Open Journal of Obstetrics and Gynecology, 2012, 2, 321-324 OJOG Published Online September 2012 (
Association between etiopathogenesis of morbidly
adherent placenta and adenomyosis
Christopher A. Enakpene1,2, Ozgul Muneyyirci-Delale1,2*
1Department of O bstetrics and Gynecology, SUNY Downstate Medical Center, New York, USA
2Department of O bstetrics and Gynecology, Kings County Hospital Center, New York, USA
Email: *
Received 25 March 2012; revised 30 April 2012; accepted 11 May 2012
The association between etio-pathogenesis of mor-
bidly adherent placenta (MAP) or placenta cretas and
adenomyosis has never been described in medical
literature. Contrary to the believe that MAP is due to
direct invasion of trophoblastic tissues into the adja-
cent normal myometrium due to prior uterine sur-
geries, this article describes how pre-existence of
adenomyosis acts as a precursor for the develop-
ment of placenta cretas. It elucidates how prior
uterine traumas such as surgeries, repeated child-
births and endometritis cause endometrial tissues to
invade the myometrium as a result of disruption of
decidua basalis. The invaded endometrial tissues
cause hyperplasia and hypertrophy of surrounding
myometrium to form the clinical entity called ade-
nomyosis. The over-expression of bcl-2 oncogene in
the endometrium causes inhibition of apoptosis of
endometrial cells removing the barrier of trophoblas-
tic tissues to invade the myometrium to form MAP.
This hypothesis is based on the similarity of their
clinical perspectives, similar pathological description
of the two disease entities and their common molecu-
lar components. Both diseases increase with age; more
in women older than 35 years and also in those with
history of previous endometrial traumas such as sur-
geries, childbirth and endometritis. Both diseases also
share common pathological factors and molecular
components due to absence of deciduas basalis and
over-expression of bcl-2 oncoprotein gene, inhibition
of cell apoptosis and failure to find genetic abnor-
malities such as mutations of K-ras, P53 or LOH. An
on-going study looking at uterine specimens from
cesarean hysterectomies and pelvic MRI evaluation of
patients with retained placentas to prove that pre-
existing adenomyosis may be a precursor to the de-
velopment of morbidly adherent placenta is near to
Keywords: Morbidly Adherent Placenta (Placenta
Accretes); Adenomyosis, Association; Epidemiology;
Etio-Pathogenesis and Clinical Persp ective
Adenomyosis is a disorder characterized by the presence
of islets within the myometrium that consist of both
epithelial and stroma elements of endometrial tissues. It
was first descri bed by Rokitansky i n 1860 and then clearly
defined by Von Reckinghausen in 1896 [1,2]. In 1991,
Sathganarayana divided adenomyosis into 3 categories
depending on the location of the lesion; basal, deep and
surface layers. The minimum myometrial invasion re-
quired for diagnosis has been debated, but a depth of 2.5
mm or half a low-power field (LPF) from the endomyo-
metrial border has been universally accepted in most
assessments [3-6]. Any site may be involved, but the
posterior wall is affected the most [7,8].
Morbidly adherent placenta is globally referred to as
placenta cretas and it is define d as the abnormal adherence
either in whole or in part of the place nta to the underlying
uterine wall. It occurs when a defect of the d ecidua basalis
results in abnormally invasive placenta implantation. Risk
factors inclu de placenta pr evia, previous cesarean section,
advanced maternal age, multiparity and previous uterine
curettage. It is classified into 2 broad categories according
to depth of myometrial invasion and amount of placenta
involvement. A partial or total absence of the deciduas
basalis and imperfect development of the fibrinoid layer
(Nitabuch layer) results in chorionic villi adherent to
superficial myometrium—placenta accreta, or chorionic
villi involving myometrium—placenta increta and chori-
onic villi penetrating full thickness myometrium and
involving the serosa—placenta percreta. Classification
based on the amount of placental involvement are: focal
adherence—when part of the cotyledon is involved, par-
tial adherence—when more than one of the cotyledon is
involved and total adherence when whole placenta is in-
*Corresponding author.
