This document summarizes a presentation on whether incidental findings from prenatal testing should always be reported to patients. It discusses the case for reporting all incidental findings by defining what incidental findings are and outlining the purpose and goals of prenatal diagnosis. It then applies principles of medical ethics including autonomy, beneficence, non-maleficence, and justice to argue that incidental findings of known clinical significance that are actionable should be reported. It acknowledges the difficulty of incidental findings of unknown significance but still argues they should be shared with parents so they can make informed decisions. Finally, it addresses concerns about discovering late-onset untreatable diseases and risks of anxiety, but concludes that an ethical approach is to

1. ISPD 2013 MEETING PRESENTATION
Current controversies in prenatal diagnosis 2: should incidental
findings arising from prenatal testing always be reported
to patients?
The-Hung Bui1*†
, Frances Lucy Raymond2†
and Ignatia B. Van den Veyver3†
1
The Karolinska Institute, Center for Molecular Medicine, Clinical Genetics Unit and Center for Fetal Medicine, Karolinska University Hospital, Stockholm, Sweden
2
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
3
Departments of Obstetrics and Gynecology and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
*Correspondence to: The-Hung Bui. E-mail: the.bui@karolinska.se
†
All authors contributed equally.
Funding sources: None
Conflicts of interest: Ignatia B. Van den Veyver is a member of the Baylor College of Medicine Department of Molecular and Human Genetics, which houses the
diagnostic Medical Genetics Laboratories that offer various forms of genetic testing, including for prenatal diagnosis, on a fee for service basis, but she does not
derive personal revenue from this activity.
INTRODUCTION (THE-HUNG BUI)
Our ability to measure and quantify variation in human
development is rapidly increasing, not least in the area of
genetic investigation. However, our understanding of the
implications of this variation is far behind our ability to
describe it. A powerful motivation for research and
development is the desire to improve knowledge and care of
those who seek medical attention but also to interpret data
correctly and to communicate findings with the appropriate
evidence and to do no harm nor create undue anxiety.
The discovery of an incidental finding as the result of a
diagnostic or screening procedure has complicated nearly
all aspects of clinical research and diagnostics.1–4
Traditionally, such findings were relatively rare, and
decisions about how and when to report them were mostly
left to the judgment of healthcare providers within the
confines of individual physician–patient relationships. With
recent technical advances in diagnostic methodologies,
combined with more ready access and willingness to use
them, incidental findings have become more common,
and the findings themselves have become more complex.4
The debate on reporting of incidental findings is motivated
by this massive increase in genetic information available
and our current deficiencies of knowledge about the clinical
significance of much of these data, rather than by general
principles of communicating and observing incidental
findings in prenatal diagnosis. The essence of the debate
is whether all variants should be communicated to users
of prenatal services or whether there are limits as to what
should be returned and what would be the basis of this
selection or restriction.
THE CASE FOR REPORTING ALL INCIDENTAL FINDINGS
(IGNATIA B. VAN DEN VEYVER)
There are two main types of incidental findings in prenatal
diagnosis and screening. First are those associated with
prenatal imaging, including high-resolution ultrasound and
fetal magnetic resonance imaging. While important, they are
not reviewed in detail for this report but can be contrasted with
those of the second category, which are the incidental findings
that arise during genetic screening or a genetic diagnostic test.
Reporting incidental findings in genetic research and clinical
testing is currently highly debated,4–7
but debates or proposed
guidelines typically exclude considerations relevant to prenatal
testing.4,8
Nevertheless, we can learn from other genetic
diagnostic circumstances to help address whether and how such
findings should be reported prenatally. This is an important
question that must be considered by the prenatal diagnosis
community, individual prenatal healthcare providers, and parents
who choose to undergo prenatal genetic screening and/or
testing.9,10
To arrive at the best answer, we must first define what
is an incidental finding and then consider practical and ethical
aspects 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 significance
unexpectedly discovered in patients or in healthy subjects
unrelated to the purpose of the diagnostic study or test’.8,11–13
This definition implies that an incidental finding carries with
it clinically useful information that may benefit the health of
the individual being tested, but that information was unrelated
Prenatal Diagnosis 2014, 34, 12–17 © 2013 John Wiley & Sons, Ltd.
