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What If the Prenatal Diagnosis of a
Lethal Anomaly Turns Out to Be Wrong?
André Kidszun, MD,
a
Jennifer Linebarger, MD,
b
Jennifer K. Walter, MD, PhD, MS,
c
Norbert
W. Paul, MA,
d
Anja Fruth, MD,
e
Eva Mildenberger, MD,
a
John D. Lantos, MD
b
Departments of
a
Neonatology, and
e
Obstetrics and
Gynecology, and
d
Institute for the History, Philosophy,
and Ethics of Medicine, University Medical Center, Mainz,
Germany;
b
Children’s Mercy Hospital, Kansas City, Missouri;
and
c
Children’s Hospital of Philadelphia, Philadelphia,
Pennsylvania
Drs Kidszun, Linebarger, Lantos, Walter, Paul, Fruth,
and Mildenberger contributed to the design of
this paper, the drafting of the manuscript, and the
review of the manuscript; and all approved the fi nal
version.
DOI: 10.1542/peds.2015-4514
Accepted for publication Dec 15, 2015
Address correspondence to John D. Lantos, MD,
Children’s Mercy Hospital, 2401 Gillham Rd, Kansas
City, MO 64108. E-mail: jlantos@cmh.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
1098-4275).
Copyright © 2016 by the American Academy of
Pediatrics
FINANCIAL DISCLOSURE: The authors have
indicated they have no fi nancial relationships
relevant to this article to disclose.
FUNDING: Parts of this work were funded by the
Deutsche Forschungsgemeinschaft, grant 2015/1,
GRK “Life sciences–Life writing.”
POTENTIAL CONFLICT OF INTEREST: The authors
have indicated they have no potential confl icts of
interest to disclose.
As a result of advances in prenatal
diagnosis, doctors can now conduct a
much more sophisticated and precise
diagnostic and prognostic evaluation
of the fetus than has ever been
possible before. Genetic screening,
radiologic imaging, and biophysical
profiling generate information
that can inform discussions with
parents about both prenatal and
postnatal medical management. But
sometimes, prenatal evaluation leads
to expectations that are not confirmed
on postnatal evaluation. Usually,
this is not the result of a completely
mistaken diagnosis. Instead, it is
because many diseases manifest
across a range of specific findings and
may be less severe, or more severe,
than anticipated. We present a case in
which a prenatal diagnosis was made
of severe osteogenesis imperfecta
(OI), leading to a decision to induce
delivery at 31 weeks. On postnatal
evaluation, the infant’s disease did
not appear to be as bad as had been
anticipated. We present comments
from the treatment team and 2 experts
in pediatric palliative care.
CASE PRESENTATION
During routine midtrimester
ultrasound screening, the fetus of
a 21-year-old primigravida was
diagnosed with a severe skeletal
malformation. In the following days,
amniocentesis and serial ultrasound
examinations were performed to
establish the exact diagnosis. At 30
weeks of gestation, severe OI was
diagnosed. The identified point
mutation “c.3008G>a, p.Gly1003Asp”
in the Col1A2 gene had been
previously associated with OI type II:
the so-called “perinatal-lethal” type.
1
Evidence of thoracic hypoplasia,
decreased bone density of the
cranium, and multiple intrauterine
bone fractures supported this
diagnosis of a very severe and most
likely “lethal” type of OI.
Parents had been involved in all
stages of the diagnostic process and
abstract
Advances in prenatal diagnosis create a unique set of clinical ethics
dilemmas. Doctors routinely obtain genetic screening, radiologic images,
and biophysical profiling. These allow more accurate diagnosis and
prognosis than has ever before been possible. However, they also reveal a
wider range of disease manifestations than were apparent when prenatal
diagnosis was less sophisticated. Sometimes, the best estimates of
prognosis turn out to be wrong. The infant’s symptoms may be less severe
or more severe than anticipated based on prenatal assessment. We present
a case in which a prenatal diagnosis was made of severe osteogenesis
imperfecta, leading to a decision to induce delivery at 31 weeks. On
postnatal evaluation, the infant’s disease did not appear to be as bad as had
been anticipated. We discuss the ethical implications of such diagnostic and
prognostic errors.
ETHICS ROUNDS
PEDIATRICS Volume 137 , number 5 , May 2016 :e 20154514
To cite: Kidszun A, Linebarger J, Walter JK, et al.