C. A. Enakpene, O. Muneyyirci-Delale / Open Journal of Obstetrics and Gynecology 2 (2012) 321-324
2.1. Epidemiology of Adenomyosis
Accurate determination of the prevalence of adenomyosis
is difficult because the diagnosis can reliably be made
with certainty by microscopic examination of extirpated
uterus. It has been estimated to affect 20% of women,
however, it was fo und in appr oximat ely 65% of w omen in
one study of meticulous histopathological analysis of
multiple myometrial sections [9]. Adenomyosis most
often co-exi st s w i t h other organi c pel vi c pathologie s such
as leiomyoma, endometriosis and pelvic inflammatory
disease. The co-existence of adenomyosis and leiom yoma
has been reported in up to 60% of cases studied. Black
women have been reported to have a higher incidence of
leiomyomas than Adenomyosis [10]. Adenomyosis is
usually found in women 35 - 50 years of age who are
multiparous and present with abnormal uterine bleeding,
usually hypermnorrhea and secondary dysmenorrheal
2.2. Epidemiology of Morbidly Adherent
Morbidly adherent placenta (MAP) was first reported by
Plater in a case of a noble woman; Galla who was deli-
vered on March 25 in the year 88 AD [12]. The placenta
was retained and she die d. Upon autopsy, the placenta was
found to be firmly adherent to the uterine wall above the
internal Os. The incidence ranges between 1:2500 to
1:110 [13-15]. The increasing incidence of morbidly ad-
herent placenta is link to the rising cesarean section rate.
This is suggested to result from the consequences of
failure of reconstitution of the endometrium/decidua ba-
salis after repair of a cesarean incision. Histopathology of
the placental bed usually shows that the trophoblasts in-
vade the myometrium without interv ening deciduas [16].
Adenomyosis has been variously described by different
experts as “ elusiv e dis ease” or “dé jà vu” d is ease base d on
the little knowledge of its pathogenesis. However, the
universal agreement is that it is associated with accentua-
tion of the myometrial muscle pattern, multiparity, and
endometrial hyperplasia. Common proposed etiologies
are hereditary, hormonal influences, trauma, viral trans-
mission, and chronic postpartum endometritis. Some
authors suggest that the myometrium is vulnerable to
invasion by endometrial hyperplasia. Other authors pos-
tulate that the myometrium is vulnerable to invasion by
endometrial glands because of the absence of a basal
membrane—decidua basalis [17]. A retrospective study
by Panganamamula et al. found a link between prior
uterine surgery and adenomyosis. The hypothesis is that
there is a disruption of the junction of the endometrium
and myometrium by any surgical intervention. This re-
sults in the endometrial glands growing into the uterine
muscle leading to the developmen t of Adenomyosis [18].
However, there is a strong suggestion that adenomyosis
does not originate from the basal endometrium based on
the variation of cell death repressor activity, bcl-2 gene
expression and proliferative marker, ki-67 expression as
compared with eutopic Endometrium [19]. Other theories
proposed are: invasive tissue growth, developmental ori-
gins and uterine inflammation related to childbirth. Risk
factors incl ude uterine surgeri es such as previous cesar ean
section, dilatation and curettage, myomectomy , and child-
The ectopic endometrial tissue appears to induce hy-
pertrophy and hyperplasia of the surrounding myome-
trium, which results in a diffusely enlarged uterus called
“globular enlar gement”. A focal occurrence of a denomyo-
sis can result to nodules; called “adenomyoma” which
clinically resemble leiomyoma. The uterus generally does
not exceed the size of a pregnant uterus at 12 weeks of
The hypothesis of an association between adenomyosis
and future de vel opm ent of se con d or t hird trim est er ret ain
placenta and morbidly adherent placenta such as placenta
accretas can be viewed at three different levels: Clinical,
pathological and molecular perspective.
4.1. Clinical Perspective
Age and prior uterine surgeries such as cesarean section
are inde pend ent r isk fac tors for placenta prev ia—placenta
accreta as well as Adenomyosis [11,20]. T he incide nce of
both disease entities are increased in women older than 35
years and history of previous uterine surgeries. Disruption
of endomyometrial junction by any surgical intervention
allows in-growth of endometrial tissue into the myo-
metrium and this creates a pathway for trophoblasts to
invade the myom et r i um during pl a centation . The ass oci a -
tion between etiology of morbidly adherent placenta and
adenomyosis is based on the hypothesis that pre-existing
adenomyosis heralds the development of placenta cretas.
Our hypothesis is proposing that patients with suspected
adenomyosis based upon its clinical, radiological and
hysteroscopy features are more likely to develop placenta
cretas. The clinical symptom s of a denomy osis include but
not limited to dysmenorrhea, menorrhagia, metrorrhagia,
dyspareunia and/or dyschezia. Global shape uterus, hy-
poechoic or slightly heterogeneous appearance on trans-
Copyright © 2012 SciRes. OPEN ACCESS
C. A. Enakpene, O. Muneyyirci-Delale / Open Journal of Obstetrics and Gynecology 2 (2012) 321-324 323
vaginal sonogram and MRI features of widening of the
junctional zone of 12 mm or greater increase the risk of
future de velopment of placenta accretas in pregnancy. The
presence of irregular endometrium, endometrial defects,
hypervascularization, strawberry pattern or cystic hem-
orrhagic lesions which are hysteroscopic characteristics of
possible adenomyosis are also proposed in this hypothesis
as risk factors for the development of placenta cretas.
