The timing for seeking consent.

The PAGE project, adopted a trio design. That is, the study involved a comparison of the exomes of both parents and the foetus [7]. The foetal sample for PAGE was obtained from a sample taken during routine amniocentesis: an invasive procedure offered as part of the clinical screening programme aimed at better understanding abnormalities observed on ultrasound. Participants for PAGE were recruited at several centres. In some, participants were recruited before amniocentesis, in others recruitment to the PAGE project took place after amniocentesis had been completed.

Health professionals who recruited patients prior to amniocentesis first introduced the PAGE project to them at the time the consultant offered the amniocentesis to the parents. Formal consent was obtained a few days later when the parents came back for the amniocentesis procedure. Health professionals we interviewed, and whose centres had adopted this approach, thought that the time given to parents between the initial contact and the actual recruitment was very important:

People need time to think about things, they want a day or two to go away and consider whether they want to go ahead with the amniocentesis, and so in those situations we would talk to them also a little bit about PAGE, give them the information to take away with them and then when they come back [we would take consent]. (MW1)

One genetic consultant who recruited parents prior to amniocentesis expressed concerns about post-amniocentesis recruitment (the approach taken by some other centres):

Once they [women]’ve had an amnio they’re in a bit of pain and […] it’s almost like, ‘oh thank God that test is done. I think they’d be more inclined to say, ‘Yeah do whatever you want.’ (GC1)

However, other interviewees who were actually involved in recruiting parents after amniocentesis emphasised the benefits of this approach. They explained that it is very convenient to recruit parents during the period following amniocentesis, while women are waiting to leave the hospital after the intervention. They emphasised the benefit of making use of the parents’ waiting time, and reported that these situations facilitated recruitment.

Having said this, despite their tendency to emphasise the benefits of post-amniocentesis recruitment, some of the interviewees acknowledged the emotional distress of parents in this particular situation:

They are very vulnerable at that point [after amniocentesis]. The feedback that I’ve had from it has been that it’s been very positive for them to have someone like me spending an extra 20, 30 minutes talking through this other process. (MW2)

Although parents who were recruited experienced the additional time professionals spent with them as positive and reassuring, this is not the purpose of valid consent. The professionals’ acknowledgment of the parents’ vulnerability inevitably leads to questions about the extent to which it might be more difficult to achieve valid consent in the context of post-amniocentesis recruitment. It also highlights the importance of paying particular attention to the need for sensitivity to the emotional context [12].

Transmitting and comprehending complex information.

Apart from these important contextual features of prenatal genomics, health professionals also highlighted the challenges of achieving valid consent to genomic testing per se and acknowledged its importance as an issue.

Several midwives involved in recruitment for PAGE, questioned the ability of parents to really comprehend the study information at a time when they are anxious about their pregnancy:

We’re seeing families at an extremely vulnerable time. (MW2)

It’s quite a stressful time and quite an upsetting time so it can be difficult to sort of get a sense of, you know, how much they really understand. (MW3)

Another midwife confirmed:

If you’ve just come here and there’s a suspected diagnosis, it’s been confirmed, and then you’ve had that discussion about what it could mean for your baby […] I don’t know how much you take in. (MW1)

This reflects the findings of other studies which have highlighted the difficulty of communicating complex genomic information to a parent when they are under stress after a foetal abnormality has been detected [13, 14].

Importantly, health professionals distinguished between parents’ understanding of the procedural aspects of participation and their understanding of the broader implications of prenatal genomics. They were confident that parents who consented to participate in PAGE understood the procedure, but had doubts about parents’ understanding of the meaning and scope of genomic research and medicine.

