Conflict of interest: none.
Views and preferences for the implementation of non-invasive prenatal diagnosis for single gene disorders from health professionals in the united kingdom
Article first published online: 21 MAY 2013
Copyright © 2013 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 161, Issue 7, pages 1612–1618, July 2013
How to Cite
2013. Views and preferences for the implementation of non-invasive prenatal diagnosis for single gene disorders from health professionals in the United Kingdom. Am J Med Genet Part A 161A:1612–1618., , , , .
Melissa Hill and Madhavi Karunaratna contributed equally to this work.
- Issue published online: 19 JUN 2013
- Article first published online: 21 MAY 2013
- Manuscript Accepted: 4 MAR 2013
- Manuscript Received: 17 DEC 2012
- National Institute for Health Research (NIHR) (RP-PG-0707-10107)
- Central and East London NIHR Comprehensive Local Research Network
- Great Ormond Street Hospital Children's Charity
- The NIHR Biomedical Research Centre at Great Ormond Street Hospital
- Non-invasive prenatal diagnosis;
- cell-free fetal DNA;
- single gene disorders
Non-invasive prenatal diagnosis (NIPD) will offer new options in prenatal diagnosis for carriers of single gene disorders. This will affect carrier couples and health professionals involved in prenatal care. The aim of this study was to determine health professional opinions on NIPD for single gene disorders to guide development of infrastructure required for implementation. A qualitative approach was adopted using focus groups (N = 17) and one-to-one interviews (N = 30) with health professionals from a range of backgrounds involved in caring for carriers of single gene disorders. Data were digitally recorded, transcribed verbatim and analyzed using thematic analysis. Participants were very positive about the introduction of NIPD, describing benefits arising from no risk of miscarriage, earlier testing and a simple procedure. A number of concerns for implementation were raised. Participants emphasized the need for the new test to be highly accurate and thoroughly validated. There was concern that people may not give as much thought to having a blood test compared to an invasive test or that it may be viewed as routine and as such NIPD may negatively impact on informed consent. In addition there was concern that the simplicity of a blood test may lead to increased pressure to test and terminate. However, participants felt these concerns could be overcome with thorough pre- and post-test counseling. To ensure high quality care, offering NIPD through genetics or other specialist services is essential. Ongoing education and training of health professionals will be important, and guidelines and regulation are needed for effective implementation. © 2013 Wiley Periodicals, Inc.
Non-invasive prenatal diagnosis (NIPD) based on cell-free fetal DNA (cffDNA) is set to transform prenatal care for women at risk of single gene disorders by allowing prenatal diagnosis using a maternal blood test. Maternal blood contains a mixture of maternal and fetal cell free DNA and new technologies are allowing researchers to develop prenatal tests for a range of single gene disorders [Hill et al., 2012a]. The clinical benefits of NIPD are clear as it eliminates the risk of miscarriage associated with invasive diagnostic tests (chorionic villus sampling (CVS) or amniocentesis) and can be performed early in pregnancy (7–9 weeks) [Hill et al., 2011]. Consequently, NIPD promises both safer and earlier testing for couples at risk of single gene disorders.
There are a number of ways parents find out they are at risk of having a child with a single gene disorder and this will influence the types of health professionals they encounter prior to and during pregnancy. Carrier status will often be established before conception if there is a family history of a genetic condition. Alternatively, carrier status could also be revealed during pregnancy as routine prenatal carrier screening is increasingly common for some conditions, for example, cystic fibrosis (CF) [American College of Obstetricians and Gynecologists, 2011] and the hemoglobinopathies [American College of Obstetricians and Gynecologists, 2007; NHS Sickle Cell and Thalassaemia Programme, 2011] as well as within some population groups such as the Ashkenazi Jewish carrier screening programs [Scott et al., 2010]. Ultrasound findings can also lead to a recommendation for prenatal testing as they may indicate that a new mutation has arisen de novo for an autosomal dominant condition such as achondroplasia [Chitty et al., 2011] or soft markers for some conditions, such as CF, may be present [Berlin et al., 1999].
