The Journal of Maternal-Fetal & Neonatal Medicine

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ijmf20

Chronic abruption-oligohydramnios sequence

(CAOS) revisited: possible implication of premature
rupture of membranes

Yoshitsugu Chigusa, Haruta Mogami, Sachiko Minamiguchi, Aki Kido, Ayami

Ishida, Yasuhisa Kurata, Eriko Yasuda, Kaoru Kawasaki, Akihito Horie, Ken
Yamaguchi, Masaki Mandai & Eiji Kondoh

To cite this article: Yoshitsugu Chigusa, Haruta Mogami, Sachiko Minamiguchi, Aki Kido, Ayami
Ishida, Yasuhisa Kurata, Eriko Yasuda, Kaoru Kawasaki, Akihito Horie, Ken Yamaguchi, Masaki
Mandai & Eiji Kondoh (2021): Chronic abruption-oligohydramnios sequence (CAOS) revisited:
possible implication of premature rupture of membranes, The Journal of Maternal-Fetal & Neonatal
Medicine, DOI: 10.1080/14767058.2021.1929159

To link to this article: https://doi.org/10.1080/14767058.2021.1929159

Published online: 20 May 2021.

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THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
https://doi.org/10.1080/14767058.2021.1929159

ORIGINAL ARTICLE

Chronic abruption-oligohydramnios sequence (CAOS) revisited: possible

implication of premature rupture of membranes
Yoshitsugu Chigusaa , Haruta Mogamia, Sachiko Minamiguchib, Aki Kidoc, Ayami Ishidab,
Yasuhisa Kuratac, Eriko Yasudaa, Kaoru Kawasakia, Akihito Horiea, Ken Yamaguchia, Masaki Mandaia and
Eiji Kondoha
a
Department of Gynecology and Obstetrics, Kyoto University, Kyoto, Japan; bDepartment of Diagnostic Pathology, Kyoto University,
Kyoto, Japan; cDepartment of Diagnostic Imaging and Nuclear Medicine, Kyoto University, Kyoto, Japan

ABSTRACT ARTICLE HISTORY

Aim: The pathogenic mechanism of chronic abruption-oligohydramnios sequence (CAOS) Received 13 November 2020
remains unknown, and there are no objective standards for diagnosis on imaging or using Accepted 9 May 2021
pathological evidence. We aimed to reconsider and clarify the true pathology of CAOS by inte-
KEYWORDS
grating clinical, magnetic resonance imaging (MRI) and histopathological findings of
Amniotic necrosis; chronic
the placenta. abruption-oligohydramnios
Material and Methods: This is a case series of patients with CAOS managed at our hospital sequence; diffuse
between 2010 and 2020. The clinical data of the patients, including MRI findings and placental chorioamniotic hemosidero-
pathology, were reviewed retrospectively. sis; premature rupture of
Results: A total of 18 patients were eligible. Preterm birth occurred in 17 (94%) cases; the membranes; preterm birth;
median gestational age at delivery was 25. Three neonates (17%) died within two years, and 10 subchorionic hematoma
neonates (56%) developed chronic lung disease. MRI was performed in 13 cases and clearly
showed intrauterine hematoma and hemorrhagic amniotic fluid. Pathologically, in all cases, ret-
roplacental hematoma was not detected, and fetal membranes were extremely fragile and rag-
ged. Shedding and necrosis of the amniotic epithelium was a characteristic finding, which was
confirmed in 17 cases (94%). Diffuse chorionic hemosiderosis (DCH) was detected in all cases.
Conclusions: The fundamental cause of CAOS is repeated intrauterine hemorrhage and subse-
quent subchorionic hematoma, which induces hemorrhagic amniotic fluid and DCH.
Consequently, these factors result in the necrosis and weakening of the amnion. Therefore, the
true pathology of CAOS is believed to be premature rupture of membranes rather than
chronic abruption.