I think they [parents] fully understand the process that they have been enrolled into. I’m very happy that they understand what they’ve signed up to as far as the process is concerned […]. But genetics is a complex topic. So how much they properly understand when I’m talking about finding specific genes, um. (MW2)

An interview study explicitly exploring the experiences of parents recruited for PAGE, confirmed the difficulties they faced in fully comprehending the meaning of genomics [13]. Reflecting discussions in the academic literature [8] about the best ways to assess how much [parents] do fully understand (MW4), our interviewees argued that consent should be seen as an ongoing process and participants should be provided with as much information as they require at several stages along the journey from initial identification of the anomaly through to genomic testing [15–17]. As one of the midwives stated:

I think it’s repetition as well. You know, if they’re able to talk to a few people about it and ask questions, and have an ongoing opportunity to ask questions, they always have my contact number and things so I think that kind of can help with continuing to develop their understanding. (MW3)

It was recognised however that continuity is sometimes difficult to achieve. Taking PAGE as an example, as research staff changed throughout the project, continuity in the participant contact, and hence in the consent process, could not always be guaranteed.

The hope to ‘get an answer as to what went wrong’.

In addition to the complexities of genomics and the stressful context in which consent is obtained, the difficulty of communicating effectively about the implications of participation in the PAGE study was also compounded by parents’ strong clinical reasons for choosing to participate in the study. According to the health professionals interviewed, parents consented to the study because they wanted to understand the abnormality observed in their foetus and its implications for future pregnancies. Yet, it was clear from the outset that in many cases these expectations would not be possible to meet because; a) the interpretation of sequencing data to explain an abnormality seen on a scan is difficult and cannot always be guaranteed [7], and b) as discussed above, it is difficult to comprehensively communicate complex genomic information to parents. In order to avoid disappointment and misunderstanding, health professionals involved in recruitment considered it to be crucial to discuss parents’ expectations and to ensure that the limits of genomics were understood prior to taking consent [18, 19]. Our interviewees acknowledged the difficulties of achieving this, however. They consistently reported that parents wished to get ‘an answer as to what’s gone wrong with baby and why. [They] just want information’ (RA).

In the PAGE project, the challenges of interpretation and of establishing a reliable and rapid pipeline for testing and feedback in the context of the lifetime of the project were recognised. Hence, a decision was made that results would not be returned to women and their partners until after the pregnancy. This was explained, along with the reasons for it, at the time of consent. The health professionals reported that this was not always well received by some couples:

‘Some have raised their eyebrows and said, ‘Well what’s the point? If you can’t give me any information, then I’m not sure we want to do this’ (MW4).

In general, however, interviewees reported that the majority of parents accepted this and were mainly hoping to be given ‘information which could be relevant for future pregnancies or for that child, if the child survives’ (MW3). The health professionals described that parents ‘want a good thing to come out of a bad situation’ (MW4) and ‘be able to contribute in some way to the development of knowledge’ (MW3). The desire for more information which the professionals we interviewed reported as the main drive for parents’ participation in PAGE, was confirmed also by a study exploring the experiences of parents who took part in the PAGE project [20].

Preparing for genomic findings and no findings.

Health professionals reported that even for those participants who acknowledge that feedback would only be relevant to future pregnancies, the wish to get ‘to the bottom of what’s actually caused [the abnormality]’ (MW2), sometimes led to high expectations that would be difficult or impossible to meet in genomic research and medicine. This mirrors the findings of Cacioppo et al. who also observed frequent discrepancy between parental expectations and actual results in genomic research studies [18]. The complexity of genomic information, and the challenges of establishing the meaning and the interpretation of research results mean that, as one genetic consultant noticed, parents who hope (as most of them will) to get an answer as to what is wrong with their baby need to have their expectations managed prior to receiving results:

Sit down and talk them through it, because probably the most important thing is to have the conversation before [you get] the results. (GC2)

Another interviewee, a genetic scientist, supported this, arguing that misunderstandings and false expectations can often be avoided through thorough counselling:

The problems arise when people haven’t been told in advance, so then they look, ‘where did that come from’? […] I think it’s important that before the test is undertaken the counselling explores some options with some examples potentially for them, because that makes it real for people. (GS1)

