AJPH HISTORYAugust 2017, Vol 107, No. 8 AJPH Bayer .docx

AJPH HISTORY
August 2017, Vol 107, No. 8 AJPH Bayer Peer Reviewed
Public Health Then and Now 1259
The End of Written Informed Consent for HIV
Testing: Not With a Bang but a Whimper
Ronald Bayer, PhD, Morgan Philbin, PhD, and Robert H.
Remien, PhD
In 2014, only two states in the United States still mandated
specific written informed consent for
HIV testing and, after years of controversy, New York ended
this requirement, leaving only Ne-
braska. New York’s shift to opt-out testing meant that a singular
feature of what had characterized
the exceptionalism surrounding HIV testing was eliminated. We
trace the history of debates on
written informed consent nationally and in New York State.
Over the years of dispute from when
HIV testing was initiated in 1985 to 2014, the evidence about
the benefits and burdens of written
informed consent changed. Just as important was the
transformation of the political configuration
of HIV advocacy and funding, both nationwide and in New York

State. What had for years been the
subject of furious debate over what a rational and ethical
screening policy required came to an
end without the slightest public protest. (Am J Public Health.
2017;107:1259–1265. doi:10.2105/
AJPH.2017.303819)
In 2014, New York and Nebraska were the only
states that still required written
informed consent for HIV
testing, a signature element of
public policy that dated from
the 1980s. New York then
abandoned the requirement.
Remarkably, despite a long and
often bitterly contested past
that engaged public health offi -
cials, clinicians, AIDS advocacy
groups, and civil liberties orga-
nizations, the fi nal elimination
of written informed consent for

HIV testing occurred with little
public debate.
Conventionally, the story of
HIV testing policy involves the
commitments that began when
the evidence for addressing both
the clinical and public health
challenges of AIDS was still very
uncertain. The conventional
narrative argues that public
health offi cials slowly became
convinced by evidence demon-
strating that written informed
consent impeded the rollout of
HIV testing on a mass scale, a
process that culminated in 2006
when the Centers for Disease
Control and Prevention (CDC)

issued recommendations for an
opt-out approach without writ-
ten informed consent. Those
who opposed this opt-out
approach were equally certain
that the evidence did not sup-
port the claim that written in-
formed consent was a barrier to
sound public health practice. In
time, however, the overwhelm-
ing evidence—coupled with
political and funding shifts—
convinced many individuals
who had been most deeply
committed to written consent.
Deeply rooted opposition did
not, however, vanish.
We seek to locate the con-

troversy over written informed
consent in a broad political
context. We take account of
how and why groups that had
confronted each other for years
came to see the evidence so dif-
ferently and why the advocacy
community eventually yielded.
Although the evidence about the
burdens and benefi ts of written
informed consent had not signif-
icantly changed in the last years
of the controversy, the political
confi guration surrounding HIV/
AIDS policy had. What may
appear to be remarkable was, in
fact, a long time in coming.
LOOKING BACK

When HIV antibody test-
ing fi rst became possible in
1985, there was considerable
uncertainty about the signifi -
cance of a positive fi nding and
the prognosis of HIV-infected
individuals. Within a year public
health offi cials embraced HIV
testing as a potentially signifi -
cant contribution to confront-
ing the evolving epidemic, but
many of the fi rst generation of
AIDS activists greeted the test
with alarm.1 The psychological
impact of the diagnosis in the
context of therapeutic impo-
tence, coupled with very realistic
concerns about discrimination,

stigmatization, and anxiety
about the prospect of a turn to
coercive public health policy,
shaped the worldview of activists
who sought to protect vulner-
able populations from privacy
intrusions and the deprivation of
the fundamental right to choose
whether to be tested. Advocates
argued that written informed
consent would provide necessary
protection for those who might
otherwise be dragooned by pub-
lic health offi cials. The national
AIDS activist movement quickly
succeeded in making written
informed consent, along with
pre- and posttest counseling, the

standard of care nationwide. The
fi rst ethical framework for con-
fronting the challenge of AIDS
and HIV testing embraced this
position2; HIV exceptionalism
defi ned the moment.3
AJPH HISTORY
AJPH August 2017, Vol 107, No. 81260 Public Health Then
and Now Peer Reviewed Bayer
New York State’s experi-
ence exemplifi ed the situa-
tion. Looking back after three
decades, the director of New
York State’s AIDS Institute, part
of the State’s Health Depart-
ment, wrote,
New York State was an early
adopter of strong statutory

protections for persons seek-
ing HIV testing, including
required pretest counseling and
written informed consent.4
Under a 1989 law, written con-
sent became the legal norm, and
violations could result in civil
and criminal sanctions, includ-
ing fi nes of up to $5000 and
imprisonment for one year.
By the early 1990s public
health offi cials were increasingly
able to manage opportunistic
infections and create targeted
prevention programs, which
challenged the empirical and
ethical justifi cations for the
protective framework grounded

in written informed consent.
The discovery in the mid-1990s
that highly active anti-retroviral
therapy could prolong the lives
of HIV-infected individuals
shifted the national conversa-
tion. Nevertheless, it would
take years of debate before
the requirements of pre- and
posttest counseling and written
informed consent could be
dislodged.5 In the face of ongo-
ing sociopolitical anxieties and
the persistence of stigmatiza-
tion, evidence alone could not
override the politics of HIV
exceptionalism.
The erosion of the ear-

lier consensus was powerfully
underscored by the 2005 World
AIDS Day editorial by Thomas
Frieden, then commissioner
of health in New York City.
Written fi ve years before the
passage of the Aff ordable Care
Act provided protection against
denial of insurance coverage on
the basis of preexisting condi-
tions, the editorial asserted,
Given the availability of drugs
that can effectively treat HIV
infection and progress on anti-
discrimination initiatives per-
haps society is ready to adopt
traditional disease control prin-
ciples and proven interven-

tions that can identify infected
persons, interrupt transmission,
ensure treatment and case
management and monitor
infection and control efforts
throughout the population.6
Policies that made such identifi -
cation diffi cult could no longer
be justifi ed from the perspec-
tive of public health or clinical
medicine. The failure to adopt
more aggressive testing policies
and eliminate written consent
and routinize opt-out testing
would entail a wholesale denial
of the evidence that, “routine
voluntary screening for HIV is
indicated on the basis of clinical

effi cacy and cost-eff ectiveness.”7
Two months after Frie-
den’s editorial, the New York
City Department of Health
and Mental Hygiene issued a
detailed set of recommendations
that mirrored his views.8 It made
clear that the recommenda-
tions did not call for mandatory
testing but instead proposed the
routinization of HIV testing;
HIV testing laws would con-
tinue to require that all testing
be voluntary with specifi c docu-
mented oral consent. Penalties
for HIV testing without consent
would be increased.
Frieden’s forceful move

received backing from the New
York Times editorial board:
While there is a danger that
some patients might be hood-
winked into taking a test
they would otherwise shun,
it seems reasonable to treat
AIDS like any other infectious
or sexually transmitted disease.
Wider testing might save some
lives and alert people not to
spread the virus. . . . Surely
most patients would rather get
life extending treatments than
languish in neglect.9
Deeply concerned by the esti-
mate that 20% of HIV-
infected Americans did not know

their status, the CDC worked to
update its practices and poli-
cies. In September 2006, after a
careful review of the evidence,
the CDC issued new recom-
mendations for the routinization
of HIV screening that involved
an opt-out approach to consent
and the elimination of specifi c
“These new recommendations,”
said Kevin Fenton, director of
the National Center for HIV/
AIDS, Viral Hepatitis, STD,
and TB Prevention, “will make
routine HIV screening feasible
in busy medical centers where it
previously was impractical.”11

Thus the stage was set for a
cascade of regulatory and legisla-
tive changes across the nation.
The speaker of the American
Medical Association’s House of
Delegates called on states “to
reexamine legislation to allow
physicians to carry out the
new CDC recommendation.”12
Before the publication of the
CDC’s recommendations, 20
states required separate writ-
ten informed consent for HIV
testing. A review published in
the Journal of the American Medical
Association in 2011 concluded,
Nearly all states’ laws and
administrative codes were

compatible with current CDC
HIV testing recommendations
on consent and counseling.13
Some individuals, such as Peter
Staley, a founder of the AIDS
Coalition to Unleash Power,
supported this shift:
AJPH HISTORY
I realize that abandoning
written informed consent
raises issues. People are
worried about privacy and
stigma. But the bottom line
is that this would probably
save lives and that’s why I’m

very much in favor of it.14
But many AIDS advocacy
groups dismissed such assess-
ments. After the CDC’s call
for the routinization of HIV
screening, 33 AIDS-related
groups, including the American
Foundation for AIDS Research,
Gay Men’s Health Crisis, the
HIV Law Project, Housing
Works, and Λ Legal, issued a
joint challenge.15 Although
acknowledging that expanded
voluntary counseling and testing
was “good public health policy,”
they dismissed the necessity of
such reforms:
An expanded focus on test-
ing without counseling and

written informed consent will
put people at risk for testing
without their prior knowledge
or approval—a clear violation
of medical ethics and human
rights.
One activist claimed,
This is not informed consent,
and it is not even consent, it
was an attempt to ram HIV
testing down people’s throat
without their permission.16
NEW YORK NINE
YEARS OF CONTENTION
In the face of such opposi-
tion, legislators in New York
State tried repeatedly from 2006
to 2010 to address the restrictive

legal constraints under which
HIV testing could occur. In this
period, 169 HIV-related bills
were introduced to the state
legislature, 12 of which explicitly
addressed informed consent.17
What unfolded was a mor-
ally charged debate regarding
whether written informed
consent impeded what all agreed
was crucial: that individuals who
were infected but unaware be
able to learn their HIV status.
The New York State Medical
Society, which exemplifi ed one
side of this argument, wrote a
letter to Assemblywoman Nettie
Myerson, a leading proponent of

routinizing HIV testing:
For over 20 years, physicians
and other health care person-
nel have not been allowed to
offer HIV testing as part of the
standard tests that are offered
patients.18
Paradoxically, the very excep-
tionalism that was designed to
protect those at risk had stigma-
tized the test for the disease.
In a New York State Assem-
bly public hearing in 2006,19
Richard Gottfried—who was
the chair of the Assembly’s
Health Committee and had
long-established links to New
York’s lesbian, gay, bisexual,

and transgender community—
continued to defend written
informed consent while making
clear his moral commitment to
both privacy and evidence-based
practice. He proposed an idea
fi rst developed by the Legal Ac-
tion Center called “mandatory
off er,” which required an explicit
off er of HIV counseling and
testing to all patients in health
care facilities without regard
to risks factors while retaining
Paradoxically, this new approach
would actually serve to increase
the time burdens associated with
testing in the clinic. Mandatory

