Implantation and development of a human embryo requires both space
and an abundant blood supply. Normally both are readily available
within the uterine cavity.
In the nonpregnant state, the uterine cavity is primarily a potential
space (with a 5-10 milliliter volume) between the anterior and
posterior muscular walls of the uterus. Under pressure (such as
during operative hysteroscopy) the uterine muscular walls can
be distended to about 10-30 milliliters. During pregnancy, the
walls of the uterus rapidly adapt to increase the intracavitary
volume for the developing fetus. The ability of the uterine walls
to adapt is largely due to the muscular composition and ample
blood supply. In conditions that compromise either the muscular
composition of the uterus or its blood supply there is a tendency
for recurrent pregnancy loss.
An estimated 15% of couples (1 in 6) with recurrent pregnancy
loss have an anatomic abnormality of the uterus as the primary
reason. The four categories of anatomic defects that cause recurrent
pregnancy loss are abnormalites in
- the normal process of uterine fusion during embryonic development
(Mullerian duct abnormalities)
- the development of the uterus and cervix due to maternal diethylstilbestrol
(DES) ingestion
- the size of or circulation to the uterus due to fibroids,
endometrial polyps or scar tissue (Ashermann's syndrome)
- the function of the cervix
(1) Defects in uterine fusion and resorption
The incidence of congenital uterine fusion defects is not well
established since these defects are not readily apparent without
radiologic imaging (or the equivalent). Therefore, the incidence
rates in the literature have a potential selection bias, since
they reflect a selected group of women (that is, a population
selected to have the testing required for diagnosis). Understanding
this, the available reports generally cite incidences of about
1 in 200 to 1 in 600 women. Therefore, these defects are not common
but also not rare. About 1 in 4 women with a congenital anomaly
of the uterus due to a fusion defect will have significant difficulty
with reproduction, possibly including recurrent pregnancy loss.
Mullerian duct abnormalities include
- septate uterus: a partial lack of resorption of the
poorly vascularized tissue within the uterine cavity. The remaining
tissue creates a wedge shaped septum in the fundus (top) of the
uterine cavity. Implantation of an embryo onto this septum, and
within a septate uterus, has a markedly greater chance of spontaneous
abortion (miscarriage) compared with a normally developed uterus.
There is also an increase in preterm labor and delivery as well
as abnormal fetal lie or presentation (such as breech). Fortunately,
the repair of the septate uterus is fairly straightforward and
usually very effective, requiring an outpatient surgical procedure
(hysteroscopy). Reportedly, repair of a septate uterus will improve
the miscarriage rate from about 80-90% if untreated to about 10-15%
following treatment.
- unicornuate uterus: failure in development of 1 of
the Mullerian ducts most likely due to a failure in the migration
(movement) of the duct to the proper location prior to its time
for fusion (resulting in its loss). The resulting unicornuate
or half uterus has connection to only 1 fallopian tube since the
other tube was to be formed from the "lost" Mullerian
duct. The caliber (size) of the cavity in the unicornuate uterus
is very important in determining the likelihood of reproductive
success. Generally, a unicornuate uterus is associated with the
highest rate of loss of any of the congenital abnormalities of
uterine fusion. Unfortunately there is no accepted benefit for
the treatment of these uterine defects. The unicornuate uterus
is associated with renal abnormalities (renal agenesis, lack of
a kidney, on the side of the missing Mullerian structures) and
other reproductive problems (abnormal lie or presentation, intrauterine
growth retardation, preterm labor and delivery, incompetent cervix).
An incompetent cervix is essentially a "weak" cervix
that tends to open without contractions during the course of pregnancy
and can result in the delivery of a markedly premature baby or
a nonviable fetus (miscarriage).
- bicornuate uterus: a partial lack of fusion of the
Mullerian ducts resulting in a single cervix and two uterine cavities
in a "heart shaped" partially unified uterus. Reproductive
outcome may be normal so no treatment is indicated unless reproductive
problems are identified. Reports suggest an increase in spontaneous
abortion (miscarriage), preterm labor and delivery, and abnormal
presentation (breech). The patient with recurrent pregnancy loss,
a bicornuate uterus, and treatment for all other identified causes
for the losses may reasonably consider repair of the uterus. The
treatment is surgical repair requiring a laparotomy with unification
of the uterine cavities. The laparotomy requires a lengthy (few
weeks) postoperative recovery period. Success with this surgery
is generally quite good, improving the miscarriage rate from about
90-95% if untreated (and the cause for the recurrent losses) to
about 25-30% if treated.