One of the consultants interviewed emphasised the importance of discussing all possible results with the parents in advance and of helping them think through possible decisions, or ‘exit strategies’, before feeding back results:

I detail the three possibilities [no finding, uncertain finding, finding] that might come, and I go through each of those individual possibilities with the couple and make sure they almost have considered an exit strategy for each of those. (GC1)

Notwithstanding these difficulties, health professionals who recruited parents were confident that, by the time consent was given, they understood the likelihood of receiving no further information regarding the foetal abnormality identified,

[…] because [the difficulty to get clear results] is explained well to patients initially and we’re kind of managing their expectations. (MW4)

Within medicine there is always an element of uncertainty […]. And I think most families know that this testing might not give them an answer. (MW3)

The health professionals’ confidence with regard to their management of parental expectations can, to a certain extent, be explained by the set-up of the PAGE study, which required that it was explained to parents at the outset that study results were to be fed back to them only after pregnancy. Furthermore, PAGE opted to return only information on variants that explained the structural abnormality seen on the ultrasound scan; that is, no incidental or uncertain findings were communicated to parents [7].

The right to know or not to know.

The health professionals and researchers in the PAGE project have had early experience with uncertain or incidental findings and reflected on their wider implications for clinical practice. In the interviews, they placed important value on the parents’ right to choose which information they wish to receive.

It’s [about] whether they have a choice about the information they want to know, which they should have really. (MW1)

It was their view that even though in the particular research context of the PAGE study no incidental or uncertain findings were being reported, once prenatal genomics is introduced into clinical practice, it will not be right to hold back information:

‘If the information is out there, people are entitled to know it.’ (MW2)

Yet, they also acknowledged that:

[…] blissful ignorance sometimes is not a bad thing! [Only] if we do the test we’re going to have to report it. (GC2)

The key concern for the professionals we interviewed was patient centred-ness. For example, as much as they emphasised the importance to give parents the choice to decide what they want to know, they also considered it important to also give them a choice not to know:

I don’t think we should force genetic information on people that don’t want it […] an opt-in and opt-out system would be good for that sort of thing. (LS1)

The ‘usefulness’ of information.

Despite the fact that the health professionals and researchers placed a great deal of emphasis on patient choice, most of them thought that the scope of the right to know should be limited by the ‘usefulness’ of information for the decision-making. ‘Usefulness’ here was mostly defined in terms of ‘clinical usefulness’.

I think [actionable findings] should definitely be fed back. [But if] the penetrance of a certain mutation isn’t 100% […], just because someone tells me I have a mutation doesn’t mean that I’m going to die from that mutation.’ I think not feeding back [those] findings is largely the right thing to do. (LS2)

One of the genetic scientists took an even stronger stance when arguing that feedback should not be guided by the principle of autonomy if there is no clinical usefulness of the result:

I think it’s a wider context, and the autonomy is a positive side effect but I wouldn’t put it as a priority. What is the clinical value of a Class 3 [variant where pathogenicity or lack of it cannot be assigned based on current knowledge]? Not much […] there’s nothing we can do about it in the present time. (GS1)

Interestingly, some of our interviewees were willing to go further than limiting information to that which was ‘clinically useful’ to that which was ‘useful’ in the specific context at hand. That is, to the actual situation, the ‘here and now’. This was particularly true of health professionals who had face-to-face contact with parents. They tended to emphasise the importance of only returning data relevant to the actual pregnancy or early childhood:

There is sometimes too much information, it’s not useful for the situation that they’re in. […] They either want to be prepared for when their baby is born so that they know the challenges their baby might face, or it’s because they’re considering the option of termination. (GC3)

The broader impact of PWGES.

