Open research questions in Prenatal Screening and Diagnostics

What the literature leaves open

• Additionally, single-time- point luteal phase assessments may not capture dynamic uterine changes across the menstrual cycle, and the effects of different peristaltic directions were not explored. Although LASSO and bootstrap internal validation were applied, validation in larger, multicenter cohorts is warranted.

  Predictive value of a nomogram based on multiparameter quantitative ultrasound for pregnancy outcomes in infertile women attempting natural conception · 2026 · DOI

• Preimplantation genetic testing for aneuploidy (PGT-A) has been proposed to improve reproductive outcomes through selection of euploid embryos; however, its clinical utility in RIF remains controversial.

  Mapping the evidence and research gaps on preimplantation genetic testing for aneuploidy in recurrent implantation failure: a scoping review · 2026 · DOI

• Background Recurrent implantation failure (RIF) represents a complex and heterogeneous condition in assisted reproductive technology (ART), characterized by unclear etiology and limited evidence-based management strategies.

  Mapping the evidence and research gaps on preimplantation genetic testing for aneuploidy in recurrent implantation failure: a scoping review · 2026 · DOI

• Conclusions The evidence was insufficient that NIPS failure after first‐trimester ultrasound screening could be associated with an increased risk of common autosomal aneuploidies, SCAs, and CNVs.

  Association of a failed noninvasive prenatal screening with the risk of cytogenetic abnormalities in a general‐risk population: A retrospective cohort study · 2026 · DOI

• Due to the lack of sufficient literature on fetal PCD phenotypes, the correlation between intestinal ultrasound manifestations and fetal PCD remains to be further verified in more clinical cases.

  Fetal Kabuki syndrome caused by a novel gene variation in KMT2D with primary carnitine deficiency: a case report · 2026 · DOI

• The concept of NIPT as an unintended liquid biopsy has been previously proposed and supported by several studies [19,20], but its clinical implications remain incompletely defined.

  Incidental Detection of Diffuse Large B-cell Lymphoma by Non-invasive Prenatal Testing: A Case Report · 2026 · DOI

• The methodology underpinning the model used in this study is based on the existing SCD and thalassae- mia screening pathway in England, giving a real-world dimension to the model, and designed with consideration to other, similar, screening models, such as in the War- wick trisomy 21 (T21), T18 and T13 screening model [19]. Continuous engagement with stakeholders guided the development of the model, validating both the model inputs before the analysis was conducted, and the results once obtained, adding strength and robustness to the study conclusions. A key limitation is that where there was a lack of clini- cal data available on the use of NIPT in the SCD and tha- lassaemia screening pathway, inputs from literature and stakeholder guidance were used in their stead. Where literature inputs were used, these were informed by a pragmatic literature search, rather than through a full systematic literature review, as was instead the approach taken by the Warwick model [19]. Inputs from stakehold- ers, in particular on the failure rate of NIPT, are used with the caveat that the actual failure rate in a real-world setting would be unknown, as this would be influenced by the gestational age and body mass index (BMI) of the pregnant woman, the proficiency of the test operator, and quality of the cfDNA sample taken. A further limitation is that the economic outcomes for each pathway in the model are limited to testing costs, with no consideration of the associated downstream costs (i.e. costs associated with care following diagnosis). While it will be important to compare the downstream costs associated with SoC and NIPT, this is beyond the scope of this study, which aimed to estimate the potential impact of introducing NIPT on the performance of the National Health Service Sickle Cell and Thalassaemia Screening Programme. It is noted that there are some key assumptions used in the model which may limit the applicability of the model to real-world practice. In assuming no time dependency in the model (i.e. all screening options available to all pregnancies regardless of gestational stage), the number of women who undertake NIPT is likely to be higher in the modelled population than would likely be observed in a real-world scenario. This is because data has shown that pregnant women are less likely to accept SCD and tha- lassaemia screening as the pregnancy develops, although this change in screening uptake as the pregnancy pro- gresses may be negated by the non-invasive nature of NIPT versus the current SoC [9]. Furthermore, inputs sourced from published literature, such as the assump- tion referenced from Taylor-Phillips et al. that 90.7% of women will accept the offer of a non-invasive form of screening over an invasive method, highlight areas for future large-scale research in real-world conditions [19].

