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.