Anatomic Factors in Recurrent Pregnancy Loss

Anne S. Devi Wold, MD; Norma Pham, MD; Aydin Arici, MD

Disclosures

Semin Reprod Med. 2006;24(1):25-32. 

In This Article

Congenital Uterine Anomalies

The true incidence of congenital uterine anomalies in the general population and among women with RPL is not known accurately. Although incidences of 0.16 to 10% have been reported, the overall data suggest an incidence of 1% in the general population and 3% in women with RPL and poor reproductive outcomes.[3,5,6,7,8,9] In a comparative study of women with and without a history of RPL using three-dimensional ultrasound, Salim et al found major congenial anomalies in 6.9% of women with RPL compared with 1.7% in low-risk women.[4] Overall, the prevalence of major congenital anomalies appears to be three-fold higher in women with RPL compared with women without a history of recurrent miscarriage.

Many nonobstructing uterine abnormalities are asymptomatic and may be discovered only in the evaluation of RPL, persistent menstrual irregularities, or infertility.[8] Additional complicating matters include the lack of uniform imaging modalities for diagnosis.

Müllerian Development

Sexual differentiation begins early in the fetal period. Up until the sixth week of life the male and female genital systems are identical. There are two pairs of symmetrical genital ducts, the mesonephric (Wolffian) duct and the paramesonephric (müllerian) ducts. The müllerian ducts arise as coelomic invaginations in the mesonephros, and their formation is thought to be induced by the mesonephric duct. In the female embryo, in the absence of fetal testes, testosterone, and müllerian-inhibiting substance, the Wolffian ducts begin to degenerate and allow for the maturation of the müllerian ducts. The müllerian ducts grow caudally and become enclosed in peritoneal folds that later give rise to the broad ligaments of the uterus, to which the ovaries (mesovarium), fallopian tubes (mesosalpinx), and uterus (mesometrium) are attached. The müllerian ducts approach each other and begin to fuse. At 9 weeks gestation, the septum from the fused ducts begin to resorb, forming a tube with a single lumen called the uterovaginal canal. This becomes the uterus and upper portion of the vagina, whereas the unfused cranial portions of the müllerian ducts become the fallopian tubes. The lower portion of the vagina is formed from the sinovaginal bulb of the urogenital sinus. The uterovaginal canal elongates to eventually unite with the urogenital sinus, thus forming the completion of the female reproductive tract.[1011]

Müllerian tract anomalies result from failure to complete bilateral duct elongation, fusion, canalization, or septal resorption of the müllerian ducts. They may occur in any step during this developmental process. The etiologies of such disorders are still widely unknown.

Classification

In an effort to describe the diverse müllerian anomalies encountered, Buttram and Gibbons[12] in 1979 grouped the anomalies according to their clinical morphology. This was later modified in 1988 by the American Fertility Society (currently known as the America Society for Reproductive Medicine) and is now the most commonly accepted means of characterizing müllerian tract defects (Fig. 1).[13]

Figure 1.

The American Society for Reproductive Medicine classification of müllerian anomalies. *Uterus may be normal or take a variety of abnormal forms. **May have two distinct cervices. DES, diethylstilbestrol. (From Anonymous. The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, müllerian anomalies and intrauterine adhesions. Fertil Steril 1988;49(6):944–955.

  • Class I: Müllerian agenesis or hypoplasia

  • Class II: Unicornuate uterus

  • Class III: Didelphys uterus

  • Class IV: Bicornuate uterus

  • Class V: Septate uterus

  • Class VI: Arcuate uterus

  • Class VII: Diethylstilbestrol (DES)-exposed uterus

Uterine Septum

The septate uterus is a result of absent or incomplete resorption of the intervening uterovaginal septum following fusion of the müllerian ducts. It is the most common congenital anomaly of the uterus, comprising approximately 55% of all anomalies.[14] A septum is primarily composed of fibromuscular tissue that may project minimally from the uterine fundus or may extend to the cervical os, almost completely dividing the uterine cavity in two. Septa also may be segmental, resulting in partial communications between the two sides.[6]

