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\begin{document}

\title{Accuracy of antepartum ultrasound in evaluating placental pathology
using superb microvascular imaging: main research article}



\author[1]{Natsumi Furuya}%
\author[2]{JUNICHI HASEGAWA}%
\author[2]{Masatomo Doi}%
\author[2]{Junki Koike}%
\author[3]{Nao Suzuki}%
\affil[1]{Sei Marianna Ika Daigaku}%
\affil[2]{St. Marianna University School of Medicine}%
\affil[3]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 20, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objectives: To clarify whether microvascular ultrasound Doppler (SMI:
superb microvascular imaging) can detect antenatal histological findings
in pathologic placentas. Methods: In this prospective diagnostic
observational study (STROBE), pregnant women who were admitted to our
perinatal center for perinatal management were enrolled. Ultrasound
examinations to identify placental pathologies using SMI were performed
before delivery. After delivery, the placental tissue was clipped for
microscopic examination, as the location of the placenta obtained
ultrasound findings. The accuracy of antenatal ultrasound detection of
placental pathologies was compared between women who were admitted due
to fetal growth restriction (FGR), pre-eclampsia, and other indications.
Results: The highest accuracy was observed with placental infarction in
FGR (positive predictive value {[}PPV{]}, 100\%; sensitivity, 89\%; area
under the curve {[}AUC{]}, 0.945), whereas PPV, sensitivity, and AUC in
cases of preeclampsia were relatively low (AUC 0.540). Additionally,
PPV, sensitivity, and AUC for avascular villi were 100\%, 57\%, and
0.785 in cases with FGR, 67\%, 67\%, and 0.780 in cases with
preeclampsia, and 80\%, 80\%, and 0.920, respectively. The diagnostic
accuracies predictive of congestion of stem villi and chorangiosis were
insufficient (AUC\textless{}0.700). Conclusions: SMI can accurately
detect placental pathologic findings, such as placental infarction and
avascular villi. This modality may improve the perinatal management in
cases of placental abnormalities.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Superb microvascular Imaging (SMI), a recent blood flow imaging
technique produced by Canon Medical Systems (Japan), employs a unique
algorithm to minimize motion artifacts by eliminating signals based on
the analysis of tissue movement. Compared to the conventional color
Doppler imaging methods, SMI can significantly better visualize
low-velocity blood flow in small vessels \textsuperscript{1}, which
allows depiction of the pathology and diagnoses of placental
abnormalities. Placental pathological examination is retrospectively
performed after delivery to evaluate placental abnormalities that could
have resulted in complications during pregnancy. However, if it is
possible to predict the pathological findings antenatally using
ultrasound examination, it would be useful to understand the disease
state and predict the prognosis. Therefore, we investigated the
evaluation of placental pathologic findings using SMI.

Using SMI, in a normal placenta, villous blood vessels can be visualized
from the umbilical cord insertion to the stem villi and terminal villi.
Additionally, slow blood flow in the intervillous space from the spiral
artery is also visualized as a ''scatter'' that matches the heart rate
of the mothers. In contrast, we previously demonstrated, in placenta
increta, not only the thin myometrium with invasive placental tissue,
but also the avascularity of the peripheral villous tree and congested
stem vessels using SMI \textsuperscript{2}.

Furthermore, in a pilot study, we demonstrated various placental
pathological findings antenatally using SMI and compared them with
placental pathological findings \textsuperscript{3}. According to our
investigations, pathologically confirmed placental infarctions are
expressed in echo-free space without both villous trees and background
scatters. In cases of avascular villi, only background 'scatter' was
expressed in SMI. Consequently, it was confirmed that the findings of
SMI match the pathological findings.

In the present study, in order to demonstrate objectivity and
reproducibility, the diagnostic accuracies of various ultrasound
findings of the pathologic placenta were evaluated. The aim of the
present study was to clarify the accuracy of antenatal ultrasound
evaluation using SMI for placental pathological findings.