- didelphic uterus: a complete lack in fusion of the
Mullerian ducts with duplication of the uterus and cervix so that
the patient has 2 cervices and two uteruses (each smaller than
normal). Commonly also associated with a vaginal septum so that
there are 2 separate vaginal canals at the top of the vaginal
vault. Occasionally, one of the sides will become obstructed and
result in pain as blood accumulates in the obstructed hemiuterus.
There is an association with abnormal lie or presentation as well
as preterm labor and delivery.
- rare abnormalities: there are an entire host of intermediate
or somewhat unique problems associated with abnormal development
of the Mullerian structures. Isolated endometrial (lining of the
uterus) or cervical agenesis (lack of development) are rare. Communicating
and noncommunicating uterine horns that failed to fuse and canulate
properly are possible.
(2) DES exposure in utero
Maternal diethylstilbestrol (DES) ingestion during pregnancy was
intended to reduce the likelihood for spontaneous abortion (miscarriage).
DES was the first orally active commercially available estrogen
compound and as it gained popularity it was widely used from the
1940s to 1971. In 1971, the association between DES exposure in
utero and the subsequent development of a rare vaginal cancer
(in the female offspring) named "clear cell adenocarcinoma"
was established. The FDA promptly removed the pregnancy related
indications for DES when these findings were revealed. Therefore,
females born in 1971-1972 are the youngest to be exposed to this
medication. In 1997, these women are 25 years old so reproductive
consequences of the medication for this population of women is
still important. The abnormalities associated with DES of reproductive
importance include:
- structural abnormalities of the upper vagina, including transverse
vaginal ridges or a vaginal hood over the cervix
- structural abnormalities of the cervix, including cervical
collars, a cervical cockscomb appearance, and inadequate development
of the cervix
- abnormal size and shape of the endometrial cavity, generally
including a small uterine cavity with possibly a T shape (due
to incomplete resorption of the lateral walls of the cavity),
constricted regions at the ostia (entrance of the tubes into the
cavity) to give an hourglass like image on HSG, and an irregular
contour of the cavity
The risk of spontaneous abortion in women who were exposed to
DES in utero is far greater than normal, especially when the abnormalities
listed above are present.
No currently available treatment for any of these DES changes
in terms of spontaneous abortion has been convincingly shown to
be effective in the available literature. A common practice is
placement of a cerclage into the cervix, since the abnormally
developed cervix may have a strong association with pregnancy
loss. The literature on the techniques and benefits of this treatment
do not allow for a uniform recommendation. Another treatment that
has been proposed but of unclear benefit is the hysteroscopic
transsection of the lateral walls of the uterus to increase the
size of the cavity. This surgery is potentially dangerous since
the incisions are close to major uterine blood vessels.
(3) Abnormalities in uterine circulation
The size of the uterine cavity and its circulation is critically
important for pregnancy. Uterine circulation can be altered by
the presence of fibroids, endometrial polyps or scar tissue (Ashermann's
syndrome).
Uterine fibroids, known as leiomyoma uteri, are tumors
of the smooth muscle cells in the wall of the uterus. The uterine
wall is primarily composed of smooth muscle cells (the myometrium).
A uterine fibroid is thought to originate as a mutation within
one of these myometrial (smooth muscle) cells that leads to the
progressive loss of it own growth regulation. Each fibroid tumor
grows from a single progenitor cell (each tumor arises from one
single cell) and all the cells within a particular fibroid contain
the same abnormal DNA that favors growth. Different fibroid tumor
originate from different muscle cells, each with their own genetic
(DNA) abnormality so that each tumor may grow at its own rate
(some faster and some slower). Fibroid tumors are not malignant
(cancer) yet there is an uncommon cancer called "leiomyosarcoma"
that is composed of malignant smooth muscle cells. It is not clear
whether these cancers develop from benign fibroids or whether
they arise independently. Fibroid tumors of the uterus are common.
