Current controversies in prenatal diagnosis 2 should incidental

ISPD 2013 MEETING PRESENTATION

Current controversies in prenatal diagnosis 2: should incidentalfindings arising from prenatal testing always be reportedto patients?The-Hung Bui1*†, Frances Lucy Raymond2† and Ignatia B. Van den Veyver3†

1The Karolinska Institute, Center for Molecular Medicine, Clinical Genetics Unit and Center for Fetal Medicine, Karolinska University Hospital, Stockholm, Sweden2Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK3Departments of Obstetrics and Gynecology and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA*Correspondence to: The-Hung Bui. E-mail: [email protected]†All authors contributed equally.

Funding sources: NoneConflicts of interest: Ignatia B. Van den Veyver is a member of the Baylor College of Medicine Department of Molecular and Human Genetics, which houses thediagnostic Medical Genetics Laboratories that offer various forms of genetic testing, including for prenatal diagnosis, on a fee for service basis, but she does notderive personal revenue from this activity.

INTRODUCTION (THE-HUNG BUI)

Our ability to measure and quantify variation in humandevelopment is rapidly increasing, not least in the area ofgenetic investigation. However, our understanding of theimplications of this variation is far behind our ability todescribe it. A powerful motivation for research anddevelopment is the desire to improve knowledge and care ofthose who seek medical attention but also to interpret datacorrectly and to communicate findings with the appropriateevidence and to do no harm nor create undue anxiety.

The discovery of an incidental finding as the result of adiagnostic or screening procedure has complicated nearlyall aspects of clinical research and diagnostics.1–4

Traditionally, such findings were relatively rare, anddecisions about how and when to report them were mostlyleft to the judgment of healthcare providers within theconfines of individual physician–patient relationships. Withrecent technical advances in diagnostic methodologies,combined with more ready access and willingness to usethem, incidental findings have become more common,and the findings themselves have become more complex.4

The debate on reporting of incidental findings is motivatedby this massive increase in genetic information availableand our current deficiencies of knowledge about the clinicalsignificance of much of these data, rather than by generalprinciples of communicating and observing incidentalfindings in prenatal diagnosis. The essence of the debateis whether all variants should be communicated to usersof prenatal services or whether there are limits as to whatshould be returned and what would be the basis of thisselection or restriction.

THE CASE FOR REPORTING ALL INCIDENTAL FINDINGS(IGNATIA B. VAN DEN VEYVER)There are two main types of incidental findings in prenataldiagnosis and screening. First are those associated withprenatal imaging, including high-resolution ultrasound andfetal magnetic resonance imaging. While important, they arenot reviewed in detail for this report but can be contrasted withthose of the second category, which are the incidental findingsthat arise during genetic screening or a genetic diagnostic test.

Reporting incidental findings in genetic research and clinicaltesting is currently highly debated,4–7 but debates or proposedguidelines typically exclude considerations relevant to prenataltesting.4,8 Nevertheless, we can learn from other geneticdiagnostic circumstances to help address whether and how suchfindings should be reported prenatally. This is an importantquestion that must be considered by the prenatal diagnosiscommunity, individual prenatal healthcare providers, and parentswho choose to undergo prenatal genetic screening and/ortesting.9,10 To arrive at the best answer, we must first define whatis an incidental finding and then consider practical and ethicalaspects that are unique to prenatal screening and diagnosis,taking into account the purpose and goals of prenatal diagnosis.

What are incidental findings?An incidental finding or secondary finding can be defined as‘an observation (result) of potential clinical significanceunexpectedly discovered in patients or in healthy subjectsunrelated to the purpose of the diagnostic study or test’.8,11–13

This definition implies that an incidental finding carries withit clinically useful information that may benefit the health ofthe individual being tested, but that information was unrelated

Prenatal Diagnosis 2014, 34, 12–17 © 2013 John Wiley & Sons, Ltd.