Introduction
In 1998, Elliott et al. published the concept of chronic
abruption-oligohydramnios sequence (CAOS) for the
first time [1]. This disease concept canonically consists
of the following triad: (1) clinically significant vaginal
bleeding in the absence of an identifiable source of
bleeding; (2) amniotic fluid volume initially docu-
mented as normal; and (3) oligohydramnios eventually
developing without concurrent evidence of ruptured
membranes [1]. Since then, the existence of this
sequence has been clinically realized, and the concept
has been widely accepted. Moreover, accumulating
evidence has revealed very poor pregnancy and fetal
outcomes in patients with CAOS [1–3].
Despite being the pressing issue, the nature and
pathophysiology of CAOS have remained enigmatic,
and indeed, in the last two decades, there has been
no significant progress in research on or understand-
ing of this disease. One of the reasons for this might
be the ambiguous and cryptic diagnostic criteria: vagi-
nal bleeding without a source and amniotic fluid
decreases in the absence of rupture of membranes.
Moreover, there are no objective standards for diagno-
sis on imaging inspection or using pathological evi-
dence. The aim of this study, therefore, is to
reconsider and clarify the true pathology of CAOS by
integrating clinical, magnetic resonance imaging (MRI)
and histopathological findings.
Materials and methods
We retrospectively reviewed patients with CAOS man-
aged at Kyoto University Hospital from January 2010

CONTACT Yoshitsugu Chigusa chigusa@kuhp.kyoto-u.ac.jp Department of Gynecology and Obstetrics, Kyoto University, 54 Shogoin Kawahara-cho,
Sakyo-ku, Kyoto 606-8507, Japan
ß 2021 Informa UK Limited, trading as Taylor & Francis Group
2 Y. CHIGUSA ET AL.

CLD, pulmonary hypertension, death at 2 years old

GA: gestational age, SCH: subchorionic hematoma, DCH: diffuse chorioamniotic hemosiderosis, CAM: chorioamnionitis, BW: birth weight, P: primipara, M: multipara, R: ritodrine, Mg: magnesium sulfate 17 P:17-
a-hydroxyprogesterone caproate, Nif: nifedipine, CS: cesarean section, VD: vaginal delivery, PDA: patent ductus arteriosus, IVH: intraventricular hemorrhage, CLD: chronic lung disease, PPHN: persistent pulmonary
to March 2020. The diagnosis was in principle based

CLD, retinopathy of prematurity, hypothyroidism

on Elliott’s triad [1]. Patients who had a miscarriage
before 22 weeks and 0 days of gestation were

CLD, retinopathy of prematurity, PPHN

excluded. The medical records of the patients were

Neonatal outcomes
reviewed, and clinical data were extracted, including

Early-onset neonatal sepsis, PDA

CLD, retinopathy of prematurity

CLD, retinopathy of prematurity

CLD, retinopathy of prematurity

age, obstetric history, gestational age on admission

Retinopathy of prematurity
IVH, death at one day old
and at delivery, mode of delivery, and ultrasound,

Normal development
Normal development

Normal development

Normal development
MRI, and placental pathological findings. Generally,
placental hematoma consists of marginal hematoma,
subchorionic thrombus, subamniotic hematoma,

CLD, IVH
hematoma extending outside of the placenta, and

Death
retroplacental hematoma. In assessing the intrauter-

CLD

CLD

CLD
ine hematoma by ultrasound, we did not distinguish

Apgar
them except retroplacental hematoma but defined

5
4
7
7
6
4
5
5
6
1
0
7
5
6
4
8
7
7
2,
1,
6,
1,
1,
2,
2,
1,
2,
1,
0,
6,
3,
5,
1,
6,
2,
5,
them collectively as a subchorionic hematoma. For
MRI findings, two board-certified radiologists (AK and

578
562
948
1140
839
721
684
716
1788
672
365
626
643
809
667
1178
1891
706
BW
YK) evaluated the following MRI findings independ-
ently: hemorrhagic amniotic fluid; marginal hema-

Amniotic necrosis
toma; subchorionic thrombus or subamniotic
hematoma; hematoma extending outside the pla-

þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ

þ
þ
þ
þ
–
centa; hematoma in the cervix; and retroplacental
hematoma. If the evaluation differed between the
readers, then they discussed the findings and reached
CAM
þ

þ
þ

þ
þ

þ
–

–
–
–

–
–
a consensus. For pathological findings, two patholo-
gists (SM and AI) and one obstetrician (EY) independ-
DCH
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
ently reviewed and evaluated macroscopic pictures of
placenta and membranes, hematoxylin and eosin
SCH
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
slides, and Berlin blue staining slides. If the evaluation
differed between them, then they discussed the find-
Mode of delivery

ings and reached a consensus. Moreover, data of the

neonates were also collected, such as birth weight,
VD

VD
VD
VD

VD
CS

CS
CS
CS
CS
CS
CS

CS
CS
CS
CS
CS

CS
Apgar scores, morbidity and mortality.
This study was approved by the ethics committee
of Kyoto University (Registration number: R2276).
Mg, 17 P, Nif

Mg, 17 P, Nif

Mg, 17 P, Nif

Mg, 17 P, Nif
Mg, 17 P, Nif
Mg, 17 P, Nif
Mg, 17 P, Nif
Mg,17 P, Nif
Treatment

Mg, 17 P
Mg, 17 P
Mg, 17 P
Mg, 17 P

Mg, 17 P
Mg, 17 P

Mg, 17 P

Mg, Nif

Results
Mg

Mg
R,
R,
R,
R,
R,
R,
R,
R,
R,
R,
R,
R,
R,
R,
R,
R,
R,
R,

During the study period, 18 females were admitted

Table 1. Clinical courses and neonatal outcomes.

to our hospital and finally diagnosed with CAOS.

GA at birth
23w3d
23w6d
25w0d
27w5d
27w0d
26w3d
25w2d
25w5d
32w1d
23w3d
22w0d
24w1d
25w5d
26w4d
24w6d
30w1d
37w0d
24w5d

Table 1 shows patient details and neonate outcomes.

Nine (50%) patients were primiparae, and all had epi-
sodes of repeated vaginal bleeding from the first tri-
GA at diagnosis

mester of pregnancy. On admission, none of the

20w0d
19w3d
20w5d
19w3d
20w6d
22w3d
23w6d
21w5d
26w5d
21w4d
20w0d
23w1d
23w1d
24w0d
21w0d
26w2d
26w4d
23w4d

patients had any obvious signs of premature rupture

of membranes (PROM). At the onset of vaginal bleed-
hypertension of the newborn.

ing, some patients had intrauterine hematoma, while

others did not. Notably, however, during the course
Parity

M
M
M

M
P

P
P
P

of treatment, subchorionic hematomas were clearly

detected using transvaginal or transabdominal ultra-
Age
33
35
28
33
30
19
29
29
31
26
28
26
35
35
33
33
30
27

