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OBSTETRICS AND GYNECOLOGY ADVANCES

OVARIAN ENDOMETRIOSIS:
DIVERSE MODIFICATIONS
DURING PREGNANCY

YUTAKA UEDA
TAKAYUKI ENOMOTO

NS
TAKASHI MIYATAKE
KIYOSHI YOSHINO

P
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MASAMI FUJITA
TAKUJI TOMIMATSU
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ISBN: 978-1-61728-901-9 2011
 OBSTETRICS AND GYNECOLOGY ADVANCES

OVARIAN ENDOMETRIOSIS:
DIVERSE MODIFICATIONS
DURING PREGNANCY

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 OBSTETRICS AND GYNECOLOGY ADVANCES

OVARIAN ENDOMETRIOSIS:
DIVERSE MODIFICATIONS
DURING PREGNANCY

YUTAKA UEDA
TAKAYUKI ENOMOTO
TAKASHI MIYATAKE
KIYOSHI YOSHINO
MASAMI FUJITA
TAKUJI TOMIMATSU
AND
TADASHI KIMURA

Nova Science Publishers, Inc.

New York
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 CONTENTS

Preface vii
Abbreviations ix
Chapter 1 Introduction 1
Research Methods 3
Chapter 1 An Update of Our Previous Work 5
Chapter 2 Literature Review 7
Achievements 9
Chapter 3 Apparent Increasing Incidence of Ovarian
Endometriosis-Complicated Pregnancy 11
Chapter 4 Dramatic Changes in Ovarian
Endometriosis during Pregnancy 15
Chapter 5 Discussion: A Suggested Management of
Ovarian Endometriosis during Pregnancy 25
Chapter 6 Conclusion 33
Acknowledgments 35
References 37
Index 43
 PREFACE

An adnexal ovarian mass including ovarian endometriosis is one of

the most common (1-3%) complications during pregnancy. Frank
neoplastic ovarian tumors are surgically removed early in the second
trimester to avoid acute abdomen during pregnancy. On the other hand,
ovarian endometriosis is usually managed conservatively during
pregnancy. Until now, there has been scant evidence for the efficacy of
this wait-and-see strategy. Further, effects of pregnancy upon ovarian
endometriosis have not been well studied; however, pseudo-pregnancy
therapy, including low-dose contraception pills, has been successfully
used to treat endometriosis.
In this chapter, we extend our previous study on the frequency and
magnitude of changes observed in ovarian endometriosis during
pregnancy. The literature database was also searched for reports of other
ovarian endometriosis cases exhibiting modification during pregnancy.
Between 1995 and 2008, a total of 8173 deliveries were performed at
the Osaka University and Izumiotsu Municipal Hospitals of Osaka,
Japan. Adnexal masses were detected in 88 (1.1%) of them. The
frequency of ovarian endometriosis increased to 0.53% of all pregnancies
in the second half of this 14-year period, a significant 4.2-fold increase
over the 0.13% in the first half of the period (p=0.0016). In fact, ovarian
endometriosis has become the most common adnexal mass during
pregnancy. Among the 27 ovarian endometriosis cases observed in our
practices, the size of the cyst decreased or remained static with time in 20
cases (74%). The tumor increased in size in only 7 cases (26%). Among
the latter, 4 lesions (15% of 27 cases) demonstrated marked
decidualization, one lesion (4%) formed an abscess, and another lesion
viii Yutaka Ueda, Takayuki Enomoto, Takashi Miyatake et al.

(4%) ruptured during the pregnancy, leaving only one of the seven to
progress in size purely as a result of tumor growth. Surgical intervention
during the pregnancy was performed on 5 (71%) of the 7 enlarging
masses.
In the literature, there are reports of 6 pregnancy cases wherein
ovarian endometriosis demonstrating marked decidualization was
observed conservatively until the postpartum period. In these reports, the
cyst shrunk and the papillary excrescences disappeared after delivery,
suggesting that decidualization of ovarian endometriosis during
pregnancy is a transient modification under control of pregnancy
hormones. The findings support the widely accepted obstetrical policy
that ovarian endometriosis should be observed conservatively during
pregnancy. However, further investigation is needed to predict which
cases will develop abscess formation or rupture and to distinguish
enlargements due to malignant transformation from those resulting from
extensive but benign decidualization.
 ABBREVIATIONS

ART assisted reproductive technology

GnRH gonadotropin releasing hormone
GnRHa gonadotropin releasing hormone agonist
H&E hematoxylin and eosin
IVF-ET in vitro fertilization and embryo transfer
LOH loss of heterozygosity
pPROM preterm premature rupture of membrane
USG ultrasonography
Chapter 1

INTRODUCTION

The prevalence of endometriosis has been reported to be anywhere

from 2% to as high as 78% (Mahmood and Templeton 1991, Gruppo
Italiano per lo Studio dell’Endometriosis 1994, Moen and Schei 1997,
Eskenazi et al. 1997). This reported heterogeneous frequency can be
largely attributed to the different patient populations studied, which
included fertile and/or infertile women.
According to a review by Guo and Wang (2006), the average
prevalence of endometriosis among previously fertile patients was 4.2%
(1.4-50.0%), and that among infertile patients was 20.6% (2.1-77.1%),
suggesting that the prevalence of endometriosis in infertile women was
higher than that in previously fertile women. They plotted the predicted
prevalence of endometriosis in fertile and infertile women at 95%-
confidence intervals against the year of publication, based on a mixed-
effects regression model that included sample size and the year of
publication. Interestingly, a positive correlation between prevalence
estimates and year of publication was clearly demonstrated. The
prevalence estimate increased nearly 10-fold the fertile women, from
approximately 2% in 1976 to approximately 20% in 1996, and increased
4.5-fold in infertile women, from approximately 10% in the 1960s to
approximately 45% in 2000. Although this analysis implies an increasing
prevalence of endometriosis, other possibilities could contribute to these
numbers, including an increasing awareness of the various phenotypes of
endometriosis, the increased opportunity to detect and diagnose
endometriosis by less invasive means, such as laparoscopy, and the
2 Yutaka Ueda, Takayuki Enomoto, Takashi Miyatake et al.

