The incremental yield of prenatal exome sequencing over chromosome microarray for congenital heart abnormalities: A systematic review and meta-analysis.

OBJECTIVES: To determine the incremental yield of prenatal exome sequencing (PES) over standard testing in fetuses with an isolated congenital heart abnormality (CHA), CHA associated with extra-cardiac malformations (ECMs) and CHA dependent upon anatomical subclassification. METHODS: A systematic review of the literature was performed using MEDLINE, EMBASE, Web of Science and grey literature January 2010-February 2023. Studies were selected if they included greater than 20 cases of prenatally diagnosed CHA when standard testing (QF-PCR/chromosome microarray/karyotype) was negative. Pooled incremental yield was determined. PROSPERO CRD 42022364747. RESULTS: Overall, 21 studies, incorporating 1957 cases were included. The incremental yield of PES (causative pathogenic and likely pathogenic variants) over standard testing was 17.4% (95% CI, 13.5%-21.6%), 9.3% (95% CI, 6.6%-12.3%) and 35.9% (95% CI, 21.0%-52.3%) for all CHAs, isolated CHAs and CHAs associated with ECMs. The subgroup with the greatest yield was complex lesions/heterotaxy; 35.2% (95% CI 9.7%-65.3%). The most common syndrome was Kabuki syndrome (31/256, 12.1%) and most pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease causing genes (114/224, 50.9%). CONCLUSION: The likelihood of a monogenic aetiology in fetuses with multi-system CHAs is high. Clinicians must consider the clinical utility of offering PES in selected isolated cardiac lesions.

Fetal exome sequencing for isolated increased nuchal translucency: should we be doing it?

OBJECTIVE: To evaluate the utility of prenatal exome sequencing (ES) for isolated increased nuchal translucency (NT) and to investigate factors that increase diagnostic yield. DESIGN: Retrospective analysis of data from two prospective cohort studies. SETTING: Fetal medicine centres in the UK and USA. POPULATION: Fetuses with increased NT ≥3.5 mm at 11-14 weeks of gestation recruited to the Prenatal Assessment of Genomes and Exomes (PAGE) and Columbia fetal whole exome sequencing studies (n = 213). METHODS: We grouped cases based on (1) the presence of additional structural abnormalities at presentation in the first trimester or later in pregnancy, and (2) NT measurement at presentation. We compared diagnostic rates between groups using Fisher exact test. MAIN OUTCOME MEASURES: Detection of diagnostic genetic variants considered to have caused the observed fetal structural anomaly. RESULTS: Diagnostic variants were detected in 12 (22.2%) of 54 fetuses presenting with non-isolated increased NT, 12 (32.4%) of 37 fetuses with isolated increased NT in the first trimester and additional abnormalities later in pregnancy, and 2 (1.8%) of 111 fetuses with isolated increased NT in the first trimester and no other abnormalities on subsequent scans. Diagnostic rate also increased with increasing size of NT. CONCLUSIONS: The diagnostic yield of prenatal ES is low for fetuses with isolated increased NT but significantly higher where there are additional structural anomalies. Prenatal ES may not be appropriate for truly isolated increased NT but timely, careful ultrasound scanning to identify other anomalies emerging later can direct testing to focus where there is a higher likelihood of diagnosis.

Fetal hydrops and the Incremental yield of Next-generation sequencing over standard prenatal Diagnostic testing (FIND) study: prospective cohort study and meta-analysis.