The availability of NIPD for the prenatal detection of single gene disorders will affect couples who are carriers of the condition and the health professionals involved in their care. In addition, current care pathways and the prenatal testing options provided to patients may need to change with the implementation of NIPD. Research examining stakeholder views of NIPD is growing [Sayres et al., 2011; Tischler et al., 2011; Hill et al., 2012b; Kelly and Farrimond, 2012; Lewis et al., 2012a, 2012b; Sayres et al., 2012; Yotsumoto et al., 2012]. However, no previous studies have looked in-depth at health professional views of NIPD for single gene disorders. This study explores the views and preferences of health professionals from a variety of backgrounds with the aim of informing the development of educational packages and implementation strategies for NIPD for single gene disorders. We chose to focus on three common single gene disorders where parental carrier status can be established either prior to pregnancy or through prenatal carrier screening programs; CF, sickle cell disease and thalassemia. These are also conditions where it is feasible that non-invasive tests will be available in the near future [Lun et al., 2008; Barrett et al., 2012].
This study forms part of the RAPID program which is evaluating standards for the implementation of NIPD in the United Kingdom (UK) National Health Service (NHS; www.rapid.nhs.uk). Focus groups and one-to-one interviews following a semi-structured question schedule were used to enable an in-depth exploration of the perspectives and attitudes of health professionals. This study was considered a Service Evaluation as defined by the UK's National Research Ethics Service and did not require review by a research ethics committee.
Health professionals working in the UK from a range of clinical backgrounds who would speak to carriers of CF, sickle cell disease and thalassemia about their prenatal testing options were invited to participate (purposive sampling). This included obstetricians and midwives who specialized in fetal medicine, clinical geneticists, genetic counselors, hemoglobinopathy specialists, hemoglobinopathy screening coordinators, CF specialists, and general practitioners (GPs).
Potential participants for the focus groups were identified from the list of 127 participants attending a RAPID Dissemination Meeting at their own initiative in November 2010. They were sent a study invitation prior to the meeting that asked whether they would be willing to participate in a focus group to be held at the meeting and to contact the research team if interested in taking part. Potential participants for the interviews were identified from online UK service directories and NHS Hospital websites. Snowballing was also used as several health professionals suggested others that would be appropriate for the study. Potential participants were sent a study invitation via email that gave details about the study and asked them to contact the research team if interested in taking part. The interviews were conducted between February and July 2012.
Each focus group was facilitated by two researchers from the RAPID team (CC/ZD and LML/FF). Interviews were conducted by one researcher (MK) either face-to-face or by telephone. Prior to the focus groups and interviews it was explained to participants that NIPD for CF, sickle cell disease and thalassemia were not currently available, but were in development, and that we anticipated that the test would be diagnostic and available from 9 weeks gestation. The semi-structured discussion guides included three topic areas: (1) current practice in prenatal care, (2) possible advantages and disadvantages of NIPD, and (3) preferred approaches for service delivery and implementation. Interviews and focus groups were digitally recorded and transcribed verbatim. The transcripts were anonymized and pseudonyms assigned to each participant.
Data were analyzed using thematic analysis [Braun and Clarke, 2006]. NVivo version 7 (QSR International, Pty Ltd) software was used to facilitate coding and data analysis. Transcripts were initially read and coded by either MH or MK and were then verified by the other person to ensure inter-rater reliability. A subset (10%) of the transcripts were coded by two additional researchers (CL or FF) and overall themes discussed to add weight to the validation process. Any discrepancies in coding were discussed to achieve consensus. Emerging themes were identified and then grouped to form broader categories. The categories were reviewed and redefined as the analysis progressed. Emerging themes were explored in more detail in subsequent interviews. When no new themes or categories emerged (saturation), no further participants were recruited.