Adenomyosis and placenta cretas share common other
risk factors such as multiparity, endometritis and previous
uterine surgeries such as dilatation and curettage, myo-
mectomy and cesarean section. Any condition that leads
to disruption of the endometrium can alter decidualization
and placentation during pregnancy which can lead to
invagination of placenta tissues.
4.2. Pathological and Molecular Perspectives
The apparent similarity between the etio-pathogenesis of
morbidly adherent placenta and adenomyosis is based on
the common pathological factors such as absence of de-
ciduas basalis and over expression of bcl -2 in both disease
entities. There is a possibility that the invading endo-
metrial tissues leaves the decidua basalis devoid of nor-
mal endometrium covering leading to invasion of corre-
sponding myometrium by immortal endometrial tissues
due to over-expression of the bcl-2 oncoprotein gene, an
inhibitor of cell apoptosis. The pathogenesis of placenta
cretas is multi-dimensional involving increased but in-
complete trophoblast invasion in a background of absent
decidua. Placenta cretas result from prim ary deficie ncy of
decidua, abnormal maternal vascular remodeling and
excessive trophoblastic invasion of the myometrium [21].
4.3. The Role of Bcl-2 Oncoprotein Gene in the
Etiology of Morbidly Adherent Placenta
and Adenomyosis
Morbidly adherent placenta is associated wit h retention of
a piece or the whole placenta tissue resulting in uterine
sub-involution and delayed secondary postpartum hem-
orrhage. Increase bcl-2 oncoprotein is associated with
inhibition of apoptosis and prolonged cell survival. It is
seen mostly in sub-involuted placenta bed as compared
with involuted bed. The expression of bcl-2 gene is asso-
ciated with sub-involution of the utero-placental arteries
which inhibit complete resolution of pregnancy induced
changes [22]. There is also a decrease cellular apoptosis
in adenomyosis and ectopic endometrium due to high
bcl-2 gene e xpression in ectopi c endometrium tissues. In a
study by Ueki et al, occurrence of adenomyosis was cor-
related to bcl-2 expression regulated by estrogen and
estrogen receptor rather than genetic mutation [23]. Con-
stant expression of bcl-2 with estrogen receptor (ER) and
hyper-estrogenic metabolic states promote invagination
and spreading of a denomyosis into the myomet rium. This
hypothesis is also an chored on the failure to find genetic
abnormalities such as mutations of K-ras, P53 or LOH
Any patient with retained placental tissues following
delivery should be evaluated for prior history of sym-
ptoms, ra di ol o gi c or hyster oscopic feat ures of adenomy o-
sis. Till date, transvaginal sonogram and magnetic reso-
nance im aging are the m ainstay of pre-operative diagnosis
of adenomyosis with sensitivity of 68% and 70% and
specificity of 65% and 86% respectively [24]. When
available, they should be utilized without hesitation.
Other diagnostic approaches are pre-operative biopsy,
hysterosalpingography and hysteroscopy. The definitive
treatment and diagnosis of adenomyosis is hysterectomy
and pathological examination of extirpated uterus. How-
ever, conservative management such as norethindrone
acetate, levonorgestrol impregnated IUD (mirena), est-
rogen, danazol, GnRH agonists, resection of lesions, hys-
teroscopic endometrial ablation, uterine artery emboli-
zation (UAE) and magnetic resonance guided focused
ultrasound surgery (MRgFUS) can be employed [24,25].
Our hypothesis suggesting an association between etiopa-
thogenesis of placenta cretas and pre-existing adeno-
myosis may be factual rather than a mere proposition.
Fertility preserving management of adenomyosis may
play a great role in reducing the incidence of placenta
cretas. More research study to explore temporal associa-
tion between the etiology of MAP and adenomyosis is
under way. The result of our on-going study on this topic
will finalize whether this association is true or not.
[1] Rokitansky, K. (1860) Ueber uterus-neubildung. Aerzte
zu Wien Ztsc hr K Gesellsch, 16, 577.
[2] Von Recklinghausen, F. (1896) Die adenomyoma die
uterus und tuberwandung ihne abkunft von resten des
wolffschen korpeus. August Hirschwald, Berlin.
[3] Atzori, E., Tronci, C. and Sionis, L. (1996) Transvaginal
ultrasound in the diagnosis of diffuse adenomyosis. Gy-
necologic and Obstetric Investigation, 42, 39-41.