OBJECTIVE: To determine the incremental yield of exome sequencing (ES) over chromosomal microarray analysis (CMA) or karyotyping in prenatally diagnosed non-immune hydrops fetalis (NIHF). METHODS: A prospective cohort study (comprising an extended group of the Prenatal Assessment of Genomes and Exomes (PAGE) study) was performed which included 28 cases of prenatally diagnosed NIHF undergoing trio ES following negative CMA or karyotyping. These cases were combined with data from a systematic review of the literature. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov databases were searched electronically (January 2000 to October 2020) for studies reporting on the incremental yield of ES over CMA or karyotyping in fetuses with prenatally detected NIHF. Inclusion criteria for the systematic review were: (i) at least two cases of NIHF undergoing sequencing; (ii) testing initiated based on prenatal ultrasound-based phenotype; and (iii) negative CMA or karyotyping result. The incremental diagnostic yield of ES was assessed in: (i) all cases of NIHF; (ii) isolated NIHF; (iii) NIHF associated with an additional fetal structural anomaly; and (iv) NIHF according to severity (i.e. two vs three or more cavities affected). RESULTS: In the extended PAGE study cohort, the additional diagnostic yield of ES over CMA or karyotyping was 25.0% (7/28) in all NIHF cases, 21.4% (3/14) in those with isolated NIHF and 28.6% (4/14) in those with non-isolated NIHF. In the meta-analysis, the pooled incremental yield based on 21 studies (306 cases) was 29% (95% CI, 24-34%; P < 0.00001; I2 = 0%) in all NIHF, 21% (95% CI, 13-30%; P < 0.00001; I2 = 0%) in isolated NIHF and 39% (95% CI, 30-49%; P < 0.00001; I2 = 1%) in NIHF associated with an additional fetal structural anomaly. In the latter group, congenital limb contractures were the most prevalent additional structural anomaly associated with a causative pathogenic variant, occurring in 17.3% (19/110) of cases. The incremental yield did not differ significantly according to hydrops severity. The most common genetic disorders identified were RASopathies, occurring in 30.3% (27/89) of cases with a causative pathogenic variant, most frequently due to a PTPN11 variant (44.4%; 12/27). The predominant inheritance pattern in causative pathogenic variants was autosomal dominant in monoallelic disease genes (57.3%; 51/89), with most being de novo (86.3%; 44/51). CONCLUSIONS: Use of prenatal next-generation sequencing in both isolated and non-isolated NIHF should be considered in the development of clinical pathways. Given the wide range of potential syndromic diagnoses and heterogeneity in the prenatal phenotype of NIHF, exome or whole-genome sequencing may prove to be a more appropriate testing approach than a targeted gene panel testing strategy. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Evidence to Support the Clinical Utility of Prenatal Exome Sequencing in Evaluation of the Fetus with Congenital Anomalies: Scientific Impact Paper No. 64 [February] 2021.

Structural differences (congenital anomalies) in the makeup of the baby's heart, brain and other organs are found on antenatal ultrasound scans in up to 3% of pregnancies. These often have a genetic cause, arising because of changes in the chromosomes (which store our genetic material) or the DNA code that make up the genes. The more differences a baby has the more likely the risk of underlying genetic disease. If a structural difference is found, parents are usually offered a genetic test, which may be carried out on cells taken either from the placenta (chorionic villous sampling) or the fluid surrounding the baby (amniocentesis). At the moment, these cells are only tested for changes in the chromosomes and are only able to reveal the underlying cause in about 40% of unborn babies. Prenatal exome sequencing (ES) is a new genetic test, which, when combined with testing the DNA of both parents can find changes in the baby's genetic code. If a DNA change is found that can explain the structural changes seen on ultrasound, specific information about the underlying diagnosis can be given to the parents. Having this information can help parents make important decisions about their ongoing pregnancy, as well as help doctors to care for the mother and baby. Finding a genetic change can also help to understand how the condition has arisen and whether it might happen again in another pregnancy. It may also be possible to test for the genetic condition in future pregnancies. Although prenatal ES is an exciting new way to improve diagnosis rates for structural differences, it has some challenges. While the test is very detailed, it may not always find a genetic explanation and sometimes the results are difficult to interpret. For example, genetic changes can be found where their significance for the pregnancy is unclear. More recently, two studies have now shown that prenatal ES can find a genetic diagnosis in at least 10% of pregnancies with structural differences where standard chromosome testing has been negative. This paper reviews these studies, along with earlier evidence on ES and provides clinicians with guidance for future practice.

COngenital heart disease and the Diagnostic yield with Exome sequencing (CODE) study: prospective cohort study and systematic review.

