Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:

1. Distinguish the most common types of uterine anomalies.

2. Identify the prevalence and impact of uterine anomalies on reproductive outcomes.

3. Develop evidence-based counseling and treatment recommendations.

Congenital Uterine Anomalies

Prevalence

The prevalence of congenital uterine anomalies (CUAs) is difficult to determine, because many women are asymptomatic and go undiagnosed. Typically, mullerian anomalies are not detected until issues of infertility or pregnancy maintenance arise. The prevalence of CUAs is approximately 4.3% in fertile asymptomatic women, 8% in infertile women, 12.3% in women with a history of spontaneous abortion, and 24.5% in women with spontaneous abortion and infertility.1,2 In women with recurrent first-trimester abortion, the prevalence of CUAs is 5% to 10%, and in women with late first-trimester or second-trimester loss, the prevalence of CUAs is 25%.3 The septate uterus is cited as the most common CUA, with a mean incidence of 35%, with bicornuate uterus being the second most common (25%), followed by arcuate uterus (18%), unicornuate uterus (10%), didelphys uterus (8%), and mullerian agenesis (3%).2 It should be noted that the relative prevalence of the septate uterus is most likely to be significantly underestimated in much of the literature. First, the external configuration of the uterus is normal, so many patients with a uterine septum are not diagnosed unless they have reproductive difficulties. Second, many would lump the septate and arcuate uterus together, the arcuate being basically a small septum. Finally, the term "bicornuate" is often used improperly in describing a septate uterus by those not entirely familiar with the proper nomenclature.

Pathogenesis

The mullerian ducts first begin to develop at 6 weeks of gestation. The ducts migrate medially where they meet and extend caudally. The cranial, unfused portions of the mullerian ducts develop into the fallopian tubes and fimbria, whereas the fused caudal portions form the uterus and upper vagina. The fused ducts are initially composed of solid tissue, which then undergoes internal canalization to produce 2 channels divided by a septum. This septum is then absorbed in the caudal to cephalad direction by 20 weeks' gestation. CUAs can generally be categorized according to the etiology of the abnormal development including defective lateral fusion or resorption, defective vertical fusion, and agenesis/failure of descent.4 Chromosomal analysis of women with CUAs shows that their karyotype is normal 92% of the time.

The bicornuate uterus is a lateral fusion defect resulting from incomplete fusion of the 2 mullerian ducts leading to varying degrees of separation between the 2 uterine cavities. Malformations can range from mild to severe, with the mildest form resulting in a minimal indentation at the uterine fundus and the most severe form resulting in an external separation of the uterine horns to the level as low as the lower uterine segment or even the upper cervix.5

The uterus didelphys is the most extreme form of a lateral fusion defect in that the uterine horns are completely unfused. The septate uterus results from failure of resorption of a uterine septum, after lateral fusion of the mullerian ducts occurred normally. This failure of resorption can be complete (continuous from the fundus to the external cervical os), or incomplete with a central caudal cavity divided cephalad into 2 upper compartments by the uterine septum.5 Defective vertical fusion result in a transverse uterine septum. Some also include an imperforate hymen in this group, but this defect is generally considered a failure of resorption rather than absence of fusion. Failure of growth or descent results in uterine agenesis when complete or a unicornuate uterus when unilateral. These categories of CUAs will not be discussed in this review.

Women with CUAs are at increased risk of other congenital abnormalities, most notably renal defects, which are found in 20% to 30% of women with mullerian defects. Skeletal and abdominal wall abnormalities are also fairly common. Interestingly, ovarian abnormalities are rarely found in conjunction with CUAs.

Diagnosis

Most CUAs are discovered during the evaluation of recurrent miscarriage, early pregnancy loss, or infertility. Others may be found incidentally during the evaluation of a different gynecologic symptom, or when imaging studies are performed for a completely unrelated problem such as trauma. CUAs are less commonly suspected and diagnosed when symptoms such as primary amenorrhea or physical findings such as a longitudinal vaginal septum are present.

