among the strategies evaluated, first-tier GW-NIPT had the greatest diagnostic yield and the lowest cost per diagnosis, improving detection rates and supporting reproductive autonomy at lower costs. Implementation decisions should also consider local pricing, laboratory capacity, and counseling resources. Future research that links screening outcomes to long-term health consequences (e.g., quality-adjusted life years or life-years), healthcare utilization, costs, and psychosocial outcomes will enable formal cost-effectiveness evaluations and support further refinement of prenatal screening policy.

Introduction Our objective was to evaluate the efficacy of expanded non‐invasive prenatal testing (NIPT) that includes both trisomies and copy number variants (CNVs) in high‐risk twin pregnancies. Material and Methods A prospective, double‐blinded cohort study was conducted, enrolling 73 high‐risk twin pregnancies characterized by increased risk of genetic disorders due to factors such as increased nuchal translucency, structural anomalies, fetal growth restriction, and other factors associated with chromosomal abnormality. Participants underwent invasive karyotyping and chromosomal microarray analysis, alongside separate expanded NIPT for research purposes. The sensitivity, specificity, positive predictive value, and negative predictive value of expanded NIPT were calculated. Results The cohort included 24 monochorionic and 49 dichorionic twin pregnancies. The median cell‐free fetal DNA concentration in expanded NIPT was 16.7% (range 3.86%–49.1%), with a test failure rate of 1.4% (1/73). High‐risk findings for trisomy 21/13/18 were identified in five cases (6.8%), Turner syndrome in one case (1.4%), and CNVs indicative of high risk for clinically significant microdeletion/microduplication syndromes (MMS) in ten cases (13.7%). Of these, 56 cases (76.7%) tested NIPT negative, revealing one false‐negative for 45, X and five false‐negatives for CNVs. Expanded NIPT achieved a detection rate of 100% (5/5) for trisomy 21/13/18 with a false‐positive rate of 0% (0/5), a detection rate of 33.3% (1/3) for sex chromosome abnormalities with a false‐positive rate of 0% (0/3), and a detection rate of 66.7% (4/6) for MMS with a false‐positive rate of 3.0% (2/67). The positive predictive values for trisomy T21/13/18, sex chromosome abnormalities, and known MMS were 100% (5/5), 100% (1/1), and 66.7% (4/6) in the expanded NIPT, respectively. Conclusions The expanded NIPT demonstrated high detection rates for common trisomies and moderate detection rates for prenatal MMS in high‐risk twin pregnancies. Further studies with large sample sizes in low‐risk populations are needed. The efficacy of expanded non‐invasive prenatal testing (NIPT) in twin pregnancies has been less clear. This study presents a relatively optimistic view: expanded NIPT demonstrates high detection rates for common trisomies and moderate DRs for prenatal microdeletion/microduplication syndromes in high‐risk twin pregnancies.

Dystrophinopathies are X-linked diseases, including Duchenne muscular dystrophy and Becker muscular dystrophy, due to DMD gene variants. In recent years, the application of new genetic technologies and the availability of new personalised drugs have influenced diagnostic genetic testing for dystrophinopathies. Therefore, these European best practice guidelines for genetic testing in dystrophinopathies have been produced to update previous guidelines published in 2010.These guidelines summarise current recommended technologies and methodologies for analysis of the DMD gene, including testing for deletions and duplications of one or more exons, small variant detection and RNA analysis. Genetic testing strategies for diagnosis, carrier testing and prenatal diagnosis (including non-invasive prenatal diagnosis) are then outlined. Guidelines for sequence variant annotation and interpretation are provided, followed by recommendations for reporting results of all categories of testing. Finally, atypical findings (such as non-contiguous deletions and dual DMD variants), implications for personalised medicine and clinical trials and incidental findings (identification of DMD gene variants in patients where a clinical diagnosis of dystrophinopathy has not been considered or suspected) are discussed.