OBJECTIVE: To determine the incremental yield of antenatal exome sequencing (ES) over chromosomal microarray analysis (CMA) or conventional karyotyping in prenatally diagnosed congenital heart disease (CHD). METHODS: A prospective cohort study of 197 trios undergoing ES following CMA or karyotyping owing to CHD identified prenatally and a systematic review of the literature were performed. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov (January 2000 to October 2019) databases were searched electronically for studies reporting on the diagnostic yield of ES in prenatally diagnosed CHD. Selected studies included those with more than three cases, with initiation of testing based upon prenatal phenotype only and that included cases in which CMA or karyotyping was negative. The incremental diagnostic yield of ES was assessed in: (1) all cases of CHD; (2) isolated CHD; (3) CHD associated with extracardiac anomaly (ECA); and (4) CHD according to phenotypic subgroup. RESULTS: In our cohort, ES had an additional diagnostic yield in all CHD, isolated CHD and CHD associated with ECA of 12.7% (25/197), 11.5% (14/122) and 14.7% (11/75), respectively (P = 0.81). The corresponding pooled incremental yields from 18 studies (encompassing 636 CHD cases) included in the systematic review were 21% (95% CI, 15-27%), 11% (95% CI, 7-15%) and 37% (95% CI, 18-56%), respectively. The results did not differ significantly when subanalysis was limited to studies including more than 20 cases, except for CHD associated with ECA, in which the incremental yield was greater (49% (95% CI, 17-80%)). In cases of CHD associated with ECA in the primary analysis, the most common extracardiac anomalies associated with a pathogenic variant were those affecting the genitourinary system (23/52 (44.2%)). The greatest incremental yield was in cardiac shunt lesions (41% (95% CI, 19-63%)), followed by right-sided lesions (26% (95% CI, 9-43%)). In the majority (68/96 (70.8%)) of instances, pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease genes. The most common (19/96 (19.8%)) monogenic syndrome identified was Kabuki syndrome. CONCLUSIONS: There is an apparent incremental yield of prenatal ES in CHD. While the greatest yield is in CHD associated with ECA, consideration could also be given to performing ES in the presence of an isolated cardiac abnormality. A policy of routine application of ES would require the adoption of robust bioinformatic, clinical and ethical pathways. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Non-invasive prenatal diagnosis and screening for monogenic disorders.

Cell-free fetal DNA (cffDNA) can be detected in the maternal circulation from 4 weeks gestation, and is present with cell-free maternal DNA at a level of between 5 % and 20 %. Cell-free DNA (cfDNA) can be extracted from a maternal blood sample and, although it is not possible to separate the fetal from the maternal cfDNA, it has enabled non-invasive prenatal diagnosis (NIPD) without the associated miscarriage risk that accompanies invasive testing. NIPD for monogenic diseases was first reported in 2000 and since then there have been many proof of principle studies showing how analysis of cfDNA can provide a definitive diagnosis early in pregnancy for a wide range of single gene diseases. Testing for a number of these diseases has been available in the UK National Health Service (NHS) since 2012. This review highlights the main techniques that are being used for NIPD and discusses the technical limitations of the methods, as well as the advances that are being made to overcome some of the issues. NIPD is technologically challenging for a number of reasons. Firstly, because it requires the detection of low level fetal variants in a high maternal background. For de novo and paternally-inherited variants this has been achieved through the use of techniques such as next-generation sequencing (NGS) and digital PCR to detect variants in the cffDNA that are not present in the maternal cfDNA. However, for maternally-inherited variants this is much more challenging and relies on dosage-based techniques to detect small differences in the levels of mutant and wild-type alleles. Alongside the technical advances that are making NIPD more widely available in both the public healthcare and commercial settings, it is crucial that we continue to monitor the social and ethical impact to ensure that patients are being offered safe and accurate testing.

PREIMPLANTATION GENETIC TESTING: Non-invasive prenatal testing for aneuploidy, copy-number variants and single-gene disorders.