association of higher prevalence estimates with higher mean-age-at-

surgery in the reported studies.
The purported rise in prevalence of endometriosis is of major
medical concern, since it is one of the most serious causes of female
infertility. The treatment of endometriosis-related infertility is dependent
on the age of the women, duration of infertility, stage of endometriosis,
involvement of the ovaries and tubes, previous therapy history,
associated symptoms and financial resources of the women (Berek
2002). Recently, Assisted Reproductive Technology (ART) has made
excellent progress in assisting various causes of infertility, including
endometriosis (Dokras and Olive 1999). In Vitro Fertilization and
Embryo Transfer (IVF-ET) is now a useful therapeutic ART option to
improve the pregnancy rate for women who are otherwise infertile as a
consequence of severe endometriosis (The Practice Committee of the
American Society for Reproductive Medicine 1999).
Now that ovarian endometriosis can be easily diagnosed by
ultrasonography (USG), the ovary has been found to be involved in 17-
44% of all endometriosis patients (Chapron et al. 2002). With adnexal
masses detected in 1-2% of all pregnancies, ovarian endometriosis
represents around 6% of the adnexal masses reported in late 1980s and
1990s (reviewed by Barbara et al. 2000) and 11% in a more recent study
(Turkcuoglu et al, 2009). Given the successful treatment of
endometriosis-associated infertility, the frequency of ovarian
endometriosis during pregnancy is expected to increase accordingly.
In this chapter, we update our previous study (Ueda et al. 2009)
concerning the incidence of ovarian endometriosis-complicated
pregnancy and we extend it to include two consecutive periods of 1995-
2001 and 2002-2008. Further, case reports of ovarian endometriosis
exhibiting diverse manufacturers during pregnancy, including our own
new cases, are reviewed. Finally, the proper management of ovarian
endometriosis before and during pregnancy is discussed.
RESEARCH METHODS
Chapter 1

AN UPDATE OF OUR
PREVIOUS WORK

In our previous 12-year study, the frequency of pregnancy

complicated by ovarian endometriosis diagnosed during the two
consecutive periods of 1996-2001 and 2002-2007 was analyzed
retrospectively (Ueda et al. 2009). We also investigated the effect of
pregnancy of ovarian endometriosis size during gestation to demonstrate
the mostly beneficial effect of pregnancy on ovarian endometriosis. Here,
we update that initial report with an extended study period.
During the fourteen-year period of 1995 to 2008, a total of 8174
deliveries were performed in the Departments of Obstetrics and
Gynecology of the Osaka University and Izumiotsu Municipal Hospitals
of Osaka, Japan. Pelvic examination and USG were routinely performed
in the first trimester for all pregnant women. Adnexal masses, except for
functional corpus lutein cysts, ovarian endometriosis and relatively small
asymptomatic cystadenoma, were routinely surgically removed in the
second trimester, except the of cases in which the patients refused
surgery during the pregnancy. The complications arising from their
adnexal masses were reviewed from the patients’ clinical records,
including physical exam notes, USG reports, operation records and
pathology reports. Functional corpus lutein cysts were excluded from this
study.
Twenty-three out of 27 cases of ovarian endometriosis, in which
surgical removal of the lesions was not performed, were diagnosed as
such by their USG features. In the remaining four cases, the diagnosis of
6 Yutaka Ueda, Takayuki Enomoto, Takashi Miyatake et al.

ovarian endometriosis was made by pathology sections of the lesions

removed surgically in the second trimester or at the time of Cesarean
section. The USG criteria for diagnosis of ovarian endometriosis were (1)
a cystic structure with a low, homogeneous echogenicity, (2) having a
thick cystic wall with regular margins, as described in previous reports
(Guerriero et al. 2005, Fruscella et al. 2004).
Cases of ovarian endometriosis detected in the first trimester were
followed carefully by USG into the postpartum period or until surgical
intervention. The maximum diameter of the cyst was measured in the
ovarian endometriosis cases and a change in the maximum diameter of
the mass equal to or larger than 1 cm was regarded as significant.
Chapter 2

LITERATURE REVIEW

The PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) database was

searched for any ovarian endometriosis cases exhibiting diverse types of
alterations during pregnancy, using combinations of the following
keywords: ovarian endometriosis, endometrioma, chocolate cyst, change,
modification, decidualization, decidual, abscess, infection, rupture,
torsion, malignant, or pregnancy. In order to evaluate the incidence and
the clinical characteristics of these various phenomena, we required the
report to be based on an accurate diagnosis by USG or pathology and not
solely on a manual pelvic examination or inspection. We confined our
review of ovarian endometriosis cases which demonstrated various
changes during pregnancy to those reported in the last 25 years, a period
when USG was used routinely in clinical obstetrics and gynecology.
ACHIEVEMENTS
Chapter 3

APPARENT INCREASING INCIDENCE OF

OVARIAN ENDOMETRIOSIS-
COMPLICATED PREGNANCY

Historically, the leading maternal adnexal mass has been shown to

be the mature cystic teratoma. According to a review of data from
between 1984 and 1999 (Barbara et al. 2000), a mature cystic teratoma
represented 43% of all the maternal adnexal masses, excluding the
normal functional corpus lutein cyst. Serous and mucinous cystadenomas
occupied 29% of the masses, and malignant tumors represented 6%. The
reported frequency of ovarian endometriosis was only 8% in this earlier
time period.
In this update of our previous study (Ueda et al. 2009), we now
report that maternal adnexal masses were detected in 33 cases (0.83%)
during the 1995-2001 period and 55 cases (1.3%) during the more recent
2002-2008 period. Adnexal masses were diagnosed during the pregnancy
in 1.1% of the total deliveries occurring during the 14 years between
1995 and 2008.
The most common mass, mature cystic teratoma, occupied 39% of
all the masses in the first seven-year period, from 1995 to 2001 (Table 1).
Serous and mucinous cystadenomas occupied 33%, and the frequency of
malignancy was 3%. Ovarian endometriosis represented only 15% of the
masses. These results were similar to those in the previous review of data
during the similar periods shown above (Barbara et al. 2000).
12 Yutaka Ueda, Takayuki Enomoto, Takashi Miyatake et al.

