*6.1.1 Congenital Müllerian duct anomalies*

Congenital uterine anomalies (CUA) arise from defects along any stage of the Müller duct development process during embryonic development, whether in formation, fusion, or reabsorption. The frequency of CUA has been reported between 1.8 and 37.6% in women with a history of RLP. This variation is due to the different diagnostic methods and criteria [37]. Septate uterus is the most common anomaly in patients with a history of abortion. Arched, septate, and bicornuate uterus account for up to 85% of anomalies [38].

In a meta-analysis it was observed that patients with septate or bicornuate uterus had a higher rate of miscarriage in the first and second trimester than a control group [39]. In another meta-analysis, the evaluation of uterine abnormality subtypes resulting from fusion defect showed that women with unicornuate and bicornuate uterus were more likely to have first-trimester abortion compared to those with normal uterus [40].

ASRM's original classification system for congenital uterine anomalies has been modified and adapted and is still the most widely used today [41]. In 2012, ESHRE/ ESGE published a classification system aiming to replace the subjective criteria of ASRM's classification by the absolute morphometric criteria [42]. Based on this classification, up to 58% of women previously diagnosed with ASRM arched uterus would be reclassified as having a partial septate uterus. There would be a potential increase in the number of surgical corrections for uterine anomaly, without any evidence showing that such a practice would be beneficial [43]. Therefore, caution is needed in using this new classification until further prospective, randomized,

controlled, long-term studies are available to associate the severity of uterine cavity distortion with reproductive results.

Given the suspicion, it is necessary to use diagnostic methods that can clearly visualize the external contour of the uterus and endometrial cavity. Both 3D ultrasound with inversion mode (3D US) and magnetic resonance imaging (MRI) can be used for this purpose, with good correlation between them [44]. The disadvantages of MRI are that it is a more expensive and less available method than ultrasound.

In a comparative study of different diagnostic modalities, higher accuracy of 3D hysterosonography compared with 3D US and 2D hysterosonography was observed, although the differences between these imaging techniques did not reach statistical significance in the diagnosis of arched, bicornuate, and septate uterus [45].

The uterine septum is the most common abnormality related to RPL [36] and the only remediable one. Despite the lack of randomized and controlled prospective studies comparing surgery to expectant treatment, limited studies indicate that hysteroscopy septal resection is associated with a reduction in subsequent abortion rates and an improvement in live birth rates in patients with RPL [41]. After hysteroscopic resection of the septum, an interval of at least 2 months should be expected for complete healing of the endometrial cavity before a new pregnancy [41].

In general, CUA may be associated with renal abnormalities in approximately 11–30% of individuals [41]; for this reason there is a need for urinary tract investigation in these cases.

### *6.1.2 Cervical incompetence*

Cervical incompetence (CI) is the inability of the cervix to keep the intrauterine fetus in the absence of uterine contractions or labor (painless cervical dilatation) due to a functional or structural defect. It is a recognized cause of RPL in the second trimester, but the true incidence is unknown, as the diagnosis is essentially clinical [2].

The CI can be congenital or acquired. The most common congenital cause is a defect in the embryological development of the Müllerian ducts. The most common acquired cause is cervical trauma, such as cervical lacerations during childbirth, cervical conization, or forced cervical dilation during uterine procedures [46].

The diagnosis is usually based on a history of miscarriage in the second trimester, preceded by spontaneous rupture of membranes or painless cervical dilation. There are currently no objective tests capable of identifying women with cervical weakness in the nonpregnant state [2].

Transvaginal ultrasound may be used in at-risk patients during pregnancy. CI might be suspected when there is a short cervical length, less than or equal to 25 mm, or funneling, protrusion of the membrane into a dilated internal orifice but with closed external orifice [46].

Many surgical and nonsurgical modalities have been proposed to treat cervical incompetence. Among nonsurgical activities, restriction of activities and bed rest were not effective in the treatment of cervical incompetence. Its isolated use is discouraged. The use of vaginal pessary is another option, but the evidence is still limited. Surgical approaches include transvaginal and transabdominal cervical cerclage [46].

### **6.2 Acquired anatomical factors**

Acquired anatomical factors commonly associated with RPL include uterine fibroids, endometrial polyps, and uterine synechiae. They usually develop after puberty due to physical or hormonal stimuli and are present in about 12% of patients with RPL [47].

**167**

*Recurrent Pregnancy Loss: Investigations and Interventions*

Fibroid is reported in 8,2% of women with RPL [48]. Submucosal fibroids deform the endometrial cavity, thus affecting implantation and embryonic development [47]. Hysteroscopy is considered the gold standard for the diagnosis of submucosal fibroids, but this pathology can be identified through other imaging exams, such as ultrasound mapping [2]. The evaluation of the uterine cavity is strongly recommended for all women with RPL, since the removal of submucosal fibroids in infertile patients seems to reduce the chance of miscarriage [2, 49]. Regarding fibroids that do not distort the uterine cavity, there is no evidence indicating that myomectomy may reduce the chances of an abortion [2, 49].