sound in all cases. The diagnosis of CAOS was made

when Elliott’s triad were present, which basically coin-
Case

cided with the development of oligohydramnios. The

10
11
12
13
14
15
16
17
18
1
2
3
4
5
6
7
8
9

gestational age at the diagnosis of CAOS was 22
(19–26) weeks of gestation (median and range). All
patients presented with uterine contraction, and toco-
lytic agents such as ritodrine, magnesium sulfate and
nifedipine, and 17-a-hydroxyprogesterone caproate
were required. Nevertheless, 17 (94%) cases resulted in
preterm birth: the gestational age at delivery was 25
(22–37) weeks of gestation (median and range).
Although there was no definite evidence of rupture of
membranes on admission, oligohydramnios eventually
developed in all cases. In terms of neonatal outcomes,
3 neonates (17%) died within two years, and 10 neo-
nates (56%) developed chronic lung disease (CLD).
Other diseases due to prematurity, such as sepsis or
retinopathy, were also detected.
Next, we analyzed the MRI findings in these cases.
Among the 18 cases, MRI was performed in 13 cases.
Figure 1 shows three representative cases: A and B
represent case 8 at 21 weeks and 6 days of gestation,
C and D represent case 16 at 27 weeks and 1 day of
gestation, and E and F represent case 18 at 23 weeks
and 4 days of gestation, respectively. Oligohydramnios
was apparent on sagittal T2-weighted imaging (T2WI)
(Figure 1(a,c,e)). The signal intensity of the amniotic
fluid on sagittal fat-saturated T1WI was relatively high
compared with that of urine in the bladder, indicating
hemorrhagic amniotic fluid (Figure 1(b,d,e), asterisks).
The portions of low signal intensity on the margins of
the placenta on T2WI (Figure 1(a), circle) showed high
signal intensity on fat-saturated T1WI, suggesting mar-
ginal hematomas (Figure 1(b), circle). Similar areas of
low signal intensity on T2WI that showed high signal
intensity on fat-saturated T1WI were detected on the
surface of the placenta (Figure 1(c,d), arrowheads).
These were subamniotic hematomas. The hematomas
were very widespread in some cases, even extending
outside of the placenta (Figure 1(e), dotted lines). The
area of high signal intensity lining the muscle layer of
the uterus suggested that bleeding extended outside
of the fetal membranes (Figure 1(d,f), arrows). The
area of high signal intensity in the uterine cervix
showed that blood from the subchorionic hematoma
was about to be expelled from the uterus (Figure
1(d)). Table 2 lists the specific MRI findings in these 13
cases. Intrauterine hematoma was observed in all
cases; however, retroplacental hematoma was not
detected on MRI in our cases.
Finally, pathological findings of the placenta and
membranes were reviewed in all cases. Representative
macroscopic images of placenta and fetal membranes
are shown in Figure 2 (a and b represent case 7, and
c and d represent case 14). In all cases, a
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3
retroplacental hematoma was not detected, although
a marginal hematoma was delivered in some cases
(Figure 2(a,b)). Both placenta and membranes were
stained brown, and membranes were extremely fragile
and ragged in all cases (Figure 2(a,c)). Representative
histological findings of fetal membranes are also
shown Table 2 (e and f represent case 6, g and h rep-
resent case 4, i represents case 7, and j represents
case 15). Shedding and necrosis of the amniotic epi-
thelium was a very characteristic finding, which was
confirmed in 17 of 18 cases (94%) (Figure 2(e,i,j),
arrowheads). Macrophages containing brown pigment
were observed on the chorioamniotic plate (Figure
2(g)). Prominent blue staining in macrophages on
Berlin blue staining was observed at the chorioamni-
otic plate, indicating hemosiderin deposition (Figure
2(f,h), arrows). These findings indicate diffuse chorionic
hemosiderosis (DCH), and in all our cases, DCH was
detected. Pathological chorioamnionitis was detected
in 9 (50%) cases.
Discussion
To the best of our knowledge, this is the second larg-
est retrospective case series of patients with CAOS
meeting classical Elliott’s triad. Our data remind us of
the adverse perinatal outcome of CAOS, despite the
development of perinatal care. Elliott et al. retrospect-
ively reviewed 14 cases of CAOS and reported that the
mean gestational age at delivery was 26.1 weeks, with
neonatal mortality occurring in 6 (43%) cases [1]. In
another case series including 15 patients with CAOS,
the mean gestational age at delivery was 25.7 weeks,
with neonatal mortality occurring in 4 (26.7%) cases
and CLD occurring in 11 (73.3%) cases [2]. In the cur-
rent study, the rate of neonatal mortality (17%) and
the incidence of CLD (56%) slightly improved, but the
gestational age at delivery was almost the same as
that in previous studies. Thus, the neonatal morbidity
rate due to prematurity is very high. In addition, in
preterm infants delivered from mothers with CAOS,
neonatal lung injury due to the aspiration of hemor-
rhagic amniotic fluid might contribute to a severe
prognosis. Indeed, intrapulmonary blood induced a
macrophage-dominated inflammatory response in an
animal model [4]. Previously, we reported that the
concentrations of iron lactose dehydrogenase (LDH)
and 8-hydroxy-20 -deoxyguanosine (8-OHdG), a marker
of oxidative DNA damage, in the uterine cavity in
CAOS were high, and repeated amnioinfusion signifi-
cantly diluted them and contributed to a favorable
neonatal prognosis [5].
4 Y. CHIGUSA ET AL.