The discovery of cell-free fetal DNA (cffDNA) in maternal plasma has enabled a paradigm shift in prenatal testing, allowing for safer, earlier detection of genetic conditions of the fetus. Non-invasive prenatal testing (NIPT) for fetal aneuploidies has provided an alternative, highly efficient approach to first-trimester aneuploidy screening, and since its inception has been rapidly adopted worldwide. Due to the genome-wide nature of some NIPT protocols, the commercial sector has widened the scope of cell-free DNA (cfDNA) screening to include sex chromosome aneuploidies, rare autosomal trisomies and sub-microscopic copy-number variants. These developments may be marketed as 'expanded NIPT' or 'NIPT Plus' and bring with them a plethora of ethical and practical considerations. Concurrently, cfDNA tests for single-gene disorders, termed non-invasive prenatal diagnosis (NIPD), have been developed for an increasing array of conditions but are less widely available. Despite the fact that all these tests utilise the same biomarker, cfDNA, there is considerable variation in key parameters such as sensitivity, specificity and positive predictive value depending on what the test is for. The distinction between diagnostics and screening has become blurred, and there is a clear need for the education of physicians and patients regarding the technical capabilities and limitations of these different forms of testing. Furthermore, there is a requirement for consistent guidelines that apply across health sectors, both public and commercial, to ensure that tests are validated and robust and that careful and appropriate pre-test and post-test counselling is provided by professionals who understand the tests offered.

Minimally invasive perinatal and pediatric autopsy with laparoscopically assisted tissue sampling: feasibility and experience of the MinImAL procedure.

OBJECTIVE: Less invasive autopsy techniques in cases of fetal or infant death have good acceptability among parents, but the published sampling adequacy in needle biopsy studies is generally poor. Minimally Invasive Autopsy with Laparoscopically assisted sampling (MinImAL) has the potential to increase the diagnostic yield of less invasive autopsy by improving the quality and quantity of tissue samples obtained, whilst permitting visualization, extraction and examination of internal organs through a small incision. The aim of this study was to present the findings of our experience with the MinImAL procedure in cases of fetal, neonatal and pediatric death. METHODS: This was a retrospective analysis of 103 prospectively recruited unselected cases of fetal, neonatal or pediatric death that underwent the MinImAL procedure at a tertiary referral center over a 5-year period. Following preprocedure 1.5-T whole-body postmortem magnetic resonance imaging, MinImAL autopsy was performed. Procedure duration, sampling adequacy and cause of death were assessed. Chi-square analysis was used to compare the 'unexplained' rate of intrauterine deaths in the cohort with that in a previously published cohort of > 1000 cases of intrauterine death examined by standard autopsy. RESULTS: MinImAL autopsy was performed successfully in 97.8% (91/93) of the cases undergoing a complete procedure. There was a satisfactory rate of adequate histological sampling in most major organs; heart (100%, 91 cases), lung (100%, 91 cases), kidney (100%, 91 cases), liver (96.7%, 88 cases), spleen (94.5%, 86 cases), adrenal glands (89.0%, 81 cases), pancreas (82.4%, 75 cases) and thymus (56.0%, 51 cases). Procedure duration was similar to that of standard autopsy in a previously published cohort of intrauterine deaths. The unexplained rate in stillbirths and intrauterine fetal deaths that underwent MinImAL autopsy was not significantly different from that following standard autopsy. CONCLUSIONS: The MinImAL procedure provides good histological yield from major organs with minimal cosmetic damage and can be learned by an autopsy practitioner. The MinImAL procedure is an appropriate minimally invasive alternative for the investigation of perinatal and pediatric deaths in which consent to full autopsy is withheld, and may have applications in both high- and low/middle-income settings. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Availability of less invasive prenatal, perinatal and paediatric autopsy will improve uptake rates: a mixed-methods study with bereaved parents.