off er became the rallying cry
of those who believed that the
protection of individual rights
was not at odds with the public’s
health. Gay Men’s Health Crisis,
among the oldest and most es-
tablished AIDS service organiza-
tion in New York, declared,
There is absolutely no scien-
tific evidence that the statu-
tory requirements of written
informed consent and counsel-
ing pose an actual barrier to
testing.21
Though activists anchored their
opposition in their view of the
evidence, what drove the pas-
sion to retain written informed

consent was a conception of
what respect for autonomy
and human dignity necessi-
tated. Housing Works, another
community-based organiza-
tion, also denounced the 2006
proposals made by New York
City’s health commissioner as
“One of the greatest threats ever
posed in the State of New York
to the privacy rights of people
living with AIDS and HIV.”22
The Long Island Minority AIDS
Coalition asserted that it was
“unconscionable” that patients
would no longer have the right
to written informed consent.23
In 2006 the fi rst crack

emerged in the previously solid
wall of opposition. The avail-
ability of powerful HIV-related
treatments was central to this
change, as was the mission shift
among AIDS advocacy orga-
nizations toward becoming
AIDS services organizations.
Harlem United became the
fi rst community-based AIDS
organization to assert that the
prevailing approach to testing
was inadequate:
It is difficult . . . not to view
separate written consent as
part of a broader practice of
testing that is failing us. . . .
Although our stance may dis-

turb colleagues, new realities
demand new tactics to stop
the spread of HIV and fur-
ther reduce AIDS deaths. We
should routinize HIV testing
AJPH HISTORY
in accordance with CDC’s
new guidelines. . . . [Current]
HIV testing policy, amounts to
arguing that those most at risk
have a civil right to a greater
likelihood of spreading HIV
infection within their own
community or dying sooner of
AIDS.24
At an organizational level, a

striking racial/ethnic divide
had begun to emerge within
the AIDS advocacy community.
Harlem United was joined by
the Latino Commission on
AIDS and the National Black
Leadership Commission on
AIDS, which issued a summary
of evidence that unequivo-
cally demonstrated that written
consent was in fact a bar-
rier to routine HIV testing.25
Their opponents were largely,
although not exclusively, orga-
nizations led by gay White men,
longtime veterans of AIDS-
related battles.
As the legislative battle un-

folded from 2006 to 2010, the
divide between what most AIDS
activist groups held as morally
necessary and empirically un-
ambiguous and the views of the
public health and medical com-
munities continued to widen.
The New York State Associa-
tion of County Health Offi cials
in 200726 and the American
College of Obstetricians and
Gynecologists in 200827 joined
the Medical Society of the State
of New York to call for an end
to the exceptionalism sur-
rounding the state’s HIV testing.
In 2007, the deeply divided
state-appointed AIDS Advisory

Council voted fi ve to three to
support a resolution stating,
“The requirement for written
informed consent for HIV test-
ing in medical settings should be
removed.”28
Despite the certitude with
which opponents of written
consent described the evidence,
the bulk of the AIDS advo-
cacy community continued to
maintain that written informed
consent did not impede testing.
In 2007, a joint statement of the
American Civil Liberties Union
Law Project and Lambda Legal
asserted that a confl ict between
increased testing and strict

consent was “fi ctional.”29 In
2008, a Gay Men’s Health Crisis
commissioned review of the
literature asserted,
Some have cited written
consent as a barrier to testing.
. . . Such claims have proven
baseless and have not been
empirically documented in any
major peer reviewed academic
journal.30
CHANGE COMES TO
NEW YORK
After decades of debate,
in 2010 the New York State
legislature voted overwhelm-
ingly to modify the state’s legal
framework for HIV testing;

the assembly voted 97 to 0, the
senate 42 to 10. The result was
a carefully crafted compromise.
The statute required a manda-
tory off ering of testing to people
aged 13 to 64 years in hospitals,
emergency departments, and
primary care settings. Rapid
HIV testing could be conducted
using oral consent except in jails
and prisons. Consent for testing
could be integrated into general
consent as long as a specifi c part
of the form provided the clear
option to decline the HIV test.
It is of singular importance that
once consent had been given
it was to be considered durable

and could be terminated only
when a patient explicitly sought
to withdraw it.31
Although this statute fi nally
permitted New York State to
move forward, the long-fought
controversy was not over. Patrick
McGovern, the chief executive
offi cer of Harlem United,
declared in 2010,
New York’s’ debate on HIV
testing . . . has been passionate
and sometimes contentious . . .
while this legislation falls short
on a true opt out approach,
the required offer of HIV test-
ing in all primary care settings
foretells an end to the current

practice of segregated and stig-
matized HIV testing.32
Gay Men’s Health Crisis, by
contrast, underscored that it had
protected written informed con-
sent under challenging political
circumstances:
For years we have held up the
standard of written informed
consent as a marker for ac-
ceptable legislation to expand
HIV testing. Although GMHC
[Gay Men’s Health Crisis] has
compromised on some long
standing principles to sup-
port this bill we still strongly
believe in the value of written
informed consent. This legisla-

tion contains as many adequate
safeguards to informed consent
as the current environment in
the legislature will allow.33
The compromise of 2010 was
clearly only a fi rst step for those
committed to ending written
informed consent. In 2012, the
state health department issued
a report that concluded that to
increase testing uptake the state
might “consider additional steps
to streamline and fully routin-
ize the off er of HIV testing.”34
One possibility would be to
accept the CDC’s recommenda-
tion for routine HIV screening
without specifi c consent but

with an option for patients to
decline to be tested. Indicative of
the importance of the evidence
derived from clinical experience,
the AIDS Institute concluded,
“Written consent was consis-
tently identifi ed as a barrier to
implementing the 2010 law.”35
AJPH HISTORY
Refl ecting on his own shift,
Dan O’Connell, director of the
AIDS Institute, stressed that
“developments in science,” the
massing of evidence at both
state and national levels, had
compelled him to rethink policy.

For O’Connell, the deeply held
values of his opponents had
become an expression of an
evidence-resistant rigidity:
For a long time advocates were
not grappling with the need to
protect people’s health and get
the care they need. It took a
long time for the community
to catch up.
It was in this context that
Gottfried was noted as having
said how much of an outlier
New York State had become:
“For God’s sake it’s just us and
Nebraska.”36
In 2014, the AIDS Institute
forcefully moved to end written

informed consent through a
provision included (some critics
would say buried) in the gover-
nor’s 2014–2015 executive bud-
get. The more stringent written
requirements were retained only
in the potentially coercive con-
text of correctional settings. The
changed testing regulations were
packaged with other measures of
great importance to AIDS activ-
ists: creating a 30% salary rent
cap for HIV-infected people and
facilitating the sharing of clinical
data among health care providers
to promote “linkage and reten-
tion in care.”37 Commenting on
the milestone, O’Connell stated,

Eliminating most written con-
sent for HIV testing in New
York heralds the end of an
era in the decade’s long fight
against the epidemic.38
That New York took this step
was unsurprising, but that the
ultimate elimination of writ-
ten informed consent occurred
without a public battle was
stunning. The advocates, who
for years described written
consent as a pillar of an eff ec-
tive, rights-informed approach
to public health and who feared
that the elimination of such con-
sent would allow coercion and
mandatory testing, were silent.

Assemblyman Gottfried, a
veteran of the testing wars, noted
his surprise that he “had not
heard a peep” from advocates on
the proposed testing provisions
in the governor’s budget. His
offi ce therefore contacted the
leaders of New York’s advocacy
community:
What we heard back was that
nobody had a problem with
the change. . . . I didn’t re-
ceive a single e-mail or phone
call. [There was] almost a wall
to wall of unbroken silence.39
In large measure, the silence that
Gottfried encountered refl ected
a shift in priorities within the

advocacy community to pressing,
above all else, for programs and
policies to expand care for HIV-
infected persons. Committed to
ending AIDS in New York State,
AIDS advocates now viewed
collaboration with the AIDS
Institute as of central importance.
Most striking in this regard was
Housing Works’s shift after years
of publicly resisting the CDC’s
2006 recommendations and
not joining Harlem Untied, the
Latino Commission on AIDS,
and the Black Leadership Com-
mission on AIDS in their earlier
calls for change. Charles King,
the executive director of Hous-

ing Works, noted that treatment
availability was a “game changer.”
To make the promise of the end
of AIDS real, it was essential to
bring people into care. This was
not, he underscored, a politi-
cal tradeoff to win the support
of the AIDS Institute for the
new radical goal; abandoning a
long-held policy perspective was
not easy. Deeply rooted ideas do
not yield without organizational
strain. With clear reference to
those who had refused to shift, he
said, “We have an emotional at-
tachment to ideas. No one wants
to admit they had been wrong.”
Speaking of himself he continued

“I get a twinge. . . . We are on the
opposite side of an issue than we
were years ago.”40
Ten weeks after this policy
shift, Governor Andrew Cuomo
clarifi ed what the new targets
were: reduce new HIV infec-
tions in New York from 3000 to
750 by 2020 and reduce the rate
at which HIV-infected persons
progressed to AIDS by 50%.
These combined eff orts would
cause the prevalence of AIDS in
New York State to decrease for
the fi rst time since the start of
the epidemic.41
But what of those who had
not publicly embraced an end

to written informed consent but
who chose not to engage in fur-
ther debate? For some, the pros-
pect of battling the AIDS Institute
with whom it would be necessary
to develop programmatic eff orts
over the next years seems stra-
tegically counterproductive. But
much more was at stake.
Corrine Carrie of the New
York Civil Liberties Union
acknowledged that it was
increasingly diffi cult to argue
that written informed consent
did not impede HIV testing and
that instead they should frame
the argument with protecting
people’s right to choose to be

tested. In 2009, she had already
noted, “It’s gotten to the point
where only lawyers and sophisti-
cated advocates understand these
arguments.”42 Because of the
shifting institutional realities of
the AIDS advocacy community
in New York, that constitu-
ency was shrinking. “Lawyers
AJPH HISTORY
funding [has been] decimated,”
said Catherine Hanssens, who
had for years been among the
most vocal opponents of limiting
consent-related protections in