Overall, 47 health professionals participated in the study with data collected in two focus groups and 30 interviews. There was no overlap between the participants in the focus groups and interviews. Participant details are summarized in Table I. All health professionals who were invited to participate in a focus group accepted. Of 77 health professionals invited to participate in an interview, 30 agreed, two declined and 45 did not respond to the invitation email (response rate = 39%). Interviews were conducted by telephone (N = 27) or face-to-face at the participants workplace (N = 3). Overall, there was a great deal of overlap between the themes that emerged from the focus groups and the interviews, thus they were treated as a single data set.
|Focus group participants||17|
|Fetal medicine obstetrician||11|
|Fetal medicine midwife||4|
|Hemoglobinopathy screening coordinator||5|
|Adult consultant respiratory physician||3|
|Child respiratory medicine specialist||1|
|Offers cffDNA test for fetal sex determination or fetal RHD typing|
Perceived Advantages of NIPD for Single Gene Disorders
Overall, participants viewed NIPD for single gene disorders very positively, using terms such as “exciting,” “brilliant,” “useful,” and “huge impact” to describe the introduction of NIPD. The advantages of NIPD described by participants included both practical and psychological points which centered on the test being: non-invasive; available early in pregnancy; and a simple procedure.
NIPD is non-invasive
Participants thought that the main practical advantage of NIPD was that there is no risk of miscarriage. Many also felt that women would view a blood test as a more appealing procedure than an invasive test which involves “a great big needle” and “invades the fetal space.” NIPD was also described as potentially being “emotionally easier” for women as it reduced anxiety associated with decision-making.
Well straightaway you take away the worry over the miscarriage and the actual procedure.
Lisa, hemoglobinopathy screening coordinator
Many participants felt that in addition to providing an attractive alternative for women who currently take up invasive testing, NIPD would be valued by women who would like diagnostic information for planning and preparation only and currently decline invasive testing because of the miscarriage risk.
I think that that's one of the big advantages to it is that it could be made available to people who actually wouldn't consider a termination anyway, just so they've got some time to come to terms with it and go through the bit of the grieving process which they're going to go through.
Jamie, Consultant Respiratory Physician
Several participants commented that the availability of NIPD may lead to an increase in the numbers of women taking up prenatal testing for information only. One participant raised concerns about the cost of offering NIPD to women when it would not change pregnancy management.
NIPD allows earlier testing
Participants felt that women making decisions around termination of pregnancy would value early diagnostic testing as it was important for “reassurance” and would allow increased time for decision-making and preparation at a time when the pregnancy is not physically obvious and recognizable features of the fetus are not visible on scan. For couples who know their carrier status prior to pregnancy, having a test earlier was thought to be beneficial as prenatal testing is associated with a great deal of anxiety and “even shaving off 2 weeks is a big deal”. Many participants also felt that an early test was better because the woman could have a surgical termination of pregnancy by vacuum aspiration. Another advantage was that NIPD would “expand the choices” for women whose religion only sanctions termination before 12 weeks of pregnancy.
NIPD is a simple procedure
Another reported advantage of NIPD was that it would be easier to access than invasive testing as it is a blood test that women can have locally without needing to go to a specialist center. One participant commented that it would also be easier for health professionals to organize for the women to have a blood test than invasive testing.
Concerns Around NIPD for Single Gene Disorders
Discussion of participants' concerns revealed five overarching themes: accuracy is critical; impact of “just another blood test” on informed choice; increased pressure to test and terminate; misuse of technology; and NIPD may provide less information than invasive tests.
Accuracy is critical
A key concern many participants raised was that the test had to be “highly accurate” and thorough validation would be essential. They emphasized that it would be important to clearly explain the limitations of the test to women. In addition, if NIPD needed to be confirmed by invasive testing, this would need to be made clear to women and considered when setting up care pathways.
Impact of “just another blood test” on informed choice
Participants were concerned that people may not view a blood test as seriously as an invasive test and could take up testing when “they haven't really thought through what they're going to do with those results and how they are going to act”. Several participants also commented that as NIPD was a blood test and therefore easy to access and administer, that it may “trivialize” testing.
When you are told you might lose your baby if you have this test, you really, really concentrate on whether you need to go through this test or not.… Whereas if you don't have to think about that it's quite easy for you to stick out your arm and say OK fine take another blood test
Camela, Fetal Medicine Consultant
Many participants also suggested that as one of a large number of blood tests offered during pregnancy that, in some circumstances, NIPD could be viewed as a routine test. For example, one participant felt that routinization of testing was a particular concern for carriers newly diagnosed in universal carrier testing, where “people could get on a path that they don't realize the consequences of that path until they're along way down it.”
Increased pressure to test and terminate
The potential for NIPD to engender feelings of pressure to take up prenatal testing and to terminate an affected fetus were raised as a concern by two participants.