DOI: 10.1002/pd.4275

2. to the primary goal of the diagnostic study. This can be difficult
to define,5,8
and we must consider to whom ‘useful’ applies. Is
it the fetus, or also the parents, siblings, or even the extended
family of the fetus? We must also consider what clinically useful
means.11,14
Should we only report findings that are of well-
defined clinical relevance, and within that category, should we
only report incidental findings for which an intervention is
possible that has therapeutic benefit? What should we do with
the findings of defined clinical significance but for which there
is no known therapy? What should we do with the findings of
uncertain significance that we know may have clinical impact
but not in all cases? What should we do with incidental findings
for which it is unknown but possible that there is clinical impact?
What about genetic changes that are causative for late-onset
adult disorders for which it has been argued that the ‘right to
an open future’ should be a barrier to reporting such mutations
prenatally or in childhood. These are complex questions that
require thoughtful consideration.
Purpose and goals of prenatal diagnosis
The purpose of prenatal screening and diagnosis is to provide
information to prospective parents about the current and
future health of their unborn children. Considering that
decisions regarding fetal and neonatal care resulting from
prenatal diagnostic information may have implications not
only for the fetus but also for the mother and the nuclear
family, the diagnostic information provided should benefit
the well-being of the family, including first not only the future
child, but also the parents, siblings, and even other extended
family members. In this context, well-being encompasses not
only the physical but also the mental and social aspects.
Under ideal circumstances, all prenatal diagnosis would be
noninvasive 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 common aneuploidies. We would also prefer that all tests
are cost-effective; widely available; and easy to explain, interpret,
and counsel about and that the results are conclusive, only
relevant to the conditions for which we test without incidental
findings of potentially uncertain significance. Clearly, we cannot
achieve all of these goals, but it is our ethical responsibility as
prenatal care providers to manage rather than to avoid these
complexities of our profession, keeping in mind the best interest
of the fetus and the family.
Applying principles of medical ethics
The four principles of medical ethics – autonomy, beneficence,
non-maleficence, and justice (Table 1) – provide an ethical
framework for healthcare professionals whenever difficult
clinical decisions arise for which there may be real or perceived
competing interests for providers or patients.15
The principle
of autonomy embodies respect for the patient’s right to choose
or to refuse treatment.15
This is at the core of the informed
consent process for testing and treatment and carries with it
the obligation for good communication between healthcare
providers and patients. Important for a debate on reporting
incidental findings is that patients (or their legal representative
decision makers) cannot exert autonomy if not provided with
full information4,5,16
and equally important is whether a
generic consent that bins categories of results,14
although
practical, can be considered fully informed.10
Beneficence requires that a practitioner act in the best
interest 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 as
the child’s representatives, are also bound by the beneficence
principle to act in the best interest of the fetus.10
It has therefore
been argued that the right of parents to know or not to
know diagnostic information (autonomy) conflicts with the
beneficence-based responsibility towards the fetus in the setting
of prenatal diagnosis.17
Under these circumstances, beneficence
is considered more important than autonomy.10
However, when
the ultimate goal that prenatal diagnostic information should
benefit the well-being of the fetus within the context of the
family’s well-being is considered, the capacity of parents to
exercise autonomy in their decisions is reconcilable with the
principle of beneficence.
The principle of non-maleficence together with beneficence
encompasses the ‘first do no harm’ and ‘duty to warn’
responsibilities of the healthcare provider.4,15
This supports
reporting of actionable incidental findings, that is, those results
for which it is known that a preventive measure or intervention
is available to reduce risk or improve health.8
Not reporting such
prenatal diagnostic results to parents carries a risk of causing
harm and is a strategy that is difficult to endorse. Furthermore,
incidental results from prenatal diagnostic testing on the fetus
may have direct implications for the health of the parent. For
example, incidentally discovered cancer-predisposing mutations
may be inherited from a parent, who can be placed on a cancer
screening and prevention protocol.10,18
Equality of access to care
and of distribution of health care resources, as well as respect for
people’s rights and the law are components of the principle of
justice. While important in multiple aspects of healthcare, it
provides less guidance for the specific question of reporting
incidental findings, which is more easily considered in view of
the 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
Prenatal Diagnosis 2014, 34, 12–17 © 2013 John Wiley & Sons, Ltd.

3. The difficulty with incidental findings (variants) of unknown
significance
The aforementioned reasoning supports reporting incidental
findings of known clinical significance that are actionable,8,11
but it may not be immediately obvious that the same applies
to the findings or variants of unknown significance (VOUS)19
These are results that may be of clinical significance but with
variable expressivity so that we cannot predict what the
phenotype will be after birth, such as for example, a 16p11.2
deletion detected by chromosomal microarray. This is a
relatively common deletion in individuals ascertained for
developmental delay, intellectual disability, and autism.
