JOURNAL OF PATHOLOGY,

MICROBIOLOGY AND IMMUNOLOGY

APMIS 126: 621–625 © 2018 APMIS. Published by John Wiley & Sons Ltd.
DOI 10.1111/apm.12832

Review Article

The placenta in intrauterine demise

THEONIA K. BOYD

Boston Children’s Hospital, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Boyd TK. The placenta in intrauterine demise. APMIS 2018; 126: 621–625.
Placental changes in intrauterine demise can be similar to antemortem pathologic processes. This chapter provides an
overview of postmortem placental changes, and provides an algorithmic set of considerations for discriminating
between ante- and postmortem pathology.
Key words: Placenta in fetal death; placenta in stillbirth; placenta in intrauterine demise; postmortem placental
pathology.
Theonia K. Boyd, Boston Children’s Hospital, Brigham and Women’s Hospital, Harvard Medical School, 300 Long-
wood Avenue, Boston, MA 02115, USA. e-mail: theonia.boyd@childrens.harvard.edu

Following intrauterine demise, regardless of etiol-
ogy, the placenta begins to undergo postmortem
changes that evolve as the interval between fetal
death and delivery progresses in time. These
changes can be classified as consequences of the fol-
lowing processes:
1. Cessation of fetal blood flow;
2. Altered maternal perfusion;
3. Maternal inflammation to non-viable products
of conception; and
4. Labor associated changes related to placental
separation.
Not all changes are present in every placenta;
and the extent to which changes occur in a given
placenta is related in large measure to the demise-
to-delivery interval, but also to the gestational age
at demise, the membrane rupture–to-delivery inter-
val, and likely to additional inscrutable factors.
POSTMORTEM CHANGES
Cessation of fetal blood flow
Villous capillary changes
When fetal cardiac output ceases, there is no longer
perfusion pressure nor metabolic substrates present
in fetal blood. Both are required to maintain villous
integrity and the integrity of fetal nucleated blood
Received 29 January 2018. Accepted 9 February 2018
cells. At the capillary level, the first recognizable
changes following fetal demise are those of
intravascular karyorrhexis. Thereafter, endothelial
integrity is compromised, leading to endothelial
karyorrhexis, loss of luminal integrity, and extrava-
sation of erythrocyte fragments onto the villous
stroma (Fig. 1A). Too, capillary lumens may
appear reduced in caliber, a consequence of lost
fetal perfusion, which is necessary to maintain nor-
mal luminal patency. As time elapses, villous capil-
laries fully involute, resulting in the terminal
phenotype of avascular villi (Fig. 1B) (1).
Muscular (stem, chorionic) vessel changes
There is a similar process of postmortem progres-
sion in muscular fetal vessels in stem villi and the
chorionic plate, although the full temporal evolution
requires a longer time frame than that of villous cap-
illary changes. This is likely due at least in part to
the fact that the luminal caliber of muscular vessels
is greater than that of capillaries. Therefore, pro-
gression to fully avascular chorionic and stem ves-
sels requires obliteration of larger cross-sectional
areas (a two-dimensional observation, as seen micro-
scopically) than at the capillary level. First there is,
as with villous capillaries, intravascular karyor-
rhexis, followed by loss of endothelial integrity, and
extravasation of erythrocytes into the peri-luminal
mural wall. Later in evolution, there is fibroblast
ingrowth into the vessel lumen, resulting in progres-
sive luminal obliteration. The full evolutionary pro-
cess is termed stem villous obliteration (Fig. 2) (1).