DOI: 10.1002/pd.4275

to the primary goal of the diagnostic study. This can be difficultto define,5,8 and we must consider to whom ‘useful’ applies. Isit the fetus, or also the parents, siblings, or even the extendedfamily of the fetus? We must also consider what clinically usefulmeans.11,14 Should we only report findings that are of well-defined clinical relevance, and within that category, should weonly report incidental findings for which an intervention ispossible that has therapeutic benefit? What should we do withthe findings of defined clinical significance but for which thereis no known therapy? What should we do with the findings ofuncertain significance that we know may have clinical impactbut not in all cases? What should we do with incidental findingsfor which it is unknown but possible that there is clinical impact?What about genetic changes that are causative for late-onsetadult disorders for which it has been argued that the ‘right toan open future’ should be a barrier to reporting such mutationsprenatally or in childhood. These are complex questions thatrequire thoughtful consideration.

Purpose and goals of prenatal diagnosisThe purpose of prenatal screening and diagnosis is to provideinformation to prospective parents about the current andfuture health of their unborn children. Considering thatdecisions regarding fetal and neonatal care resulting fromprenatal diagnostic information may have implications notonly for the fetus but also for the mother and the nuclearfamily, the diagnostic information provided should benefitthe well-being of the family, including first not only the futurechild, but also the parents, siblings, and even other extendedfamily members. In this context, well-being encompasses notonly the physical but also the mental and social aspects.

Under ideal circumstances, all prenatal diagnosis would benoninvasive and risk-free to the pregnant woman and fetus,would be oriented towards diagnosis rather than screening,and would be comprehensive or more broadly ‘disease-optimized’ rather than focused on a small number of disorders,such as commonaneuploidies.Wewould also prefer that all testsare cost-effective; widely available; and easy to explain, interpret,and counsel about and that the results are conclusive, onlyrelevant to the conditions for which we test without incidentalfindings of potentially uncertain significance. Clearly, we cannotachieve all of these goals, but it is our ethical responsibility asprenatal care providers to manage rather than to avoid thesecomplexities of our profession, keeping in mind the best interestof the fetus and the family.

Applying principles of medical ethicsThe four principles of medical ethics – autonomy, beneficence,non-maleficence, and justice (Table 1) – provide an ethicalframework for healthcare professionals whenever difficultclinical decisions arise for which there may be real or perceivedcompeting interests for providers or patients.15 The principleof autonomy embodies respect for the patient’s right to chooseor to refuse treatment.15 This is at the core of the informedconsent process for testing and treatment and carries with itthe obligation for good communication between healthcareproviders and patients. Important for a debate on reportingincidental findings is that patients (or their legal representative

decision makers) cannot exert autonomy if not provided withfull information4,5,16 and equally important is whether ageneric consent that bins categories of results,14 althoughpractical, can be considered fully informed.10

Beneficence requires that a practitioner act in the bestinterest of the patient.15 Within the context of fetal diagnosis,the individual being tested cannot be the one providing consent.Parents, who provide consent on behalf of the unborn child asthe child’s representatives, are also bound by the beneficenceprinciple to act in the best interest of the fetus.10 It has thereforebeen argued that the right of parents to know or not toknow diagnostic information (autonomy) conflicts with thebeneficence-based responsibility towards the fetus in the settingof prenatal diagnosis.17 Under these circumstances, beneficenceis consideredmore important than autonomy.10 However, whenthe ultimate goal that prenatal diagnostic information shouldbenefit the well-being of the fetus within the context of thefamily’s well-being is considered, the capacity of parents toexercise autonomy in their decisions is reconcilable with theprinciple of beneficence.