What If the Prenatal Diagnosis of a Lethal Anomaly
Turns Out to Be Wrong?. Pediatrics. 2016;137(5):
e20154514
by guest on May 24, 2016Downloaded from
KIDSZUN et al
appeared to be highly committed
to care for their infant irrespective
of any anticipated health disorders.
However, being faced with a disease
that was considered “lethal, ” the
mother felt incapable of continuing
her pregnancy. She was horrified
by the idea that her infant suffered
from fractures in utero and then
subsequently died around or shortly
after birth. On the other hand,
feticide was out of question for both
parents. An ethics consultation with
participation of obstetricians and
neonatologists was held. Mothers’
and child’s best interests were
balanced and a medical induction
of labor and primary palliative care
of the infant was considered an
acceptable therapeutic approach.
At 31+0 weeks of gestation, a
male preterm infant was delivered
vaginally from a breech position.
His birth weight was 1170 g. Under
close observation of the neonatal
team, the boy was given to mother’s
breast immediately after birth. His
respiratory adaption was uneventful
without any medical intervention. No
signs of discomfort were observed.
After a while, he was placed in an
incubator and after another while
he was transferred to the neonatal
unit where intravenous fluids were
administered. He was eupneic and
breathing in room air. His parents
asked that his do not resuscitate
order be cancelled and that he be
given life-prolonging treatment.
The next day, an ethics consultation
was summoned as the medical team
was uncertain whether it should
continue palliative care.
The Treatment Team Comments
OI is a genetic disorder with
a prevalence of ∼1:20 000. It
is characterized by a distinct
predisposition to multiple bone
fractures and can be diagnosed
in utero at the end of the first
trimester.
2, 3
Ultrasonography
findings of multiple fractures, bone
demineralization, and shortening
and deformity of the long bones have
been used to distinguish the “lethal”
OI type II from other forms of OI
and other skeletal disorders.
4, 5
But
this way of differentiating “lethal”
from milder forms of OI is deeply
flawed. OI subtypes were developed
by using retrospective data such as
radiograph findings, genetics, and
clinical course. By these criteria,
OI type II was diagnosed when the
affected individual had died in utero
or shortly after birth. The criteria
were not developed to be predictive.
The sensitivity or specificity of
different findings as predictors of
prognosis has never been validated.
Nevertheless, these categories are
still used and type II is considered the
most severe type.
A significant limitation of these
diagnostic and prognostic criteria is
that they were developed without
taking into account the effect of
medical interventions. A recent
review stated that OI “type II is
lethal, usually because of respiratory
failure resulting from multiple rib
fractures.”
6
This is the case only if
one decides not to treat respiratory
failure due to rib fractures.
We did not find any respective study
that was not biased by self-fulfilling
prophecy or patient selection. In
one retrospective study of “lethal”
congenital anomalies, approximately
three-quarters of pregnancies were
terminated and 90% of the live-born
infants died before 4 months of
age. When the diagnosis was made
prenatally, the infants received less
intensive care compared with those
who were diagnosed postnatally.
Because aggressive treatment was
not associated with prolonged
survival, the authors concluded that
it should not be offered.
7
This is a
classic self-fulfilling prophecy. It is
hard to know what the mortality
rate would be with treatment if
current outcome statistics are based
on cohorts in which many affected
infants die after termination of
pregnancy and another large number
of infants receive palliative care after
birth.
8, 9
We believe that classification
is not useful today and that the
spectrum of clinical severity of OI
should be considered as continuous
rather than classified into discrete
categories.
With an explicit aim of preventing
early postnatal death, the treatment
of respiratory failure due to rib
fractures is likely to be effective.
However, death also may result
from an undersized thorax, overall
thoracic wall instability, and
pulmonary hypoplasia.
10
When such
features are present, they are likely
to be associated with high mortality,
even with treatment.
Genetic results are also problematic.
OI is a highly heterogeneous disorder
in which no reliable genotype-
phenotype correlation exists.
11, 12
Nevertheless, in cases of diagnostic
uncertainty, clinicians and especially
parents might be tempted to attach
high importance to a distinctive and
verifiable genetic feature. In any case,
parents should be counseled carefully
and the limitations of genetic test
results should be discussed in detail.
The most influential problem is
not specific to OI. It arises with
the concept of “lethal” congenital
malformations. The term “lethal”
is very imprecise.
13
However, a
common understanding is that
a “lethal” diagnosis implies an
irresistible progression of a disease
that inevitably leads to death in the
near future.
