Introduction
Noninvasive prenatal testing (NIPT) using cell‐free fetal DNA has increasingly been adopted as a screening tool for fetal aneuploidies. Several studies have discussed benefits and ...limitations of NIPT compared with both ultrasound and invasive procedures, but in spite of some shortcomings NIPT has become extensively used within the last 5 years. This study aims to describe the current use of NIPT in Europe, Australia and the USA.
Material and methods
We conducted a survey to describe the current use of NIPT. Colleagues filled in a simple email‐based questionnaire on NIPT in their own country, providing information on (a) access to NIPT, (b) NIPT’s chromosomal coverage, (c) financial coverage of NIPT for the patient and (d) the proportion of women using NIPT in pregnancy. Some data are best clinical estimates, due to a lack of national data.
Results
In Europe, 14 countries have adopted NIPT into a national policy/program. Two countries (Belgium and the Netherlands) offer NIPT for all pregnant women, whereas most other European countries have implemented NIPT as an offer for higher risk women after first trimester screening. In Australia, either combined first trimester screening (cFTS) or NIPT is used as a primary prenatal screening test. In the USA, there are no national consensus policies on the use of NIPT; however, NIPT is widely implemented. In most European countries offering NIPT, the proportion of women using NIPT is well below 25%. In the Netherlands, Austria, Italy, Spain and most Australian and American States, 25%‐50% of women have NIPT performed and in Belgium testing is above 75%. In most countries, NIPT reports on trisomy 13, 18 and 21, and often also on sex chromosome aneuploidies. Only in Belgium, the Netherlands, Lithuania, Greece, Cyprus and Italy is NIPT offered predominantly as a genome‐wide test (including some microdeletions or a whole genome coverage).
Conclusions
Noninvasive prenatal testing has been widely adopted throughout Europe, Australia and the USA, but only a few countries/states have a national policy on the use of NIPT. The variation in NIPT utilization is considerable.
Introduction
Denmark was the first country in the world to implement a national, free‐for‐all offer of prenatal screening for Down syndrome to all pregnant women. It has a high uptake (>90%) compared ...to other countries. Thus, Denmark offers an interesting case for investigating the consequences of implementing comprehensive, national prenatal screening guidelines. The aim of this study was to describe the historical developments in invasive procedures, pre‐/postnatal diagnoses of Down syndrome and Down syndrome live births in the period 1973–2016 in Denmark.
Material and methods
Data on invasive procedures, pre‐ and postnatal Down syndrome diagnoses were retrieved from the Danish Cytogenetic Central Registry.
Results
From 1973 to 1993, screening based on maternal age and high‐risk indications resulted in a constant increase in invasive procedures. After the introduction of the triple test in 1994, invasive procedures decreased for the first time in 20 years. Following the introduction of an offer of combined screening to all pregnant women in 2004, the number of invasive procedures decreased markedly, while there was a concurrent increase in prenatal diagnoses of Down syndrome. Additionally, the number of Down syndrome live births decreased suddenly and significantly, but subsequently stabilized at 23–35 annual live births. Of these, the majority were diagnosed postnatally.
Conclusion
Though prenatal screening technologies constantly improve, it was the introduction of and adherence to national guidelines that resulted in marked shifts in screening procedures and outcome in Denmark.
More knowledge about the long-term impact of sperm donation is essential as the donor's attitude towards donation may change over time. Personal and social developments may prompt a rethinking of ...previous actions and decisions, or even regret. Thus, the aim of this study was to explore the experiences and attitudes of men who were sperm donors more than 10 years ago.
From May to September 2021, semi-structured, qualitative interviews were conducted with 23 former donors (> 10 years since last donation) from Cryos International sperm bank. Two participants were non-anonymous donors and 21 were anonymous. The interviews were conducted by phone or via video (mean 24 minutes). All interviews were recorded, transcribed verbatim and rendered anonymous. Data were analyzed using thematic analysis.
The analysis showed that most men had been donors for monetary and altruistic purposes, and now considered sperm donation as a closed chapter that was 'unproblematic and in the past'. Most men valued anonymity and emphasized the non-relatedness between donor and donor conceived offspring. Knowledge about recipients and donor offspring was seen as 'damaging' as it could create unwanted feelings of relatedness and responsibility towards them. All men acknowledged donor conceived persons' potential interests in knowing about their genetic heritage in order to understand appearance and personal traits, but also emphasized the donors' rights to anonymity. Potential breach of anonymity was generally considered 'highly problematic' as it was expected to disturb their families and force a relationship on them.