Table 1. Maternal adnexal masses

detected during pregnancy

Type of tumor The former The latter period Total period

period (2002-2008) (1995-2008)
(1995-2001)
Ovarian endometriosis 5 (15%) 22* (40%)** 27 (31%)
(Endometriotic cyst)
Mature cystic teratoma 13 (39%) 14 (25%) 27 (31%)

Serous cystadenoma 7 (21%) 8 (15%) 15 (17%)

Mucinous 4 (12%) 5 (9%) 9 (10%)

cystadenoma
Paraovarian cyst 3 (9%) 2 (4%) 5 (6%)

Struma Ovarii 0 (0%) 1 (2%) 1 (1%)

Serous cystic tumor of 0 (0%) 1 (2%) 1 (1%)

borderline malignancy
Serous 1 (3%) 0 (0%) 1 (1%)
cystadenocarcinoma
Mucinous 0 (0%) 1 (2%) 1 (1%)
cystadenocarcinoma
Metastatic mucinous 0 (0%) 1 (2%) 1 (1%)
adenocarcinoma
Total 33 (0.83%) 55 (1.3%) 88 (1.1%)
Delivery 3998 4176 8174
In two consecutive seven-year periods, from 1995 to 2001 and from 2002 to
2008, 33 (0.83%) and 55 (1.3%) adnexal masses were detected during
pregnancy, respectively. The types of adnexal tumors detected during
pregnancy are shown in the order of their total frequency. Mature cystic
teratomas were the most common tumor type in the former period and
endometriotic cyst the most common in the latter seven-year period.
*The frequency of endometriotic cyst in all the pregnant women increased
significantly (p=0.0016 by Fisher’s exact test).
**The proportion of ovarian endometriosis among all the adnexal masses
increased significantly (p=0.017 by Fisher’s exact test).

However, in the later seven-year period, from 2002 to 2008, ovarian

endometriosis became the leading adnexal mass detected during
pregnancy, occupying 40% of all the masses. The frequency of ovarian
endometriosis among all deliveries was 0.53% in the latter period, a 4.2-
fold increase compared with the 0.13% of the previous period (p=0.0016
 Apparent Increasing Incidence of Ovarian Endometriosis… 13

by Fisher’s exact test). The proportion of pregnancies with the other

types of the masses did not change significantly.
Another study showed that, of pregnancy-associated adnexal mass
diagnosed between 2001 and 2007, a time period similar to the later
period in our study, the most frequent histological type was mature cystic
teratoma, and ovarian endometriosis represented only 11% of their cases
(Türkçüoğlu et al. 2009). In their study, diagnosis of the adnexal masses
was made solely on surgically resected tumors removed during the
pregnancy. They followed a strategy that a pregnant woman with an
adnexal mass usually requires surgical removal, because of the
significant risk of complications, including torsion, rupture, hemorrhage
and infection, which are all associated with an increased risk of
spontaneous abortion and preterm labor (Barbara et al. 2000).
The exception to surgical removal of adnexal masses might be for
ovarian endometriosis, which can be managed conservatively throughout
the pregnancy period. This wait-and-see approach is followed because
endometriosis has been widely believed to regress during the pregnancy.
Endometriosis is also thought to cause adhesion of the lesion to other
organs, resulting in less frequency of torsion events and more difficulty
of surgery. Based on the tendency to avoid surgery for ovarian
endometriosis during pregnancy, the real incidence of ovarian
endometriosis during pregnancy is estimated to be higher than that in
their study (Türkçüoğlu et al. 2009) in which diagnosis was only
histologically made on surgically resected masses. In our original report,
the diagnosis of ovarian endometriosis during pregnancy was always
initially made by ultrasonography (USG), based on its high reliability.
Surgically removed cases were then confirmed by pathology. Therefore,
the frequency of ovarian endometriosis found in our study seems to more
likely represent the real incidence of the disease.
The possible reasons for the recent increase of ovarian endometriosis
detected during pregnancy include the remarkable success of ART to
overcome previously untreatable infertility without removal of the
ovarian endometriosis, or better diagnosis of ovarian endometriosis, and
to a real increase of the disease itself. Because our updated study found
that in the earliest 7-year period, from 1995 to 2001, the five pregnancies
complicated with ovarian endometriosis were all unassisted
(spontaneous) pregnancies and that even in the more recent 7-year
period, 2002 to 2008, when ART has been more widely used, the vast
14 Yutaka Ueda, Takayuki Enomoto, Takashi Miyatake et al.

majority, 20 of 22 endometriosis-complicated pregnancies, were

spontaneous ones. Because the diagnosis of ovarian endometriosis in our
study was made using the same criteria by authorized specialists in
obstetrics and gynecology, using the same USG device throughout both
study comparison periods, we believe that a better diagnosis of the
disease doesn’t account for the increase either. Therefore, the increase of
ovarian endometriosis-complicated pregnancy seems to result from the
overall increase of endometriosis itself, as described by Guo and Wang
(2006), and only partially from the remarkable success of ART.
Chapter 4

DRAMATIC CHANGES IN OVARIAN

ENDOMETRIOSIS DURING PREGNANCY

PREVIOUSLY REPORTED
CASES AND OUR NEW CASES
Because estrogen stimulates endometriosis, medical therapy has been
designed to suppress the effect (Berek 2002). Pseudo-pregnancy therapy
using progestins, with or without estrogens, is one of the most cost-
beneficial treatments for endometriosis. Beecham stated “Nature (since
the beginning of time) has employed an efficient prophylactic and
curative measure for endometriosis, i.e. pregnancy.” (Beecham 1949).
McArthur and Ulfelder reviewed the suppressive effect of pregnancy on
endometriosis in 1965 (McArthur and Ulfelder 1965), and showed that
pregnancy was frequently accompanied by a reduction in the size of non-
ovarian endometriotic lesions. Because USG and other diagnostic
procedures such as CT and MRI were not available in those days, only
endometriotic lesions diagnosable by manual pelvic examination were
analyzed.
The ovary is variously reported to be involved in 17-44% of
endometriosis patients (Chapron et al. 2002). During the last 25 years,
during which USG was used routinely in clinical obstetrics and
gynecology, ovarian endometriosis has been easily diagnosed and
followed by USG. We have now systematically reviewed the literature
16 Yutaka Ueda, Takayuki Enomoto, Takashi Miyatake et al.

