What is uncertain in prenatal genomics?
Most prospective parents enter into the screening and diagnostic process with the assumption that the information they receive will be clear-cut and straightforward. In the face of potential risks, for example, advanced maternal age, a family history of a specific condition, or an abnormality identified on ultrasound, there are beneficent reasons to offer expanded testing to patients. Such testing may increase the diagnostic yield and minimize the diagnostic odyssey that patients would face postnatally. It can allow parents to plan for medical care, including in utero treatment, delivery planning, and perinatal palliative care as needed ( ), and also can allow parents to make informed choices to continue or terminate the pregnancy when such options are legally available. And yet, testing can also pose risks, even those beyond the procedure itself. In addition, it can increase anxiety, provide information without clinical utility, and could lead to the termination of potentially healthy fetuses if there is a high degree of uncertainty in the results.
Some test results are relatively straightforward: for example, a karyotype obtained through amniocentesis or chorionic villus sampling that shows trisomy 21 has high analytic validity and clinical validity. Even then, there are prognostic ranges and uncertainties about what the lived experience will be for any specific child. There are many other types of results that can lead to uncertainty for parents. As testing has expanded to include broader tests [e.g., chromosomal microarray (CMA), panel testing, and exomes], the range of severity, penetrance, and clinical features that can be identified through testing has expanded to include conditions for which we have moderate prognostic clarity and others that are unknown. For example, a microduplication of 15q13.3 can be incompletely penetrant with variable expression, ranging from mild to severe neuropsychiatric symptoms that may include intellectual disability, behavioral impacts (e.g., bipolar disorder, Obsessive-compulsive disorder (OCD), schizophrenia), and epilepsy ( ). Results can be broader than the specific indication for which the test is performed, including unexpected diagnoses related to the primary indication, or even incidental or secondary findings, such as the identification of a variant that increases the chance of cancer in adulthood. The more —genes that are examined, the higher the chance of obtaining a variant of unknown clinical significance (VUS) or identifying a variant in a gene of unknown significance. And finally, some percentage of potential parents are left with no explanation for the abnormal findings that prompted the testing in the first place.
Medicine is full of uncertainties, which arise from many different sources, and genetic testing is no different. One major source of uncertainty includes probability : of penetrance, of the frequency of certain features, and of the chances of survival. In genetics the limited knowledge base is often exacerbated by the small number of individuals affected by rare conditions. There is also an ascertainment bias, such that the most severely impacted individuals are most likely to be diagnosed, which potentially overestimates penetrance and expression of symptoms. In addition, fetal genotype–phenotype correlations are rarely available, and genes associated with more moderate risks have been recently identified, meaning that knowledge about the phenotype is newer and less well understood. Some conditions such as intellectual disability may not present prenatally, and the presentation of other conditions such as tuberous sclerosis may vary even within the same family. Other sources of uncertainty include limited knowledge about the condition because it is so rare, its natural history and prognosis, and the age of onset. Patients may be frustrated that their providers do not have much more information than is available to them by googling and on social media ( ). Additionally, diagnostic sensitivity may depend on the expertise of the health-care professional (HCP) (in the case of fetal imaging) and on the technology itself. Test limitations also present uncertainty such as the depth of sequencing, insufficient DNA material, or maternal cell contamination in the sample. And finally, there can be uncertainty about treatment efficacy.
These biases are especially impactful and challenging when considering the prenatal diagnosis of conditions where the natural history is limited by postnatal diagnosis, potentially exaggerating risk estimates. One example is the prenatal diagnosis of fetuses with 46,XX/46,XY ( ). This condition has been reported in childhood diagnoses of diseases of ambiguous genitalia, but those followed prospectively after prenatal diagnosis are most often phenotypically normal males.
Parents’ experiences of uncertainty in the prenatal setting
Prospective parents usually enter into prenatal testing hoping to receive certainty and reassurance about their pregnancy. Generally, patients desire knowledge, imagining that “knowledge is power” and that genetic information would have clinically useful impact ( ). However, they may be faced with information that is uncertain and difficult to navigate. A recent systematic review of the literature highlighted a myriad of uncertainties that parents had experienced ( ). There were different sources of uncertainty, including those related to the procedure, diagnosis, and prognosis. There was the clinical impact of the uncertainty, including how parents struggled to make clinical decisions with the information they had been given, and finally, there was the emotional impact of the uncertainty, which included shock, worry, and decisional regret.
Some parents are unaware, even at the time of consenting to undergo testing, that they may receive inconclusive results, including VUS. In a qualitative study with couples who received uncertain CMA results, couples reported being “blind-sided” and unprepared to receive results for which clear risk estimates or diagnostic meaning were unknown ( ). Where a result was given, parents experienced difficulty recalling the diagnosis ( ) or there was very limited or imprecise information available about what the diagnosis meant prognostically, for example, whether it will result in the child having learning difficulties and, to what extent ( ), or what the child will look like ( ). In some cases, parents have been left uncertain around whether their baby will survive, creating a major source of anxiety ( ).