Women will feel they're being coerced into having it because it's just a blood test
Leanne, hemoglobinopathy screening coordinator
When we asked other participants if they agreed, most felt that pressure from health professionals, partner, family and society to take up testing was already present and could increase with the introduction of NIPD. In addition, it was acknowledged that health professionals had to be careful when describing prenatal testing options not to “sell” NIPD because there is no miscarriage risk.
Misuse of technology
There were general concerns about where new technologies in prenatal testing were headed, where we should “draw the line” and the anxiety that would be associated with incidental findings or difficult to interpret results. Four participants emphasized the need for care in implementing new tests and not offering tests just because they are available. In addition some participants felt “uneasy” that “parents might go looking for more and more trivial things” and that tests should not be offered unless there is a clear indication.
If the couple is only coming for you to look for hemoglobinopathies, then it would be wrong to then say ok let's look for everything else that there is. Where would you draw the line?
Leanne, hemoglobinopathy screening coordinator
NIPD may provide less information than invasive tests
It is not yet clear whether NIPD will offer the opportunity for karyotype information alongside the specific genetic diagnosis that you can have with invasive testing. Participants did not think this would be a major problem as most women are primarily concerned with the disorder they are at risk of, unless individual circumstances such as a high risk Down syndrome screening result or abnormality detected by scan arise. In these cases participants felt women “might be better off just having an invasive.”
Impact of NIPD for Single Gene Disorders on Clinical Practice
All participants felt strongly that NIPD for single gene disorders should be offered through specialist services already offering prenatal testing such as genetic services, fetal medicine, or other specialist providers such as hemoglobinopathy screening programs or hemophilia centers. Health professionals within these services have specialist knowledge of the condition being tested for, are aware of the genetic testing options and are skilled in pre- and post-test counseling. Health professionals who see carriers of single gene disorders as part of their practice but would not directly offer prenatal testing, such as GP's or consultant physicians, still need to know about NIPD so they can give general information and make appropriate referrals.
The importance of good counseling was emphasized by all participants. Many felt counseling would be critical to ensure informed choice was maintained and to mitigate feelings of pressure to take up testing. Accordingly, several participants thought that NIPD should not be offered direct to consumer (DTC) and as couples may not have access to suitable information, counseling and support. There was also concern about NIPD being offered in the private sector which could leave the NHS “picking up the pieces.”
Most health professionals' reported that only minor modifications to current practice would be required to implement NIPD as another option for prenatal testing that they would discuss with patients. All participants agreed that patients should receive as much counseling for NIPD as they would for invasive testing. Less time would be required to explain the procedure and the minimal risks, but the information for making an informed choice and the need for a discussion of the implications of the results would not change.
The end product is the same, it's the access which has changed but the information that women need to make an informed choice should not change… so I don't think in that respect it should affect it.
Candice; screening coordinator
In addition, there may be a change in care pathways due to a different type of sampling being organized, potentially earlier in pregnancy. However, this would be dependent on local services. The exception was the fetal medicine teams, who acknowledged that NIPD would mean a dramatic change to their practice as there would be a decrease in the number of invasive tests performed. As non-invasive testing will not entirely replace invasive testing, the loss of technical skills resulting from performing fewer invasive procedures is an issue that will need to be addressed. One suggestion was to provide invasive tests through fewer specialist centers.
Participants with a background in pre-implantation genetic diagnosis (PGD) felt that the introduction of NIPD was unlikely to impact on PGD services and NIPD would not replace PGD as couples seeking PGD do so because they would not consider a termination. There was, however, a role for NIPD in confirming the results of PGD for carrier couples.
Practical Structures Will Be Needed to Support Implementation
The need for clear guidelines and adequate regulation of NIPD and other new technologies was highlighted. Participants also emphasized the need for appropriate ongoing training and education of health professionals. The importance of providing patient information leaflets or other types of educational material describing NIPD was discussed. Additional reassurance and explanations about the test may be needed for some patients as two participants raised concerns that women may not believe in blood test results compared to an invasive test where the needle is inserted close to the fetus. Participants from hemoglobinopathy screening programs thought that women often did not present in time for screening and prenatal testing because they would not have an invasive test. Consequently, education for the general public was thought to be needed to make women aware that a non-invasive prenatal test was available. This may allow some women, who would not have sought testing in the past because of the miscarriage risk, to present earlier. Written information on NIPD in multiple languages would be of benefit, but participants did not identify any other culturally specific modifications that would be required.