The principle of non-maleficence together with beneficenceencompasses the ‘first do no harm’ and ‘duty to warn’responsibilities of the healthcare provider.4,15 This supportsreporting of actionable incidental findings, that is, those resultsfor which it is known that a preventive measure or interventionis available to reduce risk or improve health.8 Not reporting suchprenatal diagnostic results to parents carries a risk of causingharm and is a strategy that is difficult to endorse. Furthermore,incidental results from prenatal diagnostic testing on the fetusmay have direct implications for the health of the parent. Forexample, incidentally discovered cancer-predisposingmutationsmay be inherited from a parent, who can be placed on a cancerscreening and prevention protocol.10,18 Equality of access to careand of distribution of health care resources, as well as respect forpeople’s rights and the law are components of the principle ofjustice. While important in multiple aspects of healthcare, itprovides less guidance for the specific question of reportingincidental findings, which is more easily considered in view ofthe other three principles of medical ethics.

Table 1 Principles of medical ethics

Autonomy

• Respect for the patient’s right to choose or refuse treatment

• Obligation for informed consent, requires good communication

Beneficence

• A practitioner should act in the best interest of the patient

• Clinical care should benefit the patient

Non-maleficence

• Is the ‘first do no harm’ principle

• Carries with it the ‘duty to warn’ obligation

Justice

• Fair adjudication between competing claims – ‘Equality’ is central

• Fair distribution of scarce health resources

• Respect for people’s rights and for morally acceptable laws

Reporting incidental findings in prenatal diagnosis 13


The difficulty with incidental findings (variants) of unknownsignificanceThe aforementioned reasoning supports reporting incidentalfindings of known clinical significance that are actionable,8,11

but it may not be immediately obvious that the same appliesto the findings or variants of unknown significance (VOUS)19

These are results that may be of clinical significance but withvariable expressivity so that we cannot predict what thephenotype will be after birth, such as for example, a 16p11.2deletion detected by chromosomal microarray. This is arelatively common deletion in individuals ascertained fordevelopmental delay, intellectual disability, and autism.However, the phenotype associated with deletion 16p11.2 ishighly variable, even within families, and apparentlyunaffected or very mildly affected cases exist. Thus, it isdifficult to predict how severe these manifestations will bewhen it is detected prenatally. In other cases, there may be agenetic change for which there is not enough information asto whether the finding will result in a clinically significantphenotype, for example, an unclassified sequence variant in aknown disease-associated gene for a disorder with no prenatalphenotype. Findings of uncertain significance are not uniqueor new to genetic testing and have always complicatedprenatal diagnosis. While they often create difficult andcomplex counseling situations, they are health-relatedinformation that has the potential to be relevant to thewell-being of the tested individual.9 The ethical principle ofautonomy supports that the information is shared with parentsto allow them to make decisions with the availableinformation. A detailed discussion of VOUS is beyond thescope of this report, but they come with many practicalchallenges involving pretest counseling and informed consentprocedures, definition and classification of VOUS, and whoshould report them.9,19,20 Whereas it is the responsibility ofthose developing new tests and the diagnostic laboratories thatoffer the tests to aim for testing platforms that avoid thediscovery of true VOUS, they cannot be fully eliminatedwithout compromising diagnostic power for importantdisorders. Therefore, when VOUS occur, we should beprepared to share this information with parents in the bestpossible way so that they can exert their autonomy in decisionsabout the care for their pregnancy and future child.

Incidental discovery of late-onset untreatable disease and the‘right to an open future’It has long been held that children should not undergopresymptomatic genetic testing for late-onset disorders forwhich no cure is available, such as familial Alzheimer disease,Huntington disease, or spinocerebellar ataxias to preserve thechild’s right to an open future and to an education that isunbiased by the prior knowledge that there will be impairmentin later adulthood.21 Genetic societies have endorsed ordeveloped guidelines in support of this approach,22 but thistopic has become more debated recently.21 The sameprinciples have been extended to prenatal andpreimplantation genetic diagnosis, with adaptations that takeinto account the option of avoiding (through preimplantation

genetic diagnosis) or terminating affected pregnancies, as wellas the unavoidable presymptomatic discovery of the disorderin a carrier parent through fetal testing.23,24 Whereas theseguidelines are very beneficial for targeted testing, theypreceded the explosion of genome-wide genetic tests that arecapable of incidentally discovering mutations that cause theseconditions. Most laboratories have taken the approach of notreporting them in children and presymptomatic adults, but itremains an open question how best to handle them in prenataldiagnosis for two important reasons. First, when discoveredduring prenatal diagnosis, the disorder can be prevented ifparents choose the option of not continuing a pregnancy.Second, it should be examined what the right to an open futuresignifies and whether we infringe autonomy by shieldinginformation that may allow parents and young adults to makedecisions about their future that take into consideration allaspects of their current or future health. It is not wellestablished that not providing this predictive information isthe only direction to preserve the right to an open future.25