from these last 25 years for reports of cases of ovarian endometriosis

which demonstrated changes during pregnancy.
We found 39 such cases of ovarian mass modification, including our
own new case of decidualization. Marked decidualization was observed
in 26 of the 39 cases, the endometriotic cyst ruptured in 7 cases, an
abscess was formed in 4 cases, torsion of the cyst was detected in one
case, and malignant transformation was observed in another (Table 2).
Normally decidualization is a postovulatory process of endometrial
stroma remodeling that occurs to enable implantation of the embryo. The
process includes modifying endometrial stromal cells and secretory
transformation of the uterine glands, influx of specialized uterine natural
killer immune cells, and vascular remodeling. The endometrial stroma
forms a dense cellular matrix called a decidua. In humans,
decidualization is independent of the blastocyst's presence in the uterine
cavity and also takes place in the late secretory phase of the menstrual
cycle, evoked by progesterone as well as by other regulatory agents.
Decidualization continues during the course of pregnancy, and it is
thought to regulate subsequent trophoblast invasion and placenta
formation. A p function of the dense decidua is to impede the invasion of
trophoblasts migrating toward the uterine spiral arteries, a feat it
accomplishes not only by forming the physical barrier but also by
generating cytokines promoting attachment of the trophoblast.
(http://ajp.amjpathol.org/cgi/content/full/157/6/1759,http://www.biology-
online.org/articles/control-human-trophoblast-function/decidualization).
 Table 2. Ovarian endometriosis exhibiting dramatic changes during
pregnancy reported in the last 25 years

Decidualization Rupture Abscess Torsion Malignant Total

change
Number (cases) 26 7 4 1 1 39
(Our cases including a new case) (4) (1) (1) (0) (0) (0)
Age (year) 32 (20-41) 29 (25-39) 35 (29-40) - 31 32 20-41)
Time of detection of change (week) 15 (7-28) 21 (6-35) 18 (5-35) - 9 15 (5-35)
Size before detection of change* (mm) 48 (32-66) 60 (51-68) 30 (15-52) - 100 48 (15-100)
Size on detection of change (mm) 63 (38-160) 61 (40-83) 63 (40-80) - 140 63 (38-160)* *
Surgical Intervention during Pregnancy (%) 77 (20/26) 100 (7/7) 50 (2/4) 100 (1/1) 100 (1/1) 79 (31/39)
Abortion and preterm delivery (%) 16 (3/19) 67 (4/6) 50 (2/4) - 0 (0/1) 30 (9/30)
In total, 39 cases which demonstrated various modifications during pregnancy were reported in the most recent 25 years, when USG
was used routinely in clinical obstetrics and gynecology, including our new additional case of decidualization.
*Ovarian endometriosis which was first recognized on dramatic changes was excluded.
**The median of the maximum diameter of the ovarian endometrioses exhibited a significant increase from 48 mm (15-100 mm)
before pregnancy-related changes (including decidualization, rupture, abscess and malignant transformation) to 63 mm (38-160
mm) upon detection of the changes (p=0.0005 by the Mann-Whitney U-test).
18 Yutaka Ueda, Takayuki Enomoto, Takashi Miyatake et al.

What is becoming apparent is that endometriotic tissue in the ovary

is responsive to these same signals and can undergo parallel
decidualization during pregnancy. In the previous reports summarized in
Table 2, such ovarian mass decidualization was detected at a median
time of 15 weeks (7-28 weeks) of pregnancy, relatively earlier than for
cyst rupture, which occurred at a median time of 21 weeks (6-36 weeks);
however, no statistical significance for the two outcomes was observed
(p=0.16 by Mann-Whitney U-test). Before pregnancy-related changes
(including decidualization, rupture, abscess and malignant
transformation) occurred to the ovarian endometriosis, the median of the
maximum diameters was 48 mm (15-100 mm) and following the changes
became 63 mm (38-160 mm). This increase was statistically significant
(p=0.0005 by the Mann-Whitney U-test). Surgical intervention during
the pregnancy was performed in 79% of these cases (31 of 39). Impaired
obstetrical outcome, including abortion and preterm delivery, was
observed in 30% (9 out of 30 cases). Spontaneous abortion at 10 weeks
of pregnancy was detected in a case of decidualization. Preterm delivery
was reported in one (6%) of 17 informative cases of decidualization, 4
(67%) of 6 informative cases of rupture and two (50%) of 4 informative
cases of abscess. Neonatal death due to preterm delivery occurred in one
case each of decidualization and abscess.

INCIDENCE OF PREGNANCY-RELATED
MODIFICATION IN OVARIAN ENDOMETRIOSIS
The torsion of an adnexal mass is a relatively common event during
pregnancy, with a reported incidence of 5-15% (Barbara et al. 2000).
Torsion occurs mostly when the uterus expands out of the pelvis or when
the uterus is rapidly involuting.
Rupture of the cyst wall occurred in 0% to 9% of cases (Leiserowitz
2006). Hemorrhage into the mass and infection are less common
complications (Barbara et al. 2000, Leiserowitz 2006). Adverse fetal and
neonatal outcomes are most commonly the result of torsion and rupture
of the adnexal mass, and are associated with emergency surgery
(Leiserowitz 2006). Hess et al. reported that an emergency exploratory
laparotomy was performed in 15 (28%) of 54 pregnant women with an
adnexal mass (1988). Struyk and Treffers reported that in 90 pregnancies
 Dramatic Changes in Ovarian Endometriosis during Pregnancy 19