\textbf{Methods}

Patient population

In this prospective, diagnostic observational study, pregnant women who
were admitted to our perinatal center for perinatal management between
March 2019 and February 2020 were enrolled. Placental ultrasound
evaluation using SMI was performed during pregnancy every 1--2 weeks.
Therefore, the SMI findings in the present analysis were of those within
1--2 weeks before delivery. The findings on SMI were compared to those
of the placenta submitted for pathological examination.

Ultrasound findings using SMI

Ultrasound examinations in the present study were performed by two
authors (NF and JH). The placenta and umbilical cord were evaluated
using B-mode to detect gross abnormalities, such as velamentous cord
insertion, hyper-coiled cord, and entanglement. The placenta was then
evaluated precisely using SMI from the decidual layer to the chorionic
plate. When some ultrasound findings were found, the exhibited findings
were mapped to the respective location on the placenta based on the
location and form of the placenta and the spatial relationship with the
umbilical cord insertion site.

In the normal findings of the placenta using SMI, the villous trees are
identified on the fetal side---from the umbilical cord insertion to the
stem villi---connecting to the terminal villi into the maternal side.
Tertiary stem vessels in the villous tree are homogenous and sharply
diminished. Additionally, maternal blood flow from the spiral artery is
observed as 'scatter' in the intervillous space \textbf{(Figure 1,
Appendix S1)} . In contrast, abnormal findings were defined as follows.

\textbf{Infarction}

Since both the villous blood vessels and intervillous space disappear,
both the background ''scatter'' and ``villous tree'' are not detected,
thus, resulting in an echoic space \textbf{(Figure 2a, Appendix S2).}

\textbf{b. Avascular terminal villi}

Since only the villous blood flow is absent but the intervillous space
is present, only the background ''scatter'' is observed without normal
villous trees \textbf{(Figure 2b, Appendix S3).}

\textbf{c. Dilatation of stem villi (Congestion)}

Congestion of the stem vessels as an SMI finding is defined as clearly
dilated stem villi compared with the surrounding villous stem vessels

\textbf{(Figure 2c, Appendix S4).}

\textbf{Hyper-vascular terminal villi (Chorangiosis)}

Chorangiosis as a SMI findings is defined as high-echoic terminal villi
compared with the standard villi and appear ''fluffy''. \textbf{(Figure
2-d, Appendix S5).}

The ultrasound equipment used in the present study was an Aplio i700
with 1--8 MHz Convex probe (Canon Medical Systems, Japan). Setting for
visualization in B-mode and SMI, including gain, dynamic range, PRF
(Pulse Repectition Frequency), and Doppler sensitivity were
preliminarily adjusted and determined for placental evaluation. The
investigation in each case was performed using these preset parameters.

Pathological findings

After delivery, the placental tissue was clipped for microscopic
examination in the locations according to ultrasonically mapped and
macroscopic investigation of the placenta. The following pathological
findings were histologically confirmed in the placenta after delivery.
Pathological examinations were performed by obstetricians and
pathologists (NF, JH, MD, and KJ).

\textbf{a. Infarction}

Infarctions reveal a collapse of the intervillous space with associated
villous aggregation and coagulative necrosis, and all nuclear structures
disappear over time. They are accompanied by neutrophil infiltration

\textbf{(Figure 3a).}

\textbf{b. Avascular terminal villi}

Villous stromal-vascular karyorrhexis villi with disappearance of all
blood vessels and \textbf{uniformly fibrotic and vitrified} stroma

\textbf{(Figure 3b).}

\textbf{d. Dilatation of stem villi}

Dilatation of stem villi is defined as an enlargement of a stem villous
vessel to \textgreater{} 4 times that of neighboring vessels of similar
caliber \textbf{(Figure 3c).}

\textbf{c. Hyper-vascular terminal villi}

At least 10 or more blood vessels are found in one terminal or
intermediate villus; 10 or more of these villi are found in a visual
field at 10x and 10 or more of them are found in [?] 3 random cotyledon
sections \textbf{(Figure 3d).}

Accuracy analysis

Diagnostic sensitivity and specificity as well as positive (PPV) and
negative (NPV) predictive values of ultrasound findings and pathological
findings were calculated. Receiver operating characteristics (ROC)
curves were generated to estimate the diagnostic accuracy of each
finding using the area under the binomial ROC curve (AUC).