About 75% (3 of 4) of uterine specimens removed during abdominal
hysterectomy contain fibroids (many are quite small) and about
15-20% of hysterectomies performed in the USA are for problems
involving fibroids.
The role of uterine fibroids in reproduction is usually not clear.
If the fibroid is presenting (bulging) into the uterine cavity
(submucosal) then it may obstruct one of the fallopian tube entrances
or it may present a mechanical or other barrier to implantation.
If the fibroid replaces an entire wall of the uterus, then it
might interfere with the blood supply to the uterine structures
around it or an embryo implanting near it. If the fibroid is predominantly
on the outside of the uterus with projection into the pelvis and
abdomen then it may outgrow its own blood supply and become degenerate
or infected. Degenerating or infected fibroids may result in pain
and irritability (contractions) of the uterus that can be associated
with complications of pregnancy (preterm labor, severe pain).
Most fibroids do not seem to interfere with fertility and should
not be removed unless (a) a reproductive problem is identified
and (b) all other treatable causes for the reproductive problem
have been evaluated and excluded. An exception is the presence
of a large intrauterine filling defect seen on HSG, which should
be removed. Another exception is a fibroid compressing the fallopian
tubes or creating a tremendous distortion of the uterine cavity.
Endometrial polyps appear to be organized overgrowths of
the uterine endometrium, although the precise mechanisms leading
to their development are not clearly defined. The endometrial
lining of the uterine cavity grows in response to estrogen and
is architecturally restructured in response to progesterone. If
the response to estrogen is excessive, either in the presence
of unopposed estrogen (such as during periods of anovulation)
or whenever the bioactivity of the circulating estrogen is increased
(such as with increased numbers of estrogen receptors or with
decreased metabolism of estrogen) overgrowth of the endometrium
may occur. If these overgrowths organize and develop their own
blood supply then they become polyps.
The mere presence of polypoid overgrowths in the uterine cavity
may (at least theoretically) interfere with implantation and fertility.
I have envisioned polyps as acting sort of like IUDs in the cavity,
creating a hostile environment for embryo implantation. I remove
endometrial polyps in women with reproductive problems and these
women (anecdotally) seem to do remarkably well in subsequent fertility
efforts. A well designed research project describing fertility
outcome after treatment for different types of endometrial polyps
would be valuable.
Endometrial polyps are not always benign. I removed one normal
appearing endometrial polyp hysteroscopically and this was found
to contain an endometrial adenocarcinoma (cancer) on pathology
report. Therefore, in the presence of any atypical overgrowth
of tissue it is always important to think about the possibility
of cancer.
Ashermann's syndrome is the occlusion or obliteration of
the uterine cavity due to damage to the lining of the cavity (endometrium).
This is not common but is important to recognize it if indeed
present. When the endometrium is destroyed beyond a certain depth
(believed to be the basalis level which is the level that promotes
subsequent growth) in the context of hypoestrogenism (a low circulating
estrogen concentration) then permanent scar tissue can easily
form within the cavity. Clinical situations that increase the
chance of Ashermann's Syndrome include
- overzealous dilatation and curettage (especially for a missed
abortion, postpartum bleeding, or septic abortion),
- intrauterine surgery to remove fibroid tumors, uterine structural
defects (septum, bicornuate uterus, large polyps), or at cesarean
section
- infections related to IUD use (or the placement of any foreign
object within the uterine cavity),
- some uncommon infections of the uterus (such as intrauterine
tuberculosis or Schistosomiasis)
- radium insertion into the uterus for the treatment of gynecologic
cancers
The finding for Ashermann's Syndrome on hysterosalpingogram (HSG)
exam is intrauterine filling defects These are irregular areas
within the normally triangular shaped cavity where the distending
media is excluded due to the presence of the adhesions. Thin adhesions
may be primarily composed of fibroconnective tissue with little
blood supply. The thicker the adhesions, the greater the likelihood
that they are vascular and possibly also partially muscular. Vascular
and muscular adhesions are much more difficult to repair and seemingly
pose a greater problem for fertility.
Repair of intrauterine adhesions is most easily and safely performed
by hysteroscopy. Operating scissors can be used through some hysteroscopes
but tend to be a bit flimsy for any but very thin filmy adhesions.