OBJECTIVE: To investigate whether less invasive methods of autopsy would be acceptable to bereaved parents and likely to increase uptake. DESIGN: Mixed methods study. SETTING: Bereaved parents recruited prospectively across seven hospitals in England and retrospectively through four parent support organisations. SAMPLE: Eight hundred and fifty-nine surveys and 20 interviews with bereaved parents. METHODS: Cross-sectional survey and qualitative semi-structured telephone interviews. MAIN OUTCOME MEASURES: Likely uptake, preferences, factors impacting decision-making, views on different autopsy methods. RESULTS: Overall, 90.5% of participants indicated that they would consent to some form of less invasive autopsy [either minimally invasive autopsy (MIA), non-invasive autopsy (NIA) or both]; 53.8% would consent to standard autopsy, 74.3% to MIA and 77.3% to NIA. Regarding parental preferences, 45.5% preferred MIA, 30.8% preferred NIA and 14.3% preferred standard autopsy. Participants who indicated they would decline standard autopsy but would consent to a less invasive option were significantly more likely to have a lower educational level (odds ratio 0.49; 95% CI 0.35-0.70; P = 0.000062). Qualitative findings suggest that parents value NIA because of the lack of any incision and MIA is considered a good compromise as it enables tissue sampling while easing the parental burden associated with consenting to standard autopsy. CONCLUSION: Less invasive methods of autopsy are acceptable alternatives for bereaved parents, and if offered, are likely to increase uptake and improve parental experience. Further health economic, validation and implementation studies are now required to assess the viability of offering these in routine widespread clinical care. TWEETABLE ABSTRACT: Mixed methods UK study finds less invasive methods of autopsy are acceptable alternatives for bereaved parents, and if offered, are likely to increase uptake and improve parental experience.

Factors affecting uptake of postmortem examination in the prenatal, perinatal and paediatric setting.

BACKGROUND: Postmortem examination is the single most useful investigation in providing information to parents about why their baby or child died. Despite this, uptake remains well below the recommended 75%. OBJECTIVE: To address the question 'what are the barriers and motivators to perinatal, prenatal and paediatric PM examination?' SEARCH STRATEGY: Key databases including Pubmed and CINAHL; Cochrane library, websites of relevant patient organisations, hand search of key journals, first and last authors and references. SELECTION CRITERIA: Peer-reviewed qualitative, quantitative or mixed methods research examining factors affecting uptake or decline of perinatal or paediatric postmortem examination. DATA COLLECTION AND ANALYSIS: Narrative synthesis; findings were compared across studies to examine interrelations. MAIN RESULTS: Seven major themes describing barriers to postmortem uptake were identified: dislike of invasiveness, practicalities of the procedure, organ retention issues, protective parenting, communication and understanding, religion and culture and professional or organisational barriers. Six major themes related to factors which facilitated parental consent were identified: desire for information, contributing to research, coping and well-being, respectful care, minimally invasive options, and policy and practice. There were a number of themes in the literature that reflected best practice. CONCLUSION: Findings highlight the need for better health professional education and the fact some concerns may be mitigated if less invasive methods of postmortem were routinely available. New consent packages and codes of practice may have a positive impact on perception of examination after death. The landscape is changing; further research is necessary to assess the impact on postmortem uptake rates. TWEETABLE ABSTRACT: Systematic review to explore the barriers and motivators to perinatal, prenatal and paediatric postmortem examination.

Cell-Free Fetal DNA Testing for Prenatal Diagnosis.

Prenatal diagnosis and screening have undergone rapid development in recent years, with advances in molecular technology driving the change. Noninvasive prenatal testing (NIPT) for Down syndrome as a highly sensitive screening test is now available worldwide through the commercial sector with many countries moving toward implementation into their publically funded maternity systems. Noninvasive prenatal diagnosis (NIPD) can now be performed for definitive diagnosis of some recessive and X-linked conditions, rather than just paternally inherited dominant and de novo conditions. NIPD/T offers pregnant couples greater choice during their pregnancy as these safer methods avoid the risk of miscarriage associated with invasive testing. As the cost of sequencing falls and technology develops further, there may well be potential for whole exome and whole genome sequencing of the unborn fetus using cell-free DNA in the maternal plasma. How such assays can or should be implemented into the clinical setting remain an area of significant debate, but it is clear that the progress made to date for safer prenatal testing has been welcomed by expectant couples and their healthcare professionals.

Body weight lower limits of fetal postmortem MRI at 1.5 T.