Figure 1. Pelvic magnetic resonance imaging of three representative cases. The left panels are the results of sagittal T2-weighed
imaging (T2WI), and the right panels are the results of sagittal fat-saturated T1-weighted imaging (T1WI). (a,b) Case 8. The areas
of low signal intensity on the margins of the placenta on T2WI show high signal intensity on fat-saturated T1WI, suggesting mar-
ginal hematomas (circle). (c,d) Case 16. An area of low signal intensity on T2WI, which shows high signal intensity on fat-saturated
T1WI, is detected on the surface of the placenta (arrowheads). These are subamniotic hematomas. (e,f) Case 18. Hematoma
extends outside of the placenta (dotted lines). This hematoma is likely derived from a marginal hematoma. The area of high signal
intensity lining the muscle layer of the uterus suggests that bleeding extends outside of the fetal membranes (arrows). The signal
intensity of the amniotic fluid on sagittal fat-saturated T1WI is relatively high compared with that of urine in the bladder, indicat-
ing hemorrhagic amniotic fluid (b, d and e, asterisks). The high signal intensity in the uterine cervix shows that blood from the
subchorionic hematoma is about to be expelled from the uterus (d).

Our study revealed that MRI findings of the pla- cases other than our previous report of three cases
centa and intrauterine cavity are very useful for the [6]. Elliott et al. described “vaginal bleeding in the
objective understanding of the pathology of CAOS. To absence of placenta previa or other identifiable source
date, no studies have examined MRI findings in CAOS of bleeding” [1]. However, in all of our cases,