Alternative Prenatal Testing Pathways May Be More Attractive With NIPD
A small number of participants raised the possibility of offering NIPD for some single gene disorders such as CF or sickle cell disease as a universal screening test for all pregnant women. When other participants were asked about this suggestion many felt that NIPD should not be used at the population level and favored “targeted screening” for carrier status of the couple, followed by NIPD for at risk pregnancies.
Several participants commented that NIPD may be useful for those women whose partner refuses carrier testing as they could find out whether the fetus had the condition without risking the pregnancy with an invasive test. When other participants were asked for their opinion, the responses were mixed; some thought it would be beneficial and others were concerned about the ethical implications of revealing the partner's carrier status without his permission.
The technology to allow NIPD for single gene disorders is advancing rapidly. It is already possible to offer some NIPD tests for single gene disorders [Raymond et al., 2010; Chitty et al., 2011], and it is likely that NIPD will be applicable to a wider range of conditions in the near future [Lun et al., 2008; Barrett et al., 2012]. Here we report on the views of health professionals involved in the management of pregnancies at risk of CF, sickle cell disease and thalassaemia in order to identify key features required for service delivery of NIPD for single gene disorders. Gathering health professional views is critical as they influence decisions on how and when new tests are introduced: they input into the development of policy and guidelines, and most importantly they play a central role in facilitating patient decision-making. The key recommendations for implementing NIPD for single gene disorders which arose from this research are listed in Table II.
|● NIPD for single gene disorders should be offered through existing specialist services and should not be part of routine prenatal care to avoid routinization and enable maximum information provision to families|
|● Counseling should include ensuring informed choice, implications of results and mitigation of feelings of pressure to take up NIPD testing which may occur as the test has no risk for the pregnancy and is easy to perform|
|● Uptake of NIPD may be greater than for invasive diagnosis and consideration of resource allocation may be required|
|● Education and training of health professionals offering the test is required.|
|● Written patient information and other public educational material needs to be developed|
|● The application of new technologies should be carefully considered before implementation|
|● New tests should not be introduced until they are shown to be accurate through thorough accredited validation processes|
|● Regulation of testing and clear guidance from policy makers and professional bodies is essential|
|● Research into views of couples who have used or will use NIPD for single gene disorders is required to inform service delivery|
In line with reports from high risk families who have had NIPD for fetal sex determination [Lewis et al., 2012a, 2012b], attitudes to introducing NIPD for single gene disorders were very positive. Participants felt the main benefits were that NIPD was safe, could be conducted early in pregnancy and would be easy to access with no need to attend a specialist center to have the test. Health professionals from all backgrounds felt that it was important that NIPD be offered through the existing specialist services such as genetics units or hemoglobinopathy screening programs, because health professionals would have experience and training in counseling for prenatal testing and up-to-date knowledge of the condition and its treatment. This preference for implementing NIPD within existing care pathways concurs with patient preferences for offering NIPD for fetal sex determination where patients valued their relationship with the specialist, and wanted pre- and post-test counseling from someone with expert knowledge of genetic testing and the relevant condition [Lewis et al., 2012a].
Participants anticipated that women would welcome the introduction of NIPD for single gene disorders. It was speculated that there may in fact be an increase in the number of requests for prenatal testing as women might opt for NIPD when previously they would not have had invasive diagnostic testing, which puts the pregnancy at risk, to obtain information to prepare for the birth of an affected child. It has been suggested that in a State-funded health care system there is a need to consider the cost implications of offering tests that will not change pregnancy management [Deans et al., 2012]. However, the option of only offering NIPD to those couples considering a termination of pregnancy was considered unreasonable by most participants, as having information for preparation without putting the pregnancy at risk was seen as an important advantage of NIPD. It is also important to consider the dynamic nature of the decision-making process, as some couples might change their mind once the test results become available. For example, in a study looking at reproductive decision-making for carriers of CF, there was not always a good correlation between what couples said they would do and what they actually did when decisions were reviewed 5 years later [Sawyer et al., 2006].