  Modelling the cost-effectiveness of non-invasive prenatal testing in the English sickle cell and thalassaemia screening pathway · 2026 · DOI

• It is noted that the implementation of a new technology into an existing screening pathway requires more than an assessment of just the efficacy of the new technology, an aspect of which it outlined as part of step 2 of the Korevaar et al. process. Other outcomes, notably the cost of the new technology, and specific to the SCD screening pathway, the number of PND diagnoses undertaken versus the standard of care are important dimensions which need to be evaluated when determining whether NIPT should be implemented. While these outcomes are not discussed in the present analysis, so as not to influence the MAC presented for NIPT in each scenario, these have been reported elsewhere, in order to provide a holistic overview of NIPT within the wider SCT screening pathway. Utilising the approach outlined in Korevaar et al. provided a robust framework to guide the present analysis. Due to the relatively novel use of cfDNA testing in a screening context, key stakeholders from the SCD screening programme and field of cfDNA research provided guidance during workshops throughout the study. One key role of these stakeholders was to validate the inputs used in the model, including any assumptions made in lieu of missing data, or to simplify the modelling process, outlined in Tables 1 and 2. Vardanega et al. Diagnostic and Prognostic Research (2026) 10:18 Page 12 of 14 Obtaining stakeholder input at various points of the project, and in particular during the first and second workshops, provides additional strength and robustness to the study approach. Guidance from stakeholders was used to identify the issue of attendance at the paternal testing stage, which may not have otherwise been identified through literature, providing a real-world context to this study, and clear applicability to the screening pathway to be evaluated in a diagnostic study. Discussions with stakeholders assisted with the main aspects to be determined when identifying the MAC, and in particular weighing the consequence of test misclassifications, and specifically about the relative importance of PPV in the screening pathway. Furthermore, validating the inputs sourced from literature and assumptions to be used in the model with stakeholders during workshop one increased confidence that they would be representative of what would be observed in clinical practice, providing further robustness to the model and outcomes. Despite the stakeholder validation, the assumptions made represent a limitation of the study.

  Minimally acceptable criteria and required sample size for an accuracy study of non-invasive prenatal testing of sickle cell disease in screen positive women in England: results of a decision tree model · 2026 · DOI

• Future work should focus on quantifying the frequency of diploid/euploid outcomes among embryos derived from atypical PN zygotes using standardized methods, defining developmental/morphokinetic features associated with dip- loidy, and establishing consensus criteria for any conditional rescue approach that ensures patient safety, ethical oversight, and clear counseling [1, 2].

  Live birth following transfer of a euploid blastocyst derived from a 5PN zygote: a case report · 2026 · DOI

• Looking Ahead: The Future of Fetal MedicineWe are standing on the brink of a revolution in prenatal genetics. The goal is shifting from simply identifying problems to actively preventing and treating them before a baby is even born. To get there, we need to make high- tech care accessible to everyone, embrace new genomic tools, and work together across borders. Why India Needs National ScreeningIndia faces a significant challenge with inherited disorders, yet many families still lack access to basic testing. We need a unified national strategy to change this. The Goal: Standardized guidelines that ensure every expectant mother—regardless of where she lives—has access to quality ultrasounds, carrier screening, and NIPT (Non-Invasive Prenatal Testing).The Impact: By catching risks early, we can significantly reduce the incidence of conditions like Thalassemia and ensure healthier outcomes for both moms and babies. True progress means ensuring a mother in a remote village gets the same quality of care as one in a major city. Making Genomics Part of Everyday CareSoon, genetic testing won’t be a "special case" scenario—it will be a standard part of pregnancy care.What’s Coming: We’ll see tools like whole-exome sequencing and AI-driven data analysis become routine. Why It Matters: Instead of waiting for symptoms to appear, doctors will use personalized risk models to predict and manage health issues with pinpoint accuracy. This moves us away from "waiting and seeing" toward precision medicine tailored to each baby’s unique DNA. Global Teamwork for Rare DiseasesBecause rare diseases are, by definition, uncommon, no single country has all the answers. Solving these puzzles requires a global "brain trust." www.wjpr.net │ Vol 15, Issue 11, 2026. │ ISO 9001: 2015 Certified Journal │ 558 Vinothini et al. World Journal of Pharmaceutical Research The Strategy: By sharing genetic databases and running international clinical trials, we can speed up the development of cutting-edge treatments like gene editing (CRISPR) and stem cell therapy. The Benefit: When developed and developing nations share their expertise and resources, breakthroughs happen faster, and life-saving tech becomes more affordable for everyone.

