CASE REPORT

Death of a Fetus With Myeloproliferative Disorder

and Trisomy 21
Danielle Prentice, DO; Raymond Deiter, DO; John Stanley, MD

From the Department of A 27-year-old woman, gravida 2, para 1, presented at 24 weeks gestation with
Obstetrics and Gynecology at
an intrauterine death. She previously consulted with maternal-fetal medicine
St Anthony Hospital in
Oklahoma City, Oklahoma because of a high suspicion of trisomy 21 after abnormal maternal serum
(Drs Prentice and Deiter) and
screen and cell-free DNA test results. The patient elected to have chromo-
the Perinatal Center of
Oklahoma in Oklahoma City
somal analysis following the death of the fetus, which confirmed a trisomy 21
(Dr Stanley). Dr Prentice is a diagnosis. Placental pathologic findings suggested that the cause of fetal
fourth-year resident.
death was total occlusion of the major vessels due to the accumulation of
Financial Disclosures: myeloid precursor cells, a novel mechanism. This case report discusses the
None reported.
rare finding of myeloproliferative disorder as a cause of death of a fetus with
Support: None reported.
trisomy 21.
Address correspondence to J Am Osteopath Assoc. 2019;119(3):208-211
Danielle Prentice, DO, doi:10.7556/jaoa.2019.032
St Anthony Hospital, 1000 N
Lee Ave, Oklahoma City, Keywords: Down syndrome, fetal death, myeloproliferative disorder, trisomy 21

OK 73102-1036.

Email: dkirch8@gmail.com

Submitted

M
February 5, 2018; yeloproliferative disorder (MPD) is well described in children with trisomy
final revision received 21 (Down syndrome).1-3 Two cases of fetal MPD in live neonates with
May 7, 2018;
trisomy 214 and 3 cases of MPD in intrauterine fetal death with confirmed
accepted
May 8, 2018.
trisomy 215 have been described. These cases occurred after documented hydrops
fetalis on ultrasonography.4,5 The current patient consented to chromosomal analysis
and placental pathologic analysis, which enabled the identification of a novel mechanism
of fetal death.

Report of Case
A 27-year-old woman, gravida 2, para 1, with previous term cesarean delivery presented
to the maternal-fetal medicine clinic at 20 weeks and 4 days of gestation. Noninvasive
cell-free DNA screening revealed a high risk of trisomy 21. Confirmatory testing by
amniocentesis was declined. Ultrasonography at 20 weeks showed no fetal anomalies
and growth within normal limits. The bowel was slightly echogenic (Figure). Maternal
physical examination findings were normal, and osteopathic structural examination
showed slightly increased lumbar lordosis, a common finding in pregnancy. The patient
was scheduled for serial ultrasonography every 4 weeks.
The fetal death was discovered at 24 weeks during a routine obstetrics and gynecology
appointment. Labor was induced, and delivery was uncomplicated. Because of the
trisomy 21 screening finding, the patient elected for fetopsy and placental pathologic
testing. Chromosomal analysis confirmed a diagnosis of trisomy 21. Pathologic analysis
of the placenta revealed umbilical and intravillous vascular distention/obliteration by