A range of concerns were raised by the health professionals in this study that mirror issues discussed in the ethics literature around non-invasive prenatal testing for Down syndrome and for single gene disorders [Benn and Chapman, 2009; de Jong et al., 2010; Hall et al., 2010; Deans and Newson, 2011, 2012; Deans et al., 2012], most commonly the potential for NIPD to have a negative impact on informed decision-making. Participants felt that couples may not give as much thought to the implications of the test results when there is no risk to the fetus. Another common consideration was the potential for NIPD to be viewed as a routine test, particularly for women whose carrier status is revealed during pregnancy, as time pressures and ease of testing may result in women finding themselves on a pathway for testing and termination before they fully realize the implications [Deans et al., 2012]. There is already evidence of difficulties in gaining informed consent and avoiding routinization of testing in prenatal carrier screening program [Tsianakas et al., 2010, 2012; Brown et al., 2011]. As such, careful counseling will be especially important in this setting to ensure NIPD is not seen as a routine test which automatically follows a positive carrier result. Another concern about NIPD raised here was the possibility that there may be increased pressure to test and terminate because of the simplicity of the test. Appropriate pre-and post-test counseling were acknowledged by all participants as essential requirements for the implementation of NIPD to ensure informed consent and mitigate feelings of pressure to test.
Health professionals raised concerns around test accuracy and the possibility NIPD may be introduced before it had been properly validated. We also found that there was unease about how new technologies such as NIPD would be used in the future and where the limits on testing and reporting of results would be. This is perhaps a reflection of the many ways prenatal testing is rapidly changing and the ongoing debate in the literature about results of unknown significance which is pertinent to all areas of prenatal testing [de Jong et al., 2011]. Exactly how NIPD for single gene disorders will be offered in clinical practice in the future is yet to be established. For example, participants suggested that NIPD may be a viable tool for population screening of all pregnant women for relatively common conditions such as CF. It is also possible that new technologies, such as genome wide sequencing, may ultimately allow NIPD for multiple conditions with a single assay [Lo et al., 2010; Fan et al., 2012]. Health professionals' hesitance about expanding testing options without a clear indication suggests further debate, and establishing regulation of testing and guidance from professional bodies will be critical when implementing NIPD.
Study Limitations and Future Research
This study presents the views of health professionals working in a range of disciplines in the UK. The participants in this study were, however, self-selected and as such it is possible that there was responder bias towards those who have strong views on NIPD. It is also possible that health professionals in other countries will have different views. As the sample size for the different specialist groups was quite small it was not possible to confidently draw out differences between health professional groups. It is also important to note that the conditions primarily discussed here (CF, sickle cell disease and thalassemia) do not cause significant cognitive impairment or visible physical disability and health professionals may have different views about using NIPT for other single gene disorders. This is an important area for future research. Research is also needed to assess the views of potential service users: as such, it will be important to gather the views of couples at risk of single gene disorders who will be offered NIPD in the future. In addition, as NIPD is already available in the UK for some single gene disorders, it is critical to explore the experiences of these first users of the technology.
This study has revealed positive views of health professionals on NIPD for the detection of CF, sickle cell disease and thalassemia, but has emphasized the requirements for informed consent and appropriate counseling as well as the need for education and training of health professionals before widespread implementation can occur. Other key messages are that NIPD for single gene disorders should be delivered through genetics or other specialist services, and guidelines and regulation are needed for effective implementation.
We are grateful to the health professionals who were interviewed as part of this study. We thank Elizabeth Dormandy for her assistance with study recruitment and for her critical review of the manuscript. We thank Cecilia Compton, Zuzana Deans, and Lih-Mei Liao for facilitating the focus groups. This manuscript presents independent research funded by the National Institute for Health Research (NIHR) under the Programme Grants for Applied Research Programme (RP-PG-0707-10107) (the “RAPID” project) and the Central and East London NIHR Comprehensive Local Research Network. L.S.C. is partially funded the Great Ormond Street Hospital Children's Charity and the NIHR Biomedical Research Centre at Great Ormond Street Hospital. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
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