Analysis of intra- and inter-observer error

SMI findings in pathological placentas were used to calculate the
inter-observer agreement. An inter-observer error was determined by
examining the four types of findings between the two examiners (NF and
JH) in 22 findings. Additionally, an inspector (NF) evaluated the
findings of 22 places as 4 types of findings twice at intervals, and
calculated the intra-observer error.

Ethics statement

This study was approved by the ethics board of St. Marianna University
School of Medicine, Kawasaki, Japan (No. 4543; Sep. 27, 2019). This
investigation was conducted in accordance with the principles of the
Declaration of Helsinki. Written informed consent was obtained from all
patients.

\textbf{Results}

The pre-evaluated \selectlanguage{greek}κ-\selectlanguage{english}values of inter- and intra-observer errors were 0.76
and 0.88, respectively. Thirty-four pregnant women admitted to the MFICU
(Maternal-fetal intensive care unit) in our hospital were enrolled. The
characteristics of the participants are presented in \textbf{Table 1} .
The median maternal age was 33.5 years. The participants included 19
cases of FGR and/or preeclampsia and 15 cases of admissions due to other
indications; in these cases, the median gestational age at ultrasound
examination was 34 and 33 weeks of gestation, respectively.

The comparisons of SMI findings with histological findings are presented
in \textbf{Table 2} . The accuracy of antenatal ultrasound detection of
placental pathological findings and ROC curves are presented
in\textbf{Table 3 and Figure 4} . The most accurate diagnostic finding
was placental infarction in cases with FGR (PPV, 100\%; sensitivity,
88.9\%; AUC, 0.945), whereas PPV, sensitivity, and AUC in cases with
preeclampsia were relatively low. PPV, sensitivity, and AUC for
avascular villi were 100\%, 57.1\%, and 0.785 in cases with FGR, 66.7\%,
66.7\%, and 0.780 in cases with preeclampsia, and 80\%, 80\%, and 0.920,
respectively.

\textbf{Discussion}

\textbf{Main findings}

Main outcomes in the present study is placental pathological findings,
especially, infarction and avascular villi, could be detected during
pregnancy with high PPV using SMI.

\textbf{Strength and limitation}

The limitations of the current study are that the results were examined
based on subjective evaluation of both SMI and pathology, although
pathologic evaluations are usually performed based on subjective
evaluations. While it is considered that a certain degree of consensus
is achieved between pathologists regarding the pathological findings,
there is no established consensus for diagnosing using SMI even though
few inter-observer errors have been established. Previous studies have
quantitatively evaluated placental Doppler intensity, such as vascular
index and flow index \textsuperscript{4}. Conventional color Doppler
detects both villous blood flow and gross intervillous blood flow .
However, we believe that the strength of placental pathological
evaluation using SMI is that the blood flow from the mother and fetus
can be distinguished. The method of qualitative evaluation based on the
pathology, instead of quantitative evaluation, would be more exact and
useful in the perinatal management of placental abnormalities.

\textbf{Interpretation}

Early onset preeclampsia and placenta-related FGR are associated with
incomplete transformation of the spiral arteries, which result in
hypoperfusion of the placenta and induced placental
infarction\textsuperscript{5, 6}. SMI is good for visualizing minute
blood flow; therefore, it can easily help identify lesions of placental
infarction as lack of vascularity surrounding normal placental blood
flow. In contrast, in tissues with avascular villi, only capillaries are
absent in the villous tissue \textsuperscript{7}, which is not
distinguishable from normal placenta using B-mode ultrasound. Even with
conventional color Doppler, it is difficult to visualize the minute
blood flow of the capillaries in the terminal villi. If the flow
velocity range is lowered to detect such minute flow, motion artifacts
would disturb the expression of real blood flow. However, SMI enables
the expression of such thin and sharp terminal villous blood vessels.
Therefore, ultrasound diagnosis of avascular villi can be established by
identifying the presence of slow congested maternal blood flow in the
intervillous space with absent peripheral villous blood vessels. We
believe that this is a breakthrough outcome of the current study.