Risks, benefits, and guidelinesOne argument put forward for not reporting incidental findingsis the risk of causing parental anxiety about a finding that is ofuncertain significance for which there are no interventionsavailable. This is indeed an unavoidable consequence ofreporting incidental findings but not one that is new to prenataldiagnosis. As providers we need to assume responsibility for thisby providing expert counseling and support for the families weare caring for, rather than hiding this information from families.Advances in technologies for genetic testing will likely generatemore incidental findings, creating the need for more geneticcounseling professionals, and for better appreciation of theirservices. As a discipline, we must assume responsibility fortraining more genetic counselors and for motivatinggovernments and regulatory instances to recognize theirservices with appropriate licensing and reimbursement. Wemust also proactively become involved in educating otherproviders, such as general practitioners and obstetrician–gynecologists, and various fetal care-related subspecialists, inthe intricacies of newer genetic tests. Vice versa, we should beprepared to integrate their knowledge with how we mostoptimally interpret the test results and counsel patients.

Some incidental findings from prenatal diagnosis may causeunnecessary or justified anxiety that may be prolonged while thechild grows into adulthood. However, in this era, a paternalisticapproach to medical care is no longer considered acceptable,and the ethical principle of autonomy therefore mandates thedisclosure of the information.9 Furthermore, considering that thepace and scope of advances in medicine are unpredictable, wecannot have the foresight in many cases what the future benefitof knowing an incidental finding could be. From that perspective,putting the decision as to what constitutes the ‘right to an openfuture’ only in the hands of health professionals may conflict withautonomy and beneficence.

In summary, reporting incidental findings in prenataldiagnosis is a complex issue, but it is not limited to the resultsof genetic testing and has been part of our field since the start.There are no good arguments to treat genetic testing differently

The-Hung Bui et al.14


from other diagnostic testing on how to manage theseunanticipated results. In general, as the benefit or harm fromreporting them will vary depending on the individual patientwithin his or her family structure, we have to assume theprofessional responsibility to report them and allow patients(parents) the autonomy to make decisions on the basis of theresults. We also have the responsibility to do so under the mostsupportive counseling circumstances possible.

Unfortunately, we do not yet have professional guidelines onhow to handle these complex issues in prenatal diagnosis andmost guidelines available or in preparation explicitly excludeprenatal diagnosis situations. Thus, it will be up to ourprofessions to assume the responsibility for generatingguidelines that are applicable to prenatal diagnosis.

THE CASE AGAINST REPORTING ALL INCIDENTALFINDINGS (LUCY RAYMOND)There are three areas that merit consideration when discussingwhether incidental findings should be reported to patients: (1)The mandate to do no harm and the misuse ormisinterpretation of the data. (2) How accurately does agenotype predict a phenotype in individuals? and (iii) Geneticdata as a ‘product’ and the potential effect of parentalinformation about a baby with respect to the ongoingrelationship between parent and child.

The misuse or misinterpretation of incidental findingsExcept in rare circumstances of X-linked genetic diseases ordisorders of sex, knowing the gender of a fetus is of no medicalimportance. However, fetal selection by terminationof pregnancyand preferences for one sex is still widespread in cultures wherethe perceived value of each gender is different.26,27 This is apowerful illustration that incidental knowledge of the genome isnot always medical and is used as a social tool by some, whilstothers would regard this as unacceptable.