621

BOYD
A Altered maternal perfusion
B (e.g., multifetal gestations with remote fetal loss of
Fig. 1. (A) Villous stromal-vascular karyorrhexis at high
power, represented by erythrocyte extravasation and frag-
mentation. As a postmortem phenomenon in fetal demise,
these changes are widespread and temporally homoge-
neous. Disregard the undulating air bubble line. (B) Avas-
cular villi at high power, the capillary end stage
phenotype of fetal blood flow cessation into the placenta.
As a postmortem phenomenon in fetal demise, these
changes are widespread and temporally homogeneous.
Fig. 2. Stem villous obliteration, with near-total (upper
left) and total (lower right) stem vessel obliteration.
See Table 1 for time points in the evolution of
the above noted changes.
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Following intrauterine demise, maternal perfusion
persists, which is why the majority of the placental
parenchyma (save for fetal vasculature) remains lar-
gely unperturbed in the short run. As the demise-
to-delivery interval lengthens, however, maternal to
placental perfusion diminishes – by mechanisms
that have not been the subject of recent research
publications. Older literature touches upon this
topic if somewhat tangentially (2), with cited prior
publications suggesting that postmortem maternal
perfusion diminishes by spiral arteriolar vasocon-
striction and/or thrombosis (3, 4 respectively).
Regardless, examination of placentas with pro-
longed retention in utero following fetal demise
one fetus and continued pregnancy of the other(s))
demonstrates chronic maternal ischemic changes:
interruption of villous growth and development, vil-
lous fibrosis with pauci-to acellularity, and replace-
ment of the maternal intervillous space with
laminated or solid fibrin deposition. This latter pat-
tern can mimic massive perivillous fibrin deposi-
tion.
Maternal inflammation, presumptively a reaction to
non-viable products of conception
In placentas retained for days or longer following
intrauterine demise, there may be a bland and rel-
atively paucicellular maternal neutrophil migration
into the extraplacental membranes, in fetuses with-
out any other evidence of antemortem amniotic
fluid infection, and with demise attributable to an
entirely separate pathologic process (Fig. 3). This
pattern likely represents ‘postmortem chorioam-
nionitis,’ in which there is maternal neutrophil
activation by non-infectious tissue ischemia.
Though scientific evidence for this in the context
of retained placentas post-fetal demise is lacking,
by analogy there is a body of literature regarding
neutrophil activation in ischemia/reperfusion mod-
els of other human and animal organ systems
(e.g., 5).
Table 1. Placental histologic features of fetal vascular
changes following stillbirth (modified from Genest (1))
Good predictors
Intravascular karyorrhexis ≥6 h
Stem vessel luminal abnormalities
i.e., stem villous obliteration
Multifocal ≥48 h
Extensive ≥14 days
Extensive villous fibrosis ≥14 days
i.e., avascular villi
© 2018 APMIS. Published by John Wiley & Sons Ltd

THE PLACENTA IN INTRAUTERINE DEMISE
Delivery associated changes related to placental
separation
In fetuses with demise prior to the initiation of
labor, there may be changes secondary to placental
separation during the third stage of labor. For
example, the placenta may exhibit features of pla-
cental abruption, with adherent retroplacental
blood and microscopic recent placental infarction.
The key to recognizing this as a postmortem pro-
cess is to compare the temporal evolution of pla-
cental changes to other evidence of the demise-to-
delivery interval, such as the time fetal death was
recognized clinically, the degree of external macera-
tion (skin slippage), and the extent of organ autoly-
sis (6, 7).
DIFFERENTIAL DIAGNOSIS
Fetal vascular malperfusion
When fetal demise occurs, fetal blood flow into
and out of the placenta ceases. Therefore, the
postmortem fetal vascular involutional changes
described above evolve uniformly at all levels of
the fetal vascular tree. By contrast, when fetal
vascular malperfusion occurs prior to demise,
there should be temporal and spatial heterogene-
ity to the patterns present (Fig. 4). The demise-
to-delivery interval, as determined by other clini-
cal and pathologic measures (clinical identification
of fetal demise, extent of fetal maceration and
autolysis), can also be compared with the placen-
tal changes in order to assess whether fetal
malperfusion is postmortem vs antemortem (and
therefore with the latter, potentially causative of
stillbirth).
Fig. 3. Acute chorionitis in the setting of fetal demise
attributable to a non-infectious etiology based on other
placental processes.
© 2018 APMIS. Published by John Wiley & Sons Ltd
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Maternal vascular and inflammatory pathologies
A variety of postmortem patterns of perturbed
maternal perfusion and inflammation can be seen
when fetal death precedes delivery by days to
weeks. Changes that may evolve within the interval
of days between demise and delivery can include a
histologically mild or bland chorioamnionitis, and
apparent acute placental abruption. More chronic
changes may mimic maternal vascular malperfusion
and massive perivillous fibrin deposition. Compar-
ison of demise-to-delivery interval and identification
of alternate causes of death can aid in separating
these maternal changes as postmortem vs ante-
mortem (and therefore with the latter, as poten-
tially the causative of stillbirth).
ASSOCIATED FINDINGS
Nucleated red blood cells
Nucleated red blood cells are released into the fetal
circulation in response to variable mechanisms of
hypoxia and infection, among less common other
causes (8). As a general concept, the number of
nucleated red blood cells is a function of the dura-
tion and/or severity of the inciting stimulus. Nucle-
ated red blood cells are recognizable by virtue of
their hyperchromatic round nuclei and their cyto-
plasm that is similar to, or slightly more basophilic
than, their anucleate counterparts (Fig. 5). Other
general statements include the following: hypoxia is
a more robust stimulus than infection, and preterm
fetuses release nucleated red blood cells more read-
ily than do fetuses at term. Observing at least occa-
sional nucleated red blood cells in the fetal
circulation is common in stillbirth placentas, with
Fig. 4. Antemortem fetal vascular malperfusion, repre-
sented by remote avascular villi (left) and more recent vil-
lous stromal-vascular karyorrhexis (right).
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BOYD