Maternal vascular malperfusion, such as pre-eclampsia and FGR, cause
utero-placental hypoxic disorder due to incomplete remodeling of the
spiral arteries in the first trimester, thus, resulting in placental
infarction \textsuperscript{8}. Isolated small infarcts can be found
pathologically in uncomplicated pregnancies; however, multiple central
infarcts often associated with intervillous fibrin deposition are found
in severe preeclampsia and FGR \textsuperscript{7}. Although
conventional ultrasound can detect these large lesions as complex
echogenic intra-placental masses close to the basal
plate\textsuperscript{9}, SMI enables the detection of these small
lesions even in tertiary villous tissues. However, the diagnostic
accuracy for predicting infarction and avascular villi using SMI was
higher in cases with FGR than that in cases with pre-eclampsia. Cases
more adversely affected by maternal malperfusion, such as those with FGR
and preeclampsia, are likely to have many and/or large pathologic
findings in the placenta, which we believe might be the reason that much
larger lesions could be easily detected. Diffuse small infarctions might
be difficult to distinguish from avascular villi expressed as scatter
without villous trees \textbf{(Figure 5, Appendix S6)} .

Contrary to maternal vascular malperfusion, occlusion or compression of
the umbilical cord, such as hyper-coiled cord, can cause a dilation of
stem villi \textsuperscript{7}. Consequently, fetal vascular
malperfusion, which is characterized by thrombosis and ischemic villi
due to umbilical cord blood flow stasis result in
FGR\textsuperscript{10}. Therefore, in cases of FGR, we hypothesized
that various placental causes of FGR, both maternal and fetal vascular
malperfusion, could be distinguished using SMI. We focused on the
dilatation of stem villi as one of the findings of fetal vascular
malperfusion; however, the accuracy of ultrasound diagnosis was low.
Since SMI is an ultrasound Doppler method, SMI blood flow image can be
easily enhanced. Furthermore, in histological evaluation, the slice of
the tissue does not always include the cross section of the blood vessel
in the center. Therefore, we believe the discrepancy between the
ultrasound findings and sliced histological findings to be large. The
findings of congestion in stem villi are relatively large compared to
the other findings in the present study. In such a large vascular
evaluation, comparison between the B-mode ultrasound and macroscopic
placental findings might be superior to the comparison between SMI and
histological findings.

Placental histological findings of chorangiosis are often investigated
in the placenta in cases of preeclampsia. Chorangiosis is believed to
form due to an adaptive response to placental
hypoxia\textsuperscript{11}. In the present study, we defined
chorangiosis as an ultrasonographic finding when the Doppler strength of
SMI was higher than that of the surrounding villi. However, it was
difficult to distinguish the exact chorangiosis from normal placental
tissue. We believe that this is because of the relative comparison of
echogenicity with the standard villous findings. Originally, the
diagnosis of chorangiosis should be pathologically made when
hyperbranching is confirmed \textsuperscript{12}. Radically, we noticed
that the definition of ultrasound findings of chorangiosis should be
reconsidered.

\textbf{Conclusion}

The diagnostic accuracy of antenatal ultrasound diagnosis in predicting
the placental pathology using SMI is guaranteed in placental infarction
and avascular villi. We believe that prospective determination of
maternal or fetal vascular malperfusion or problems with terminal villi
formation during pregnancy using the present method can improve the
perinatal management in the future.