Septate uteri have some of the poorest reproductive outcomes of müllerian duct anomalies.[3,4] The spontaneous abortion rate is high, averaging approximately 65% of pregnancies in some studies.[15] Raga et al[3] reported a 25.5% incidence of early miscarriage (< 13 weeks) and a 6.2% incidence of late miscarriage (14 to 22 weeks) in women with septate uterus. Premature birth rates are increased at approximately 21% and fetal survival rates are estimated at 32%.[3,7,14,16,17,18] The mechanism by which the septate uterus causes pregnancy loss in not clearly understood. The conventional view is that the septum is rather avascular and this lack of vascularization may compromise decidual and placental growth. Also proposed is the idea that a uterine septum may impair fetal growth as a result of reduced endometrial capacity or a distorted endometrial cavity, and therefore result in second-trimester miscarriage and premature labor.[15]

Fedele et al[19] used scanning electron microscopy to compare endometrial biopsy specimens obtained from the septum and the lateral uterine wall in the preovulatory phase. They found that the septal endometrium showed defective development, indicative of a reduction in sensitivity to steroid hormones. This suggests that there may be local defects that interrupt normal early embryo development after implantation, resulting in first-trimester miscarriage.

Surgical intervention should be considered when a septate uterus is found in association with adverse reproductive outcome. Most studies evaluating the efficacy of metroplasty are observational, retrospective, and include small sample sizes, and therefore are not ideal. However, they seem to indicate that reproductive outcomes are improved after hysteroscopic resection. Fedele et al[20] evaluated the reproductive outcome after hysteroscopic metroplasty in 31 women with infertility and 71 women with miscarriage, and reported a cumulative pregnancy rate of 89% at 36 months for patients with complete septum and 80% for those with partial septum. The overall miscarriage rate was 15%. Homer et al[6] reviewed the reproductive outcome before and after hysteroscopic metroplasty in published series and showed a dramatic decrease in the overall miscarriage rate from 88% to approximately 15% after surgery.[21,22]

Hysteroscopic septal incision is now the preferred method for treatment of the septate uterus.[6] The technique involves incision of the septum between the anterior and posterior uterine walls extending up to the fundus but not into the fundal myometrium. Hysteroscopic septal incision can be performed using microscissors, electrosurgery, or fiberoptic laser energy. A theoretical advantage of scissors over electrosurgery or laser is that there is no risk of thermal myometrial vascular damage, which may predispose to intrauterine synechiae. Thick septa, however, may be easier to incise with an electrical technique than with the scissors.[23] In addition, hemostasis is easily achieved at the same time with use of coagulation current. Although lasers have the advantage of speed and good hemostasis, they are expensive and usually more difficult to manipulate.[24] Transabdominal metroplasty has been used in the past but has been abandoned because of the higher risk of complications, including postoperative reduction of intrauterine volume, formation of intrauterine and pelvic adhesions, and tubal occlusion.[6]

Laparoscopic guidance frequently is used during hysteroscopic metroplasty to reduce the risk of uterine perforation. It also allows the surgeon to differentiate accurately between a septate and bicornuate uterus. Ultrasonographic guidance has been suggested for difficult cases where laparoscopy is contraindicated.[6,25]

Unicornuate Uterus

Agenesis or hypoplasia of one of the müllerian ducts results in the unicornuate uterus arising in approximately 20% of uterine anomalies.[14] There are many variations of this anomaly. The functional uterus may exist alone or may be accompanied by a rudimentary uterine horn. The rudimentary horn, in turn, may be categorized into groups based on the presence or absence of a cavity. Further classification is determined by whether or not the uterine horn communicates with the fully differentiated uterus. If a rudimentary horn is present with a cavity, the patient may present with unilateral cyclical pelvic pain secondary to hematometra. Associated renal anomalies occur in 40% of patients (higher than in any other class), and are usually ipsilateral to the hypoplastic horn.[26]

Spontaneous abortion rates in these women approach 51%, premature birth rates approach 15%, and fetal survival is estimated at 39%.[15] Other pregnancy complications include malpresentation, IUGR, uterine rupture, and ectopic pregnancies.[27,28] The pathogenesis of pregnancy loss appears to be related to reduced intraluminal volume and/or inadequate vascular supply to the developing fetus and placenta.[29] There are no surgical procedures to enlarge the uterus. The higher prevalence of cervical incompetence in uterine anomalies, however, has led some authors to recommend that cervical cerclage be placed to improve obstetrical outcome.[28,30] These are mostly anecdotal reports and small case series and they report some improvement in obstetrical outcome. However, there are no studies addressing the prophylactic and empirical use of cervical cerclage. Therefore, based on the current available evidence, women with a unicornuate uterus and no previous history of second-trimester loss or premature birth should be managed expectantly with frequent assessment of cervical length and anatomy. It is recommended that unicornuate uteri with rudimentary horns be resected because of dysmenorrhea and hematometra as well as the potential for ectopic pregnancy and uterine rupture.[28,30]