HIV testing.43 Simultaneously,
the HIV Law Project, which had
played such a prominent role in
earlier battles, had been absorbed
by Housing Works. Housing
Works now supported elimi-
nating written consent, while
focusing energy on providing
treatment and ancillary services
to those in need.
It was in this political context
that an urgent online discussion
among those who still supported
written informed consent took
place. None thought a renewed
battle could have a meaningful
impact, “the horse was out
of the barn.” Tracy Gardner

of the Legal Action Center
spoke candidly of being “worn
out, sick of the fi ght.”44 For each
organization that might lead the
battle, however futile, a strategic
decision had to be made. Hans-
sens said,
When you are thinly funded,
thinly staffed you have to
make choices. . . . We have
lost the battle in the context of
HIV testing.45
For Carrie, a new battle
would not be a wise invest-
ment. . . . [We must ask]
which threat is most serious?
Where are we likely to win?46
With no one willing to assume

leadership of a renewed battle, a
collective decision was made to
abandon what had been a defi n-
ing issue for the HIV advocacy
community. By deed if not by
word, the struggle to preserve
written informed consent had
come to an end. With an obvi-
ous need to view this outcome
in its broader contemporary
context and to maintain a sense
that the struggle had not been in
vain, it was possible for some to
say that the legacy of advocates’
work was alive even though
written informed consent was
over.
CONCLUSIONS
There is a rich literature on

the history of science-related
controversies that seeks to
explain how they emerge, persist
over time, and are resolved.47
That literature shows that only
part of the story is told by nar-
ratives that frame the end of
such confl icts as the result of the
triumph of evidence in the face
of uncertainty or because of the
emergence of new evidence.48
The careful examination of
scientifi c controversies sug-
gests that, whatever the role of
evidence, more is involved: that
epistemic, political, and social
factors are virtually always at
play. How evidence is under-

stood and indeed disagreement
about what should count as
evidence must be examined in
historical context.
The controversy over written
informed consent did not end
because the evidence had at last
become defi nitive. A similarly
fraught and linked debate oc-
curred on pretest and posttest
counseling for HIV. There was
also a protracted struggle49 for
evidence and ethics, but the
persistence of those arguing
for counseling diff ered greatly
from those arguing for writ-
ten consent. Important funding
streams had long underwritten

support for such eff orts, and a
virtual army of counselors were
employed across the nation with
an institutional commitment to
maintaining their role—and em-
ployment. Institutional resistance
helps to explain the politics of
de-implementation, but the
written consent story was very
diff erent. There was no army
of workers whose professional
identities depended on testing,
and the numbers of individuals
who found the issue of written
consent to be morally compel-
ling had dramatically declined.
Written informed consent could
no longer marshal the numbers

to resist change.
At an individual level, the
controversy ended because of
the exhaustion of those who,
under diff erent circumstances,
might have persisted. New York
was left behind, and so were lo-
cal activists, who knew that their
allies across the nation had also
conceded. A bandwagon-like
process had occurred.50 Those
involved in HIV advocacy, care,
and policy had come to agree on
a new paradigm for testing. On
a political level, AIDS advocates
had concluded that because of
the social and funding context
they should adjust their agendas

to best serve those they were
committed to. In doing so, they
made it clear that despite its cen-
tral role in the formative years of
the AIDS epidemic, both locally
and nationally, written informed
consent for HIV testing was
no longer a priority, no longer
worth the fi ght.
ABOUT THE AUTHORS
Ronald Bayer is with the Center for the
History and Ethics of Public Health, Mail-
man School of Public Health, Columbia
University, New York, NY. Morgan Philbin is
with the Department of Sociomedical Sciences,
Mailman School of Public Health. Robert H.
Remien is with the HIV Center for Clinical
and Behavioral Studies, New York State Psy-

chiatric Institute, Columba University Medical
Center, New York.
Correspondence should be sent to Ronald
Bayer, PhD, Center for the History and Ethics
of Public Health, Mailman School of Public
Health, Columbia, University, Professor, 722
West 168th Street, Room R928, New York,
NY 10032 (e-mail: [email protected]).
Reprints can be ordered at http://www.ajph.
org by clicking the “Reprints” link.
This article was accepted March 27, 2017.
doi: 10.2105/AJPH.2017.303819
CONTRIBUTORS
All authors contributed to the conceptual-
ization, research, and writing of this article.
AJPH HISTORY

9. “Modifying the AIDS Laws,” New
York Times, February 6, 2006:22.
10. Centers for Disease Control and
Prevention, “Revised Recommen-
dations for HIV Testing of Adults,
Adolescents and Pregnant Women in
Health Care Settings,” MMWR Recom-
mendations and Reports 55, no. RR–14
(2006):1–17.
11. V. S. Elliott, “CDC Moves to Put
HIV Testing Into Routine Care,” Amer-
ican Medical News 49, no. 39 (2006):1.
12. Ibid.
13. Bernard Branson, personal com-
munication.
14. S. Sternberg, “CDC: Make HIV
Tests Part of Routine Care for All,”
http://usatoday30.usatoday.com/news/

health/2006-09-21-hiv-testing_x.htm
(accessed August 18, 2016).
15. AIDS Foundation of Chicago,
“Federal HIV Testing Initiatives Can
Only Succeed With Expanded Health-
care, Patient and Provider Education,”
http://www.aidschicago.org/pdf/2006/
adv_testing_statement.pdf (accessed
April 24, 2017).
16. R. Bayer and A. L. Fairchild, “Chang-
ing the Paradigm of HIV Testing—The
End of Exceptionalism,” New England
Journal of Medicine 355, no. 7 (2006):649.
17. O’Connell et al., “Evolution of
Human Immunodeficiency Virus,” S5.
18. Letter to Assemblywoman Nettie
Mayersohn.
19. New York State Assembly Standing

Committee on Health, “HIV Testing,
Counseling and Informed Consent,”
December 20, 2006 [Public Hearing].
20. Ibid., 51.
21. Ibid., 171.
22. Ibid., 65.
23. Ibid., 320.
24. P. J. McGovern and M. G. Farley,
“The Routinization of HIV Testing
as a Civil Right.” [Unpublished
manuscript]
25. “Harlem United, Latino Commission
on AIDS, NBLCA, ‘The Research Shows
. . .’” 2009. [Unpublished manuscript]
26. J. Bennison, “Legislation Implement-
ing the Centers for Disease Control HIV
Testing Guidelines” [Letter to Assembly-
woman Nettie Mayersohn].

27. American College of Obstetricians
and Gynecologists, “An Act to Amend
the Public Health Law, in Relation to
HIV Testing,” June 6, 2008 [memoran-
dum in support].
28. AIDS Advisory Council, “Reso-
lution for Consideration Related to
Proposed Changes to Article 27F of
the Public Health Law,” https://www.
health.ny.gov/diseases/aids/providers/
regulations/testing/section_2781.htm
(accessed April 24, 2017).
29. American Civil Liberties Union,
“Increasing Access to Voluntary HIV
Testing: The Importance of Informed
Consent and Counseling in HIV Testing,”
https://www.aclu.org/increasing-access-
voluntary-hiv-testing-importance-

informed-consent-and-counseling-hiv-
testing (accessed April 24, 2017).
30. D. J. Cochrane, “Gay Men’s Health
Crisis: HIV Testing and Written, In-
formed Consent: An Analysis of Current
Debates,” 2008, http://img.thebody.
com/gmhc/pdfs/2008_testing_white.pdf
31. G. S. Birkhead, D. A. O’Connell,
S. Y. Leung, and L. C. Smith, “Evaluat-
ing the New York State 2010 HIV
Testing Law Amendments: Context,
Challenges, and Conclusions,” Journal of
Acquired Immune Deficiency Syndromes 201,
no. 68 (2015):s1–s4.
32. Harlem United, “Harlem United
Commends the NYS Legislature for
Passing Testing Legislation and Urges

Governor Paterson Sign,” July 1, 2010
[press release].
33. Gay Men’s Health Crisis, “Memo-
randum of Support S8227 (Duane)/
A11487 (Gottfried),” 2010.
34. New York State Department of
Health, “Laws of 2010 HIV Testing
Law: Mandated Report,” https://www.
health.ny.gov/diseases/AIDS/providers/
testing/law/docs/chapter_308.pdf
36. R. Bayer Interview of Dan
O’Connell, August 19, 2014.
37. New York State Assembly, 2013–
2014 Regular Sessions, http://assembly.
ny.gov/leg/?default_fld=&leg_video=&b

n=A07782&term=2013&Text=Y
(accessed March 17, 2016).
39. R. Bayer Interview of Richard
Gottfried, September 18, 2014.
40. R. Bayer Interview of Charles King,
August 15, 2014.
41. New York State, Department of
Health, “Get Tested. Treat Early. Stay
Safe. End AIDS,” http://www.health.
ny.gov/diseases/aids/ending_the_epi-
demic/docs/blueprint.pdf (accessed
March 17, 2016).
42. R. Bayer Interview of Corrine
Carrie, September 23, 2009.
43. R. Bayer Interview of Catherine
Hanssens, September 18, 2014.

44. R. Bayer Interview of Tracy
Gardner, August 26, 2014.
45. R. Bayer Interview of Catherine
Hanssens, September 18, 2014.
46. R. Bayer Interview of Corrine
Carrie, September 23, 2009.
47. B. Martin and E. Richards, “Sci-
entific Knowledge Controversy and
Public Decision-Making,” in Hand-
book of Science and Technology Studies,
ed. S. Jassanoff, Gerald E. Markle,
James C. Peterson, and Trevor J.
Pinch (Newbury Park, CA: Sage,
1995), 506–526.
48. S. Sismondo, An Introduction to Sci-
ence and Technology Studies (Oxford, UK:
Wiley, 2009).
49. Johns et al., “Rise and Decline.”

50. J. H. Fujimura, “The Molecular Bio-
logical Bandwagon in Cancer Research:
Where Social Worlds Meet,” Social Prob-
lems 35, no. 3 (1988):261–283.
ACKNOWLEDGMENTS
This work was supported by the HIV
Center for Clinical and Behavioral
Studies (grant NIMH P30MH43520);
the National Institute on Drug Abuse
(grant Ko1DA039804A to M. P.); and the
HIV Center for Clinical and Behavioral
Studies (grant NIMHP30MH43520 to
R. H. R.).
ENDNOTES
1. R. Bayer, Private Acts, Social Conse-
quences: AIDS and the Politics of Public
Health (New York, NY: Free Press,
1989).
2. R. Bayer, C. Levine, and S. Wolf,

“HIV Antibody Screening: An Ethical
Framework for Evaluating Proposed
Programs,” Journal of the American Medical
Association 256, no. 13 (1986):1768–
1774.
3. R. Bayer, “Public Health Policy and
the AIDS Epidemic: An End to HIV
Exceptionalism?” New England
Journal of Medicine 324, no. 21
(1991):1500–1504.
4. D. A. O’Connell, E. G. Martin, B.
Culter, and G. S. Birkhead, “The Evolu-
tion of Human Immunodeficiency Virus
Testing Requirements in New York
State, 1989–2013,” Journal of Acquired
Immune Deficiency Syndromes 68, suppl. 1
(2015):S55.
5. D. M. Johns, R. Bayer, and A. L.

Fairchild, “Evidence and the Politics
of Deimplementation: The Rise and
Decline of the Counseling and Testing
Paradigm for HIV Prevention at the
US Centers for Disease Control and
Prevention,” Milbank Quarterly 94, no. 1
(2016):126–162.
6. T. R. Frieden, M. Das-Douglas, S. E.
Kellerman, and K. J. Henning, “Apply-
ing Public Health Principles to the HIV
Epidemic,” New England Journal of Medi-
cine 353, no. 22 (2005):2397–2402.
7. Ibid., 2400.
8. New York City Department of
Health and Mental Hygiene, “Stopping
the HIV/AIDS Epidemic in New York”
(New York, NY; 2006) [PowerPoint
presentation].