\textbf{Acknowledgments}

\textbf{Author contributions} : NF and JH conceived the study. NF and JH
drafted the initial protocol, analyzed the data, and prepared the first
draft of the manuscript. All authors collected data and analyzed each
maternal death. NF and JH coordinated the study and developed the
database and analyzed the data. All authors contributed to the drafting
of the manuscript. JH, MD, JK and NS are the guarantors for the study.
All authors had full access to all of the data in the study and take
responsibility for the integrity of the data and the accuracy of the
data analysis.

\textbf{Competing financial Interest statement:} All authors declare
that they have no conflict of interest.

\textbf{Data availability:} The data related to this study was collected
from medical records, paying attention to confidentiality\textbf{.}

\textbf{Ethical approval and informed consent:} All procedures performed
in studies involving human participants were in accordance with the
ethical standards of the institutional and/or national research
committee and with the 1964 Helsinki declaration and its later
amendments or comparable ethical standards. The study protocol was
approved by the Institutional Review Boards (IRBs) of St Marianna
university hospital (No.4543). Written informed consent was obtained
from patients. Although the analysis was retrospective and the
confidentiality of the patients involved was protected. All patients'
records/information was anonymized and de-identified prior to analysis.



\textbf{References}

\textbf{1} Hasegawa J, Suzuki N. SMI for imaging of placental
infarction. Placenta. 2016;47:96-8.

\textbf{2} Hasegawa J, Kurasaki A, Hata T, Homma C, Miura A, Kondo H, et
al. Diagnosis of placenta accreta spectrum using ultra-high-frequency
probe and Superb Microvascular Imaging. Ultrasound Obstet Gynecol.
2019;54:705-7.

\textbf{3} Furuya N, Hasegawa J, Homma C, Kawahara T, Iwahata Y, Iwahata
H, et al. Novel ultrasound assessment of placental pathological function
using superb microvascular imaging. J Matern Fetal Neonatal Med.
2020:1-4.

\textbf{4} Hata T, Tanaka H, Noguchi J, Hata K. Three-dimensional
ultrasound evaluation of the placenta. Placenta. 2011;32:105-15.

\textbf{5} von Dadelszen P, Magee LA, Roberts JM. Subclassification of
preeclampsia. Hypertens Pregnancy. 2003;22:143-8.

\textbf{6} Arakaki T, Hasegawa J, Nakamura M, Takita H, Hamada S, Oba T,
et al. First-trimester measurements of the three-dimensional ultrasound
placental volume and uterine artery Doppler in early- and late-onset
fetal growth restriction. J Matern Fetal Neonatal Med. 2020;33:564-9.

\textbf{7} Amy Heerema-McKenney EP, Monique De Paepe. Diagnostic
Pathology: Placenta. 2nd ed; 2018.

\textbf{8} Ernst LM. Maternal vascular malperfusion of the placental
bed. Apmis. 2018;126:551-60.

\textbf{9} Burton GJ, Jauniaux E. Pathophysiology of placental-derived
fetal growth~restriction. Am J Obstet Gynecol. 2018;218:S745-s61.

\textbf{10} Redline RW, Ravishankar S. Fetal vascular malperfusion, an
update. APMIS. 2018;126:561-9.

\textbf{11} Stanek J. Chorangiosis of Chorionic Villi: What Does It
Really Mean? Arch Pathol Lab Med. 2016;140:588-93.

\textbf{12} Altshuler G. Chorangiosis. An important placental sign of
neonatal morbidity and mortality. Arch Pathol Lab Med. 1984;108:71-4.

\textbf{Conflict of Interest:} There are no conflicts of interest to
declare.