Background Since the discovery of cell-free DNA (cfDNA) in maternal plasma, it has opened up new approaches for non-invasive prenatal testing. With the development of whole-genome sequencing, small subchromosomal deletions and duplications could be found by NIPT. This study is to review the efficacy of NIPT as a screening test for aneuploidies and CNVs in 42,910 single pregnancies. Methods A total of 42,910 single pregnancies with different clinical features were recruited. The cell-free fetal DNA was directly sequenced. Each of the chromosome aneuploidies and the subchromosomal microdeletions/microduplications of PPV were analyzed. Results A total of 534 pregnancies (1.24%) were abnormal results detected by NIPT, and 403 pregnancies had underwent prenatal diagnosis. The positive predictive value (PPV) for trisomy 21(T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies (SCAs), and other chromosome aneuploidy was 79.23%, 54.84%, 13.79%, 33.04%, and 9.38% respectively. The PPV for CNVs was 28.99%. The PPV for CNVs ≤ 5 Mb is 20.83%, for within 5–10 Mb 50.00%, for > 10 Mb 27.27% respectively. PPVs of NIPT according to pregnancies characteristics are also different. Conclusion Our data have potential significance in demonstrating the usefulness of NIPT profiling not only for common whole chromosome aneuploidies but also for CNVs. However, this newest method is still in its infancy for CNVs. There is still a need for clinical validation studies with accurate detection rates and false positive rates in clinical practice.

The invasiveness of a medical intervention is considered to be morally important and can have a significant influence on acceptability and uptake. De Marco et al propose a novel account of the invasiveness of medical interventions that better reflects the common understanding of the term. Using the example of non-invasive prenatal testing, I develop this account and argue that comparisons should only occur between medical interventions of clinically and morally significant differences.

Artificial intelligence (AI) tools like ChatGPT-4o are increasingly utilized in prenatal care. However, their reliability and clinical applicability for healthcare providers in first-trimester screening remain unclear. This study aimed to evaluate the reliability, readability, and clinical utility of ChatGPT-4o’s responses to support clinicians in counseling regarding combined first-trimester screening and non-invasive prenatal testing (NIPT). Fifteen risk-stratified clinical scenarios were used to prompt ChatGPT-4o. Fourteen perinatologists rated the responses using mDISCERN and Global Quality Scale (GQS). Readability was assessed via five indices. Inter-rater agreement and internal consistency were evaluated using ICC and Cronbach’s alpha. AI responses showed high inter-rater reliability (ICC = 0.998) and internal consistency (α = 0.975). GQS and mDISCERN scores were highest in high-risk scenarios. Readability did not significantly differ across risk levels, nor correlate with quality scores. ChatGPT-4o demonstrates potential as a clinical decision-support and counseling tool for clinicians involved in prenatal screening, particularly in high-risk scenarios. Further refinement is needed for consistent performance across risk levels.

Increasingly, high-risk pregnant women opt for non-invasive prenatal testing (NIPT) instead of invasive diagnostic testing. Since NIPT is less accurate than invasive testing, a normal NIPT result might leave women less reassured. A questionnaire study was performed among pregnant women with elevated risk for fetal aneuploidy based on first-trimester combined test (risk ≥1:200) or medical history, who were offered NIPT in the nationwide Dutch TRIDENT study. Pre- and post-test questionnaires ( n  = 682) included measures on: experiences with NIPT procedure, feelings of reassurance, anxiety (State-Trait Anxiety Inventory, STAI), child-related anxiety (PRAQ-R), and satisfaction. The majority (96.1%) were glad to have been offered NIPT. Most (68.5%) perceived the waiting time for NIPT results (mean: 15 days, range 5–32) as (much) too long. Most women with a normal NIPT result felt reassured (80.9%) or somewhat reassured (15.7%). Levels of anxiety and child-related anxiety were significantly lower after receiving a normal NIPT result as compared to the moment of intake ( p  < 0.001). Women with inadequate health literacy or a medical history (e.g. previous child with trisomy) experienced significantly higher post-test-result anxiety (Mean (M) STAI = 31.6 and 30.0, respectively) compared to those with adequate health literacy (M = 28.6) and no medical history (M = 28.6), indicating these women might benefit from extra information and/or guidance when communicating NIPT test-results. Introducing NIPT as an alternative to invasive testing, led to an offer that satisfied and largely reassured high-risk pregnant women.