[4] Vercellini, P., Cortesi, I., De Giorgi, O., et al. (1998)
Transvaginal ultrasound versus uterine needle biopsy in
the diagnosis of diffuse adenomyosis. Human Reproduc-
tion, 13, 2884-2887. doi,10.1093/humrep/13.10.2884
[5] Ascher, S.M., Arnold, L.L., Patt, R.H., et al. (1994) Ade-
nomyosis, prospective comparison of MRI and trans-
vaginalsonography. Radiology, 190, 803-806.
[6] Bazot, M., Darai, E., Rouger, J., et al. (2002) Limitations
of transvaginalsonography for diagnsosis of adenomyosis
Copyright © 2012 SciRes. OPEN ACCESS
C. A. Enakpene, O. Muneyyirci-Delale / Open Journal of Obstetrics and Gynecology 2 (2012) 321-324
Copyright © 2012 SciRes.
with histopathological correlation. Ultrasound in Obstet-
rics & Gynecology, 20, 605-611.
[7] Benson, R.C. and Sneeded, V.D. (1958) Adenomyosis, a
reappraisal of symptomatology. American Journal of Ob-
stetrics & Gynecology, 76, 1044-1061.
[8] Vercellini, P., Ragni, G., Trespidi, L., et al. (1993) Ade-
nomyosis, a déjà vu? Obstetrical & Gynecological Survey,
48, 789-794. doi,10.1097/00006254-199312000-00004
[9] MCelin, T.W. and Bird, C.C. (1974) Adenomyosis of the
uterus. Obstetrics and Gynecology Annual, 3, 425.
[10] Owolabi, T.O. and Strickler, R.C. (1977) Adenomyosis a
neglected diagnosis. Obstetrics & Gynecology, 50, 424-
[11] Pavlik, R.M. (1995) Adenomyosis, an ignored uterine
disease. Nursing Practitioner, 20, 32-43.
[12] Plater, F. (1937) Quoted in Surgery. Obstetrics & Gyne-
cology, 64, 178.
[13] Gielchinsky, Y., Rojansky, N., Faouliotis, S.T. and Ezra, Y.
(2002) Placenta accrete-summary of 10 years, a survey of
310 cases. Placenta, 23, 210-214.
[14] ACOG committee on obstetric practice (2002) ACOG
committee opinion number 266 January 2002, placenta
accrete. Obstetrics & Gynecology, 99, 169-170.
[15] Morken, N.H. and Henriksen, H. (2001) Placenta percreta
two cases and review of the literature. European Journal
of Obstetrics & Gynecology and Reproductive Biology,
100, 112-115. doi,10.1016/S0301-2115(01)00422-5
[16] Benirschke, K. and Kaufmann, P. (2000) Pathology of the
human placenta. 4th Edition, Springer, New York.
[17] Thompson, J.R. and Davion, R.J. (1986) Adenomyosis of
the uterus, an enigma. Journal of the American Medical
Association, 78, 305-307.
[18] Panganamamula, U.R., Harmanli, O.H., Isik-Akbay, E.F.,
et al. (2004) Is prior uterine surgery a risk factor for ade-
nomyosis? Obstetrics & Gynecology, 104, 1034-1038.
[19] Matsumoto, Y., Iwasaka, T., Yamasaki, F. and Sugimori,
H. (1999) Apoptosis and ki-67 expression in adenomyotic
lesions and the corresponding eutopic endometriosis. Ob-
stetrics & Gynecology, 94, 71-77.
[20] Miller, D.A., Chollet, J.A. and Goodwin, T.M. (1997)
Clinical risk factors for placenta previa-placenta accreta.
American Journal of Obstetrics & Gynecology, 177, 210-
214. doi,10.1016/S0002-9378(97)70463-0
[21] Tantbirojn, P., Crum, C.P. and Parast, M.M. (2008) Patho-
physiology of placenta creta, the role of decidua and ex-
travilloustrophoblast. Placenta, 29, 639-645.
[22] Kong, T.Y. and Abdul Rahman, H. (1997) Bcl-2 expres-
sion delays postpartum involution of pregnancy-induced
vascular changes in the human placenta bed. Interna-
tional Journal of Gynecological Pathology, 16, 138-142.
[23] Ueki, K., Kumagai, K., et al. (2004) Expression of apop-
tosis related protein in adenomyotic uteri treated with
danazol and GnRh agonists. International Journal of Gy-
necological Pathology, 23, 248-258.
[24] Rabinovici, J. and Stewart, E.A. (2006) New intervene-
tional techniques for adenomyosis. Best Practice and Re-
search Clinical Obstetrics and Gynecology, 20, 617-636.
[25] Muneyyirci-Delale, O., Chandrareddy, A., Battala, N., et
al. (2008) Norethindrone acetate in the medical manage-
ment of adenomyosis. Obstetrics and Gynecology, 111 ,