complicated with an adnexal mass there were three cases of fetal death
and seven cases of neonatal death, a fatality rate of 11% (1984). This is
why elective surgery is usually performed early in the second trimester,
before the uterus has risen out of the pelvis, to minimize the risk of
subsequent fetal loss (Marino and Craigo 2000, Leiserowitz 2006).
In previous studies, adverse outcomes, including torsion and rupture,
were demonstrated in maternal adnexal masses that were mainly mature
cystic teratomas or serous and mucinous cystadenomas; ovarian
endometriosis occupied only a small fraction of the adverse outcomes.
Until now, the characteristic outcome of ovarian endometriosis during
pregnancy has never before been systematically analyzed; only the case
reports shown in Table 2 have been published. Our updated study now
clarifies for the first time the incidence of various modifications of
ovarian endometriosis during pregnancy (Figure 1).
We found 27 ovarian endometrioses which were followed by USG
from at least the first trimester until surgery, or into the postpartum
period. The maximum diameter of the cyst decreased in 13 of the 27
cases (48%) and had no other significant modifications of the mass or
adverse obstetric problems during the pregnancy. The size of the lesion
was static in 7 cases (26%) in which the course of the pregnancy was
also uneventful and no significant modifications of the mass were
detected. In only 7 of the 27 cases (26%) did the cyst become larger
during the pregnancy. Decidualization, abscess formation and rupture
during pregnancy all occurred in the enlarging lesions. Among the seven,
4 cases (15% of 27) exhibited marked decidualization.
Rupture of the cyst wall was detected in one case (4%), and abscess
formation was observed in another (4%). In both cases, USG
examination had revealed a typical pattern for ovarian endometriosis
before these adverse events occurred; the cysts exhibited a solid and
cystic pattern inside the thickened cyst wall (Figure 2). Both patients
complained of severe abdominal pain and surgical intervention, including
peritoneal washing and drainage, was performed immediately. The
affected ovary could not be removed because of a severe adhesion of the
cyst to the uterus and intestines in these cases.
20 Yutaka Ueda, Takayuki Enomoto, Takashi Miyatake et al.

Among 27 ovarian endometriosis (followed from the first trimester until surgery,
or into the postpartum period) in our updated study, the maximum diameter
of the cyst decreased in 13 cases (48%), went unchanged in 7 cases (26%)
and increased in 7 cases (26%). Marked decidualization (15%), rupture
(4%) , and abscess formation (4%) was observed only in enlarging cysts.

Figure 1. Modifications of ovarian endometriosis during pregnancy.

In both a rupture and an abscess cases, on USG the cyst exhibited a solid and
cystic pattern inside the thickened cyst wall.

Figure 2. USG images of abscess formation and rupture observed in ovarian

endometriosis.
 Dramatic Changes in Ovarian Endometriosis during Pregnancy 21

A USG image (a), macroscopic view (b) and HE sections (c) x40 and (d) x200 in
cases of ovarian endometriosis with marked decidualization where salpingo-
oophorectomy was performed.

Figure 3. A USG image, a macroscopic view and H&E sections of a single

decidualized ovarian endometriosis.

Among the four decidualization cases, surgical removal of the

affected ovary was performed in three patients when malignant
transformation couldn’t be ruled out; the fourth patient refused to
undergo the surgery during her pregnancy. A USG image of a single case
of ovarian endometriosis with marked decidualization where salpingo-
oophorectomy was performed is shown in Figure 3, as well as a
macroscopic view and two images of a hematoxylin and eosin (H&E)
section of the removed tumor. Papillary excrescences were observed by
USG to be protruding into the lumen of the cyst. The cyst contained a
chocolate-like bloody fluid, and soft and round solid tissue with a smooth
surface was observed along the internal wall. Histological examination
revealed that the papillary projections were massive decidualization of
the stroma, characterized by large cells with small round nuclei and
abundant cytoplasm.
22 Yutaka Ueda, Takayuki Enomoto, Takashi Miyatake et al.

Fetal and neonatal death was not observed in any of the 27 cases.
Preterm delivery (at 33 weeks of pregnancy) resulting from a preterm
premature rupture of membrane (pPROM) was detected in only one case
(a twin pregnancy), in which a rupture of the ovarian endometriosis
occurred at 21 weeks of pregnancy and surgical drainage was performed
immediately.

TRANSIENT DECIDUALIZATION
OBSERVED DURING PREGNANCY
In this chapter, we report that in three of four cases of ovarian
endometriosis exhibiting marked decidualization the cyst was removed
surgically during the pregnancy. We were forced to follow the fourth
through the pregnancy when the patient refused surgery. There are as of
now only 6 reported cases, including this case, where an ovarian
endometriosis demonstrating papillary excrescences protruding into the
lumen of the cyst on USG was conservatively followed throughout the
pregnancy, without surgical intervention, into the postpartum period
(Table 3). In these 6 cases, decidual change was first recognized at a
median of 14 weeks (9-20 weeks) of the pregnancy. The cyst size ranged
from 38-72 mm (median: 50 mm) at the first sign of decidualization, and
in all the cases either shrunk significantly or disappeared completely
after delivery or abortion.
Interestingly, not only did the size of the cyst decrease in the
postpartum period, but on USG the decidualization was reported to
disappear in two cases. In one case, the decidualized ovarian
endometriosis detected at 10 weeks of pregnancy resumed a more typical
USG appearance 6 weeks after endometrial curettage for a missed
abortion (retention in the uterus of an abortus that has been dead for at
least eight weeks). In our most recent case, the ovarian endometriosis
when first observed was 50 mm and exhibited typical a USG appearance
at 10 weeks of pregnancy. At 16 weeks, the cyst increased to 72 mm and
developed an echogenic cyst center (Figure 4). A malignant
transformation was not able to be ruled out. However, as mentioned
above, the patient did not agree to undergo a prophylactic surgery, and
was thus conservatively followed during the rest of her pregnancy.
Fortunately, she vaginally delivered a healthy baby and the cyst shrunk
 Dramatic Changes in Ovarian Endometriosis during Pregnancy 23

postpartum to 27 mm in maximum diameter with a typical benign USG

appearance.
This result clearly suggests that the USG appearance of
decidualization of ovarian endometriosis during pregnancy may be a
transient, reversible and benign modification occurring under the
dynamic change of hormones during pregnancy.
Chapter 5

DISCUSSION: A SUGGESTED
MANAGEMENT OF OVARIAN
ENDOMETRIOSIS DURING PREGNANCY

An adnexal mass including ovarian endometriosis is one of the most

common complications of pregnancy (1-3%). Neoplastic ovarian tumors
are surgically removed early in the second trimester to avoid acute
abdomen during pregnancy, which occurs mainly due to torsion or
rupture of the cyst, or sometimes due to hemorrhage or infection. In
cases whose adnexal masses were not electively removed before adverse
events occurred, torsion and rupture of the cyst occurred in 5-15% and in
0-9% of cases, respectively (Barbara et al. 2000, Leiserowitz 2006),
resulting in an emergency exploratory laparotomy which was required in
28% of pregnant women with an adnexal mass (Hess et al. 1988), and in
one report, 11% fetal and neonatal motility (Struyk and Treffers 1984).
However, these mostly resulted from the complications of mature cystic
teratoma and serous and mucinous cystadenomas, which had, until
recently, been the most frequent histological type detected during
pregnancy.
Endometriosis is one of the most common diseases of women during
their reproductive years, with the number of affected patients increasing
steadily. We have recently shown that ovarian endometriosis detected
during pregnancy has been increasing steadily recently, and it is the most
common adnexal mass complicating pregnancy. However, until now, the
incidence and characteristic outcomes of ovarian endometriosis during
26 Yutaka Ueda, Takayuki Enomoto, Takashi Miyatake et al.

pregnancy have not been systematically analyzed, except for largely

individual case reports. Historically, ovarian endometriosis is usually
managed conservatively during pregnancy; however, there has been scant
hard scientific evidence for the efficacy of this strategy. Although the
evolution of ovarian endometriosis during pregnancy has never itself
been precisely studied, pseudo-pregnancy therapy with low dose estrogen
is a routine and highly successful treatment for endometriosis.