Table 2. MRI findings of 13 cases.
n (%)
Hemorrhagic amniotic fluid 12 (92)
Marginal hematoma 13 (100)
Subchorionic thrombus or subamniotic hematoma 10 (77)
Hematoma extending outside the placenta 13 (100)
Hematoma in the cervix 12 (92)
Retroplacental hematoma 0 (0)
MRI: Magnetic resonance imaging.
subchorionic hematomas were observed using ultra-
sound or MRI. In particular, the area of high signal
intensity of the placental marginal hematoma separat-
ing the peripheral placenta with extensive spreading
along the uterine wall on fat-saturated T1WI strongly
suggested that the hemorrhage was derived not from
an unidentifiable source but from a subchorionic
hematoma. Furthermore, the relatively high signal
intensity of the decreased amniotic fluid on T1WI
could help to distinguish the hemorrhagic amniotic
fluid of CAOS from oligohydramnios due to other
causes. Consequently, MRI findings reliably reflect the
clinicopathological findings of CAOS, such as subchor-
ionic hematoma and hemorrhagic amniotic fluid, and
are valuable for the objective diagnosis of CAOS.
Our present study provides histopathological sup-
port for CAOS: DCH and amniotic necrosis. First, DCH
is diffuse iron-stain-positive pigment deposition in the
chorioamniotic layers of fetal membranes, and this
histological feature was reported by Redline et al. [7]
the year after Elliott et al. announced CAOS.
Appropriately, Redline et al. described DCH as the
pathological correlate of CAOS [7]. Ohyama et al. ana-
lyzed the neonatal morbidity and mortality rates
among 46 cases of DCH and reported that the mean
gestational age was 27 weeks, with neonatal mortality
and CLD occurring in 6 (15%) and 18 (51%) patients,
respectively [3]. These outcomes are very similar to
those of CAOS, and in fact, 26 cases of CAOS were
included in their study. Second, amniotic necrosis is a
prominent feature of CAOS, and it might have close
relevance to DCH. Ohyama reported amniotic necrosis
in 29 cases (63%) among 46 cases of DCH [3], and
another study showed a similar incidence: 10 cases
(63%) among 16 cases of DCH [8]. In the present
study, amniotic necrosis was observed in 17 of 18
cases (94%), and in the remaining 1 case, thinning of
the amniotic membrane was confirmed. These findings
are strongly associated with weakening of the fetal
membrane and PROM. Recently, Iizuka et al. revealed
that the severity of DCH correlated with amniotic
necrosis and that amniotic epithelial cells were posi-
tive for 8-OHdG in cases of DCH [9]. Based on these
observations, they speculated that amniotic necrosis
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 5
might lead to the disruption of the balance of the
amniotic fluid volume [9]. Importantly, both DCH and
amniotic necrosis are not diseases but pathological
features, and we believe that these features are patho-
logical evidence for an objective diagnosis of CAOS.
Our clinical data and pathological analysis strongly
indicate that CAOS is a special form of preterm PROM.
Previously, we elucidated the precise mechanism by
which intrauterine bleeding during pregnancy causes
PROM and preterm labor [10–12]. According to our
basic medical research, thrombin generated by blood
clotting releases fetal fibronectin, a clinical marker of
preterm labor, from amniotic epithelial cells. Fetal
fibronectin is a potent ligand of Toll-like receptor 4
(TLR4) and activates TLR4 on amnion mesenchymal
cells. TLR4 activation results in the induction of cyclo-
oxygenase 2, prostaglandin E2, inflammatory cytokines
and matrix metalloproteinases, leading to cervical rip-
ening, uterine contraction, and collagen degradation.
Furthermore, thrombin directly degrades collagen.
Finally, PROM and preterm labor are caused. In all of
our cases, the fetal membranes were fragile and rag-
ged. When this information is combined with our
basic findings, it is quite reasonable to assume that
minor rupture of membranes occurred, thereby even-
tually causing oligohydramnios in CAOS.
This study was limited due to its retrospective
nature and the small number of patients. Although we
shed light on one part of the pathogenic mechanism
of CAOS and objective diagnostic findings, the funda-
mental cause of intrauterine bleeding in the 1st trimes-
ter has yet to be elucidated. Moreover, effective
management and treatment strategies for CAOS
remain unclear.
Conclusion
Our clinical observations, imaging findings, and patho-
logical evidence call for a drastic change in our under-
standing of the pathology of CAOS. The fundamental
cause of this disease is intrauterine hemorrhage and
subsequent subchorionic hematoma, which induces
hemorrhagic amniotic fluid. These lesions show high
signal intensity on T1WI and cause the diffusion of
chorioamniotic hemosiderosis. Consequently, these
factors that start with H result in the necrosis and
weakening of the amnion. Oligohydramnios is the
ultimate phenotype and not a diagnostic criterion.
Therefore, the true pathology of CAOS is PROM rather
than chronic abruption, and we propose a new desig-
nation “H-induced RROM: Hi RPOM”.
6 Y. CHIGUSA ET AL.

Figure 2. Macroscopic and microscopic findings of placentas and fetal membranes. (a,b) Case 7. (c,d) Case 14. Both the placenta
and membranes were stained brown, and the membranes were extremely fragile and ragged. A marginal hematoma was deliv-
ered (a and b). (e) Case 6. Shedding and necrosis of the amniotic epithelium were observed (arrowheads). Hematoxylin and eosin
(H&E) staining, x400. (f) Case 6. Blue staining in macrophages is observed at the chorioamniotic plate, indicating hemosiderin
deposition (arrows). Berlin blue staining, 400. (g) Case 4. Macrophages containing brown pigment are observed at the cho-
rioamniotic plate. H&E staining, x200. (h) Case 4. The same portion shows prominent blue staining (arrows). Berlin blue staining,
x200. (i) Case 7. Amniotic epithelial cells are shedding or necrotic (arrowheads). H&E staining, x400 (x100 in the box). (j) Case 15.
Amniotic necrosis is prominent. H&E staining, x400.

Disclosure statement
The authors declare that there are no conflicts of interest
regarding the publication of this article.
Funding
This work was supported by Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan [No.19K09801].
ORCID
Yoshitsugu Chigusa http://orcid.org/0000-0001-9629-5912
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