\textbf{Table 1. Characteristics of the participants}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
& Cases (n=34)\tabularnewline
\midrule
\endhead
Maternal age (years) & 33.5 (22--44)\tabularnewline
Gravida & 1.5 (1--4)\tabularnewline
Para & 0 (0--3)\tabularnewline
Gestational weeks at ultrasound & 33 (23--38)\tabularnewline
Gestational weeks at delivery & 34 (24--40)\tabularnewline
Birth weight (g) & 1754 (467--3102)\tabularnewline
Apgar score at 1 min & 8 (2--9)\tabularnewline
Apgar score at 5 min & 9 (4--10)\tabularnewline
Umbilical artery pH & 7.30 (7.10--7.47)\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2: Comparison of SMI findings with histological findings}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllll@{}}
\toprule
\textbf{Case} & \textbf{Background} & \textbf{Background} & \textbf{SMI
findings} & \textbf{SMI findings} & & & \textbf{Histological findings} &
\textbf{Histological findings} & &\tabularnewline
\midrule
\endhead
& \textbf{FGR} & \textbf{PE} & \textbf{Infarction} & \textbf{Avascular
villi} & \textbf{Congestion} & \textbf{Chorangiosis} &
\textbf{Infarction} & \textbf{Avascular villi} & \textbf{Congestion} &
\textbf{Chorangiosis}\tabularnewline
\textbf{1} & \textbf{+} & \textbf{-} & \textbf{+} & \textbf{+} &
\textbf{-} & \textbf{-} & \textbf{+} & \textbf{+} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{2} & \textbf{+} & \textbf{-} & \textbf{+} & \textbf{+} &
\textbf{-} & \textbf{-} & \textbf{+} & \textbf{+} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{3} & \textbf{+} & \textbf{-} & \textbf{+} & \textbf{+} &
\textbf{+} & \textbf{+} & \textbf{+} & \textbf{+} & \textbf{+} &
\textbf{-}\tabularnewline
\textbf{4} & \textbf{+} & \textbf{-} & \textbf{+} & \textbf{-} &
\textbf{+} & \textbf{-} & \textbf{+} & \textbf{-} & \textbf{+} &
\textbf{-}\tabularnewline
\textbf{5} & \textbf{+} & \textbf{-} & \textbf{+} & \textbf{-} &
\textbf{-} & \textbf{+} & \textbf{+} & \textbf{+} & \textbf{-} &
\textbf{+}\tabularnewline
\textbf{6} & \textbf{+} & \textbf{-} & \textbf{+} & \textbf{-} &
\textbf{+} & \textbf{+} & \textbf{+} & \textbf{+} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{7} & \textbf{+} & \textbf{+} & \textbf{+} & \textbf{+} &
\textbf{+} & \textbf{-} & \textbf{+} & \textbf{+} & \textbf{-} &
\textbf{+}\tabularnewline
\textbf{8} & \textbf{+} & \textbf{+} & \textbf{+} & \textbf{-} &
\textbf{+} & \textbf{+} & \textbf{+} & \textbf{+} & \textbf{+} &
\textbf{-}\tabularnewline
\textbf{9} & \textbf{+} & \textbf{+} & \textbf{-} & \textbf{-} &
\textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{+}\tabularnewline
\textbf{10} & \textbf{+} & \textbf{+} & \textbf{-} & \textbf{-} &
\textbf{-} & \textbf{+} & \textbf{+} & \textbf{-} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{11} & \textbf{-} & \textbf{+} & \textbf{+} & \textbf{-} &
\textbf{-} & \textbf{-} & \textbf{+} & \textbf{-} & \textbf{+} &
\textbf{-}\tabularnewline
\textbf{12} & \textbf{-} & \textbf{+} & \textbf{+} & \textbf{-} &
\textbf{-} & \textbf{-} & \textbf{+} & \textbf{-} & \textbf{+} &
\textbf{-}\tabularnewline
\textbf{13} & \textbf{-} & \textbf{+} & \textbf{-} & \textbf{+} &