This study reports on former donors who might not have volunteered for research due to lack of interest or protection of privacy. The majority of men valued anonymity and clearly demarcated a line between sperm donation and fatherhood, which was enforced by not knowing about the donor offspring or recipients.
Introduction
In Denmark, first trimester screening has a very high uptake (>90%). If Down syndrome is diagnosed, termination rates are high (>95%). The aim of this study was to investigate the timing ...of the decision to terminate pregnancy following a diagnosis of Down syndrome and the factors influencing this decision.
Material and methods
Semi‐structured, qualitative interview study with 21 couples who had received a prenatal diagnosis of Down syndrome and decided to terminate the pregnancy. Participants were recruited from obstetric departments between February 2016 and July 2017. Data were analyzed using thematic analysis.
Results
Five themes were identified: “initial decision‐making”, “consolidating the decision”, “reasons and concerns shaping the termination of pregnancy decision”, “the right decision is also burdensome”, and “perceived influences in decision‐making”. For most couples, the initial decision to terminate pregnancy was made before or during the diagnostic process, but it was re‐addressed and consolidated following the actual diagnosis. Imagining a family future with a severely affected Down syndrome child was the main factor influencing the termination of pregnancy decision. The decision was articulated as “right” but also as existentially burdensome for some, due to fear of regret and concern about ending a potential life. The decision to terminate pregnancy was considered a private matter between the couple, but was refined through interactions with clinicians and social networks.
Conclusion
All couples made an initial decision prior to receiving the Down syndrome diagnosis. Knowledge of the couple's initial decision may facilitate patient‐centered communication during and after the diagnostic process. Couples may benefit from counseling to deal with grief and existential concerns.
Prenatal DNA tests, such as chromosomal microarray analysis or exome sequencing, increase the likelihood of receiving a diagnosis when fetal structural anomalies are identified. However, some parents ...will receive uncertain results such as variants of uncertain significance and secondary findings. We aimed to develop a set of attributes and associated levels for a discrete-choice experiment (DCE) that will examine parents' preferences for tests that may reveal uncertain test results. A two phase mixed-methods approach was used to develop attributes for the DCE. In Phase 1, a "long list" of candidate attributes were identified via two approaches: 1) a systematic review of the literature around parental experiences of uncertainty following prenatal testing; 2) 16 semi-structured interviews with parents who had experienced uncertainty during pregnancy and 25 health professionals who return uncertain prenatal results. In Phase 2, a quantitative scoring exercise with parents prioritised the candidate attributes. Clinically appropriate levels for each attribute were then developed. A final set of five attributes and levels were identified: likelihood of getting a result, reporting of variants of uncertain significance, reporting of secondary findings, time taken to receive results, and who tells you about your result. These attributes will be used in an international DCE study to investigate preferences and differences across countries. This research will inform best practice for professionals supporting parents to manage uncertainty in the prenatal setting.
We present the first study that investigates the effect of maternal body mass index (BMI) on the quantity of circulating fetal cells available to use in cell-based noninvasive prenatal test (cbNIPT). ...cbNIPT has been proposed as a superior alternative to noninvasive prenatal test from cell-free fetal DNA. Kølvraa et al. Prenat Diagn. 2016 Dec; 36(12): 1127–34 established that cbNIPT can be performed on as few as one fetal cell, and Vestergaard et al. Prenat Diagn. 2017 Nov; 37(11): 1120–4 demonstrated that these fetal trophoblast cells could be used successfully in cbNIPT to detect chromosomal and sub-chromosomal abnormalities. This study on 91 pregnant women with high-risk pregnancies suggests that cbNIPT should not be hampered by an increased BMI because every pregnancy, irrespective of the BMI, has rendered fetal cells for downstream genetic analysis. The mean number of fetal cells per sample was 12.6, with a range of 1–43 cells in one sample. ANOVA showed that increasing maternal BMI tends to decrease the number of fetal cells, but not significantly.
Objectives: A few adult and adolescent patients with even severe cholestatic liver disease remain unexplained after standard diagnostic work-up. We studied the value of genetic examination in such ...patients and developed a panel of eight genes with known cholestatic associations.