However, the phenotype associated with deletion 16p11.2 is
highly variable, even within families, and apparently
unaffected or very mildly affected cases exist. Thus, it is
difficult to predict how severe these manifestations will be
when it is detected prenatally. In other cases, there may be a
genetic change for which there is not enough information as
to whether the finding will result in a clinically significant
phenotype, for example, an unclassified sequence variant in a
known disease-associated gene for a disorder with no prenatal
phenotype. Findings of uncertain significance are not unique
or new to genetic testing and have always complicated
prenatal diagnosis. While they often create difficult and
complex counseling situations, they are health-related
information that has the potential to be relevant to the
well-being of the tested individual.9
The ethical principle of
autonomy supports that the information is shared with parents
to allow them to make decisions with the available
information. A detailed discussion of VOUS is beyond the
scope of this report, but they come with many practical
challenges involving pretest counseling and informed consent
procedures, definition and classification of VOUS, and who
should report them.9,19,20
Whereas it is the responsibility of
those developing new tests and the diagnostic laboratories that
offer the tests to aim for testing platforms that avoid the
discovery of true VOUS, they cannot be fully eliminated
without compromising diagnostic power for important
disorders. Therefore, when VOUS occur, we should be
prepared to share this information with parents in the best
possible way so that they can exert their autonomy in decisions
about 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 undergo
presymptomatic genetic testing for late-onset disorders for
which no cure is available, such as familial Alzheimer disease,
Huntington disease, or spinocerebellar ataxias to preserve the
child’s right to an open future and to an education that is
unbiased by the prior knowledge that there will be impairment
in later adulthood.21
Genetic societies have endorsed or
developed guidelines in support of this approach,22
but this
topic has become more debated recently.21
The same
principles have been extended to prenatal and
preimplantation genetic diagnosis, with adaptations that take
into account the option of avoiding (through preimplantation
genetic diagnosis) or terminating affected pregnancies, as well
as the unavoidable presymptomatic discovery of the disorder
in a carrier parent through fetal testing.23,24
Whereas these
guidelines are very beneficial for targeted testing, they
preceded the explosion of genome-wide genetic tests that are
capable of incidentally discovering mutations that cause these
conditions. Most laboratories have taken the approach of not
reporting them in children and presymptomatic adults, but it
remains an open question how best to handle them in prenatal
diagnosis for two important reasons. First, when discovered
during prenatal diagnosis, the disorder can be prevented if
parents choose the option of not continuing a pregnancy.
Second, it should be examined what the right to an open future
signifies and whether we infringe autonomy by shielding
information that may allow parents and young adults to make
decisions about their future that take into consideration all
aspects of their current or future health. It is not well
established that not providing this predictive information is
the only direction to preserve the right to an open future.25
Risks, benefits, and guidelines
One argument put forward for not reporting incidental findings
is the risk of causing parental anxiety about a finding that is of
uncertain significance for which there are no interventions
available. This is indeed an unavoidable consequence of
reporting incidental findings but not one that is new to prenatal
diagnosis. As providers we need to assume responsibility for this
by providing expert counseling and support for the families we
are caring for, rather than hiding this information from families.
Advances in technologies for genetic testing will likely generate
more incidental findings, creating the need for more genetic
counseling professionals, and for better appreciation of their
services. As a discipline, we must assume responsibility for
training more genetic counselors and for motivating
governments and regulatory instances to recognize their
services with appropriate licensing and reimbursement. We
must also proactively become involved in educating other
providers, such as general practitioners and obstetrician–
gynecologists, and various fetal care-related subspecialists, in
the intricacies of newer genetic tests. Vice versa, we should be
prepared to integrate their knowledge with how we most
optimally interpret the test results and counsel patients.
Some incidental findings from prenatal diagnosis may cause
unnecessary or justified anxiety that may be prolonged while the
child grows into adulthood. However, in this era, a paternalistic
approach to medical care is no longer considered acceptable,
and the ethical principle of autonomy therefore mandates the
disclosure of the information.9
Furthermore, considering that the
pace and scope of advances in medicine are unpredictable, we
cannot have the foresight in many cases what the future benefit
of knowing an incidental finding could be. From that perspective,
putting the decision as to what constitutes the ‘right to an open
future’ only in the hands of health professionals may conflict with
autonomy and beneficence.
In summary, reporting incidental findings in prenatal
diagnosis is a complex issue, but it is not limited to the results
of 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
Prenatal Diagnosis 2014, 34, 12–17 © 2013 John Wiley & Sons, Ltd.