14
Such understanding
and usage of the terminology
“lethal” unavoidably implicates that
treatment of such a condition is futile
or even detrimental. As reported
previously and now observed in
our case, such “lethal” language
predetermines medical treatment,
because it predetermines parental
and medical anticipations on the
clinical course.
15
“Lethal” language
is harmful because it may distract
parents from unprejudiced decisions
between different treatment
options. When counseling in cases
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PEDIATRICS Volume 137 , number 5 , May 2016
of life-threatening fetal anomalies,
most physicians encourage a certain
treatment option. Furthermore,
significant discrepancies in
counseling can be observed
depending on whether a condition is
considered to be “uniformly lethal” or
“uniformly severe, commonly lethal.”
Because of the inherent ambiguity
in such terms, we recommend
physicians to avoid the term “lethal”
in communication practice and,
even more importantly, in the
nomenclature of diseases.
With these considerations in mind,
we can examine the 3 options that
were offered in this case at the time
of the prenatal ethics consultation:
(1) carrying the child to full term and
perinatal palliative care, (2) feticide
and termination of pregnancy, and,
because the mother had already
rejected these options, (3) medical
induction of labor and perinatal
palliative care. Active intervention
by means of full intensive care was
not discussed as a treatment option.
Although options (1) and (2) were
identified as ethically most consistent
due to their clear consequential
effectuation of an either mother-
centered or child-centered
perspective, option (3) was finally
considered acceptable, although
concerns had been raised that this
approach might imply therapeutic
disadvantages to the infant and
neglect potential harm for the mother
at the same time. This may seem
like the worst of both worlds. We
disagree.
In a case like this, it is permissible to
allow the mother to take some risks
as long as she understands those
risks and they are consistent with her
overall goals. Many parents want to
see and hold their living infant, even
if that infant is not likely to survive.
In such situations, both aggressive
and nonaggressive intrapartum
monitoring should be considered,
depending on parents’ preferences.
Parents and health care professionals
should be prepared for a situation
in which an infant with a life-
threatening congenital malformation
will not die immediately after birth
but will survive for days or more.
16,
17
Significant outcome-relevant
discrepancies between the proposed
prenatal and the actual postnatal
diagnosis may occur.
One should also bear in mind that
palliative care does not per se limit
certain interventions. An infant with
a severe congenital OI might have
difficulties in respiratory adaption
like any other nonaffected infant. So
there might be a palliative indication
to give supplemental oxygen in
such a case or even to give some
additional respiratory support
if there is a reasonable prospect
that the infant can overcome this
temporary disturbance. In a pre-
as well as a postnatal setting of a
severe congenital malformation,
the consideration of all possible
treatment options and respectful
communication with the (future)
parents are essential prerequisites
to respect parental autonomy and
to ascertain the child’s and families’
best interests. Especially when
decision-making is informed by
prognostic concepts, the narrative
co-construction and negotiation
of therapeutic goals and strategies
between health care professionals
and parents and thus the influence
of subjective values and judgments
must be taken in account.
In this case, we decided to forego
palliative care and to start full life-
sustaining treatment. The parents
were fully aware of the anticipated
outcome of an infant with severe
OI. However, their decision to ask
for termination of pregnancy and
palliative care was likely based on
the assumption that their infant
would suffer and die shortly after
birth. We were wondering why the
outcome of our prenatal assessment
was that inaccurate and we are now
convinced that the use of the term
“lethal” distracted the parents and
the clinicians from an unprejudiced
assessment of the survival prognosis.
Jenni Linebarger, MD, Pediatric
Palliative Care Physician, Comments
Perinatal diagnosis comes with
inherent uncertainty. Providers rely
on imaging, genetic studies, and
experience (personal and published)
to formulate a prognosis before they
can truly “see” the infant. As such,
planning for care at delivery often
follows the mindset of “prepare for
the worst, hope for the best.” In this
case, the providers and the parents
prepared for the infant’s death based
on the genetic diagnosis of OI type
II and the thoracic hypoplasia noted
on ultrasound. Yet on day of life 1,
the infant is eupneic and breathing
in room air, leaving the providers
uncertain about how to proceed
and doubting whether to continue
palliative care.
Of course you provide palliative care!
Palliative care is not exclusive to the
end of life. Palliative care is provided
for patients with a wide range of
life-limiting and life-threatening
conditions; ideally beginning
when an illness is diagnosed and
continuing regardless of whether a
child receives treatment directed at
a cure or prolonging life. The role of
palliative care is to address physical,
psychological, and social stressors,
with a focus on improving the quality
of life.