Table 3. Outcome of decidualized ovarian

endometriosis after delivery

Author Age Size (mm) at dectection Size (mm) after delivery

(year) (year) ofdecidualization by
USG (week)
Takeuchi 20 50 (20 wk) shrunk or disappeared
(2008)
32 40 (16 wk) shrunk or disappeared

32 50 (9 wk) shrunk or disappeared

32 60 (12 wk) shrunk or disappeared

Barbieri 39 38 x 14 (10 wk) 18 x 15 (at next pregnancy

(2009) after early abortion)

Ueda 33 72 (16 wk) 27

(2009)
In the literature, only 6 reported cases of decidualized ovarian endometriosis
(demonstrating papillary excrescences protruding into the lumen of the cyst
on USG) were conservatively followed without surgical intervention until
the postpartum period, including our new case.

In the literature, a diversity of modifications of ovarian

endometriosis during pregnancy has reported. In contrast to much older
reports dealing with adnexal masses consisting mainly of mature cystic
tumors and serous and mucinous cystadenomas, we found that torsion of
the cyst seems to be an extremely rare event, with only one recent case
report. Malignant transformation of the cyst during pregnancy was also
shown to be a rare occurrence.
 Discussion 27

In our new case, at 16 weeks of pregnancy the cyst increased from 50 mm

(typical ovarian endometriosis at 10 weeks) to 72 mm, with an echogenic
medulla (a) and postpartum shrunk to 27 mm with a typical USG
appearance (b).

Figure 4. Transient Decidualization of Ovarian Endometriosis During

Pregnancy.

Marked decidualization was observed in the literature in 26 cases

(Miyakoshi et al. 1998, Tanaka et al. 2002, Fruscella et al. 2004,
Sammour et al. 2005, Guerriero et al. 2005, Iwamoto et al. 2006, Asch
and Levine 2007, Poder et al. 2008, Machida et al. 2008, Yoshida et al.
2008, Takeuchi et al. 2008, Barbieri et al. 2009, Ueda et al. 2009). The
endometriotic cyst ruptured in 7 of these 26 cases (Garcia-Velasco et al.
1998, Vercellini et al. 1992, Johnson and Woodruff 1986, Rossman et al.
1983, Barbazan et al. 1993, Loh et al. 1998, Ueda 2009), and an abscess
was formed in 4 cases (Phupong et al. 2004, Younis et al. 1997,
Matsunaga et al. 2003, Ueda et al. 2009) (Table 2). The relative
incidence of the modifications of ovarian endometriosis, including
marked decidualization, which occurred in 4 cases (15%) out of 27 cases
(26 literature cases plus our new reported case), rupture, which occurred
in 1 (4%) out of 27 cases, and abscess formation, which occurred in 1
(4%) out of 27 cases in our updated study, was consistent with previous
case reports. In our updated study, these modifications during pregnancy
all occurred in the enlarging lesions.
The real incidence of a disease can’t be estimated from the number
of case reports because most cases are not reported in the literature.
However, in ovarian endometriosis, we found that the number of case
28 Yutaka Ueda, Takayuki Enomoto, Takashi Miyatake et al.

reports of various modifications in the literature paralleled their

composition in our updated study, which analyzed all the reports of
ovarian endometriosis cases during pregnancy.
Based on these results, the risks of various events to the cyst during
pregnancy were compared between ovarian endometriosis in our series
and in the literature and the general adnexal masses in previous reports
(Barbara et al. 2000, Leiserowitz 2006). Torsion of the cyst, one of the
most common events to occur with general adnexal masses, was detected
in around 10% of all adnexal mass cases; however, with ovarian
endometriosis it was an extremely rare event. Torsion was not detected in
any of our cases and only a single case was reported in the recent
literature (Yen et al. 2009). Rupture of the cyst was observed in around
5% of general adnexal masses. Rupture was observed in 4% in our cases
and 7 cases were reported in the literature (Garcia-Velasco et al. 1998,
Vercellini et al. 1992, Johnson and Woodruff 1986, Rossman et al. 1983,
Barbazan et al. 1993, Loh et al. 1998, Ueda et al. 2009). Abscess
formation was rare in general adnexal masses; however, it occurred in
4% of our ovarian endometriosis cases and 4 cases were reported in the
literature (Phupong et al. 2004, Younis et al. 1997, Matsunaga et al.
2003, Ueda et al. 2009). Malignant transformation during pregnancy was
rare in both ovarian endometriosis and in general masses. No malignant
change was detected in any of our cases and only a single case of ovarian
endometriosis which progressed to ovarian clear cell adenocarcinoma
during pregnancy was reported (Kobayashi et al. 1996).
Decidualization was specific to ovarian endometriosis and was
observed in 15% in our cases. An additional 26 cases were reported in
the literature, including our new case (Miyakoshi et al. 1998, et al. 2002,
Fruscella et al. 2004, Sammour et al. 2005, Guerriero et al. 2005,
Iwamoto et al. 2006, Asch and Levine 2007, Poder et al. 2008, Machida
et al. 2008, Yoshida et al. 2008, Takeuchi et al. 2008, Barbieri et al.
2009, Ueda et al. 2009).
A previous study showed that an emergency exploratory laparotomy
was required in 28% of pregnant women with an adnexal mass (Hess et
al. 1988) and another study demonstrated fetal and neonatal motility was
detected in 11% (Struyk and Treffers 1984). On the other hand, in our
cases, decidualization, rupture and abscess were observed in 23%, and
torsion and malignant change were not detected. Surgical intervention
was performed in 19%. Fetal and neonatal death was not observed. These
 Discussion 29