OBJECTIVE: To evaluate the diagnostic yield of postmortem magnetic resonance imaging (PM-MRI) compared with conventional autopsy in fetuses of early gestational age and low body weight. METHODS: Fetuses of < 31 weeks' gestation that underwent 1.5-T PM-MRI and conventional autopsy were included. The findings of PM-MRI and conventional autopsy were reported blinded to each other. The reports of conventional autopsy and PM-MRI for each organ system (cardiovascular, neurological, abdominal, non-cardiac thoracic and musculoskeletal) were classified as either diagnostic or non-diagnostic. The likelihood of a non-diagnostic examination by PM-MRI was calculated according to fetal gestational age and body weight. RESULTS: Full datasets were examined of 204 fetuses, with mean gestational age of 20.95 ± 3.82 weeks (range, 12.0-30.7 weeks) and body-weight range of 15.9-1872 g. Body weight was the most significant predictor of diagnostic yield of PM-MRI. There was 95% confidence that 90% of fetuses will show diagnostic images by PM-MRI for all five organ systems when fetal body weight is ≥ 535 g, but < 50% of fetuses will have all five systems diagnostic on PM-MRI when body weight is < 122 g. CONCLUSION: PM-MRI is highly likely to provide adequate diagnostic images for fetuses with a body weight > 500 g. Below this weight, the diagnostic yield of standard 1.5-T PM-MRI decreases significantly. These data should help inform parents and clinicians on the suitability of performing PM-MRI in fetuses with low body weight. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Diagnostic accuracy and limitations of post-mortem MRI for neurological abnormalities in fetuses and children.

AIM: To compare the diagnostic accuracy of non-invasive cerebral post-mortem magnetic resonance imaging (PMMRI) specifically for cerebral and neurological abnormalities in a series of fetuses and children, compared to conventional autopsy. MATERIALS AND METHODS: Institutional ethics approval and parental consent was obtained. Pre-autopsy cerebral PMMRI was performed in a sequential prospective cohort (n = 400) of fetuses (n = 277; 185 ≤ 24 weeks and 92 > 24 weeks gestation) and children <16 years (n = 123) of age. PMMRI and conventional autopsy findings were reported blinded and independently of each other. RESULTS: Cerebral PMMRI had sensitivities and specificities (95% confidence interval) of 88.4% (75.5 to 94.9), and 95.2% (92.1 to 97.1), respectively, for cerebral malformations; 100% (83.9 to 100), and 99.1% (97.2 to 99.7) for major intracranial bleeds; and 87.5% (80.1 to 92.4) and 74.1% (68 to 79.4) for overall brain pathology. Formal neuropathological examination was non-diagnostic due to maceration/autolysis in 43/277 (16%) fetuses; of these, cerebral PMMRI imaging provided clinically important information in 23 (53%). The sensitivity of PMMRI for detecting significant ante-mortem ischaemic injury was only 68% (48.4 to 82.8) overall. CONCLUSIONS: PMMRI is an accurate investigational technique for identifying significant neuropathology in fetuses and children, and may provide important information even in cases where autolysis prevents formal neuropathological examination; however, PMMRI is less sensitive at detecting hypoxic-ischaemic brain injury, and may not detect rarer disorders not encountered in this study.

Non-invasive prenatal testing for trisomy 21: a cross-sectional survey of service users' views and likely uptake.

OBJECTIVE: To assess the views and likely uptake of non-invasive prenatal testing (NIPT) for trisomy 21 among potential service users in the UK. DESIGN: Cross-sectional survey. SETTING: Four antenatal clinics in England and two websites. SAMPLE: A total of 1131 women and partners. METHODS: Questionnaire conducted with women (and partners) recruited through antenatal clinics, a random sample of members of the website Mumsnet, and viewers of the website and Facebook page of the support group Antenatal Results and Choices (ARC). MAIN OUTCOME MEASURES: Factors impacting decision-making towards prenatal testing; views on NIPT, including service delivery and likely uptake; hypothetical scenarios, focused on current screening, invasive testing, and NIPT offered to women with a high-risk screening result. RESULTS: The vast majority (95.7%; 1071/1119; 95% CI 94.4-96.8%) thought NIPT was a positive development in prenatal care, with 88.2% (972/1103; 95% CI 86.1-90%) indicating that they would use the test, including respondents who would currently decline trisomy 21 screening (P < 0.001). Of the respondents who would have NIPT, 30.7% (299/973; 95% CI = 27.8-33.7%) said that they were 'likely' to terminate an affected pregnancy (including those who would currently decline screening or invasive testing), and 36.5% (355/973; 95% CI 33.5-39.6%) were 'not likely' to terminate an affected pregnancy. Respondents overwhelmingly indicated that safety for the baby was the most important attribute of NIPT (70.1%; 712/1015; 95% CI 67.2-73%). CONCLUSION: Respondents were overwhelmingly positive towards the introduction of NIPT. Uptake is likely to be high, and includes women who currently decline screening as well as those who will use the test for information only. Pre-test counselling to ensure that women understand the implications of the test result is essential.