In cases where the available genomic information would not inform pregnancy or childhood decisions, but might be relevant to the later life of the child, one of the midwives was more hesitant:

I think it’s quite easy if it’s a physical thing and it’s there from birth, but something that might develop, that’s really opening up a whole different Pandora’s box, isn’t it really. (MW5)

More generally, where there was uncertainty about the future or actual significance and meaning of the results, our interviewees argued that it would be better not to share this information. According to some of the laboratory staff, ‘when we sequence there’s a fairly high error rate to the technology we’re using’ and ‘there are a lot of technical hurdles that need to be overcome for [results to be fed back during pregnancy]’ (LS1). Health professionals and researchers were concerned that the uncertainty ‘could create more problems than we’re trying to solve’ (MW2) and ‘create unnecessary anxiety’ (MW4). Unless the broad public will be ‘educated’ and ‘understand [genomics] at a basic level through media or other influences’ (RA), they considered it difficult to give parents every information, particularly where this was deemed it to be of no clinical utility.

Taken together, this shows that health professionals and researchers believe that patients choices about information and feedback should determine what information is returned and when, but that the scope of their autonomy ought to be limited to information with clinical relevance. Our interviewees acknowledged the challenges of deciding on feedback about uncertain information within the context of even this more limited scope, however.

Turnaround times.

Within the context of the PAGE project itself, study results were fed back only after pregnancy. Health professionals expressed some concern about the fact that feedback within the research context was taking around a year. This was particularly difficult, they argued, for parents who had miscarried:

We’ve had some patients who are sort of OK not to find out during the pregnancy but they don’t want to find out a year later because […] they will try to move on and forget about what happened. (GC4)

A study exploring parents’ experiences within PAGE [20] confirmed that the long turnaround time in the study was difficult for some of the parents recruited.

Another difficulty faced by health professionals in PAGE arose in those situations in which they had to contact parents who–despite the earlier anomaly at ultrasound–had had a seemingly healthy baby, but where the WGES has shown an association between a genetic variant and the initially detected structural abnormality:

You can’t really just ring them up and say, ‘Oh by the way, is your child normal now?’ […] do you just poke all of that [worry] up with a stick when you come back with a result? Are they grateful for it? (GC1)

When prenatal genomics is introduced into clinical practice more widely–from later in 2018, results will be fed back during pregnancy in order to inform parental decision-making and problems related to a long turnaround time will not arise in the same way.

The attitudes and experiences of the health professionals and researchers reported in this paper mirror and confirm, at least in part, published accounts of patients’ views on the return of genomic results. Further analysis of these findings in the light of normative arguments will make important contributions to the development of ethical frameworks of good practice and help answering the question as to what findings ‘ought’ to be fed back.

The duty to improve knowledge and facilitate informed decisions.

Despite the difficulties discussed above, overall, health professionals and researchers valued PAGE, and more broadly prenatal genomics. The biggest benefit associated with PWGES was the possibility it offered to provide answers to parents that would not otherwise be available.

Often our women will have an invasive testing, have a karyotype or array and actually don’t get any answers or explanations, and I think PAGE can add an additional layer to that and give us a bit more information. […] There is a thirst for knowledge and a thirst for explanation of why some of these babies do develop problems in pregnancy. (MW4)

Our interviewees emphasised the importance of PWGES as a way of helping parents to prepare for difficult situations and make informed decisions:

[It] gives them a much better idea of how it will affect their children […] then preparing and coping with it might be better. (GC4)

[It offers] more information to make a more informed choice. (PR1)

They perceived the provision of information not only as one of the benefits of PAGE, but also as one of their duties towards parents:

I have an obligation to make sure that the parents have all the information they need to make the best decision for their child and their wider family if they’ve got one. (GC3)

Another important aspect associated with PAGE, was the opportunity to ‘find out more about how we can avoid major abnormalities’ and ‘eradicate [serious disability] not something like Down’s syndrome, but where I see sort of quadriplegic children, that’s not the same thing.’ (MW2). That is, to help future parents and children as well as those currently being seen. Generally, the interviewees, particularly the researchers, saw knowledge generation and advancement of technology as their duty, and as the major advantage of PAGE:

PAGE will progress the technology or help to establish the new technology of using next generation sequencing for this kind of diagnosis. (GS2)

Both clinical and scientific staff considered it as their obligation to contribute to the growth of knowledge and the development and improvement of technology:

I think as a scientist I’m in favour of progress and change, and I want to work on things that are going to improve the world and the way healthcare is operated. (LS1)

I think if we have the potential to find out information […] we can’t really shut the door now, the genie’s out, we need to refine it. (MW4)

The duty to protect patients from technology.