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SPECIAL ISSUE PAPERS
PRENATAL SCREENING: CURRENT PRACTICE, NEW
DEVELOPMENTS,
ETHICAL CHALLENGES
ANTINA DE JONG, IDIT MAYA AND JAN M.M. VAN LITH
Keywords
prenatal screening,
NIPT,
ethical issues,
informed consent,
reproductive autonomy
ABSTRACT
Prenatal screening pathways, as nowadays offered in most
Western coun-
tries consist of similar tests. First, a risk-assessment test for
major
aneuploides is offered to pregnant women. In case of an
increased risk,
invasive diagnostic tests, entailing a miscarriage risk, are

offered. For
decades, only conventional karyotyping was used for final
diagnosis.
Moreover, several foetal ultrasound scans are offered to detect
major
congenital anomalies, but the same scans also provide relevant
information
for optimal support of the pregnancy and the delivery.
Recent developments in prenatal screening include the
application of
microarrays that allow for identifying a much broader range of
abnomalities
than karyotyping, and non-invasive prenatal testing (NIPT) that
enables
reducing the number of invasive tests for aneuploidies
considerably. In the
future, broad NIPT may become possible and affordable.
This article will briefly address the ethical issues raised by
these tech-
nological developments. First, a safe NIPT may lead to
routinisation and as
such challenge the central issue of informed consent and the
aim of pre-
natal screening: to offer opportunity for autonomous
reproductive choice.
Widening the scope of prenatal screening also raises the
question to what
extent ‘reproductive autonomy’ is meant to expand. Finally, if
the same test
is used for two different aims, namely detection of foetal
anomalies and
pregnancy-related problems, non-directive counselling can no
longer be
taken as a standard. Our broad outline of the ethical issues is

meant as an
introduction into the more detailed ethical discussions about
prenatal
screening in the other articles of this special issue.
INTRODUCTION
Most developed countries have some form of prenatal
screening for Down’s syndrome and other major foetal
anomalies. This article gives a general overview of current
practice in developed countries, looks at future scenarios
and charts the main ethical challenges. As such, it serves
as an introduction to the other articles in this special issue
that will address in more depth various ethical questions
regarding current and future prenatal testing scenarios.
The contributions reflect the oral presentations and
discussions at a conference on ‘Individualised choice: a
new approach to reproductive autonomy in prenatal
screening?’, held at the Brocher Foundation, Switzerland,
on 6–7 April 2013.
In this article screening is defined as the systematic
offer by health professionals of a medical investigation to
the population, or to specific population groups, address-
ing persons who themselves have no health problems or a
family history that would give them an indication for
being tested. The core notion of the concept is that
screening is an offer on the initiative of the health system
or society, rather than a medical intervention in answer to
a patient’s complaint or health problem.
Address for correspondence: Mrs Antina de Jong, Maastricht
University – Health, Ethics &Society, PO Box 616 6200 MD
Maastricht, Netherlands.
Email: [email protected]

Conflict of interest statement: No conflicts declared
Bioethics ISSN 0269-9702 (print); 1467-8519 (online)
doi:10.1111/bioe.12123
Volume 29 Number 1 2015 pp 1–8
bs_bs_banner
© 2014 John Wiley & Sons Ltd
Screening aims at obtaining population health gains
through early detection that enables prevention or treat-
ment. Examples include prenatal screening for infectious
diseases or routine foetal rhesus typing. These tests are
offered with the aim of contributing to a healthy outcome
of the pregnancy for mother and child. But prenatal
screening is also offered for finding foetal abnormalities
such as Down’s syndrome, the detection of which does
not allow for any options other than a choice between
continuing or terminating the pregnancy. How could this
be in line with the general prevention paradigm of screen-
ing: aiming at population health gains? One might of
course say that the aim is ‘to reduce the birth prevalence
of the disorder (. . .) by identifying (. . ..) couples who can
have prenatal diagnosis and selective termination of preg-
nancy.’1 However, this interpretation is generally
regarded as morally problematic, as it would seem to
favour the use of abortion as a means of reducing the
number of people with specific disorders, handicaps or
other medical needs. This has led to the general view that
prenatal screening for foetal abnormalities should be
regarded as serving the aim of providing pregnant women
and their partners with options for reproductive choice.2

CURRENT PRACTICE: THE PRENATAL
SCREENING PATHWAY
In many Western countries such as the United Kingdom
and the Netherlands, well-organised routine foetal
anomaly screening programmes with clear guidelines
exist (Figure 1). These are issued by national screening
committees.3 These programmes include both forms of
1 J. Murray et al. Screening for Cystic Fibrosis. Health Technol
Assess
1999; 3: i–104.
2 Health Council of the Netherlands. Screening Between Hope
and
Hype. The Hague: Health Council of the Netherlands, 2008.
3 http://fetalanomaly.screening.nhs.uk/;
http://www.rivm.nl/Documen
ten_en_publicaties/Professioneel_Praktisch/Draaiboeken/Preven
tie
_Ziekte_Zorg/Draaiboek_prenatale_screening_downsyndroom_e
n
_Structureel_Echoscopisch_Onderzoek.
4 This information was originally developed by the UK National
Screening Committee/NHS Screening Programmes
(www.screening
.nhs.uk) and is used under the Open Government Licence v1.0.
Figure 1. Routine prenatal screening pathway used in the UK.4
Antina de Jong, Idit Maya and Jan M.M. van Lith2

prenatal screening identified in the introduction. It starts
at the first prenatal appointment, although for high risk
groups preconception counselling would be ideal. It is
supported by a health professional educational pro-
gramme, patient information, and regular audits of all
aspects of the programme. Underpinning the programme
is the notion that women and their families should under-
stand the purpose of all tests before they participate in
testing.
The first prenatal visit
At the first visit, either preconceptionally or prenatally,
the midwife will take a history of the prospective parents
to determine if there is any significant family, past obstet-
ric or medical history that indicates that the pregnancy
might be at increased risk. Further management of high
risk pregnancies will not be discussed further here,
because these have specific testing routes.
At this first appointment, several routine blood tests
are taken to measure maternal haemoglobin levels, screen
for potential haemoglobinopathy carriers (if results indi-
cate these may be present, further blood tests are done to
confirm status), perform routine virology to confirm
immunological status regarding rubella immunity, syphi-
lis and HIV, and to screen for red cell antibodies, and
confirm Rhesus D status (RhD). In pregnancy, RhD−
mothers with a RhD+ baby can develop antibodies to D+
blood if the foetus’ blood cells enter the mother’s blood
stream. In a future pregnancy with a D+ foetus, these
antibodies can transfer to the foetus and destroy red
blood cells causing anaemia, jaundice and potentially
postnatal death (haemolytic disease of the newborn). To
prevent this, RhD− mothers are given anti-D immuno-

globulin at 28 weeks of gestation.
At this same first visit, the midwife will discuss screen-
ing for Down’s syndrome which is optimally done in the
first trimester. Following the explanation of the purpose
of this test, the woman is asked to opt in or out of this
testing.
Down’s syndrome screening (DSS)
The next step in the prenatal pathway is screening for
Down’s syndrome (DS). In many developed countries
this is offered to all women in the first or early second
trimester. It is done by using a combination of risk factors
including maternal age, maternal serum biomarkers and
ultrasound markers5 to determine a pregnancy specific
risk of the foetus having DS. The exact format of DSS
varies depending on national and local facilities and
policy. In many countries a combination of maternal age,
serum markers (PAPP_A and beta-HCG) and nuchal
translucency (NT) (the thickness of the fluid filled area at
the back of the foetal neck) is used to determine a preg-
nancy specific risk on Down syndrome. If the risk is
estimated to be above a certain cut-off level (e.g. ≥1:150
or 1:200) the mother is offered an invasive test (chorionic
villus sampling or amniocentesis) for definitive diagnosis.
Both invasive tests carry a small risk of miscarriage that is
generally estimated to be of around 0.5–1%.6 Using this
policy, the combined test identifies approximately 85% of
DS affected pregnancies for a 3% false positive rate.
Notably, NIPT for DS is increasingly being offered as
a second-tier screening test to those woman who are
found to be at increased risk for DS. If the NIPT-result is
positive, invasive testing is offered.7

In addition to screening for DS there are other sug-
gested ‘benefits’ of screening for DS. The screening
requires an ultrasound scan to accurately date the preg-
nancy and at this scan major structural abnormalities
may be detected, for example anencephaly, anterior
abdominal wall defects and major limb anomalies.8 Fur-
thermore, multiple pregnancies may be detected. The
DSS further allows for screening for the other major
trisomies, trisomy 13 and 18. An increased NT (≥3.5mm)
in the combined test is associated with an increased risk
of a major heart anomaly and a variety of other structural
abnormalities such as diaphragmatic hernia as well as
genetic syndromes.9 If the karyotype is normal, it is usual
practice to refer women with an increased NT for a
detailed cardiac scan and also for a detailed foetal
anomaly scan at 20 weeks of gestation.10 If these scans are
both normal, the risk of other adverse findings is reduced
but still remains higher than in the general population11
and parents can find the anxiety caused significant.12
5 K.H. Nicolaides. Screening for Fetal Aneuploidies at 11 to 13
weeks.
Prenat Diagn 2011; 31: 7–15.
6 A. Tabor & Z. Alfirevic. Update on Procedure-Related Risks
for
Prenatal Diagnosis Techniques. Fetal Diagn Ther 2010; 27: 1–7.
A
recent estimation, based on a systematic review of literature and
meta-
analysis, suggests that this procedure-related risk of miscarriage
follow-
ing amniocentesis and CVS is much lower than currently
quoted: R.