\textbf{+} & \textbf{+} & \textbf{+} & \textbf{+} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{14} & \textbf{-} & \textbf{+} & \textbf{-} & \textbf{+} &
\textbf{-} & \textbf{+} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{+}\tabularnewline
\textbf{15} & \textbf{-} & \textbf{+} & \textbf{-} & \textbf{-} &
\textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{16} & \textbf{-} & \textbf{+} & \textbf{-} & \textbf{-} &
\textbf{-} & \textbf{-} & \textbf{+} & \textbf{-} & \textbf{+} &
\textbf{-}\tabularnewline
\textbf{17} & \textbf{-} & \textbf{+} & \textbf{-} & \textbf{-} &
\textbf{-} & \textbf{+} & \textbf{+} & \textbf{-} & \textbf{+} &
\textbf{-}\tabularnewline
\textbf{18} & \textbf{-} & \textbf{+} & \textbf{-} & \textbf{-} &
\textbf{-} & \textbf{-} & \textbf{+} & \textbf{-} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{19} & \textbf{-} & \textbf{+} & \textbf{-} & \textbf{-} &
\textbf{-} & \textbf{+} & \textbf{+} & \textbf{-} & \textbf{-} &
\textbf{+}\tabularnewline
\textbf{20} & \textbf{-} & \textbf{-} & \textbf{+} & \textbf{+} &
\textbf{+} & \textbf{-} & \textbf{+} & \textbf{+} & \textbf{-} &
\textbf{+}\tabularnewline
\textbf{21} & \textbf{-} & \textbf{-} & \textbf{+} & \textbf{+} &
\textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{22} & \textbf{-} & \textbf{-} & \textbf{+} & \textbf{+} &
\textbf{-} & \textbf{-} & \textbf{+} & \textbf{+} & \textbf{+} &
\textbf{-}\tabularnewline
\textbf{23} & \textbf{-} & \textbf{-} & \textbf{+} & \textbf{+} &
\textbf{-} & \textbf{-} & \textbf{+} & \textbf{+} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{24} & \textbf{-} & \textbf{-} & \textbf{+} & \textbf{+} &
\textbf{-} & \textbf{-} & \textbf{+} & \textbf{+} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{25} & \textbf{-} & \textbf{-} & \textbf{+} & \textbf{-} &
\textbf{+} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{26} & \textbf{-} & \textbf{-} & \textbf{+} & \textbf{-} &
\textbf{-} & \textbf{+} & \textbf{+} & \textbf{-} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{27} & \textbf{-} & \textbf{-} & \textbf{+} & \textbf{-} &
\textbf{-} & \textbf{+} & \textbf{+} & \textbf{+} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{28} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{+} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{29} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{+} & \textbf{-} & \textbf{+} & \textbf{-} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{30} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{31} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{-}\tabularnewline
\textbf{32} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{+}\tabularnewline
\textbf{33} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{+} &
\textbf{-}\tabularnewline
\textbf{34} & \textbf{-} & \textbf{-} & \textbf{-} & \textbf{-} &
\textbf{-} & \textbf{-} & \textbf{+} & \textbf{-} & \textbf{-} &
\textbf{-}\tabularnewline
& & & & & & & \textbf{Agreed with SMI findings} & \textbf{Agreed with
SMI findings} & \textbf{Disagreed with SMI findings} & \textbf{Disagreed
with SMI findings}\tabularnewline
\bottomrule
\end{longtable}