results seemed to be almost equal in both ovarian endometriosis and

general adnexal masses or a little worse in the latter.
No patients of marked decidualization of ovarian endometriosis
complained of any symptoms in our 4 cases. The reason why surgical
removal was proposed for those patients was to rule out malignant
transformation, which has historically been the case in similar situations.
Three of the 4 patients underwent excisional surgery during their
pregnancy and a marked decidualization was histologically diagnosed
within the removed mass. In one patient who did not agree to undergo
surgery during pregnancy, the cyst shrunk to 27 mm in maximum
diameter with typical USG appearance after delivery. A previous study
showed a similar case in which a decidualized ovarian endometriosis
detected at 10 weeks of pregnancy resumed typical USG appearance by 6
weeks after endometrial curettage for a missed abortion. The reversible
modification of USG appearance suggests that marked decidualization is
possibly a transient modification caused by the dynamic hormonal
changes occurring during pregnancy. As a consequence, decidualized
ovarian endometriosis may be conservatively observed during
pregnancy.
A problem in this strategy is the difficulty of diagnosis of
decidualization. Histological diagnosis on a removed mass is quite easy;
however, a non-invasive differential diagnosis of the decidual change
from a malignant one has not yet been established. On USG, the
papillary excrescences protruding into the lumen of the cyst can mimic
ovarian malignancy. Color Doppler sonography was reported to be
ineffective in distinguishing decidualized ovarian endometriosis from
ovarian cancer (Miyakoshi et al. 1998, Tanaka et al. 2002, Fruscella et al.
2004, Sammour et al. 2005, Guerriero et al. 2005, Iwamoto et al. 2006,
Asch and Levine 2007, Poder et al. 2008, Machida et al. 2008, Yoshida
et al. 2008, Barbieri et al. 2009), and MRI was also shown not to be
informative in distinguishing them (Miyakoshi et al. 1998, Tanaka et al.
2002, Fruscella et al. 2004, Iwamoto et al. 2006, Barbieri et al. 2009).
However, in the few cases in which the ovarian endometriosis was
followed from the preconception period or the early first trimester,
typical USG features of ovarian endometriosis observed before first
detection of papillary excrescences mimicking malignancy may provide
highly useful information. Malignant transformation of ovarian
endometriosis which had once exhibited the typical USG pattern for
30 Yutaka Ueda, Takayuki Enomoto, Takashi Miyatake et al.

ovarian endometriosis was extremely rare during pregnancy, only a

single case has been reported in the literature (Kobayashi et al. 1996).
Based on this substantiated observation, the sudden appearance of
papillary excrescences in a typical ovarian endometriosis during
pregnancy can be regarded with reasonable confidence as a case of
decidualization, and not as a malignant change. However, pregnant
women sometimes first come to an obstetrics clinic late in their first
trimester or in the second trimester. Decidual changes are first
recognized at 9-20 weeks (median: 14 weeks) of pregnancy usually. In
such late presenting cases, in which the ovarian endometriosis is already
exhibiting papillary excrescences on their first sonogram, it is currently
impossible to distinguish a benign decidual change from a malignant
transformation continuing from the preconception period, i.e., a
pregnancy complicated with endometriosis-related ovarian cancer, which
has been reported previously (Sugiyama et al. 1997, Makrydimas et al.
2003).
Ovarian endometriosis is classified by the World Health
Organization as a tumor-like lesion among ovarian tumors (Tavassoli et
al. 2003) which means it is a non-neoplastic lesion; however, recent
molecular studies have shown that ovarian endometriosis has the
neoplastic characteristic of monoclonality (Jimbo et al. 1997, Tamura et
al. 1998) and genetic alterations similar to those of carcinomas, including
K-ras and Pten mutations and loss of heterozygosity (LOH) at several
sites (Obata and Hoshiai 2000, Prowse et al. 2006, Dinulescu et al.
2005). Clear cell and endometrioid adenocarcinomas have been reported
to occur within ovarian endometriotic lesions (Sainz de la Cuesta et al.
1996).
Malignant transformation is mostly detected in women above 40
years of age (Kobayashi et al. 2007). The mean age of pregnancy has
increased due to delayed marriages caused by sociological changes,
especially in the more developed countries, including the United States
and Japan (Berek 2002), raising the possibility that a malignant
transformation of these tumors may occur in these older pregnant
women. In fact, there were 2 pregnant women with ovarian
endometriosis who were 40 years old included in our updated study,
although fortunately they did not have malignancies.
There is another concern in the strategy that decidualized ovarian
endometriosis can be conservatively followed during pregnancy. There is
 Discussion 31

a possibility that some fraction of ovarian endometriosis with marked

decidualization may cause softening of the walls of the lesion, resulting
in a rupture of the cyst (Garcia-Velasco et al. 1998, Vercellini et al.
1992). All of the 6 decidualized ovarian endometriosis followed until
postpartum period were found to shrink after delivery. Papillary
excrescences disappeared in both cases in which such details were
described.
If it were supposed that decidualized ovarian endometriosis could be
conservatively observed during pregnancy, as in our study, surgical
intervention will still be required for certain adverse events, including
rupture and abscess formation. These adverse events occurred with
ovarian endometriosis only 7% of the time (2 out of 27 cases), far less
frequently than the rate of 28% requiring an emergency exploratory
laparotomy in pregnant women with the other kinds of an adnexal masses
than ovarian endometrioma (Hess et al. 1988).
In our updated study, decidualization, abscess formation and rupture
during pregnancy all occurred in already enlarging lesions. The
prediction of the outcome of these diverse modifications of ovarian
endometriosis during pregnancy is difficult. The initial size of the cysts
before pregnancy or in the first trimester was unable to predict the size
changes that were to occur during the pregnancy. The age of the patient
also did not correlate with the size changes or outcomes. The only
finding is that ann enlarging ovarian endometriosis during pregnancy
should be more carefully observed.
Taking all these findings into account, the sudden appearance of
papillary excrescences inside the cyst wall of a previously typical-
appearing ovarian endometriosis during pregnancy may be considered to
be a result of marked decidualization. Any such ovarian endometriosis
may be conservatively managed, with caution for rupture of the cyst or
malignancy.
Pseudo-pregnancy therapy using progestins alone, or progestins and
estrogens, including low-dose pills, is a widely performed treatment for
endometriosis in non-pregnant women; however, the effects on ovarian
endometriosis of the dynamic changes of hormones occurring during a
real pregnancy have not been previously described. It is presumed that
the modifications of ovarian endometriosis described here during real
pregnancy may be also observed in patients for whom pseudo-pregnancy
therapy was performed.
32 Yutaka Ueda, Takayuki Enomoto, Takashi Miyatake et al.