Akolekar et al. Procedure-related risk of miscarriage following
amnio-
centesis and chorionic villus sampling: a systematic review and
meta-
analysis. Ultrasound Obstetr Gynecol 2014. DOI:
10.1002/uog.14636.
7 American College of Obstetricians and Gynecologists
Committee on
Genetics (ACOG). Committee Opinion No. 545: Noninvasive
prenatal
testing for fetal aneuploidy. Obstet Gynecol 2012; 120: 1532–
1534.
8 A. Syngelaki et al. Challenges in the Diagnosis of Fetal Non-
Chromosomal Abnormalities at 11–13 Weeks. Prenat Diagn
2011; 31:
90–102.
9 C.M. Bilardo et al. Increased Nuchal Translucency in Euploid
Fetuses–What Should we be Telling the Parents? Prenat Diagn
2010; 30:
93–102.
10 Practices slightly differ between countries. For example, in
Israel an
earlier ultrasound scan is offered in case of an increased NT.
11 Bilardo op.cit. note 9.
12 J. Fisher. First-trimester Screening: Dealing with the Fall-
Out.
Prenat Diagn 2011; 31: 46–49.
Prenatal Screening: Current Practice, New Developments,
Ethical Challenges 3

Varying combinations of the serum markers used for
DSS may also be used to predict other adverse pregnancy
outcomes such as intrauterine growth retardation
(IUGR) and pre-eclampsia,13 although this is still under
debate. For women with abnormal maternal biomarkers
suggestive of IUGR, serial scanning for growth is often
undertaken.
Invasive follow-up testing
Following invasive testing performed by CVS or amnio-
centesis, respectively the chorionic villi and amniocytes
are analysed. It is common practice to first perform rapid
aneuploidy exclusion using a molecular technique, either
quantitative fluorescent polymerase chain reaction
(qfPCR) or fluorescent in-situ hybridisation (FISH),
which will detect the major trisomies (13, 18 and 21) and
Turners syndrome (45XO). Results are issued in 1–3
working days. Full karyotyping is then performed follow-
ing culturing of the cells. This takes 10–14 days and
involves microscopic examination of cells and can detect
other chromosomal rearrangements, many of which
confer high risk of adverse outcome. However, this
approach will not detect very small (submicroscopic)
changes, known as copy number variations (CNVs),
some of which can confer high risk of serious develop-
mental problems and are now known to account for
around 10–25% of the underlying pathology in children
with previously undiagnosed learning and developmental
disability.14 Recent technical developments have allowed
for the use of microarray- technology as an alternative for
conventional karyotyping (see below).
Routine foetal anomaly scanning

The final point in the prenatal screening pathway is the
foetal anomaly scan. In most countries this is performed
between 18 and 21 weeks of gestation. The focus is gen-
erally on the detection of major foetal anomalies that
require treatment early in the postnatal period and so
may require special arrangements to be made for deliv-
ery. Anomalies indicating serious handicaps also lead, if
local policy permits, to discussion on the possible termi-
nation of pregnancy.15 For the majority of families a
routine scan gives reassurance that the baby shows no
abnormalities, but it must be remembered that still 2–4%
of the babies are born with a structural abnormality.
Most of these cases occur in low risk families; they
account for around 30% of perinatal deaths and are a
major cause of perinatal morbidity.16 Detection rates for
different abnormalities vary, but reasonable target rates
for detection of common major abnormalities by ultra-
sound performed by trained sonographers working to a
set protocol are given in Table 1. Sonograpic detection of
foetal anomalies gives parents options, including the
opportunity to discuss the prognosis with relevant paedi-
atric specialists, allows organisation of the timing and
place of delivery, and facilitates prompt and appropriate
postnatal treatment where required. In some situations
there may also be the opportunity for prenatal treatment,
for example the medical treatment of foetal cardiac
arrhythmias,17 or in-utero surgical intervention for foe-
tuses with diaphragmatic hernia or spina bifida.18 Whilst
the majority of women gain significant reassurance from
anomaly scanning, the detection of minor anomalies or
those associated with an uncertain prognosis, e.g. mild
ventriculomegaly, can cause significant parental anxiety
and concerns which can last well beyond the prenatal
period. Women need to be advised before scanning that a

major abnormality may be detected, but that they also
need to be aware that not all abnormalities are detected at
the time of the routine scan for a number of reasons.
Apart from being a screening test for foetal anomalies,
the routine scan at around 20 weeks also provides infor-
mation (e.g. on the growth of the foetus and the amount
of amnion fluid) that is important for optimal support of
the pregnancy and the delivery. Moreover, pregnant
13 R. van Ravenswaaij et al. First-trimester Serum PAPP-A and
fβ-hCG Concentrations and other Maternal Characteristics to
Estab-
lish Logistic Regression-Based Predictive Rules for Adverse
Pregnancy
Outcome. Prenat Diagn 2011; 31: 50–57.
14 E. Lisenka et al. Genomic microarrays in mental retardation:
from
copy number variation to gene, from research to diagnosis. J
Med Genet
2010; 47: 289–297.
15 S.H. Eik-Nes. The 18-week Fetal Examination and Detection
of
Anomalies. Prenat Diagn 2010; 30: 624–630.
16 T.-H. Bui & V. Meiner. State of the art in prenatal diagnosis.
In:
Leuzinger-Bohleber M et al., editors. The Janus Face of
Prenatal Diag-
nostics. A European Study Bridging Ethics, Psycholanalysis,
and Medi-
cine. London: Karnac Books, 2008. p. 61–86.
17 L. Hui & D.W. Bianchi. Prenatal Pharmacotherapy for Fetal
Anomalies: a 2011 Update. Prenat Diagn 2011; 31: 735–743.
18 J. Jani et al. Tracheal Diameter at Birth in Severe Congenital
Dia-
phragmatic Hernia Treated by Fetal Endoscopic Tracheal

Occlusion.
Prenat Diagn 2011; 31: 699–704. M.W. Bebbington et al. Open
Fetal
Surgery for Myelomeningocele. Prenat Diagn 2011; 31: 689–
694.
Table 1. Detection rates for routine foetal anomaly
screening programmes
Anomaly Detection rate
Anencephaly 98%
Open spina bifida 90%
Cleft lip 75%
Diaphragmatic hernia 60%
Gastroschisis 98%
Exomphalos 80%
Serious cardiac anomaly 50%
Bilateral renal agenesis 84%
Lethal skeletal dysplasia 60%
women (or couples) tend to see the scan as a first oppor-
tunity to see their future child.
NEW DEVELOPMENTS
Prenatal microarrays
The positive experience using microarrays in postnatal
testing and the fact that several research studies have

shown their usefulness in prenatal testing, has contrib-
uted to their introduction in prenatal testing cascades.
Particularly in foetuses with increased nuchal translu-
cency or structural abnormalities, pathogenic CNVs can
be detected in up to 6% of cases with a normal karyo-
type.19 This has led to many services offering microarrays
for prenatal diagnosis, particularly in foetuses with
sonographic abnormalities, but some centres also after a
positive DSS-test. Microarrays have a place in prenatal
diagnosis, although its exact application is still under
debate.20 Recently, the American College of Obstetrics
and Gynecologists (ACOG) stated that chromosomal
microarray should be recommended in any invasive pre-
natal test done due to ultrasound abnormalities, and
should be considered as a possible alternative to foetal
karyotype in every other invasive test, regardless of indi-
cation (including DSS-test, advanced maternal age, or
pure maternal anxiety).21
A microarray screens all the chromosomes in one test
and can detect many very small variants that cannot be
detected by traditional karyotyping looking at chromo-
somes down the microscope. Data generated by an array
can be compared with data on many thousands of vari-
ants held in international, anonymised databases. Conse-
quently, the clinical significance of many, but not all,
changes can be assessed. All individuals carry many of
these ‘sub-microscopic’ changes, most of which are not
clinically significant and can be inherited from a (healthy)
parent. In some cases it will be necessary to test parental
chromosomes to determine whether a change is inherited
and potentially benign.
There are several types of microarrays.22 Some are tar-
geted, e.g. bacterial artificial chromosomes (BAC) arrays,

and will only detect abnormalities in specific areas of the
chromosome. These are advantageous in that they can be
designed to cover those areas known to include the severe
microdeletion and duplication syndromes23 and that
the interpretation of results is more straightforward.
Others, oligonucleotide array comparative genomic
hybridisation platforms and single nucleotide polymor-
phism (SNP) arrays, can either be designed to target these
areas or can be used to cover the whole genome. In whole
genome arrays the detection is optimised but there is a risk
of increased detection of variants of unknown significance
(VOUS), which can result in difficulty in interpretation
and counselling. The potential for detecting a wider range
of abnormalities, as well as the variants of unknown sig-
nificance, raises significant ethical issues in the prenatal
setting and highlights the need for expert pre- and post-test
counselling.24 Because such a large number of potential
findings are possible with any type of whole genome arrays
(regardless of technology), databases are used to deter-
mine if specific copy number variants have been previously
reported and whether they are considered pathogenic,
benign or of unknown clinical significance.
Prenatal use of cell free foetal DNA in
maternal plasma: testing for foetal Rhesus
typing and aneuploidies
Current practice (as described above) means that the 40%
of mothers carrying a RhD- foetus receive anti-D unnec-
essarily. In the UK this equates to around 15,000 women
a year who are exposed to a human blood product unnec-
essarily (anti-D is generated by injecting RhD-women
with D- antibodies) and, as anti-D is expensive, it also
results in significant costs to the health service.
Cell-free foetal DNA (cffDNA) was identified in the

maternal circulation in 1997.25 It is present in the mater-
nal circulation from four weeks of gestation, but it only
represents a small fraction of total circulating DNA, the
majority being maternal in origin.26 The proportion of
cffDNA increases with gestation but is cleared from the
circulation within an hour or two of delivery.27 This
means the cffDNA is pregnancy-specific and can there-
fore be used for genetic diagnosis in the foetus. Testing
19 J.L. Callaway. The Clinical Utility of Microarray
Technologies
applied to Prenatal Cytogenetics in the Presence of a Normal
Conven-
tional Karyotype: a Review of the Literature. Prenat Diagn
2013; 33:
1–5; S.C. Hillman. Use of Prenatal Chromosomal Microarray:
Prospec-
tive Cohort Study and Systematic Review and Meta-Analysis.
Ultra-
sound Obstet Gynecol 2013; 41: 610–620.
20 J.A. Crolla, R. Wapner & J.M. van Lith. Controversies in
Prenatal
Diagnosis 3: Should Everyone Undergoing Invasive Testing
have a
Microarray? Prenat Diagn 2013. DOI: 10.1002/pd.4287.
21 The American College of Obstetricians and Gynecologists
Commit-
tee on Genetics & The Society for Maternal-Fetal Medicine.
Committee
Opinion No. 581. The use of chromosomal microarray analysis
in pre-
natal diagnosis. Obstet Gynecol 2013; 122: 1374–1377.
22 P.D. Brady & J.R. Vermeesch. Genomic Microarrays: a
Technology
Overview. Prenat Diagn 2012; 32: 336–343.

23 A. Weise et al. Microdeletion and Microduplication
Syndromes. J
Histochem Cytochem 2012; 60: 346–358.
24 G. McGillivray et al. Genetic Counselling and Ethical Issues
with
Chromosome Microarray Analysis in Prenatal Testing. Prenat
Diagn
2012; 32: 389–395.
25 Y.M. Lo et al. Presence of fetal DNA in maternal plasma and
serum.
Lancet 1997; 350: 485–487.
26 F.M.F. Lun et al. Microfluidics Digital PCR Reveals a
Higher than
Expected Fraction of Fetal DNA in Maternal Plasma. Clin Chem
2008;
54: 1664–1672.
27 Y.M.D. Zhang et al. Rapid Clearance of Fetal DNA from
Maternal
Plasma. Am J Hum Genet 1999; 64: 218–224.
this cffDNA in the blood of RhD-women can determine
the foetal RhD type. This has proven to be very accurate
at various gestational ages and is now used routinely to
type the foetal RhD status in RhD- mothers. Only those
mothers found to be carrying a RhD+ foetus are then
offered anti-D immunoprophylaxis.28 This allows for
savings in anti-D administration and prevents unneces-
sary exposure to a human blood product.