Transabdominal and/or transvaginal ultrasound are typically the first imaging study performed due to convenience and cost. This technique can often provide information on uterine contour, ovarian status, and urinary tract anatomy including kidneys. Three-dimensional (3D) ultrasound is often more accurate than standard ultrasound in the assessment of uterine abnormalities. The main advantage of this technique is the ability to describe uterine anomalies in quantitative terms, accurately quantifying the depth of indentation.6 This modality often allows for definition of the uterus and surrounding anatomy, and often offers a reliable method to differentiate similar internal anomalies with variable external appearance, such as bicornuate and septate uterus.7 MRI is the diagnostic method of choice for women with CUAs, particularly in the case of vaginal and/or obstructive lesions. MRI is not necessary for detection of all uterine anomalies-differentiation of bicornuate versus septate uterus is often possible with just ultrasound-but may be critical for patients with more complex disorders and those at higher risk of associated anomalies.7

Hysterosalpingography (HSG) is an excellent method to evaluate the impact of the anomaly on the uterine cavity, but does not allow differentiation between septate and bicornuate uteri. Indeed, efforts to differentiate these 2 anomalies on HSG were shown in one study to be correct in only 55% of bicornuate uteri.8 Definitive diagnosis is made by endoscopic imaging, typically laparoscopy plus hysteroscopy. It is critical to note that women with any lateral fusion or resorption defect can be found to have 2 cervices on physical examination. Although it is true that all women with complete absence of lateral fusion (ie, a uterus didelphys) have 2 cervices, the majority of women with 2 cervices have a septate uterus (bicollis). This can be explained by the dramatically higher prevalence of septate as opposed to didelphic or bicornuate uteri.

Pregnancy Complications/Obstetric Outcomes

Infertility

Studies examining pregnancy rates using assisted reproductive technology in infertile women with untreated CUAs revealed significantly lower implantation and pregnancy rates as compared with infertile women without CUAs.5 There are data to support optimization of the uterine cavity and restoration of normal uterine anatomy before the use of assisted reproductive technology. Infertility in patients with bicornuate and septate uteri may be associated with abnormalities in the later vascular stages of implantation. The uterine septum in particular is felt to represent a location with altered endometrial vascularization indicating an impaired vascular bed, leading to faulty implantation and embryo maintenance. In septate uteri, alterations in septal endometrium obtained from the preovulatory phase, as compared with endometrium from the lateral uterine wall, include irregular distribution of glandular ostia, incomplete ciliogenesis, and reduced ciliated cell ratio.9 These findings indicate incomplete differentiation and maturation of septal endometrium, which could also play a role in the pathogenesis of primary infertility in women with septate uteri.

Spontaneous Abortion

Despite minor effects on fertility, it appears that the reproductive challenges of women with bicornuate and septate uteri mainly lie in pregnancy maintenance rather than conception.5 Women with septate or bicornuate uterus have a significantly increased risk of both first and second-trimester spontaneous abortions as compared with controls.7 It appears that the greater the degree to which the uterine cavity is deformed, the more pronounced is the effect on pregnancy maintenance.

Recurrent Pregnancy Loss

The prevalence of major CUAs is 3-fold higher in women with a history of recurrent pregnancy loss (RPL) compared with controls, indicating that CUAs may be responsible for pregnancy loss in a small proportion of women with recurrent miscarriages.10 The most common uterine anomaly associated with RPL is the septate uterus, which is usually attributed to the relative avascularity of the septum, providing inadequate blood supply to the developing embryo.1,10,11 The likelihood of septal implantation increases with increasing ratio of septal size to functional cavity.10 It is important to note that although small septa are less likely to lead to RPL than large septa, they share the abnormal vascularity and fibrous nature of the large septum, and can present with abnormal implantation and spontaneous abortion. Pregnancy loss in women with septate uterus typically occurs between 8 and 16 weeks, due to jeopardized implantation dynamics.12

Preterm Delivery

The incidence of preterm labor and delivery is increased with both bicornuate and septate uteri. Overall term delivery rates in women diagnosed with bicornuate or septate uterus are estimated to be 40%.7 Additionally, perinatal mortality seems to be almost 2.5 times higher in women with CUAs as compared to controls.7 In establishing the risk for any given patient, it is critical to appreciate that women with septate uterus who have not had reproductive problems will often go undiagnosed. The effect of this observation is to overestimate the impact of a septum on prematurity, but the extent of this effect is not known. Many experts recommend that the obstetrician digitally evaluate the uterine cavity at the time of a premature delivery because these patients are at increased risk of a septum, which may have gone undiagnosed.