Uterus Didelphys

In this condition, there is nonobstructed failure of lateral fusion involving both the uterus and vagina. This results in the formation of a double uterus, double cervix, and double vagina. Uterus didelphys is one of the least common anomalies, representing approximately 5 to 7% of müllerian defects.[14] The reproductive outcomes are slightly better than those of women with unicornuate uterus. The spontaneous abortion rates are estimated at 43%, the premature birth rate is approximately 38%, and the fetal survival rate is approximately 54%.[28,31]

The benefits of surgical intervention are unclear. The septated vagina may cause difficulty with sexual intercourse or vaginal delivery. Resection of the vaginal septum may be necessary in symptomatic women. The recommended surgical technique to unify the uterus is the method of Strassman.[32] The procedure leaves the double cervix intact and unifies the fundus. It involves a fundal transverse incision that extends from one cornua to the other, exposing the uterine cavities. This is followed by vertical closure, which often brings both cornua together. In one report, eight patients with uterus didelphys and recurrent abortion underwent Strassman metroplasty.[33] Four of the five patients with follow-up information had living children postoperatively. Because there are only anecdotal reports and no randomized studies, surgical metroplasty should be reserved, on a case-by-case basis, for selected patients who suffer from RPL or premature births.[15]

Bicornuate Uterus

This anomaly is a result of incomplete fusion of the uterine horns at the level of the fundus. The distinguishing aspect of this anomaly is the presence of two separate but communicating endometrial cavities and a single cervix. It represents 10% of müllerian duct anomalies. The external uterus has a sagittal cleft of variable length. The cleft extends to the internal cervical os in the complete bicornuate and to a lesser degree in the partial bicornuate uteri. The degree of incomplete müllerian fusion appears to affect reproductive outcome. Heinonen et al[28] reported a 29% incidence of preterm delivery in women with a partial bicornuate uterus and a 66% incidence of preterm delivery in women with complete bicornuate uterus. Overall, the spontaneous abortion rate is approximately 32%, the premature birth rate is approximately 21%, and the fetal survival rate is approximately 60%.[15,28,34] As with the uterus didelphys, surgical intervention with the Strassman metroplasty is most often reserved for selected patients with RPL or premature births.

Arcuate Uterus

The near-complete resorption of the uterovaginal septum may leave a mild concave indentation of the endometrial cavity at the level of the fundus, giving the uterus an arcuate configuration. It is not clear if this configuration represents a true anomaly or an anatomic variant. Reproductive outcome data in this condition are conflicting and both positive and negative outcomes have been reported.[14] In a retrospective case series of 176 patients, Acien[35] reported a 45% early abortion rate in women with arcuate uterus. In contrast, Raga et al[3] in their series noted only a 13% early miscarriage rate in women with this anomaly. Treatment is usually expectant.

DES Exposure

DES is an orally active synthetic estrogen that was introduced in the 1940s for the treatment of RPL, premature delivery, and other complications of pregnancy. Uterine abnormalities are common and appear to occur in 69% of women exposed to DES in utero.[36] The most common abnormality is a T-shaped uterine cavity (70%). Other abnormalities include a small uterus, constriction rings, and intrauterine filling defects. In addition, 44% of the women have structural changes in the cervix including an anterior cervical ridge, cervical collar, cervical hypoplasia, and pseudopolyps. The use of DES in pregnancy was banned in 1971.[37] Women with a history of in utero exposure to DES appear to have a greater risk of adverse pregnancy outcome, including a two-fold increased risk of spontaneous abortion (24% in DES-exposed women versus 13% in controls) and a nine-fold increase in ectopic pregnancy rates (5% in DES-exposed women compared with 0.5% in controls).[38]

Women with in utero exposure to DES are predisposed to cervical incompetence. In one nonrandomized study, 63 women with in utero DES exposure were treated with prophylactic cerclage or expectant management. Eighty-eight percent of women who received cerclage delivered at term compared with 70% who did not receive a cerclage.[39] Prophylactic cerclage may be beneficial to DES-exposed women with history of second-trimester loss or preterm delivery.[15]

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