the exception being acute catastrophic mechanisms cellular rounding, and nuclear pyknosis, with or
of demise followed by emergent delivery, in which without recognizable interdigitating meconium
the death-to-delivery interval is too brief (< ~1 h) macrophages (Fig. 7) (9).
for preformed nucleated red blood cells to be
released from fetal somatic stores in the liver and/
Villous edema
or bone marrow.
Villous edema, a nonspecific finding, can be present
in stillbirth placentas. Villous edema is seen more
Meconium
commonly overall in preterm placentas and in pla-
Meconium is rarely released in response to fetal centas with chorioamnionitis; in these circum-
stress prior to the third trimester. Thereafter, stances, villous edema is usually multifocal but
fetuses may release meconium in response to incit- widespread. Less commonly, villous edema, when
ing stimuli, including hypoxia and infection (8). extensive, may be seen with acute and complete
Meconium is less commonly encountered in still- umbilical cord occlusion. In this context, villous
birth placentas compared to the frequency of nucle- edema likely reflects acute fetal blood flow obstruc-
ated red blood cells. The depth of meconium tion and therefore fluid balance dysregulation
uptake into the extraplacental membranes, chori- (Fig. 8).
onic plate, and umbilical cord is a function of the
meconium release-to-delivery interval (Fig. 6). This
observation can be utilized in conjunction with the
temporal evolution of pathologic processes consid-
ered as potentially or likely causative of stillbirth,
in order to consider the fetal stress-to-demise inter-
val in the larger context of stillbirth. A particular
meconium-associated finding, meconium vascular
necrosis, is seen with prolonged meconium release.
Sufficient time elapses for meconium macrophages
to be deposited deep into Wharton’s jelly and/or
the chorionic plate, such that they come into con-
tact with the umbilical and/or chorionic vessel outer
walls closest to the amniotic fluid, and induce a
chemical myonecrosis. This process is identified
microscopically as myocyte–myocyte detachment,

Fig. 6. Meconium macrophages interdigitating between

umbilical vascular myocytes; several are highlighted by
ovals.

Fig. 5. Nucleated red blood cells in the fetal circulation of

the placenta, highlighted by arrows. Note the hyperchro-
matic round nuclei, and the cytoplasm in this image is
more basophilic than neighboring anucleate erythrocytes,
reflecting fetal somatic release of slightly less mature
nucleated red blood cells. Several are highlighted with Fig. 7. Meconium myonecrosis, with detached and
arrows. rounded myoctes and nuclear pyknosis.

624 © 2018 APMIS. Published by John Wiley & Sons Ltd


THE PLACENTA IN INTRAUTERINE DEMISE
Fig. 8. Villous edema, represented in this photograph.
This pattern is common in a patchy distribution, but in
stillbirth, when widespread, likely represents acute placen-
tal to fetal blood flow obstruction.
Fig. 9. Acute intravillous hemorrhage with extravasated
but intact red blood cells.
Fig. 10. Villous stromal-vascular karyorrhexis with red
blood cell extravasation and fragmentation.
© 2018 APMIS. Published by John Wiley & Sons Ltd
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Intravillous hemorrhage
Intravillous hemorrhage, which appears as largely
intact fetal red blood cell extravasation into the
villous stroma, is seen in conditions that incite
abrupt changes in fetal capillary pressure (Fig. 9).
When polarized toward the chorionic plate, this
pattern can be the result of back pressure induced
by acute umbilical or chorionic venous obstruction,
such as with acute cord prolapse. When polarized
toward the basal plate, it can be a consequence of
acute placental abruption, with placental separa-
tion pressure inciting fetal capillary rupture. How-
ever, basally oriented intravillous hemorrhage can
also occur as a result of intended mechanical
causes of placental–uterine separation, such as with
dilatation and curettage, and with Cesarean section
(Fig. 9). Intravillous hemorrhage should not be
confused with the villous stromal-vascular karyor-
rhexis (VSK) pattern of fetal vascular malperfu-
sion. With VSK, fetal erythrocyte extravasation is
accompanied by red blood cell fragmentation, cap-
illary dissolution, and villous stromal karyorrhexis
(Fig. 10).
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