SMI, superb microvascular imaging; FGR, fetal growth restriction; PE,
preeclampsia

\textbf{Table 3: Area under the curve for accuracy of antenatal
ultrasound detection of placental pathological findings according to the
clinical condition}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& \textbf{FGR} & \textbf{Preeclampsia} & \textbf{Others} &
\textbf{Overall}\tabularnewline
\midrule
\endhead
\textbf{Infarction} & 0.945 & 0.540 & 0.800 & 0.675\tabularnewline
\textbf{Avascular villi} & 0.785 & 0.780 & 0.920 & 0.675\tabularnewline
\textbf{Congestion} & 0.655 & 0.540 & 0.540 & 0.620\tabularnewline
\textbf{Chorangiosis} & 0.380 & 0.450 & 0.420 & 0.540\tabularnewline
\bottomrule
\end{longtable}

FGR, fetal growth restriction.

\textbf{Figure legends}

\textbf{Figure 1: Normal placenta depicted using superb microvascular
imaging}

Villous blood vessels (villous trees) are depicted from the fetal
surface (bottom) to the terminal villi (top). Large arrow, stem villi;
small arrow, terminal villi. Slow blood flow in the intervillous space
from the spiral artery is also visualized like as ''scatter,'' which
matches the heart rate of the mother as the background of villous tree
(triangle).

\textbf{Figure 2: Ultrasound findings using superb microvascular imaging
of abnormal placental pathology}

\begin{enumerate}
\tightlist
\item
  \textbf{Infarction:} Neither the background ''scatter'' and ``villous
  tree'' were detected, resulting in an echoic space (triangle).
\item
  \textbf{Avascular terminal villi:} Only the background ''scatter'' is
  observed without normal villous trees.
\item
  \textbf{Dilatation of stem villi (Congestion):} The stem villi were
  clearly dilated compared with the surrounding villous stem vessels.
\item
  \textbf{Hyper-vascular terminal villi (Chorangiosis):} Terminal villi
  are highly echoic compared with standard villi and appear to be
  ''fluffy'' (triangle).
\end{enumerate}

\textbf{Figure 3: Pathological findings}

\begin{enumerate}
\tightlist
\item
  \textbf{Infarction:} Infarctions show collapse of the intervillous
  space and associated villous aggregation and coagulative necrosis, and
  over time all nuclear structures disappear. They are accompanied by
  neutrophil infiltration.
\item
  \textbf{Avascular terminal villi:} Villous stromal-vascular
  karyorrhexis with disappearance of all blood vessels and uniformly
  fibrotic and vitrified stroma.
\item
  \textbf{Dilatation of stem villi:} Dilatation of stem villi is defined
  as the enlargement of a stem villous vessel \textgreater{} 4 times
  that of neighboring vessels of similar caliber.
\item
  \textbf{Hyper-vascular terminal villi:} At least [?] 10 blood vessels
  are found in one terminal or intermediate villus; [?] 10 of these villi
  are found in a visual field at 10x; and [?] 10 of them are found in [?] 3
  random cotyledon sections.
\end{enumerate}

\textbf{Figure 4: Accuracy of antenatal ultrasound detection of
placental pathologic findings}

\begin{enumerate}
\tightlist
\item
  Receiver Operating Characteristic (ROC) curve predicting infarction
\item
  ROC curve predicting avascular villi
\item
  ROC curve predicting congestion
\item
  ROC curve predicting chrangiosis
\end{enumerate}

\textbf{Figure 5: Superb microvascular imaging findings and pathological
findings in case of diffuse small infarctions diagnosed as avascular
villi:} (a) Avascular villi was suspected because of detection of only
scatter without villous tree. (b) Diffuse small infarctions are detected
pathologically.

\textbf{Appendix}

\textbf{Appendix S1} : Normal placenta depicted using superb
microvascular imaging (SMI)

\textbf{Appendix S2} : Infarction depicted using superb microvascular
imaging (SMI)

\textbf{Appendix S3} : Avascular villi depicted using superb
microvascular imaging (SMI)

\textbf{Appendix S4} : Congestion of stem villi depicted using superb
microvascular imaging (SMI)

\textbf{Appendix S5} : Chorangiosis depicted using superb microvascular
imaging (SMI)

\textbf{Appendix S6} : Superb microvascular imaging (SMI) findings in
case of diffuse small infarctions diagnosed as avascular villi\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/figure1/figure1}

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\includegraphics[width=0.70\columnwidth]{figures/figure3/figure3}

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\includegraphics[width=0.70\columnwidth]{figures/figure4c-d/figure4c-d}

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\includegraphics[width=0.70\columnwidth]{figures/figure5/figure5}

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