  FETAL GENETIC DISORDERS IN PREGNANCY: A COMPARATVE STUDY OF TREATMENT IN INDIA VS OTHER COUNTRIES · 2026 · DOI

• The minimum fetal fraction (FF) threshold at which dPCR retains diagnostic accuracy remains unknown. Further studies should address this by evaluating performance at lower FF to better define the assay's limitations and potential in early gestation or in individuals with high maternal BMI.

  Non-invasive prenatal diagnosis of beta-thalassemia disease using digital PCR · 2026 · DOI

• Since the triple or quadruple test is usually performed between 15 and 20 weeks of pregnancy, most scientific studies are based solely on results from this period of pregnancy - limited data are available for the first and third trimesters of pregnancy.

  Influence of selected factors on serum AFP levels in pregnant women in terms of prenatal screening accuracy — literature review · 2023 · DOI

• Despite the general increase in the sensitivity of prenatal screening for CA due to the combination of clinical, biochemical and ultrasound indicators, its main disadvantage is insufficient specificity (the frequency of false positive results of 5%).

  Performance capabilities of prenatal diagnosis of chromosomal anomalies: what changed with the introduction of non-invasive prenatal test (NIPT)? · 2021 · DOI

• Increased prenatal diagnoses of sex chromosome aneuploidies (SCAs) amid limited knowledge of their prognoses heighten the need to understand how families contend with the implications of an SCA.

  Delivering the Diagnosis of Sex Chromosome Aneuploidy: Experiences and Preferences of Parents and Individuals · 2018 · DOI

• To begin addressing this gap in knowledge, we organized a four-day international workshop to explore the ethical, legal, social, economic, clinical, and practical implications of the global expansion of cell-free DNA screening.

  Toward an Ethically Sensitive Implementation of Noninvasive Prenatal Screening in the Global Context · 2017 · DOI

• While its implementation has raised both challenges and opportunities, very little is known about real-world experiences and the implications of the rapid introduction of cell-free DNA screening outside of North America and Europe, especially in low- and middle-income countries.

  Toward an Ethically Sensitive Implementation of Noninvasive Prenatal Screening in the Global Context · 2017 · DOI

• Although the prenatal diagnosis of SLOS presents a challenge due to the fact that little is known about its prenatal phenotype but it may be vital while attempting to treat the fetus in utero.

  Smith-Lemli-Opitz Syndrome- a challenging prenatal diagnosis · 2016 · DOI

• Chromosomal numerical aberrations (aneuploidies) remain to be the most frequent genetic changes diagnosed prenatally Therefore, our paper presents the latest methods used mainly in prenatal diagnosis of the most common chromosome numerical changes, as well as other methods applicable in detecting chromosome structural changes or gene mutations.

  New molecular methods in prenatal invasive diagnostics · 2013 · DOI

• WHAT IS KNOWN ALREADY: The effectiveness of chromosome aneuploidy screening is limited by the technologies available and chromosome mosaicism in the embryo.

  FISH reanalysis of inner cell mass and trophectoderm samples of previously array-CGH screened blastocysts shows high accuracy of diagnosis and no major diagnostic impact of mosaicism at the blastocyst stage · 2013 · DOI

• WIDER IMPLICATIONS OF THE FINDINGS: Finding such a high rate of aneuploidy and mosaicism in excellent quality embryos from cycles with a high implantation rate warrants further research on the origin and significance of chromosomal abnormalities in human preimplantation embryos.

  Microarray analysis reveals abnormal chromosomal complements in over 70% of 14 normally developing human embryos · 2012 · DOI

• BACKGROUND: Recent studies have suggested that biopsy of several trophectoderm (TE) cells from blastocysts followed by comparative genomic hybridization (CGH) analysis might represent an optimal strategy for aneuploidy detection, but few data on accuracy are available.

  Cytogenetic analysis of human blastocysts with the use of FISH, CGH and aCGH: scientific data and technical evaluation · 2010 · DOI

• If we are correct in assuming that mitotic non-disjunction is common by the stage of the blastocyst (and that it is much less ominous than meiotic non-disjunction), then further studies of effective PGS of blastocysts for aneuploidy require methods of analysis that cover all the chromosomes and can differentiate the triallelic and monoallelic states of meiotically derived aneuploidies from the biallelic state of mitotic aneuploidies.