Non-invasive prenatal diagnosis for single gene disorders: experience of patients.

The aim of this study is to explore women's experiences of using newly developed non-invasive prenatal diagnosis (NIPD) for single gene disorders. Methods used in this study include qualitative one-to-one interviews with eight women with pregnancies at risk of achondroplasia, Apert syndrome, thanatophoric dysplasia or a neuromuscular condition. The results of the study show that the women were positive about an accurate, safe, and early test. Where the foetus was at increased risk of inheriting a genetic condition, the benefits of NIPD over invasive testing were that it reduced the period of uncertainty and worry by being conducted within the first trimester. For those women for whom there was a low recurrence risk, the period of uncertainty could be reduced and pregnancy 'normalized' earlier. For women who would not have risked invasive testing, NIPD enabled them to have an early diagnostic test that was more accurate than ultrasound. Where ultrasound abnormalities were detected, NIPD ended the 'diagnostic odyssey', enabling women to make practical and psychological preparations for the birth. NIPD conducted through specialist services was considered most appropriate. NIPD for these particular single gene disorders was appreciated by women and appears to be satisfactory. Further exploration of stakeholder views may be required to inform more widespread implementation of NIPD for a broader range of genetic conditions.

Non-invasive prenatal testing for Down's syndrome: pregnant women's views and likely uptake.

BACKGROUND: The introduction of non-invasive prenatal testing (NIPT) for Down's syndrome into routine state-funded antenatal care in the UK is approaching. METHODS: We conducted qualitative one-to-one interviews with 40 pregnant women to ascertain their views on using NIPT for Down's syndrome. RESULTS: The overwhelming majority of women viewed NIPT as a positive advancement in prenatal care, highlighting numerous practical and psychological advantages of a safe test that was highly accurate and could be conducted early in pregnancy. Concerns raised were that testing could become routinised, and that pressure to test might occur with women feeling less justified in declining a blood test that is available and offered by trusted health professionals; the impact on the disabled community and stigma for women who decline testing was also noted. Nevertheless, the vast majority of women said they would be likely to use NIPT, including half of the women who currently decline screening. Women's preference was for pre- and post-test counselling to be delivered by a midwife. CONCLUSION: The successful introduction of NIPT into routine prenatal care will require guidelines and counselling strategies which ensure women are offered this test in a way which safeguards informed consent.

Acceptability of a minimally invasive perinatal/paediatric autopsy: healthcare professionals' views and implications for practice.

BACKGROUND: Perinatal autopsy provides essential clinical information, including cause of death; yet, autopsy rates have steadily declined because of parental refusal. Technology now enables less invasive alternatives to traditional autopsy and may increase the acceptability of post-mortem examination. OBJECTIVE: This study aimed to examine the relative acceptability among healthcare professionals of a minimally invasive autopsy (MIA; magnetic resonance imaging and laparoscopic-guided tissue sampling), compared with standard autopsy. METHODS: This study was questionnaire-based survey of healthcare professionals working in clinical settings where paediatric and perinatal deaths occur. RESULTS: Of 250 questionnaires distributed, 224 were returned (90% response rate). Autopsy was generally perceived as acceptable. Demographic factors affecting acceptability included ethnicity and religion but not professional role. MIA compared favourably with traditional autopsy, 50% of respondents reporting both equally acceptable, 40% reporting MIA more acceptable and 10% less acceptable. Healthcare professionals agreed that having a MIA option would make it easier to discuss autopsy with parents (P < 0.001). CONCLUSION: Less invasive autopsy appears an acceptable alternative to traditional autopsy for most respondents. Healthcare professionals should be aware that ethnic and religious opinions influence their own views on autopsy decisions and should be mindful of this when discussing autopsy with parents. Further research is needed to determine parental opinions.