A major advance in foetal chromosome testing has
been the development of non-invasive prenatal testing
(NIPT) for aneuploidy based on analysis of cell free
foetal DNA in maternal plasma. As described above,
cffDNA is present in the maternal circulation from early
in pregnancy. However, the high background level of
maternal chromosome 21 cfDNA in maternal plasma29
makes NIPT for DS and other aneuploidies more chal-
lenging than the testing described above for foetal Rhesus
status, because the latter searches the presence or absence
of an allele not present in the mother. For aneuploidy
diagnosis, detection of the relatively small changes in
the level of individual chromosome-specific fragments
in maternal plasma indicating that the foetus has
aneuploidy, must be very accurately quantified. Several
large-scale validation studies using next generation
sequencing have now been conducted, mostly in higher-
risk populations. Overall these report detection rates for
DS of more than 99% with a false positive rate of 0.1–
1%.30 If these results are confirmed in large-scale studies
in low-risk populations, NIPT will be regarded as a much
better alternative than present DSS-tests (combined test,
quadruple test).31 The great advantage of NIPT over
those tests is the large decrease in the need for invasive
follow-up testing, entailing an equivalent reduction of
iatrogenic pregnancy losses.32 Recent studies have
already shown that NIPT may be a highly effective
screening method for risk assessment of foetal trisomies
21, 18, and 13 in general pregnant populations as well.33
NIPT can also detect other aneuploidies including
trisomy 18, trisomy 13 and sex chromosome abnormali-
ties.34 However, there is a consistently reported false posi-
tive rate and false negative rates have been mentioned as
well.35 This is a reflection of the fact that cffDNA is shed

from the placenta,36 and that when screening for
aneuploidy it is the total cfDNA that is analysed, not just
the foetal component. Thus, discrepant results have been
reported as a result of cell lines arising in the placenta
(confined placental mosaicism):37 detection of maternal
chromosomal rearrangements38 and even maternal
tumours secreting an abnormal chromosome compliment
are mentioned.39
Whereas in the past NIPT has been projected as a
possible one-step aneuploidy test after which confirma-
tion by invasive testing of a positive result would no
longer be needed, this is not yet where we are now.
At present, NIPT for aneuploidy is considered as an
advanced screening test and most authorities recommend
invasive testing for confirmation of positive results.40
A negative NIPT result does not necessarily mean
that there is no chromosomal abnormality present. We
28 F.B. Clausen. Report of the First nationally Implemented
Clinical
Routine Screening for Fetal RHD in D- pregnant Women to
Ascertain
the Requirement for Antenatal RhD Prophylaxis. Transfusion
2012; 52:
752–758.
29 Lun, op.cit. note 26.
30 E.M. Boon & B.H. Faas. Benefits and limitations of whole
genome
versus targeted approaches for non-invasive prenatal testing for
fetal
aneuploidies. Prenat Diagn 2013; 33: 563–568.
31 D.W. Bianchi et al. DNA sequencing versus standard
prenatal
aneuploidy screening. N Engl J Med 2014; 370: 799–808.

32 D.W. Bianchi, D. Oepkes & A. Ghidini. Current
Controversies in
Prenatal Diagnosis 1: Should Noninvasive DNA Testing be the
Stand-
ard Screening Test for Down Syndrome in All Pregnant
Women?
Prenat Diagn 2013; 3: 1–6.
33 G. Fairbrother et al. Clinical experience of noninvasive
prenatal
testing with cell-free DNA for fetal trisomies 21, 18, and 13, in
a general
screening population. Prenat Diagn 2013; 33: 580–583; M.M.
Gil et al.
Analysis of Cell-Free DNA in Maternal Blood in Screening for
Aneuploidies: Meta-Analysis. Fetal Diagn Ther 2014; DOI:
10.1002/
uog.12504.
34 T. Futch et al. Initial Clinical Laboratory Experience in Non-
invasive Prenatal Testing for Fetal Aneuploidy from maternal
Plasma
DNA Samples. Prenat Diagn 2013; 33: 569–574; D. Liang et al.
Non-
invasive Prenatal Testing of Fetal Whole Chromosome
Aneuploidy by
Massively Parallel Sequencing. Prenat Diagn 2013; 33: 409–
415; G.E.
Palomaki et al. DNA Sequencing of Maternal Plasma to detect
Down
Syndrome: An International Clinical Validation Study. Genet
Med
2011; 13: 913–20; M.E. Norton et al. Non-Invasive
Chromosomal
Evaluation (NICE) Study: Results of a Multicenter Prospective
Cohort
Study for Detection of Fetal Trisomy 21 and Trisomy 18. Am J

Obstet
Gynecol 2012; 207: 137.e1–137.e8; D.W. Bianchi & L. Wilkins-
Haug.
Integration of noninvasive DNA testing for aneuploidy into
prenatal
care: what has happened since the rubber met the road? Clin
Chem 2014;
60: 78–87.
35 R.E. Reiss & A.M. Cherry. AJOG 2013; 209: 160–161; M.T.
Mennuti
et al. AJOG 2013; 209: 415–419; Y. Wang et al. Prenat Diagn
2013; 33:
1207–1230.
36 M. Alberry et al. Free Fetal DNA in Maternal Plasma in
Anembryonic Pregnancies: Confirmation that the Origin is the
Tropho-
blast. Prenat Diagn 2007; 27: 415–418.
37 T.K. Lau et al. Secondary Findings from Non-Invasive
Prenatal
Testing for Common Fetal Aneuploidies by Whole Genome
Sequencing
as a Clinical Service. Prenat Diagn 2013; 33: 602–608; M. Pan
et al.
Discordant Results between Fetal Karyotyping and Non-
Invasive Pre-
natal Testing by Maternal Plasma Sequencing in a Case of
Uniparental
Disomy 21 due to Trisomic Rescue. Prenat Diagn 2013; 33:
598–601.
38 Lau, op.cit. note 37.
39 C.M. Osborne et al. Discordant Non-Invasive Prenatal
Testing
Results in a Patient Subsequently Diagnosed with Metastatic
Disease.
Prenat Diagn 2013; 33: 609–611.
40 ACOG, op.cit. note 7; P.A. Benn et al. Prenatal Detection of

Down
Syndrome using Massively parallel Sequencing (MPS): a Rapid
Response Statement from a Committee on behalf of the Board of
the
International Society for Prenatal Diagnosis. Prenat Diagn
2012; 32:
1–2; S. Langlois & J.A. Brock. Genetics Committee. Current
Status in
Non-Invasive Prenatal Detection of Down Syndrome, Trisomy
18 and
Trisomy 13 using Cell-Free DNA in Maternal Plasma. J Obstet
Gynaecol Can 2013; 35: 177–181.
already mentioned that there is a small false-negative rate
associated with NIPT,41 and that at present NIPT gener-
ally screens for the major trisomies. This is consistent
with the scope of current combined testing, but it differs
from invasive testing because NIPT does not detect other
chromosomal rearrangements or micro-deletion syn-
dromes which might be detected by karyotyping or
microarray analysis as described above.
NIPT for a wider range of chromosomal abnormalities
may become possible as detection of other chromosomal
rearrangements using next generation sequencing has
been reported. The scope of this so-called “second gen-
eration NIPT” will range from whole-chromosome to
subchromosome abnormalities.42 The depth of sequenc-
ing required is significantly higher than for standard
NIPT, making the cost of testing currently too high for

routine use.43 However, research efforts have recently
concentrated on finding ways to make this feasible in a
routine clinical setting.44 In proof of principle studies it
has been demonstrated that using cffDNA in maternal
plasma, the whole genome of the foetus can be sequenced
and made available for analysis.45 In a still further-away
scenario, this means that it will become possible to use
maternal blood for testing the foetus for any mutations,
risk factors, or other variants that its genome may
contain.
ETHICAL ISSUES
Benefits and challenges of NIPT as a
better DSS-test
The better test characteristics of NIPT as a screening test
for Down’s syndrome is also an important benefit in view
of what is generally regarded as the aim of prenatal
screening for foetal abnormalities, namely to facilitate
reproductive choice for pregnant women (and their part-
ners). Women who decline prenatal screening with the
present DSS-tests because they do not want to expose
their pregnancy to a miscarriage risk to avoid what in 9
out of 10 cases will be a false alarm, may find screening
with NIPT more acceptable. This means that more
women or couples can benefit from the reproductive
options that the screening intends to provide. Moreover,
the higher sensitivity of NIPT means that less women or
couples will be falsely reassured by the message that they
will not have a child with Down’s syndrome. Finally,
counselling can be more straightfoward, without the need
to explain the complexity of risk-assessment. Together
these features mean that with NIPT, DSS-screening can
be safer and can better achieve its aim. Costs permitting,

this means there is a strong ethical case for replacing
current DSS-tests with NIPT.
However, the flipside of these same benefits is what
has been referred to as the risk of ‘routinisation’,46
meaning that the greater ease and safety of NIPT may
lead to it being regarded by both pregnant women and
professionals as a harmless blood test that one need not
think long about. Routinisation may thus lead to an
erosion of informed decision-making.47 A connected
concern is that there will be subtle pressure from
healthcare providers and social environments to accept
the screening offer, leading to women feeling the need to
justify their non-participation or fearing that they will
be held responsible if they turn out to have a child
with a condition or handicap that ‘could have been
prevented’.48
Furthermore, when considering NIPT it is important
to note that health professionals and women place differ-
ent values on different aspects of testing, with women
valuing safety most highly, whilst health professionals
value accuracy.49 These factors mean that careful consid-
eration must be given as to how to implement NIPT in
the public sector so that the needs of women or couples
are met whilst ensuring the fundamental principle of
maintenance of informed decision-making.50
41 Cf ops.cit. note 35; Boon, Faas, op.cit. note 30; J.M.E.
Walsh & J.D.
Goldberg. Fetal Aneuploidy Detection by Maternal Plasma DNA
Sequencing: a Technology Assessment. Prenat Diagn, 2013; 33:
514–
520.
42 Bianchi, Wilkins-Haug, op.cit. note 34.