4. from other diagnostic testing on how to manage these
unanticipated results. In general, as the benefit or harm from
reporting them will vary depending on the individual patient
within his or her family structure, we have to assume the
professional responsibility to report them and allow patients
(parents) the autonomy to make decisions on the basis of the
results. We also have the responsibility to do so under the most
supportive counseling circumstances possible.
Unfortunately, we do not yet have professional guidelines on
how to handle these complex issues in prenatal diagnosis and
most guidelines available or in preparation explicitly exclude
prenatal diagnosis situations. Thus, it will be up to our
professions to assume the responsibility for generating
guidelines that are applicable to prenatal diagnosis.
THE CASE AGAINST REPORTING ALL INCIDENTAL
FINDINGS (LUCY RAYMOND)
There are three areas that merit consideration when discussing
whether incidental findings should be reported to patients: (1)
The mandate to do no harm and the misuse or
misinterpretation of the data. (2) How accurately does a
genotype predict a phenotype in individuals? and (iii) Genetic
data as a ‘product’ and the potential effect of parental
information about a baby with respect to the ongoing
relationship between parent and child.
The misuse or misinterpretation of incidental findings
Except in rare circumstances of X-linked genetic diseases or
disorders of sex, knowing the gender of a fetus is of no medical
importance. However, fetal selection by termination of pregnancy
and preferences for one sex is still widespread in cultures where
the perceived value of each gender is different.26,27
This is a
powerful illustration that incidental knowledge of the genome is
not always medical and is used as a social tool by some, whilst
others would regard this as unacceptable.
The identification of any variant of normal during pregnancy
is always unsettling to couples and creates uncertainty. Sex
chromosome anomalies (SCA) are usually reported to families
as an incidental finding as a consequence of prenatal testing
for autosomal aneuploidy. The rate of termination of
pregnancy for SCA was initially high when introduced because
of the lack of knowledge about the prognosis for these
conditions and has gradually decreased over time as data have
emerged from long term follow-up studies, which show a good
prognosis.28
We predict that when new variants of unknown
significance are detected with more detailed analysis of the
fetal genome, the initial response to the lack of knowledge
about prognosis together with the associated increase in
uncertainty will result in an increased number of requests for
termination of pregnancies.
Only once longitudinal clinical follow-up data are available
for children and adults with novel variants that emerge to be
clinically reassuring will the termination request rate reduce
as was seen for SCA.
Whether the baby is normal is a major issue for many women
during pregnancy.29
Once data on a fetus are generated and
available, there is usually an obligation to communicate the
results, as paternalistic decisions not to communicate results
are rarely acceptable in contemporary medicine. Consequently,
communicating test results with uncertain findings generates
referrals and consultations where subspecialties are needed to
communicate these complex data to patients. Nonroutine
consultations between specialist professions and couples during
pregnancy are almost never without anxiety for the family,
however skilled the professional is at counselling. Reassuring
someone that an abnormality is not serious or is of unknown
significance is intrinsically contradictory.
How accurately does a genotype predict a phenotype in
individuals?
In the context of a structurally normal fetus, the presence of a
DNA sequence abnormality as a predictor of a disease in the
child depends on the penetrance of the variant in the
individual. This is both gene and sequence variant specific
and is one of the key challenges of contemporary human
genetics. Autosomal dominant conditions, such as tuberous
sclerosis and neurofibromatosis type 1, are highly variable
within families, and it is notoriously difficult to predict the
phenotype on the basis of the genotype alone. This probably
explains why few families opt for prenatal testing for these
conditions as the genotype alone is a poor predictor of severity
of disease. Even for autosomal recessive conditions in which
penetrance of the disease is usually more predictable, the
penetrance of the disease in the normal unaffected population
is often hard to quantify, as little data are available. Currently,
prenatal testing and termination of pregnancy are usually
offered to couples with previously affected children, thus
confirming both the pathogenicity and penetrance of the
variants in the family. When prenatal analysis is available
without knowledge of the penetrance of the variants within
the family, the interpretation of the pathogenic significance
of rare variants in disease-causing genes is highly challenging.
Recent whole exome and genome sequence analysis of healthy
fully informed adults has identified many variants that were
previously thought to be highly penetrant disease genes,
illustrating the difficulty of interpreting the clinical significance
of rare variants in the normal population.12
One way forward may be to consider offering a limited list of
genes or genomic abnormalities that predict highly penetrant,
life-limiting conditions in which prenatal diagnosis is already
offered in societies where termination of pregnancy is accepted
as ethical. Even then, there will be over interpretation of variant
data that has not yet been proven. Similarly, knowledge of
sequence variants that would affect the obstetric management
of a specific pregnancy is justified, for example, those that cause
Rhesus D alloimmunization and thrombophilia.