Despite their enthusiasm and their sense that research and innovation are important parts of their work, the health professionals and researchers we interviewed were realistic and recognised the importance of paying close attention to their social and ethical implications. Amidst the enthusiasm about innovation, some professionals mentioned that the limits and scope of the new technologies require to be discussed by society:

We have to progress, we can’t hold ourselves back unnecessarily, and we need to make a decision as scientists, as ethicists and as a society as to what we think is an acceptable use of this technology. But I absolutely think that it’s right to push the boundaries and to do the best job that we can for these people. (LS1)

Also others expressed concerns about the fast evolving field of genomics:

It is opening a sort of new chapter in medicine and we’re not fully understanding the implications. […] I think there is the potential for stress and anxiety if we don’t quite understand what we’re dealing with […] are we opening a can of worms?

(MW4)

The risk of ‘opening a can of worms’ as a metaphor for the vast amount of data that cannot be fully understood and the yet unknown implications of prenatal genomics, was mentioned by several interviewees. One of them also referred to the ‘potentially toxic knowledge’ (GC1) WGES may generate. Such knowledge was discussed as particularly problematic in the case where WGES would be offered by private providers without comprehensive counselling:

I think what’s worrying me is that [in the private sector] it’s not under a controlled environment. […] The risk that is would become too easily accessible […] not for the right reasons and not properly explained. (GC2)

In order to prevent the loss of control over new technologies, one of the interviewees, a genetic consultant, reminded of their obligation to continuously question the aim of scientific progress:

[It] is our job to protect the patients from scientists, almost. Because if you ask a scientist […] their eyes will light up and they will just go deep down a rabbit-hole, ‘Oh wow, let’s look even further, let’s dig, let’s lift up the mattress and properly look underneath! (GC1)

The duty to provide education and resources.

Other interviewees also mentioned the role education plays in how technology is used and understood. They acknowledged their obligation to contribute to this education:

We can influence the course of action by providing open, clear information, and not hiding evidence to others; just facts and data and then people can make up their minds. […] I think our responsibility is also to train the clinical teams, the frontline people, to make sure they have the facts right and they understand what they are offering the patients or not. […] I think mostly of our responsibility is how we educate people about using this information. (GS1)

However, many of the interviewees were concerned about how to guarantee education in view of the complexity of the fast evolving field of prenatal genomics and increasingly limited resources in the National Healthcare Service (NHS):

The huge challenges for us introducing this technology, is education […] there would have to be almost a mass, you know, a mass discussion about prenatal ethics, about education. […] if you are delivering this test then you have a responsibility. (GC1)

We don’t have enough genetic counsellors working prenatally […] we do not have the support that’s required. […] You do need the resources there […] the whole genomic testing will be extremely costing. (PR2)

Limited resources are an issue also in relation to access to genomics services. While the costs of the sequencing itself have dropped in the past years, the costs of data management including analysis, interpretation and storage are growing [8]. In the interviews, the genetic scientists expressed some concern about equal quality standard across the country, whereas clinical staff expressed worries regarding data protection:

It does slightly worry me on the other hand that we’ve got all this information and we’re storing it, and it’s anonymised but it’s going out of the country […] it’s meant to be secure but I’m not sure anything is secure now. (MW5)

Our interviewees emphasised research companies’ and public authorities’ obligations to meet the costs for data management, as they were worried that otherwise the quality of the information obtained as well as data protection cannot be guaranteed [22].