Receiving an uncertain result can significantly impact parents’ emotional well-being. Parents have described experiencing shock, confusion, and worry at the time of receiving results ( ). described how in their interview study with women who had received abnormal CMA results, the women felt overwhelmed when receiving uncertain information, and discussed the difficulty of emotionally and intellectually managing the uncertainty of the results given how far into their pregnancy they were.
I think what is so difficult about these decisions—on top of the shock of it, the helplessness—is the timing…We felt like we were desperately trying to build enough information to make an informed decision in a very fast amount of time and that was very, very stressful for us.
Some parents report regret about their decision to receive uncertain results ( ). Sometimes this type of knowledge is referred to as “toxic knowledge” because of the negative impact, it can have on the recipient ( ). Notably, a study conducted in Australia found that parents who chose to receive VUS results had higher decisional regret than those who chose not to receive these types of results ( ). Other longer term responses include loneliness, lingering anxiety and grief, feeling overwhelmed by the future, a lack of control over the situation, and feeling self-blame that have also been reported by parents ( ). In some cases, parents even minimize or avoid activities that might facilitate bonding with the baby (e.g., buying baby clothes or preparing the baby’s nursery) because of the uncertainty around whether the baby will survive to term ( ).
For those parents who continue with the pregnancy, anxiety may persist about the child’s development, even after birth. In the study by , one parent, whose son was found to have a mass on his stomach during an ultrasound scan that later disappeared, commented that
for the first two years of his life, whenever he had tummy problems I thought ‘oh, maybe it’s that mass again.
Similar findings have been identified elsewhere ( ), and this persistent anxiety mirrors that initially documented after false-positive newborn screening results ( ). A quantitative longitudinal study looking at the impact of receiving VUS on parental perception of child development found that parents who received VUS results rated their child as having more social-emotional and/or emotional problems and delays at 12 months than those parents who had received normal or likely benign results, although these differences were no longer statistically significant at 36 months ( ).
Parents manage uncertainty in different ways. For some, it can be helpful to focus on what is known, and there is relief that certain known disorders have been ruled out. Others focus more on the unknown and the uncertainties generated by the result, for example, the risk of learning disabilities or structural malformations ( ). Emotionally focused coping mechanisms such as remaining hopeful ( ) and making a conscious decision to suppress worry and focus on enjoying the pregnancy ( ) can help parents. For some couples, it is important to see the child in its own right and not interpret the child’s future development in light of the copy number variant ( ). Action-focused coping strategies to manage uncertainty include pursuing increased medical and developmental assessments as a way to address long-term worry ( ). Some access support groups or chat forums to speak with other parents who have had similar experiences ( ) and many search for information online or through additional clinical support (e.g., extra ultrasounds), although this sometimes creates additional anxiety or may result in misinformation ( ).
Health-care professionals’ experiences of dealing with uncertainty in the prenatal setting
Genetic HCPs frequently facilitate informed consent and promote parent-centered decision-making in the clinic. But how do they experience pre- and posttest counseling around genomic sequencing-related uncertainties in the prenatal setting? A number of studies exploring the attitudes, experiences, and preferences of genetic HCPs have been published in recent years. A key finding from this work is that there are significant differences in attitudes and approaches to dealing with uncertain findings in the prenatal setting.
First, attitudes vary regarding which types of uncertain results HCPs believe should be communicated to parents. Some HCPs feel that where there is uncertainty about the future or actual significance and meaning of a result, it would be better not to share this information, while others are reluctant to withhold uncertain results from parents, even if it might have a negative impact on the doctor–parent relationship ( ). Notably, in a study conducted in the Netherlands to determine expert consensus among prenatal experts on which chromosomal anomalies should and should not be returned to patients, there was disagreement on whether results with uncertain outcomes should be returned ( ). Attitudes are similarly mixed when looking at return of additional (e.g., secondary and incidental) findings. In a survey study conducted with genetic HCPs in the United States to determine their attitudes toward prenatal exome sequencing, the large majority of participants agreed that childhood-onset conditions with (93%) and without (80%) treatment should be returned to parents. However, attitudes regarding the return of results of adult-onset conditions were mixed, with only 50% of participants agreeing that conditions with available treatment should be returned ( ).
Second, approaches vary regarding laboratory reporting practices for uncertain results. In a recent international cross-sectional study with HCPs dealing with uncertain CMA and/or exome sequencing results, there was variation in reporting practices both between and across countries for VUS, with some participants returning only pathogenic variants, and others returning some VUS. There was also variation in who decides what results are reported; in some laboratories, it is the clinical scientist, and in others, it is the clinician. However, there was broad agreement on reporting practices for incidental findings whereby only actionable or clinically significant results are returned ( ). Similarly, conducted an international comparison study looking at whether or not laboratories reported VUS to clinicians. They found that some laboratories do not routinely report VUS to referring clinicians, but some will report VUS if they are thought to be relevant to the testing indication, but lacking sufficient evidence to classify them as pathogenic. Only a few laboratories would report VUS in candidate genes when they are not certain that they are relevant to the phenotype.