For diseases that are not life limiting or severe and for
which in utero therapeutic options are not currently available,
a postnatal assessment may be more appropriate when the
phenotypic consequences of variants can be assessed.
For postnatal reporting of incidental findings, the American
College of Medical Genetics and Genomics (ACMG) and the
European Society of Human Genetics (ESHG) propose somewhat
different strategies to address the issue of incidental findings.8,30
The American approach is to report all incidental findings to adults
and children if identified, whereas the European suggestion is
Reporting incidental findings in prenatal diagnosis 15
Prenatal Diagnosis 2014, 34, 12–17 © 2013 John Wiley & Sons, Ltd.

5. to avoid the detection of incidental findings where possible by
having 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, both
ACMG and ESHG have not yet provided recommendations.
Genetic data as a ‘product’ and the relationship between parent
and child
In a consumer-driven society where health knowledge can be
purchased, both the right to know about one’s unborn baby
and the increasing conceptualization of the baby or child as a
commodity are real. The rights of the child and the rights of the
parent to know are dependent on cultural differences and
attitudes towards parenting. Concepts of stewardship and
obligation vary across cultures, but little research has been
performed as to whether having extensive genetic knowledge
about one’s child will influence the subsequent relationship
between parent and child. For diseases such as Huntington
disease, prenatal testing for information only is not currently
offered, as it denies the right of the child to exercise his or her
own right not to know his or her risk of disease.31
The principle
of respect of the autonomy of the child has been in place since
the Huntington disease gene was identified in 1994. A change
in practice from this position needs careful consideration. The
counter argument is that for some conditions, early intervention
and therapeutics may ameliorate a disease if detected early, and
this would potentially justify the knowledge gained. At this stage,
this is true for very few diseases that would justify prenatal rather
than postnatal detection.
At this stage of knowledge, I would argue, that it is premature to
report all incidental findings to parents, as we have insufficient
evidence that this will improve health care outcomes. However,
I would advocate the development of agreed-upon principles as
to what would be appropriate to communicate to parents
prenatally, such that parents would have the possibility of
detailed information about a disease that is predictable on the
basis of genotype. Alternatively, parents would have the option
of termination of pregnancy in the event of detecting genomic
abnormalities that predict severe life limiting genetic
conditions that may have arisen de novo. I would advocate
for the use of comprehensive postnatal genomic testing where
there is evidence of a medical problem in a child, and I would
not advocate that the health gains of opportunist screening for
all incidental findings outweighs the loss of autonomy of the
child when the child is clinically normal.
CONCLUSIONS (THE-HUNG BUI)
With the advent of genomic technologies such as array-based
methods and whole exome or whole genome sequencing,
the genetic causes underlying various pediatric and adult
phenotypes in many patients are potentially identifiable.
Applications of such technologies prenatally have the potential
to provide ancillary disease risk information (incidental findings).
This potential should be considered as such tests are brought into
clinical use. Implications may vary with each type of test, but these
tests should be evaluated individually within a framework that
outlines the potential implications of ancillary information. Some
have argued against an exceptionalist approach to genetic
information, but unless actively recognized and included in
practice guidelines and other policy-making activities, the
potential harm of ancillary risk information might not be properly
considered. Policy makers will need to consider when and how
ancillary information should be provided to patients, whether
formal informed consent procedures are needed, and how risks
and benefits of ancillary risk information should be weighed. For
the foreseeable future, however, each individual whose genome
in part or whole is sequenced will have vast numbers of variants
identified that are of uncertain clinical significance at our present
state of knowledge. The major challenge to the implementation of
the technology is properly interpreting the variants found upon
analyzing any individual’s genome. Fortunately, interpretation of
incidental findings may ease as we obtain more information about
frequency and long-term outcome of certain variants of uncertain
significance. To achieve this, it will be important that such
information is collected and shared through easily accessible
databases. Even with this in place, the management of incidental
findings and the relevance for patient care decisions remain a
controversial issue. There is a need for consensus guidelines on
incidental findings in prenatal diagnosis and such a task should
be considered by an organization such as the International Society
for 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 limited
to genetic testing.
• Whereas guidelines for which findings should be reported and
how to report them are being developed in the pediatric
and adult genetic testing, little to no guidance exists for
prenatal diagnosis.
WHAT DOES THIS STUDY ADD?
• We report two opinions on how to address incidental findings on
the basis of a debate at the 17th annual conference of the
International Society for Prenatal Diagnosis.
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