Intrauterine Growth Restriction

Intrauterine growth restriction (IUGR) has been associated with anomalous vasculature accompanying mullerian anomalies. Due to compromise in uteroplacental blood flow, fetal nutrition is impaired, leading to diminished fetal size. In a study by Leible et al,13 uterine artery blood flow velocity was abnormal in 80% of pregnant women with mullerian anomalies, as compared with 10% in controls. Women with CUAs had higher systolic/diastolic ratios in the uterine artery, indicating possible abnormal flow to the placenta. Additionally, gestational capacity is thought to be compromised in both bicornuate and septate uteri. Rates of IUGR are increased due to decreased size, lack of full complement of uterine musculature, and abnormal vasculature.7

Fetal Malpresentation, Cesarean Delivery

Uterine anomalies are associated with an increased incidence of breech presentation, increasing the incidence of cesarean delivery. It seems that septate and bicornuate uteri are more commonly associated with fetal malpresentation than other uterine anomalies. This may be due to a smaller uterine cavity, which may inhibit fetal movement. The presence of a longitudinal vaginal septum, which is associated with both lateral fusion and resorption defects, is a relative contraindication to vaginal delivery.

Uterine Rupture

It is hypothesized that the myometrium of a congenitally abnormal uterus is thinner than a normal uterus. Additionally, the mural thickness diminishes as gestation advances and additional wall thinning can occur during uterine contraction, increasing the risk of uterine rupture.14

Cervical Insufficiency

Researchers have postulated that there is an abnormal ratio of muscle fibers to connective tissue in a congenitally abnormal cervix. During pregnancy, an inadequate uterine volume may lead to increased intrauterine pressure and increased stress on the lower uterine segment, which in turn can lead to cervical incompetence. Women with a bicornuate uterus have an increased rate of cervical insufficiency as compared with controls (odds ratio, 6.98; P < 0.001).15

Treatment

Hysteroscopic Metroplasty

The septate uterus is the most treatable of all mullerian malformations. Hysteroscopic techniques have a very high rate of success in correcting the uterine cavity in cases of septate uterus and also in some cases of minimally bicornuate uterus. Hysteroscopic metroplasty (resection of the intrauterine septum) is associated with a significant decrease in spontaneous abortion and preterm delivery rates. Term delivery and live birth rates have been shown to increase with metroplasty as well.2 Women who have undergone hysteroscopic septum resection seem to have normal prognoses for their pregnancies, with term delivery rates of 75% and live birth rates of 85%.2 Reuter et al8 found a substantial increase in live birth rates from 7% to 73%, pre- and post-hysteroscopic metroplasty in women with a history of RPL due to uterine septum. It is worth noting that the term "resection" in this context is a misnomer. In virtually all cases, the septum is simply incised transversely from the most caudal tip to the top of the uterine cavity. The incised septum then retracts and the raw area is re-epithelialized in approximately 6 weeks. Most surgeons do not insert an intrauterine balloon after metroplasty for a septate uterus. Postoperative estrogen treatment for 4 to 6 weeks is usually recommended.

Septum resection can be used as both a therapeutic procedure in symptomatic patients and a prophylactic procedure in asymptomatic patients. It is recommended for patients with a history of recurrent losses, abnormal presentation, or preterm deliveries due to uterine septum. Resection of the cervical septum (if present) during hysteroscopic metroplasty of the uterine septum has been recommended by some.16 This procedure is certainly less complicated than preservation of the intracervical portion of the septum, but data to date are insufficient to confirm which approach provides a better outcome.

Multiple studies have investigated the outcome of hysteroscopic metroplasty in women with septate uterus and otherwise unexplained infertility and have found it to be beneficial for infertile patients. Additionally, multiple studies have shown that hysteroscopic correction of even a modest-sized septum decreases the incidence of pregnancy loss and in vitro fertilization (IVF) failure in IVF pregnancies.17,18 Optimization of the uterine cavity is strongly recommended before initiating assisted reproductive technology due to expense of treatment and minimization of adverse obstetric outcomes once pregnancy is achieved.