208 The Journal of the American Osteopathic Association March 2019 | Vol 119 | No. 3

Figure.
Slightly echogenic bowel noted on level II ultrasonography. Myeloproliferative disorder was determined to be the cause of
death in this fetus with trisomy 21.
myeloblasts, consistent with placental involvement in
fetal MPD. The findings were accordant with MPD
observed in children with trisomy 21. The cause of
death was attributed to extensive involvement and oblit-
eration of the fetal vessels of the placenta by atypical
cells due to MPD.
Discussion
Myeloproliferative disorder involves abnormalities in
the hematopoietic cells. Evidence suggests that MPD
is caused by aberrant fetal liver hematopoiesis.
Diagnosis typically occurs at birth or within a few
1-3
weeks of birth. Myeloproliferative disorder is most
prevalent in newborns with trisomy 21 at an incidence
of approximately 10%. This estimate is likely low,
6
owing to missed diagnoses after fetal death. Reported
case studies attributing fetal death to MPD or congeni-
tal leukemia are rare, likely because of missed diagno-
sis by pathologic analysis, low fetopsy rates, and no
standard protocol for histopathologic examination in
7
these types of cases.
The pathophysiologic findings in patients with MPD
show proliferation of clonal blasts, often expressing
megakaryocytic or erythroid markers. In both MPD
and acute megakaryocytic leukemia, blast cells arise
The Journal of the American Osteopathic Association March 2019 | Vol 119 | No. 3
CASE REPORT
from the megakaryocytic cell lineage or myeloid pro-
genitor cells, which can differentiate into megakaryocy-
tic cells.4 In newborns and infants, MPD is often
self-limited but may result in hepatosplenomegaly or
cutaneous infiltrates.1 However, this condition may
cause significant morbidity and mortality in the fetus.
Myeloproliferative disorder is associated with hydrops
fetalis due to anemia and tissue infiltration by leuke-
moid cells, which may lead to pericardial, peritoneal,
or pleural effusions. When multiple organs are affected,
fetal death can occur.1
Zerres et al4 and Smrcek et al5 reported the first 2
cases of MPD in fetuses with trisomy 21. These cases
were found in the prenatal period in conjunction with
fetal hydrops, and both resulted in live births. Fetal
MPD diagnosis was confirmed after delivery.4,5 The
present case showed no evidence of fetal hydrops on
ultrasonography before fetal death. A retrospective
case series between 1993 and 1999 reported 79 cases
of trisomy 21, 11 of which had fetal hydrops. In 3 of
these cases, hepatosplenomegaly and MPD were diag-
nosed. Of the 3 cases, 1 presented with ultrasono-
graphic findings characteristic of trisomy 21, fetal
hydrops, and MPD, but karyotyping was unsuccessful.
All incidences that they found had previous findings of
fetal hydrops or hepatosplenomegaly. The study
209
 CASE REPORT
speculated but did not find evidence of MPD in the
absence of fetal hydrops or hepatosplenomegaly find-
ings as a precursor to fetal death.5 The current case
provides direct evidence for this theory.
The current case illustrates the importance of prenatal
care and screening. The MPD case reports that we
found in our analysis of the literature were published
before the current standard of care (genetic screening
and regular ultrasonography). In most reported cases,
the first sign of disease was fetal death. Our case
differs because the patient had adequate prenatal care
and close follow-up with maternal-fetal medicine.
Furthermore, the patient was offered second trimester
genetic screening as recommended by the American
Congress of Obstetrics and Gynecology.8 Genetic
screening results indicated an increased risk for
trisomy 21 in concordance with cell-free DNA results.
Amniocentesis was denied. Despite normal anatomy
on level II ultrasonography, fetal death was discovered
4 weeks later. Pathologic test results revealed disten-
tion/obliteration of the umbilical cord and the intravil-
lous space by myeloid blasts, which was revealed to
be the ultimate cause of death—a cause not previously
reported, to the authors’ knowledge.
The current case establishes a mechanism of fetal
death and provides insight for future treatment or man-
agement protocols. Currently, once fetal trisomy 21 is
diagnosed, there are no clear guidelines for monitoring.
A study9 reported that 10.2% of fetuses with trisomy 21
died at an average gestational age of 28.9 weeks, and
37.1% died prior to viability at 24 weeks. This finding
suggests that a large population of fetuses with trisomy
21 die after viability, and close fetal monitoring may
lead to increased deliveries of viable neonates.
Placental infiltration of myeloid blast cells in fetuses
with trisomy 21 could be indicated by reduced blood
flow to the placenta via a nonstress test, biophysical
profile, and umbilical artery Doppler modalities. If
reduced placental blood flow is detected, viable fetuses
could be delivered to prevent fetal death. The patient
in the current case presented with fetal death at 24
weeks. The American College of Obstetricians and
210 The Journal of the American Osteopathic Association
Gynecologists Obstetrics Consensus 610 defines the
periviable period between 20 and 25 weeks and 6 days’
gestation. Many hospitals consider 24 weeks’ gestation
as viable, yet some hospitals consider viability at 22 to
23 weeks. Although death likely occurred too soon in
the present case, increased surveillance of fetuses with
trisomy 21 is indicated based on an average 28.9
weeks’ gestational age of death.9
Placental fetopsy and pathologic and genetic analysis
after the death of a fetus with trisomy 21 is critical for
understanding MPD. While MPD is treatable in chil-
dren and adults,1,3,6 to the author’s knowledge, no treat-
ments are suggested for fetuses. Intrauterine treatment
in these cases would be ideal to allow for delivery of
neonates closer to term and thus increase survival
rates. However, current available therapies (eg,
low–molecular weight heparin) do not cross the
placenta and offer no benefit for this indication.11
Currently, the best way to manage MPD in a fetus is
delivery and administration of traditional treatments.
A core principle of osteopathic medicine states that
rational treatment is based on an understanding of the
basic principles of body unity, self-regulation, and the
interrelationship of structure and function. Although
osteopathic physicians often apply this principle to
adult and pediatric patients, it should also be applied
to the fetus.
Conclusion
The present case describes a novel mechanism of action
for death of a fetus with trisomy 21, which, when
applied to the interrelationship of structure and function
of the placenta, promotes surveillance and possible
treatment. The case stresses the importance of obtaining
chromosomal and placental pathologic analysis after
fetal death regardless of previous test results or diagnoses.
When pathologic analysis of a placenta shows MPD, it
should suggest a high likelihood of trisomy 21 in a
fetus. These findings suggest that resistance to blood
flow through the umbilical cord may be increased
owing to accumulation of myeloid precursor cells.
March 2019 | Vol 119 | No. 3

Increased fetal monitoring, including umbilical artery
Doppler velocimetry, may be useful. Future trans-
lational and observational studies are needed to
determine its utility in fetuses with trisomy 21.
References
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