43 S. Chen et al. A Method for Non-Invasive Detection of Fetal
Large
Deletions/Duplications by Low Coverage massively Parallel
Sequenc-
ing. Prenat Diagn 2013; 33: 584–590; A. Srinivasan et al. Non-
Invasive
Detection of Fetal Sub-Chromosome Abnormalities via Deep
Sequenc-
ing of Maternal Plasma. Am J Hum Genet 2013; 92: 167–176.
44 Bianchi, Wilkins-Haug, op.cit. note 34.
45 J.O. Kitzman et al. Noninvasive Whole-Genome Sequencing
of a
Human Foetus. Science Transl Med 2012; 4: 137ra76; Y.M. Lo
et al.
Maternal Plasma DNA Sequencing Reveals the Genome-Wide
Genetic
and Mutational Profile of the Foetus. Science Transl Med 2010;
2:
61ra91.
46 C. Lewis, C. Silcock & L.S. Chitty. Non-Invasive Prenatal
Testing
for Down’s Syndrome: Pregnant Women’s Views and Likely
Uptake.
Public Health Genomics 2013; 16: 223–232.
47 Ibid; A. van den Heuvel et al. Will the Introduction of Non-
Invasive
Prenatal Diagnostic Testing erode Informed Choices? An
Experimental
Study of Health Care Professionals. Patient Educ Couns 2010;
78:
24–28.
48 R. van Schendel. Attitudes of pregnant women and male
partners
towards non-invasive prenatal testing and widening the scope of
prena-

tal screening. Eur J Hum Genet 2014; DOI:
10.1038/ejhg.2014.32.
49 M. Hill et al. Women’s and Health Professionals’
Preferences for
Prenatal Tests for Down Syndrome: a Discrete Choice
Experiment to
Contrast Noninvasive Prenatal Diagnosis with Current Invasive
Tests.
Genet Med 2012; 14: 905–913.
50 M.A. Allyse et al. Best Ethical Practices for Clinicians and
Labora-
tories in the Provision of Noninvasive Prenatal Testing. Prenat
Diagn
2013; 33: 656–661; H. Skirton & C. Patch. Factors Affecting
the Clinical
Use of Non-Invasive Prenatal Testing: a Mixed Methods
Systematic
Review. Prenat Diagn 2013; 33: 532–541.
Widening scope of prenatal screening for
foetal abnormalities
As the above overview has shown, there is a tendency to
widen the scope of testing in the context of prenatal
screening for foetal abnormalities. At present, this is most
visible in the use of broad-scope microarrays as a
follow-up after abnormal ultrasound findings or an
abnormal DSS-test. As the scope of prenatal microarray
testing is often (much) wider than the outcome of the

preceding scan or screening test would require it to be,
this practice can (to that extent) be regarded as a de facto
form of additional genomic screening, although it is not
presented or justified as such.51
As soon as NIPT can be affordably and reliably used
for screening beyond the major trisomies, a further wid-
ening can be expected. A conceivable first step may be
NIPT for all chromosomal abnormalities that at present
can be seen with karyotyping, including the relatively
mild sex chromosome abnormalities. It is striking that the
normative framework for prenatal screening, with its
emphasis on ‘reproductive choice’ does not provide much
guidance when it comes to determining what the scope of
a responsible screening offer would be. Without qualifi-
cation, the classical formulation of the aim of prenatal
screening in terms of ‘providing reproductive choice’ may
end up making reproductive choice an end in itself, apart
from any connection with the realm of reproductive
health risks that would be needed to justify a publicly or
collectively funded screening programme. Moreover, it is
at least not obvious that widening the scope of testing will
lead to providing pregnant women or couples with more
meaningful reproductive choices. Findings of unclear sig-
nificance and information overload may lead to under-
mining rather than promoting such choices. Together,
these considerations call for the development of addi-
tional ethical guidance.
Same test for different aims
A third issue that arises from the above overview is that
the same prenatal tests, including NIPT, can be used for
screening with different aims. If used in screening for
anomalies such as foetal Down’s syndrome, the aim
would be reproductive choice. Whereas if the same test

is used in prenatal screening for pregnancy-related
conditions, such as foetal RhD-status, the aim is to con-
tribute to a healthy outcome of the pregnancy. What
makes this convergence challenging from an ethical point
of view is that those different aims are ideally reflected in
distinct counselling styles. With regard to prenatal
screening for foetal abnormalities, there is consensus
that, ideally, counselling should be non-directive.
However, with regard to testing that may benefit the
health of the future child and of the pregnant woman,
things are different. In that case, professionals may well
insist that women who have decided to carry the preg-
nancy to term, have a moral responsibility (within limits
of proportionality) to protect the future child from avoid-
able harm. The classical ethics of non-directive counsel-
ling is not without qualification applicable in that
context. In order to avoid confusing moral messages, it
seems important to keep the information and counselling
for these two forms of prenatal screening apart as far as
possible. This picture of overlapping aims will become
even more complex with the further development of
forms of foetal therapy, meaning that after detection of
certain foetal abnormalities, in utero treatment may be a
third option next to continuing or terminating the preg-
nancy.52 The ethics of parental (maternal) and profes-
sional responsibility with regard to such choices is still to
be worked out.
Antina de Jong, PhD, LLM, is an ethicist and lawyer. She works
as a
legal advisor at the Education Council of the Netherlands. In
2013, she
completed her PhD-thesis ‘Prenatal screening à la carte? Ethical
reflec-
tion on the scope of testing for foetal anomalies’ at the

Maastricht
University. Formerly, she was a legislative and policy advisor at
the
Netherlands Council of State and at the Dutch Data Protection
Author-
ity. The main areas of her work relate to healthcare, privacy and
education.
Idit Maya, MD, is a medical doctor specialising in Internal
Medicine
and Medical Genetics at (respectively) the Hasharon Hospital
and the
Rabin Medical Center, Peta Tikva. She is also Senior Geneticist
CMA
(Chromosomal Micro Array Analysis) in the laboratory at
Recanati
Genetic Institute, Rabin Medical Center. She is also head of the
Genomic programme for physiscians, Recanati Genetic Institute,
and
Sackler Faculty of Medicine, Tel Aviv University; all in Israel.
Jan van Lith, MD, PhD, is professor and chairman of Obstetrics
and
Fetal Medicine at the Leiden University Medical Centre
(LUMC)
and president of the International Society for Prenatal Diagnosis
and
Therapy (ISPD). He has been actively involved in the
development and
organisation of prenatal diagnosis and screening in the
Netherlands
since the early 1990s. His PhD was on first trimester Down’s
syndrome
screening (1993).
51 A. de Jong et al. Microarrays as a Diagnostic Tool in

Prenatal
Screening Strategies: Ethical Reflection. Hum Genet 2014; 133:
163–172.
52 D.W. Bianchi. From prenatal genomic diagnosis to fetal
personal-
ized medicine: progress and challenges. Nat Med 2012; 18:
1041–1051.
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The Journal of Law, Medicine & Ethics, 45 (2017): 333-340. ©
2017 The Author(s)
DOI: 10.1177/1073110517737531
controversies in clinical research ethics • fall 2017 333
The Continuing
Evolution of
Ethical Standards
for Genomic
Sequencing in

Clinical Care:
Restoring Patient
Choice
Susan M. Wolf
Introduction
Large-scale genome and exome sequencing is rapidly
moving from research investigation into clinical care.
When cancer patients fail to respond to conventional
treatment, sequencing can suggest new molecular
targets for chemotherapy and other treatment. When
children present with puzzling neurodevelopmental
anomalies, sequencing can shorten the diagnostic
odyssey by revealing potentially causative genetic vari-
ants. Sequencing can even be used to help diagnose
critically ill individuals in order to save lives.
With sequencing transitioning into clinical care,
controversy has erupted over how to manage inciden-
tal or secondary findings. Whenever a physician orders
genomic analysis for a particular indication, certain
genes are of focal concern and their analysis yields pri-
mary findings. However, sequencing, especially on a
large scale — potentially up to whole exome or whole
genome sequencing — may yield additional findings
on genes that are not germane to the original indica-
tion but nonetheless may hold clinical significance
because they indicate another risk, disease process, or
condition. An enormous literature now addresses the
question of how to handle these additional findings,
both in research and in clinical care.1
The American College of Medical Genetics and
Genomics (ACMG)2 — the leading professional soci-
ety for medical geneticists in the United States — has
issued a series of policy statements to guide manage-

ment of incidental or secondary findings that arise in
clinical sequencing. However, the complexity of this
issue has thwarted easy resolution. ACMG exercises
a leadership role in multiple domains of genomic
medicine, from clinical prescribing to laboratory prac-
tice, electronic health records (EHR), and insurance
coverage. But the question of incidental findings has
prompted College statements every year since 2012.
This article traces the evolution of ACMG policy on
incidental or secondary findings and argues that fur-
ther change is needed. Current ACMG policy urges a
regime involving a routine search for an expanding set
of extra genes, offering patients only an opt-out from
the entire set. The routinization of this search con-
tinues to constitute opportunistic screening without
the empirical foundation for this public health mea-
sure. Moreover, routine screening with an opt-out is
far different from informed consent offering patients
the opportunity to opt-in to extra testing. And forc-
Susan M. Wolf, J.D., is McKnight Presidential Professor of
Law, Medicine & Public Policy; Faegre Baker Daniels Profes-
sor of Law; and Professor of Medicine at the University of
Minnesota. She is also Chair of the University’s Consortium
on Law and Values in Health, Environment & the Life Sci-
ences.
334 journal of law, medicine & ethics
S Y M P O S I U M
2017 The Author(s)

ing patients to make a decision as to the entire set of
extra genes — a heterogeneous and growing collec-
tion including cancer risk, cardiovascular risk, and
soon pharmacogenomics genes — robs patients of the
opportunity to exercise autonomous choice based on
their health circumstances and values. These prob-
lems with current ACMG policy are even more acute
because the policy still includes children on the same
footing as adults, but the “all or nothing” opt-out
deprives parents, guardians, and adolescents of the
option to delay testing for genes associated with adult-
onset conditions.
ACMG 2012
The evolution of ACMG policy on incidental or sec-
ondary findings begins with the College’s 2012 pol-
icy statement on, “Points to Consider in the Clinical
Application of Genomic Sequencing.”3 Recognizing
that large-scale sequencing was moving into clinical
use, the policy recognized that sequencing would pro-
duce not only “diagnostic results,” but also “secondary
findings (also called incidental or unanticipated find-
ings).” The policy acknowledged that, “Such secondary
findings are highly likely, if not inevitable, whenever
WGS/WES is performed.”
The policy statement called for laboratories and
clinics to establish “clear policies…related to disclosure
of secondary findings.” The policy called for inform-
ing patients of the policies and “the types of secondary
findings that will be reported back to them and under
what circumstances.” However, the policy provided a
patient opt-out: “Patients should be given the option
of not receiving certain or secondary findings.” Noth-

ing in this policy explicitly called for restricting patient
choice on secondary findings to “all or nothing.”
ACMG 2013
In March of 2013, ACMG issued a new paper focus-
ing on the problem of incidental or secondary find-
ings, the fruit of a year’s worth of effort by a working
group examining this issue.4 This lengthier paper used
the term “incidental findings,” defining these as “the
results of a deliberate search for pathogenic or likely
pathogenic alterations in genes that are not appar-
ently relevant to a diagnostic indication for which the
sequencing test was ordered.” This paper articulated
a list of 56 extra genes that should be analyzed and
reported by the laboratory whenever sequencing was
undertaken. This roster of cancer risk, cardiovascular
risk, and pharmacogenomics genes was chosen based
on pathogenicity and clinical actionability, though the
paper noted that “[a]dditional genes may be analyzed
for incidental variants, as deemed appropriate by the
laboratory.”
The working group urged that the clinician ordering
sequencing “discuss with the patient the possibility of
incidental findings,” with patients having “the right to
decline clinical sequencing if they judge the risks of
possible discovery of incidental findings to outweigh
the benefits of testing.” However, the paper contem-
plated that patients would either accept sequencing
with a laboratory search for the full set of inciden-
tal findings or decline sequencing altogether. There
was no option to accept sequencing for the primary
indication but to opt-out of the search for incidental
findings. And there was no option to choose some
incidental findings (say, perhaps, cancer risk findings
in a patient already facing cancer) but not others (for