Although surgical treatment of the uterine septum is widely accepted, timing of treatment remains controversial. If a uterine septum is incidentally detected before attempted child-bearing, it is debatable whether the septum should be removed prophylactically before attempting conception.19 Absence of prospective, randomized, controlled studies reporting on patients with symptomatic but untreated septate uterus limits the evaluation of this outcome, and warrants further research. The uncertainty surrounding the decision to resect the uterine septum could theoretically lead to unnecessary surgery, posing unnecessary risk and financial burden.20 New diagnostic modalities are being used to correctly define the diagnosis and treatment of a septate uterus. Lastly, it is important to note that anatomic correction can be effective in some cases; however, in others, abnormal uterine vascularization, myometrial thickness, and cervical function may remain abnormal and prevent a functional outcome.

Strassman Procedure

The Strassman procedure is used to reconstruct the bicornuate uterus, creating a single uterine cavity. Unification metroplasty has been shown to decrease fetal loss, prolong gestation, and improve live birth rates. It can be useful in patients with repeated spontaneous abortions when no other obvious etiology can be found.21 A cesarean delivery with a low transverse incision is recommended after uterine reconstruction.

Cerclage

The role of cervical cerclage is not certain in the prevention of preterm delivery except when there is documented cervical insufficiency by imaging and a history of preterm delivery.22 No doubt exists as to the need for cerclage in cases of cervical incompetence, but it also shows promise as prophylactic treatment in some women with bicornuate uterus. A study by Golan et al23 demonstrated that term deliveries increased from 64% to 96%, and premature pregnancy termination dropped from 35.6% to 4%, after cerclage. A study by Yassaee and Mostafaee22 demonstrated that in patients with bicornuate uterus and cervical cerclage, term delivery occurred in 76.2% of patients. Without cerclage, term delivery occurred in only 27.3%. A study by Acien et al3 was performed using limited prophylactic cervical cerclage in patients with bicornuate uteri and demonstrated that fetal survival improved from 21% to 62%.

Conclusion

Although the impact of uterine anomalies on infertility is unclear, it is apparent that women with uterine malformations have impaired pregnancy outcomes as compared with women without uterine malformations.2 The 3 main etiologies thought to explain these adverse outcomes are diminished muscle mass, abnormal uterine blood flow, and cervical insufficiency. Possible obstetric complications include spontaneous abortion, RPL, preterm delivery, IUGR, cervical insufficiency, fetal malpresentation, and uterine rupture.7 Women with resorption defects of the uterus (septate, subseptate) are more likely to present with reduced fertility and increased rate of spontaneous abortion and preterm delivery. These effects are most pronounced in septate uteri. Lateral fusion defects (bicornuate uterus) do not seem to reduce fertility potential, but are associated with spontaneous abortion and preterm delivery. All uterine anomalies increase the risk of fetal malpresentation at delivery.10 Obstetric outcomes are generally reported to be better in cases of bicornuate uterus than in unicornuate uterus, possibly due to significant variation in bicornuate uterine anatomy and ranges in severity of malformation. Hysteroscopic metroplasty has been shown to be effective in decreasing adverse outcomes in septate uteri. The Strassman metroplasty and cervical cerclage are treatment modalities that have been shown to improve obstetric outcomes in women with bicornuate uterus.

Practice Pearls

* The septate uterus is the most common CUA, followed by the bicornuate, unicornuate, and didelphys uterus.

* Women with CUAs are at increased risk of other congenital abnormalities, such as skeletal, renal, and abdominal wall abnormalities.

* Transvaginal and transabdominal ultrasound can be used to provide information on uterine contour, evaluation of the kidneys, and confirmation of the presence of ovaries.

* 3D ultrasound and MRI are able to accurately differentiate between the bicornuate and septate uterus.

* Women with septate or bicornuate uterus are at increased risk of the following obstetric complications: spontaneous abortion, RPL, preterm delivery, IUGR, cervical insufficiency, and fetal malpresentation.

* Hysteroscopic metroplasty is effective in decreasing adverse outcomes in women with septate uterus.

* The Strassman metroplasty and cervical cerclage are treatment modalities that have been shown to improve obstetric outcomes in women with bicornuate uterus.

REFERENCES