The infant boy in this case has
genetically confirmed OI, and as
the OI Foundation Web site states,
“There is no cure for OI, but there
are ways to manage the symptoms.”
So in one sense, all treatments for
patients with OI are “palliative, ” not
meant to cure, but meant to manage.
For patients with OI type II (and
severe type III), the life expectancy is
shortened. Although the infant boy in
this case appears to be breathing well
now, we do not know whether that
will continue over time. Given such
remaining uncertainty, a palliative
care team may aid the parents and
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the treatment team in outlining goals
for this infant’s care.
The parents in this case have been
given the gift of time with their
son that they did not anticipate.
How do they want to fill it? Using
a 4-quadrant decision-making tool
may help the family outline the
goals for their son’s care by taking
into account their values as well as
the medical indications (diagnosis,
symptoms, proposed interventions),
the infant’s current and anticipated
quality of life (important activities),
and contextual issues that make up
the nonmedical side of life. It may
be, for example, that an isolette and
intravenous fluids do not fit into their
goals, and that they would prefer to
have him room-in and breastfeed ad
libitum.
Prenatal palliative care teams
are familiar with infants who
are delivered and do better than
expected, as well as infants who do
worse. In such cases, it is crucial to
talk to parents about uncertainties
and about their hopes, fears, goals,
and plans. In this case, they have
been given the gift of time with their
infant. We should help them figure
out how to best appreciate and use
that gift.
Jennifer K. Walter, MD, PhD, MS,
Pediatric Palliative Care Physician
and Clinical Ethicist, Comments
Pediatric patients with serious illness
sometimes defy expectations when
technologic support is withheld
or withdrawn, doing better than
anticipated. In such cases, clinicians
should explore 3 different potential
areas of concern: the facts of the
diagnosis and prognosis, the values
and goals of care of the family,
and the overall experience of how
to partner with families given
uncertainty. In doing so, clinical
teams can help families determine
a plan of care consistent with their
goals for their child.
In this case, let’s first focus on the
diagnostic and prognostic “facts”
and uncertainties. Prenatal genetic
testing has identified a “lethal”
type of OI. Infants with the this
genetic syndrome often do not
survive to birth and usually die in
the first 2 months, but others may
live until 1 year of age, usually
dying of respiratory infections and
insufficiency.
18
The parents and
team chose to induce preterm labor
due to a concern that the infant
would suffer significantly in utero
and after birth. However, after
delivery, the child was found to be
comfortable: not demonstrating signs
of significant pain from fractures,
able to breathe without support, and
interested in feeding (although it
would be unusual for a 31-weeker to
adequately feed without help given
his gestational age).
The child’s healthy appearance at
birth raised questions about the
accuracy of the prenatal genetic
testing. Although there is growing
evidence that the phenotype-
genotype correlation is accurate
for the gene mutations found,
19
the
child’s condition could reasonably
lead the team and parents to question
the veracity of the diagnosis.
Confirmation of the diagnosis
with other physical examination
findings by geneticists, and even
repeat genetic testing, would not be
unreasonable while acknowledging
that the diagnosis is most likely
accurate.
Although the exact progression of
this child’s disease is unknown,
his trajectory is very likely to
worsen in the coming months,
with increasing fractures requiring
pain management and the need to
balance comfort with respiratory
insufficiency. All prognostication
about what to expect should be
underscored with uncertainty
because he could decompensate
at any point. Many children with
OI type II will also suffer from
pneumonias and a progressive need
for positive pressure ventilation,
which can be painful due to mask
interfaces that result in further
fractures. Preparing families for
these declines and helping them
recognize that regardless of the
choice now, there may be a time in
the near future where the burdens
of interventions such as intubation,
continuous positive airway pressure,
or maintaining wakefulness in light
of difficult pain management may
warrant a primarily comfort-focused
approach with little or no respiratory
support.
Second, let’s turn from facts to
consider values and goals of care.
Although the diagnosis is being
confirmed and the prognostic range
clarified, the medical team should
revisit the values of the parents. In
the case we learn that the parents are
“highly committed to care for their
infant” irrespective of the disorder
he may have, yet also want to protect
him from suffering. Coupled with the
child’s unexpected condition at birth,
the clinical team then questioned
whether palliative care was still
warranted, even if the genetic
diagnosis was correct.