example, cardiovascular findings). Thus, if a patient
needed clinical sequencing (as presumably most rel-
evant patients would, given the fact that sequencing
Current ACMG policy urges a regime involving a routine search
for an
expanding set of extra genes, offering patients only an opt-out
from the entire
set. The routinization of this search continues to constitute
opportunistic
screening without the empirical foundation for this public
health measure.
Moreover, routine screening with an opt-out is far different
from informed
consent offering patients the opportunity to opt-in to extra
testing. And
forcing patients to make a decision as to the entire set of extra
genes — a
heterogeneous and growing collection including cancer risk,
cardiovascular
risk, and soon pharmacogenomics genes — robs patients of the
opportunity to
exercise autonomous choice based on their health circumstances
and values.
Susan M. Wolf
2017 The Author(s)

was ordered), then the search for incidental findings
was a required part of that process.
This represented a retreat from the 2012 position
that patients could accept clinical sequencing but opt
out of a report of secondary or incidental findings.
While the 2013 paper technically left communica-
tion of these findings to the clinician, the possibility
that the clinician might refrain from communicating
pathogenic and actionable findings in the laboratory
report seemed remote, given that patients have direct
access to their health records under HIPAA.5 (Indeed,
as of 2014, patients have direct access to their labora-
tory reports.6)
ACMG’s 2013 paper anticipated the outcry that
ensued due to the call for mandatory inclusion of sec-
ondary or incidental findings analysis whenever clini-
cal sequencing was performed. The paper itself said,
the Working Group did not favor offering the
patient a preference as to whether or not their
clinician should receive a positive finding
from the minimum list of incidental findings
described in these recommendations. We recog-
nize that this may be seen to violate existing ethi-
cal norms regarding the patient’s autonomy and
“right not to know” genetic risk information.
Vigorous objections to the 2013 policy focused on sev-
eral issues.7
First, as ACMG anticipated, mandatory analysis of

secondary or incidental findings and the reality that
clinicians would feel impelled to communicate those
results deprived patients of choice and vitiated the
“right not to know” that has long obtained in clinical
genetics. Second, ACMG acknowledged that institut-
ing routine analysis of secondary or incidental findings
whenever patients undergo sequencing constitutes
“opportunistic screening.”8 Yet opportunistic screen-
ing is a public health measure that requires empiri-
cal demonstration that the criteria for instituting such
screening have been met, including positive predictive
value and net population benefit. As Burke and col-
leagues pointed out, those criteria had not been met.9
Third, some challenged the working group’s roster
of 56 genes; given that the list was meant to capture
highly pathogenic and clinically actionable genes, crit-
ics questioned the list on grounds of both over-inclu-
sion and under-inclusion.
Finally, a robust debate erupted over ACMG’s inclu-
sion of children in its recommendations: “Incidental
variants should be reported regardless of the age of the
patient.”10 Policy had long favored confining genetic
testing of minors to those results needed for medi-
cal management in childhood, delaying other genetic
testing until the child achieved the age of majority and
could choose for him- or herself whether to undertake
that testing. Indeed, a 2012 technical report published
in early 2013 from ACMG together with the American
Academy of Pediatrics (AAP) had reiterated this view:
Early professional statements recommended that
predictive genetic testing of minors be consid-
ered only if effective medical interventions were
available to treat, prevent, or retard the course

of the disease. Since then, more than two dozen
additional national and international guidelines
have concurred.… The AAP and the ACMG
continue to support the traditional professional
recommendation to defer genetic testing for late-
onset conditions until adulthood.11
The technical report recognized that there might be
exceptional cases warranting testing for genes asso-
ciated with risk of adult-onset conditions “to resolve
disabling parental anxiety or to support life-planning
decisions that parents sincerely believe to be in the
child’s best interest.”12 However, this case-by-case
approach was in effect rejected by ACMG’s 2013 policy
that secondary or incidental findings should be rou-
tinely ascertained and reported, even in children and
even when the genes in question were associated with
adult-onset disorders.
Objections to all four dimensions of the 2013 paper
produced vigorous debate whose importance went
well beyond the question of how to handle secondary
or incidental findings. At issue was the scope of patient
autonomy in the new era of genomic medicine, the
relationship between patient autonomy and physician
paternalism, protections for children and adolescents,
the ethical use of pediatric testing to warn family mem-
bers of their own possible genetic risks, and the cri-
teria for public health screening using genomic tech-
nologies. The importance of the issues and the outcry
provoked by the 2013 paper prompted ACMG to issue
a clarification statement later in 2013 defending the
paper by emphasizing its “focus only on unequivocally
pathogenic mutations in genes in which pathogenic
variants lead to disease with very high probability and
cases in which evidence strongly supports the benefits

of early intervention.”13 On children, the clarification
attempted to reconcile the longstanding policy disfa-
voring testing for adult-onset conditions in children
(as reiterated in the ACMG/AAP technical report)
with the 2013 paper by saying, “The ACMG affirms its
recommendation not to perform diagnostic testing for
an adult-onset condition in children but believes that
reporting an incidental finding of a severe, actionable,
336 journal of law, medicine & ethics
S Y M P O S I U M
2017 The Author(s)
pathogenic mutation falls outside this recommenda-
tion.”14 The furor, however, would not abate.
ACMG 2014
To ACMG’s great credit, the organization took seri-
ously the continuing concerns. In April 2014, ACMG’s
Board issued a news release modifying the policy artic-
ulated in the 2013 paper and subsequent clarification.
The release reinstated the opt-out created by the 2012
policy, but clarified that the patient should be able to
opt out of analysis of secondary or incidental findings,
not just opt out of receiving a report of those findings:
There appears to be a consensus among ACMG
members that patients should have an oppor-
tunity to opt out of the analysis of medically
actionable genes when undergoing whole exome
or genome sequencing. While the ACMG Board

still considers the IFs to be important medical
information that can be a great value to fami-
lies, it has voted to recommend that such an
‘opt out’ option be offered to patients who are
considered candidates for clinical genome-scale
sequencing.15
Meanwhile, ACMG undertook a survey of their
membership on a range of questions raised by the 2013
paper. In early 2014, they emailed a survey link to the
membership, with the results published in November.
The survey found high agreement (80.7% combining
“agree” and “strongly agree”) that patients “should be
able to opt out of laboratory analysis of the 56 genes
on the ACMG list.”16 There was less agreement that
patients “should be able to decide which genes will
be analyzed for pathogenic variants among the 56
genes on the ACMG list” (46.2% combining “agree”
and strongly agree”), though only 34.8% rejected this
idea (combining “disagree” and “strongly disagree”).17
There was no consensus on how to manage secondary
or incidental findings in children.
ACMG 2015
Informed by this survey, the ACMG issued updated
policy in 2015.18 This policy maintained that genet-
ics professionals should seek written informed con-
sent from patients for large-scale clinical sequencing.
That consent process should address “the inevitable
generation” of secondary or incidental findings. How-
ever, rather than stating that these professionals
should seek patient consent for what the 2013 paper
made clear was a “deliberate search” for these extra
findings, the 2015 policy stated that patients “should
be made aware that, regardless of the specific indica-
tion for testing, laboratories will routinely analyze the

sequence of a set of genes deemed to be highly medi-
cally actionable so as to detect pathogenic variants that
may predispose to a severe but preventable outcome.”
Once the patient was informed of this routine search
and analysis, the patient would be offered the choice
of opting out, but with a warning as to the potential
consequences: “Patients should be informed during
the consent process that, if desired, they may opt out
of such analysis. However, they should also be made
aware at that time of the ramifications of doing so.”
There was no parallel recommendation that patients
be warned of the potential consequences of failing
to opt out (e.g., discovery of secondary or incidental
findings that proved to be false positives, creating an
unwanted record of susceptibility to disease unrelated
to the reason for sequencing, potential vulnerability
to discrimination, or other consequences). In addi-
tion, the 2015 update made clear that patients could
not choose analysis and report of some secondary or
incidental findings but not others: “it is not feasible for
patients to be offered the option of choosing a subset
of medically actionable genes for analysis. Thus, the
decision regarding routine analysis should apply to the
entire set of genes deemed actionable by the ACMG.”
Thus, the bottom line remained a routine search
for the full set of secondary or incidental findings
every time clinical sequencing was ordered for any
indication. Rather than seeking opt-in consent from
patients for this extra search with information on the
potential benefits and risks, patients could only opt
out and with a warning of the potential consequences
of exercising that option.

There was no discussion of whether this routinized
opportunistic screening was now supported by greater
evidence than when the policy was first put forth in
2013. Similarly, the 2015 update made no change to
the inclusion of children in the 2013 paper, despite the
lack of consensus on this point in the 2014 survey of
the membership. “[T]he board recommends that the
same policy should be adhered to in children as in
adults; i.e., analysis of a set of selected genes to iden-
tify pathogenic variants associated with severe but
preventable disease should be routinely performed.”
Finally, the board made clear that the list of extra
genes to search would evolve. They referred to “an
ever-changing list” and ended the policy statement by
saying, “A multidisciplinary working group has been
formed to develop a process for updating and main-
taining the list of genes to be routinely analyzed for
secondary findings.”
ACMG 2016
In late 2016, the ACMG Secondary Findings Working
Group published an update to ACMG’s policy state-
Susan M. Wolf
2017 The Author(s)
ment on secondary findings.19 The committee had
requested that ACMG members nominate genes for

inclusion or deletion from the list: “The Secondary
Findings Working Group will review nominations
periodically with a plan to publish updates to the Sec-
ondary Findings Gene List twice per year.”20 The first
update, published in November, added five genes to
the ACMG list of 56 and removed one — the “ACMG
56” became the “ACMG 59.”21
In addition, the committee indicated they would
now consider adding pharmacogenomics (PGx) genes
to the list in future updates. As the committee co-chair
explained, this was a notable shift:
Pharmacogenomics genes ‘don’t fit into the same
model of disease which we’re used to for the
other genes’…. PGx genes are fundamentally dif-
ferent from the genes that are currently on the
list because they do not predispose to disease or
an adverse event on their own, but only in com-
bination with exposure to a drug…. Secondly, the
information gleaned from PGx genes may not be
immediately actionable but might only be rel-
evant in the future, when a drug is prescribed.22
Thus, ACMG is contemplating significantly expand-
ing the scope of routine extra analysis when clinical
sequencing is undertaken.
Continuing Problems with ACMG Policy
ACMG’s 2014 clarification and 2015 update to pol-
icy on secondary or incidental findings represented
an important improvement, but failed to resolve the
underlying issues. While ACMG removed mandatory
analysis of secondary or incidental findings by creat-
ing an “opt-out,” the updated policy failed to embrace
informed consent. Instead, the presumption that such

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