The identification of any variant of normal during pregnancyis always unsettling to couples and creates uncertainty. Sexchromosome anomalies (SCA) are usually reported to familiesas an incidental finding as a consequence of prenatal testingfor autosomal aneuploidy. The rate of termination ofpregnancy for SCA was initially high when introduced becauseof the lack of knowledge about the prognosis for theseconditions and has gradually decreased over time as data haveemerged from long term follow-up studies, which show a goodprognosis.28 We predict that when new variants of unknownsignificance are detected with more detailed analysis of thefetal genome, the initial response to the lack of knowledgeabout prognosis together with the associated increase inuncertainty will result in an increased number of requests fortermination of pregnancies.

Only once longitudinal clinical follow-up data are availablefor children and adults with novel variants that emerge to beclinically reassuring will the termination request rate reduceas was seen for SCA.

Whether the baby is normal is a major issue for many womenduring pregnancy.29 Once data on a fetus are generated andavailable, there is usually an obligation to communicate theresults, as paternalistic decisions not to communicate results

are rarely acceptable in contemporary medicine. Consequently,communicating test results with uncertain findings generatesreferrals and consultations where subspecialties are needed tocommunicate these complex data to patients. Nonroutineconsultations between specialist professions and couples duringpregnancy are almost never without anxiety for the family,however skilled the professional is at counselling. Reassuringsomeone that an abnormality is not serious or is of unknownsignificance is intrinsically contradictory.

How accurately does a genotype predict a phenotype inindividuals?In the context of a structurally normal fetus, the presence of aDNA sequence abnormality as a predictor of a disease in thechild depends on the penetrance of the variant in theindividual. This is both gene and sequence variant specificand is one of the key challenges of contemporary humangenetics. Autosomal dominant conditions, such as tuberoussclerosis and neurofibromatosis type 1, are highly variablewithin families, and it is notoriously difficult to predict thephenotype on the basis of the genotype alone. This probablyexplains why few families opt for prenatal testing for theseconditions as the genotype alone is a poor predictor of severityof disease. Even for autosomal recessive conditions in whichpenetrance of the disease is usually more predictable, thepenetrance of the disease in the normal unaffected populationis often hard to quantify, as little data are available. Currently,prenatal testing and termination of pregnancy are usuallyoffered to couples with previously affected children, thusconfirming both the pathogenicity and penetrance of thevariants in the family. When prenatal analysis is availablewithout knowledge of the penetrance of the variants withinthe family, the interpretation of the pathogenic significanceof rare variants in disease-causing genes is highly challenging.Recent whole exome and genome sequence analysis of healthyfully informed adults has identified many variants that werepreviously thought to be highly penetrant disease genes,illustrating the difficulty of interpreting the clinical significanceof rare variants in the normal population.12

One way forward may be to consider offering a limited list ofgenes or genomic abnormalities that predict highly penetrant,life-limiting conditions in which prenatal diagnosis is alreadyoffered in societies where termination of pregnancy is acceptedas ethical. Even then, there will be over interpretation of variantdata that has not yet been proven. Similarly, knowledge ofsequence variants that would affect the obstetric managementof a specific pregnancy is justified, for example, those that causeRhesus D alloimmunization and thrombophilia.

For diseases that are not life limiting or severe and forwhich in utero therapeutic options are not currently available,a postnatal assessment may be more appropriate when thephenotypic consequences of variants can be assessed.

For postnatal reporting of incidental findings, the AmericanCollege of Medical Genetics and Genomics (ACMG) and theEuropean Society of Human Genetics (ESHG) propose somewhatdifferent strategies to address the issue of incidental findings.8,30

TheAmerican approach is to report all incidental findings to adultsand children if identified, whereas the European suggestion is



to avoid the detection of incidental findings where possible byhaving agreed limitations on analysis. If within the agreed limits,incidental findings are identified, then appropriate commu-nication of the findings is indicated. For prenatal testing, bothACMG and ESHG have not yet provided recommendations.