Pediatric palliative care is often
described as an extra layer of
support in decision-making and
symptom management for children
with serious illness, often provided
in conjunction with life-prolonging
treatments. The team and family
do not need to make an either-or
decision. In fact, the clinical team
may have been asking whether they
should continue to recommend a
primarily comfort-focused approach
given the child’s well appearance and
likely need for support in feeding
with a nasogastric tube (NGT).
So how should the team weigh
whether a comfort-only approach
is warranted given the parents’
wishes to care for their child while
also preventing suffering? Given the
possibility that this infant would
live longer with some life-sustaining
treatments, such as artificial
nutrition, and at some point in the
future, will likely need noninvasive
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or invasive respiratory support,
the team must consider whether
withholding these treatments
now is ethically acceptable. Some
clinicians are reluctant to start any
life-sustaining therapy given the
potential psychological challenge of
withdrawing it in the future. That
is generally not the best approach.
When it is ethical to withhold a
treatment, it is generally also ethical
to withdraw that treatment.
20
The team and family should consider
what is in the best interest of this
child from the child’s perspective,
while weighing the risks of
each possible intervention. For
example, providing the child with
supplemental nutrition by NGT
carries low risk with the potential
benefit of extending his currently
good quality of life, one that does
not include intractable pain or
repeated interventions. The clinical
team should reengage the parents,
discuss the realities of the infant’s
current good status, and recommend
NGT placement with supplemental
feeds to offer him the possibility of
extending his life, and keeping him
from feeling hungry, as long as he
maintains a good quality of life.
In making this first recommendation
for NGT feeding, the care team must
further explore the family’s values
and assess the level of suffering that
they are willing to tolerate for their
child in the future to potentially
prolong his life. The team should
also recommend home hospice
services, given the dynamic nature of
the child’s disease. Concurrent care
insurance legislation has meant that
hospice can frequently be offered
simultaneously with life-sustaining
treatments for these types of
patients.
Third, let’s consider how we can
partner in the face of uncertainty.
Parents who have struggled to
make a decision to withhold or
withdraw life-sustaining treatments
may experience increasing distress
when their child appears to be doing
better than expected. Therefore,
the uncertainty regarding possible
outcomes should be part of the
discussion of any decision to limit
interventions. Clinical teams can
anticipate potential scenarios in
advance and agree on the kinds of
interventions that they would be
willing to offer to families given the
clear expression of their goals.
Primary clinical teams, working
with pediatric palliative care
specialists and ethics consultants,
can successfully navigate these
discussions by recognizing their
role in supporting the decision-
making of parents, learning what
is most important to families, and
then making recommendations
that are consistent with those
goals and values. Merely offering
families a menu of options can be
overwhelming and unfair given our
professional responsibility to guide
families through these difficult
decisions. With careful coordination
of care and clear communication,
teams can help families realize their
hopes for a comfortable quality of
life, or a peaceful death, for their
child.
John D. Lantos, MD, Comments
This case illustrates the challenges
that pediatricians face as a result
of new technologies for prenatal
diagnosis. Although we can get much
more information about the health
and well-being of a fetus than ever
before, the wealth of new information
may be difficult to interpret.
Statisticians and epidemiologists
have long known that the availability
of more tests does not necessarily
increase the precision or the
accuracy of diagnosis. Instead, more
testing may lead to more uncertainty.
This can happen when tests give
conflicting results or when tests are
used in populations for which their
sensitivity and specificity have not
been evaluated.
21
Paradoxically,
more information can lead to less
certainty. Recognition of these
problems should lead to special
caution in discussing the results of
prenatal evaluations. There should
always be a caveat about confirming
the prenatal findings on postnatal
evaluation.
ABBREVIATIONS
NGT: nasogastric tube
OI: osteogenesis imperfecta
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DOI: 10.1542/peds.2015-4514
; originally published online April 1, 2016;Pediatrics
Eva Mildenberger and John D. Lantos
André Kidszun, Jennifer Linebarger, Jennifer K. Walter, Norbert W. Paul, Anja Fruth,
What If the Prenatal Diagnosis of a Lethal Anomaly Turns Out to Be Wrong?
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rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Grove Village, Illinois, 60007. Copyright © 2016 by the American Academy of Pediatrics. All
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
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DOI: 10.1542/peds.2015-4514
; originally published online April 1, 2016;Pediatrics
Eva Mildenberger and John D. Lantos
André Kidszun, Jennifer Linebarger, Jennifer K. Walter, Norbert W. Paul, Anja Fruth,
What If the Prenatal Diagnosis of a Lethal Anomaly Turns Out to Be Wrong?
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of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
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