These findings highlight the complexity and contextual variation that exists, not only across countries with different health-care systems but also between HCPs themselves. The disparity in views likely reflects the tension between two competing professional duties: facilitating reproductive autonomy and avoiding unnecessary harm. They may also reflect a lack of consensus from professional bodies around the reporting of uncertain results, differences in national health systems (single-payer systems vs. mixed public/private providers), and/or cultural differences in how much information parents want and tolerance for uncertainty. Further research here would be valuable.
The question then turns to why there is reluctance among genetic HCPs to return uncertain results? HCPs have concerns when it comes to interpreting uncertain results in a prenatal setting, particularly where there is a lack of published data to support variant classification, or an extremely wide spectrum of clinical phenotypes ( ). This can lead to frustration for both the patient and the HCP who is generally regarded as an expert and accustomed to providing answers to parents’ questions. HCPs are concerned that they may create unnecessary patient anxiety, as has been identified in a number of studies reporting parents’ experiences of receiving uncertain results ( ). Horn et al. found that where there was uncertainty about the future or actual significance and meaning of results, HCPs and researchers were concerned that the uncertainty “could create more problems than [they are] trying to solve” ( ). Receiving uncertain results may also put parents in a difficult situation where they either continue the pregnancy with the worry that the VUS implies the baby has a genetic anomaly or otherwise terminate, unsure whether the fetus was affected ( ). And finally, HCPs have raised concerns that uncertain information may lead to the termination of healthy pregnancies, and that is it difficult to supporting parents making decisions about whether to continue their pregnancy ( ).
Notable discrepancies may exist between providers’ and parents’ expectations for genomic sequencing and its results. In a qualitative study, genetic counselors acknowledged the low diagnostic yield of exome sequencing and their expectation that tests will often come back “normal” or uninformative, whereas they described that patients frequently overestimate the test’s ability to reveal a diagnosis and are eager to consent ( ). This prompted counselors to modify patients’ perceptions to reduce false hope through setting more realistic expectations around the diagnostic yield of the test, often through the use of probabilities. As described by one genetic counselor,
I think the most challenging thing with exome sequencing is balancing the patient’s expectation that they’re going to find an answer vs…the 30% chance that we’re actually going to find the answer.
As a result of the numerous clinical and ethical challenges associated with returning uncertain results, HCPs vary in whether they feel comfortable providing pre- and posttest counseling in this area. In a US study, nearly all genetic HCPs believed that there was potential for harm with prenatal exome sequencing due to ambiguous information and due to parents’ misunderstanding the information provided by the test ( ). found that when there is an uncertain CMA result, only 59% of genetic counselors felt comfortable providing genetic counseling to parents. Factors such as having sufficient knowledge of CMA, being familiar with current guidelines as well as having spent more time in prenatal practice, and believing that CMA is useful have all been found to be significant ( ).
Managing uncertainty—the role of counseling
So how can HCPs best help patients manage prenatal uncertainty? First, ample research has shown that the quality of the relationship between patients and HCPs creates a sense of safety and improves treatment adherence, decision-making, and health and well-being outcomes ( ). Empathy ( ) and kindness ( ) are essential to support and reinforce parents; empathic professionalism consists of the integration of professional knowledge, clinical experience, and the awareness that ones’ own lived experience and personhood will color all of one’s hypotheses and interactions ( ). The definition of genetic counseling furthermore underscores the importance of psychoeducation ( ). Psychoeducation in prenatal counseling, for instance, implies educating expectant parents about the practicalities of decision-making, the vocabulary of grief, and the psychological process of going through a prenatal diagnostic trajectory. The therapeutic effects of psychoeducation may be feelings of relief from understanding that what one is experiencing is normal and reinforced autonomy through affirmation and validation. Additionally, psychoeducation may provide a sense of direction and overview, leading to an increased sense of control for patients ( ).
Parents should specifically have the opportunity to take uncertainty into account in their decision-making process about prenatal WES. Parents highly appreciate honesty and transparency ( ), and many prior studies recommend that HCPs acknowledge uncertainty and its implications throughout the counseling process ( ). There is broad consensus about the benefits of being proactively transparent when HCPs convey to patients what is known and unknown in terms of genomics sequencing ( ), including addressing limitations of the test and uncertainties of test outcomes during pretest counseling. Clinician disclosure of uncertainty in these ways has been shown to improve trust and is a valuable aspect of patient-centered communication ( ). This type of genetic counseling approach requires sufficient self-confidence to convey what you as an HCP know, and also where the boundaries of knowledge and uncertainty exist. Ideally, counseling should be used to make the patients feel that they are part of the multidisciplinary team that works together behind the scenes and helps each other to deal with uncertainty.
There is a significant body of literature discussing the theoretical underpinnings of uncertainty in medical decision-making and relevant communication strategies ( ). However, there are few guidelines providing insights into how to address these limitations, disclaimers, and uncertainties during counseling, despite HCPs expressing a need for guidance in this area ( ). A few specific suggestions are provided later and in Fig. 4.1 .