Genetic data as a ‘product’ and the relationship between parentand childIn a consumer-driven society where health knowledge can bepurchased, both the right to know about one’s unborn babyand the increasing conceptualization of the baby or child as acommodity are real. The rights of the child and the rights of theparent to know are dependent on cultural differences andattitudes towards parenting. Concepts of stewardship andobligation vary across cultures, but little research has beenperformed as to whether having extensive genetic knowledgeabout one’s child will influence the subsequent relationshipbetween parent and child. For diseases such as Huntingtondisease, prenatal testing for information only is not currentlyoffered, as it denies the right of the child to exercise his or herown right not to know his or her risk of disease.31 The principleof respect of the autonomy of the child has been in place sincethe Huntington disease gene was identified in 1994. A changein practice from this position needs careful consideration. Thecounter argument is that for some conditions, early interventionand therapeutics may ameliorate a disease if detected early, andthis would potentially justify the knowledge gained. At this stage,this is true for very few diseases that would justify prenatal ratherthan postnatal detection.

At this stage of knowledge, I would argue, that it is premature toreport all incidental findings to parents, as we have insufficientevidence that this will improve health care outcomes. However,I would advocate the development of agreed-upon principles asto what would be appropriate to communicate to parentsprenatally, such that parents would have the possibility ofdetailed information about a disease that is predictable on thebasis of genotype. Alternatively, parents would have the optionof termination of pregnancy in the event of detecting genomicabnormalities that predict severe life limiting geneticconditions that may have arisen de novo. I would advocatefor the use of comprehensive postnatal genomic testing wherethere is evidence of a medical problem in a child, and I wouldnot advocate that the health gains of opportunist screening forall incidental findings outweighs the loss of autonomy of thechild when the child is clinically normal.

CONCLUSIONS (THE-HUNG BUI)With the advent of genomic technologies such as array-basedmethods and whole exome or whole genome sequencing,

the genetic causes underlying various pediatric and adultphenotypes in many patients are potentially identifiable.Applications of such technologies prenatally have the potentialto provide ancillary disease risk information (incidental findings).This potential should be considered as such tests are brought intoclinical use. Implicationsmay varywith each type of test, but thesetests should be evaluated individually within a framework thatoutlines the potential implications of ancillary information. Somehave argued against an exceptionalist approach to geneticinformation, but unless actively recognized and included inpractice guidelines and other policy-making activities, thepotential harm of ancillary risk informationmight not be properlyconsidered. Policy makers will need to consider when and howancillary information should be provided to patients, whetherformal informed consent procedures are needed, and how risksand benefits of ancillary risk information should be weighed. Forthe foreseeable future, however, each individual whose genomein part or whole is sequenced will have vast numbers of variantsidentified that are of uncertain clinical significance at our presentstate of knowledge. Themajor challenge to the implementation ofthe technology is properly interpreting the variants found uponanalyzing any individual’s genome. Fortunately, interpretation ofincidentalfindingsmay ease aswe obtainmore information aboutfrequency and long-term outcome of certain variants of uncertainsignificance. To achieve this, it will be important that suchinformation is collected and shared through easily accessibledatabases. Even with this in place, the management of incidentalfindings and the relevance for patient care decisions remain acontroversial issue. There is a need for consensus guidelines onincidental findings in prenatal diagnosis and such a task shouldbe considered by an organization such as the International Societyfor Prenatal Diagnosis.

WHAT’S ALREADY KNOWN ABOUT THIS TOPIC?

• Incidental findings can occur in many areas of diagnostic testing.• Incidental findings, including those of uncertain significance, have

many complicated aspects or prenatal diagnosis and are not limitedto genetic testing.

• Whereas guidelines for which findings should be reported andhow to report them are being developed in the pediatricand adult genetic testing, little to no guidance exists forprenatal diagnosis.

WHAT DOES THIS STUDY ADD?

• We report two opinions on how to address incidental findings onthe basis of a debate at the 17th annual conference of theInternational Society for Prenatal Diagnosis.

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Health & Medicine

Current controversies in prenatal diagnosis 2 should incidental