Materials and methods: Thirty-three patients with unexplained cholestasis despite a thorough clinical work-up were examined for sequence variations in the coding regions of the ABCB4, ABCB11, ABCC2, ABCG5, ATP8B1, JAG1, NOTCH2, and UGT1A1 genes and the promoter region of UGT1A1 by massive parallel sequencing of DNA extracted from whole blood. Hepatologists and clinical geneticists evaluated the causal potential of genetic variants.
Results: In 9/33 patients (27%), we identified genetic variants as a certain causal factor and in further 9/33 (27%) variants as a possible contributing factor. In most cases, a detailed family history was necessary to establish the importance of genetic variants. Genetic causes were identified in 6/13 women (46%) with intrahepatic cholestasis during pregnancy and persisting abnormal biochemistry after delivery.
Conclusions: Our study suggests that a small number of well-known genetic variants are involved in at least 27-54% of patients with unexplained cholestasis. An expanded panel will likely explain more cases. This motivates genetic testing of these patients. Genetic testing, however, cannot stand alone but should be combined with a clinical genetic work-up in collaboration between hepatologists and clinical geneticists.
Introduction:
Following the wide distribution of non-invasive prenatal genetic screening (NIPS), numerous studies have reported a decline in total invasive tests in the recent years, up to 50–70% in ...some countries. However, in Denmark and Israel we have not experienced these declines. The objective of our study was to evaluate the trends in NIPS and chromosomal microarray analysis (CMA) use in Denmark and Israel.
Methods:
This retrospective study was performed by data acquisition from the Danish Cytogenetics Central Registry throughout the years 2000–2019, and Israeli Public Health Services, Ministry of Health computerized database (from 2011).
Results:
Of the 1,243,956 live births registered in Denmark over the years 2000–2019, a relatively steady level of invasive testing around 6% was noted since 2004, as opposed to 13.0% in Israel based on 1,594,962 live births between 2011 and 2019. The average uptake of NIPS was 1.1 ± 0.5% in Denmark vs. 4.3% in Israel (2013–2019). Relatively steady rates of invasive testing were noted in both countries, compared to a slight decline in NIPS in the recent years.
Discussion:
The recent decrease in the rates of invasive testing in the NIPS era was not observed in Denmark or in Israel. These results imply that Danish and Israeli women and/or health providers might favor the high resolution and yield of CMA testing over the non-invasiveness of NIPS. We explore and discuss this phenomenon, based on five central factors.
Introduction:
Circulating fetal cells isolated from maternal blood can be used for prenatal testing, representing a safe alternative to invasive testing. The present study investigated the potential ...of cell-based noninvasive prenatal testing (NIPT) for diagnosing monogenic disorders dependent on the mode of inheritance.
Methods:
Maternal blood samples were collected from women opting for prenatal diagnostics for specific monogenic disorders (
N
= 7). Fetal trophoblasts were enriched and stained using magnetic activated cell sorting and isolated by fluorescens activated single-cell sorting. Individual cells were subject to whole genome amplification, and cells of fetal origin were identified by DNA-profiling using short tandem repeat markers. The amplified fetal DNA was input for genetic testing for autosomal dominant-, autosomal recessive-, X-linked and repeat expansion disorders by direct variant analysis and haplotyping. The cell-based NIPT results were compared with those of invasive testing.
Results:
In two cases at risk of skeletal dysplasia, caused by variants in the
FGFR3
gene (autosomal dominant disorders), cell-based NIPT correctly stated an affected fetus, but allelic dropout of the normal alleles were observed in both cases. Cell-based NIPT gave an accurate result in two cases at risk of autosomal recessive disorders, where the parents carried either different diastrophic dysplasia causing variants in the
SLC26A2
gene or the same cystic fibrosis disease-causing variant in the
CFTR
gene. Cell-based NIPT accurately identified an affected male fetus in a pregnancy at risk of Duchenne muscular dystrophy (
DMD
gene, X-linked recessive disorders). In two cases at risk of the myotonic dystrophy type 1 (
DMPK
gene, repeat expansion disorder), cell-based NIPT correctly detected an affected and an unaffected fetus, respectively.
Discussion:
Circulating fetal cells can be used to detect both maternally- and paternally inherited monogenic disorders irrespective of the type of variant, however, the risk of allelic dropout must be considered. We conclude that the clinical interpretation of the cell-based NIPT result thus varies depending on the disorders’ mode of inheritance.
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