  What next for preimplantation genetic screening (PGS)? Experience with blastocyst biopsy and testing for aneuploidy · 2008 · DOI

• However, the pathogenic genes responsible for KS remain unknown in approximately 30% of patients.

  Fetal Kabuki syndrome caused by a novel gene variation in KMT2D with primary carnitine deficiency: a case report · 2026 · DOI

• 2 microduplication in the patient, while, little is known about the relationship between 16p11. 2 microduplication syndrome, but more functional evidence and additional clinical studies are warranted.

  Genetic evaluation and pregnancy outcome of fetuses with digestive system malformations: an eight-year single-center retrospective study · 2026 · DOI

• Access to post-mortem genetic testing is limited by a lack of specialized fetal pathology services, trained personnel, and coordination between obstetrics, pathology, and genetics teams, leading to missed sampling opportunities.

  Post-Mortem Genetic Testing in Fetal Loss: Challenges and Strategies to Maximizing Diagnostic Value From Devitalized Tissues · 2026 · DOI

Most-cited papers in Prenatal Screening and Diagnostics

• Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage · Human Reproduction · 2006 · 405 citations
• ESHRE PGD Consortium ‘Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)’ · Human Reproduction · 2004 · 374 citations
• A multicenter, prospective, blinded, nonselection study evaluating the predictive value of an aneuploid diagnosis using a targeted next-generation sequencing–based preimplantation genetic testing for aneuploidy assay and impact of biopsy · Fertility and Sterility · 2020 · 252 citations
• Cytogenetic analysis of human blastocysts with the use of FISH, CGH and aCGH: scientific data and technical evaluation · Human Reproduction · 2010 · 242 citations
• Current use of noninvasive prenatal testing in Europe, Australia and the USA: A graphical presentation · Acta Obstetricia Et Gynecologica Scandinavica · 2020 · 200 citations
• Using outcome data from one thousand mosaic embryo transfers to formulate an embryo ranking system for clinical use · Fertility and Sterility · 2021 · 186 citations
• Abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage · Human Reproduction · 2012 · 178 citations
• Sequential comprehensive chromosome analysis on polar bodies, blastomeres and trophoblast: insights into female meiotic errors and chromosomal segregation in the preimplantation window of embryo development · Human Reproduction · 2012 · 178 citations
• Microarray analysis reveals abnormal chromosomal complements in over 70% of 14 normally developing human embryos · Human Reproduction · 2012 · 176 citations
• FISH reanalysis of inner cell mass and trophectoderm samples of previously array-CGH screened blastocysts shows high accuracy of diagnosis and no major diagnostic impact of mosaicism at the blastocyst stage · Human Reproduction · 2013 · 165 citations

Most recent work

• Prenatal Diagnosis and Novel Therapeutics in Treatment of Genetic Conditions: Challenges and Opportunities · Clinical Therapeutics · 2026
• Modelling the cost-effectiveness of non-invasive prenatal testing in the English sickle cell and thalassaemia screening pathway · Diagnostic and Prognostic Research · 2026
• Non-invasive prenatal diagnosis of beta-thalassemia disease using digital PCR · Frontiers in Medicine · 2026
• Cell-free DNA Screening and Maternal Cancer · New England Journal of Medicine · 2026
• A rare case of multiple congenital anomalies in a neonate: Diagnostic challenges in establishing live birth and the role of comprehensive fetal autopsy · Journal of Forensic and Legal Medicine · 2026
• Is a Fetus a Living Entity? Reframing the Question of Its Right to Survive in Contemporary Maternal–Fetal Medicine · Maternal-Fetal Medicine · 2026
• Implementation of third-generation digital PCR for non-invasive prenatal diagnosis of sickle cell disease and early detection. Pilot study · Frontiers in Medicine · 2026
• Moving beyond good intentions: a qualitative study exploring healthcare professionals’ perspectives on delivering equitable prenatal testing in the English NHS · International Journal for Equity in Health · 2026
• Recurrent Hodgkin’s Lymphoma Detected Using Abnormal NIPT in Pregnancy: A Case Report and Literature Review · Diagnostics · 2026
• Incidental Detection of Diffuse Large B-cell Lymphoma by Non-invasive Prenatal Testing: A Case Report · Cureus · 2026

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