Because of the aging of the population having their first pregnancies,

the number of pregnancies complicated with ovarian endometriosis will
inevitably increase in the future. Our achievement in better
understanding the benign nature of ovarian endometriosis changes
described in this chapter will provide strong scientific supportive
evidence for the conservative observation of ovarian endometriosis
during these complicated pregnancies. Further investigation is still
required to clarify the varied mechanisms that underlie the pregnancy-
induced decidualization of ovarian endometriosis. We will also seek
better diagnostic tools to discriminate decidual changes from malignant
changes in enlarging ovarian endometriosis to avoid unnecessary surgery
during pregnancy and also to predict and prevent other adverse events,
such as cyst rupture and abscess formation of ovarian endometriosis
during pregnancy.
Chapter 6

CONCLUSION

Ovarian endometriosis, as a complication of pregnancy, has

increased to the point where it is now the leading adnexal mass detected
during pregnancy. This benign tumor can exhibit a number of diverse
modifications during pregnancy, but by and large can be conservatively
managed without surgical removal during the pregnancy more safely
than can the other types of adnexal masses.
 ACKNOWLEDGMENTS

We would like to thank Dr. G. S. Buzard, CDCP, for his constructive

critique and editing of our manuscript.
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Reviewed by Dr. Robert N. Taylor, MD, PhD, Leach/Hendee

Professor and Vice Chair for Research, Department of Gynecology and
Obstetrics, Emory University School of Medicine: 1639 Pierce Drive,
4217-WMB, Atlanta, GA 30322.
 INDEX

control, viii, 16
A cyst, vii, viii, 6, 7, 11, 12, 16, 18, 19, 20,
21, 22, 25, 26, 27, 28, 29, 31, 32, 38,
adenocarcinoma, 12, 28, 40
40
adhesion, 13, 19
cystectomy, 40
adverse event, 19, 25, 31, 32
cytokines, 16
age, 2, 30, 31
cytoplasm, 21
agonist, ix
appendicitis, 40
arteries, 16 D
asymptomatic, 5
attachment, 16 database, vii, 7
death, 18, 19, 22, 28
delivery, viii, 18, 22, 26, 29, 31
B detection, 17, 29
developed countries, 30
beneficial effect, 5
differential diagnosis, 29
benign, viii, 23, 30, 32, 33, 40, 41
diseases, 25
distribution, 37
C diversity, 26
drainage, 19, 22
carcinoma, 40, 41 duration, 2
cell, 28, 30, 40, 41
classification, 41
E
clonality, 41
cohort, 41
embryo, ix, 16, 40
complications, vii, 5, 13, 18, 25
endometriosis, vii, viii, 1, 2, 5, 6, 7, 11,
composition, 28
12, 13, 15, 17, 18, 19, 20, 21, 22, 23,
confidence, 1, 30
25, 26, 27, 28, 29, 30, 31, 32, 33, 37,
confidence interval, 1
38, 39, 40, 41
44 Index

epithelial cells, 41
epithelial ovarian cancer, 41
M
estimating, 37
majority, 14
estrogen, 15, 26
malignancy, 11, 12, 29, 31, 38, 39, 40
evolution, 26
malignant tumors, 11
management, 2, 38
F matrix, 16
median, 17, 18, 22, 30
fertilization, ix, 40 medulla, 27
financial resources, 2 models, 1, 41
fluid, 21 MRI, 15, 29

G N

genetic alteration, 30 nuclei, 21

genetics, 41
gestation, 5
growth, 40
O

oocyte, 40
H order, 7, 12
ovarian cancer, 29, 30, 41
hemorrhage, 13, 25 ovarian tumor, vii, 25, 30, 39
hormone, ix ovaries, 2

I P

image, 21 pain, 19
images, 20, 21 parallel, 18
in vitro, ix, 40 pathology, 5, 6, 7, 13
incidence, 2, 7, 13, 18, 19, 25, 27 pelvis, 18, 19
infection, 7, 13, 18, 25 placenta, 16
infertility, 2, 13, 37, 41 population, 32
intervention, viii, 18, 28 positive correlation, 1
prediction, 31
pregnancy, vii, viii, 2, 5, 7, 11, 12, 13,
L 15, 16, 17, 18, 19, 20, 21, 22, 23, 25,
26, 27, 28, 29, 30, 31, 32, 33, 38, 39,
labor, 13 40
laparoscopy, 1 preterm delivery, 17, 18
laparotomy, 18, 25, 28, 31, 38 progesterone, 16
lesions, vii, 5, 15, 19, 27, 30, 31 progestins, 15, 31
lumen, 21, 22, 26, 29 prophylactic, 15, 22
lutein, 5, 11
 Index 45

transformation, viii, 16, 17, 18, 21, 22,

R 26, 28, 29, 30, 39, 41
tumor, vii, 12, 21, 30, 33
regression, 1
tumor growth, viii
reliability, 13
tumors, 12, 13, 26, 30, 38, 41
retention, 22
risk, 13, 19
U
S ultrasonography, ix, 2, 13
uterus, 18, 19, 22
salpingo-oophorectomy, 21
signals, 18
specialists, 14 W
spontaneous abortion, 13
strategy, vii, 13, 26, 29, 30 women, 1, 2, 5, 12, 18, 25, 28, 30, 31,
stroma, 16, 21 37, 39, 41
stromal cells, 16
surgical intervention, 6, 19, 22, 26, 31
symptoms, 2, 29 X

X chromosome, 41
T

therapy, vii, 2, 15, 26, 31 Y

tissue, 18, 21, 41
torsion, 7, 13, 16, 18, 19, 25, 26, 28, 40 young women, 38