A type of operating hysteroscope called a resectoscope allows
the surgeon to apply electrical current through a monopolar cutting
instrument attached as the operating element of the hysteroscope
and lysis (cutting) of the adhesions can then be performed. In
more complex cases of adhesions, repeated procedures may be required
to accomplish complete lysis of the adhesions. After each hysteroscopic
repair in which cautery is used or extensive lysis of adhesions
is accomplished, the patient is typically placed on higher dose
estrogen replacement (say, Premarin 1.25 or 2.5 mg by mouth each
day for 30-60 days, with a Provera withdrawal flow brought on
at the end of this time) to promote the regrowth of endometrium
(lining) over the repaired sites. Occasionally, a stent (such
as an IUD or pediatric foley balloon) is also placed within the
cavity to keep the sides of the uterus apart during the repair
period.
For mild to moderate adhesions, you might expect a 60-80% chance
of successful pregnancy after repair. For more extensive adhesions
the chance of a successful pregnancy is lower. If a pregnancy
does occur after repair of Ashermann's Syndrome there is a greater
chance of preterm labor and delivery (delivery of a premature
baby), placenta accreta (where the placenta invades the uterine
wall into the muscular component of the wall and becomes difficult
to impossible to remove) and postpartum hemorrhage (heavy bleeding
after the delivery of a baby).
(4) Abnormal cervical function
The cervix is very important in the development of a pregnancy.
The nonpregnant cervix is normally composed of a dense collagenous
fibroconnective tissue with small amounts of smooth muscle to
give it a tough texture. In pregnancy, the increased water content
and vascularity in the cervix leads to a softening and a blue
coloration. Throughout pregnancy the cervix and lower uterine
segment change but maintain a "functionally intact"
internal os.
If the internal os of the cervix dilates or effaces during pregnancy
this can be an ominous sign. In the beginning of pregnancy, cervical
dilatation with some bleeding is known as an "inevitable
abortion." In later pregnancy, cervical dilatation or effacement
associated with lower abdominal cramps or pressure is a sign of
labor (which is preterm if it occurs prior to 37 weeks gestation).
If there is painless dilatation or effacement of the cervix, usually
occurring between the mid second trimester (about 20 weeks gestation)
to the early third trimester (about 27-30 weeks), this is usually
the result of an incompetent cervix. Pregnancy losses at progressively
earlier gestational ages often reflect an incompetent cervix that
gives way earlier with each subsequent pregnancy. The fetal membranes
(chorionic and amniotic membranes) can sometimes be found bulging
from the open cervix and can indeed hourglass through the cervix
to fill the entire vaginal vault (which can be difficult to distinguish
from a fully dilated cervix).
The causes of cervical incompetence can be congenital or acquired
and include
- congenital abnormality in the composition of the cervix, with
a relative deficiency in the tougher collagenous fibroconnective
material or relative increase in concentration of the less tough
smooth muscle
- congenital hypoplasia (underdevelopment) of the cervix, such
as with in utero exposure to DES
- trauma to the cervix, such as with mechanical dilators for
dilatation and curettage (D+C), cervical conization or extensive
biopsy, and precipitous labors or cervical lacerations during
labor and delivery.
Establishing the diagnosis of cervical incompetence with certainty
can be difficult. Generally, a suggestive history of late painless
pregnancy losses with the history of a plausible cause is all
that is used to diagnose the condition. Additional testing sometimes
suggested to confirm the diagnosis (none of which have been widely
accepted) includes
- passing an 8 mm dilator into the nonpregnant uterus through
the internal os (an office procedure)
- a hysterosalpingogram (HSG) on the nonpregnant uterus to look
for funneling of the lower uterine segment and an open internal
os
- ultrasonography of especially the pregnant uterus looking
for shortening or dilatation of the cervix and bulging of the
fetal membranes
Treatment of an incompetent cervix is surgical. The cerclage is
an attempt to strengthen the cervix, with the two most commonly
used modern techniques having been developed in the 1950s by Drs.
Shirodkar and McDonald. These techniques involve the surgical
placement of a suture or Mersilene band around the cervix to hold
it closed. In appropriately selected women, the improvement of
pregnancy outcome with a cerclage is seemingly impressive. Generally,
80-90% of women with cervical incompetence as their cause for
recurrent pregnancy loss will deliver a viable live born following
cerclage placement.
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