There seems to be a higher prevalence of endometrial polyps in women with gestational loss (2.4%), but with no well-defined clinical importance [2, 47]. Hysteroscopy is considered the gold standard exam for the diagnosis and treatment of endometrial polyps but can also be identified through other imaging exams, such as ultrasound with color Doppler [2]. Although there is no evidence of the benefit of polypectomy in women with RPL, hysteroscopic removal should be considered when the polyp is larger than 1 cm when no other known etiology is found [2, 47]. ASRM reports that research for uterine polyps in women with gestational loss is controversial as there is no conclusive evidence that surgical treatment reduces the risk of

The prevalence of uterine synechiae ranges from 0.5 to 28% in patients with RPL [47]. Women with RPL are more likely to have uterine synechiae as they often undergo curettage or manual vacuum aspiration. The probable pathophysiology of abortion occurs due to a reduction in the amount of functional endometrium which may interfere with the invasion and normal development of the placenta [47]. The gold standard exam for the diagnosis of synechiae is hysteroscopy and should be the exam of choice in the cases of suspicion [2]. ESHRE concludes that there is insufficient evidence to recommend adhesiolysis in women with RPL as there are only small observational studies. ESHRE reinforces that treatment should focus on preventing recurrence of adhesions [2, 3]. However, ASRM points out that surgical correction of significant uterine cavity defects should be considered [3]. Nonsurgical experimental techniques for the treatment of uterine synechiae and endometrial fibrosis, such as stem cell therapy, should be further studied before

Hormones play a key role in placentation, and their changes may result in the

It is a condition of insufficient exposure to progesterone to maintain a secretory endometrium that will lead to normal embryo implantation and growth [50]. The

*DOI: http://dx.doi.org/10.5772/intechopen.89590*

*6.2.1 Uterine fibroids*

*6.2.2 Uterine polyps*

gestational loss [49].

*6.2.3 Uterine synechiae/Asherman syndrome*

being indicated in clinical practice [2].

**7. Endocrine factors**

risk of miscarriage [2].

**7.1 Luteal phase insufficiency**

## *6.2.1 Uterine fibroids*

*Innovations in Assisted Reproduction Technology*

distortion with reproductive results.

gation in these cases.

*6.1.2 Cervical incompetence*

weakness in the nonpregnant state [2].

with closed external orifice [46].

**6.2 Acquired anatomical factors**

patients with RPL [47].

controlled, long-term studies are available to associate the severity of uterine cavity

Given the suspicion, it is necessary to use diagnostic methods that can clearly visualize the external contour of the uterus and endometrial cavity. Both 3D ultrasound with inversion mode (3D US) and magnetic resonance imaging (MRI) can be used for this purpose, with good correlation between them [44]. The disadvantages of MRI are that it is a more expensive and less available method than ultrasound. In a comparative study of different diagnostic modalities, higher accuracy of 3D hysterosonography compared with 3D US and 2D hysterosonography was observed, although the differences between these imaging techniques did not reach statistical

significance in the diagnosis of arched, bicornuate, and septate uterus [45].

The uterine septum is the most common abnormality related to RPL [36] and the only remediable one. Despite the lack of randomized and controlled prospective studies comparing surgery to expectant treatment, limited studies indicate that hysteroscopy septal resection is associated with a reduction in subsequent abortion rates and an improvement in live birth rates in patients with RPL [41]. After hysteroscopic resection of the septum, an interval of at least 2 months should be expected for complete healing of the endometrial cavity before a new pregnancy [41].

In general, CUA may be associated with renal abnormalities in approximately 11–30% of individuals [41]; for this reason there is a need for urinary tract investi-

Cervical incompetence (CI) is the inability of the cervix to keep the intrauterine fetus in the absence of uterine contractions or labor (painless cervical dilatation) due to a functional or structural defect. It is a recognized cause of RPL in the second trimester, but the true incidence is unknown, as the diagnosis is essentially clinical [2]. The CI can be congenital or acquired. The most common congenital cause is a defect in the embryological development of the Müllerian ducts. The most common acquired cause is cervical trauma, such as cervical lacerations during childbirth, cervical conization, or forced cervical dilation during uterine procedures [46]. The diagnosis is usually based on a history of miscarriage in the second trimester, preceded by spontaneous rupture of membranes or painless cervical dilation. There are currently no objective tests capable of identifying women with cervical

Transvaginal ultrasound may be used in at-risk patients during pregnancy. CI might be suspected when there is a short cervical length, less than or equal to 25 mm, or funneling, protrusion of the membrane into a dilated internal orifice but

Many surgical and nonsurgical modalities have been proposed to treat cervical incompetence. Among nonsurgical activities, restriction of activities and bed rest were not effective in the treatment of cervical incompetence. Its isolated use is discouraged. The use of vaginal pessary is another option, but the evidence is still limited. Surgical

Acquired anatomical factors commonly associated with RPL include uterine fibroids, endometrial polyps, and uterine synechiae. They usually develop after puberty due to physical or hormonal stimuli and are present in about 12% of

approaches include transvaginal and transabdominal cervical cerclage [46].

**166**

Fibroid is reported in 8,2% of women with RPL [48]. Submucosal fibroids deform the endometrial cavity, thus affecting implantation and embryonic development [47]. Hysteroscopy is considered the gold standard for the diagnosis of submucosal fibroids, but this pathology can be identified through other imaging exams, such as ultrasound mapping [2]. The evaluation of the uterine cavity is strongly recommended for all women with RPL, since the removal of submucosal fibroids in infertile patients seems to reduce the chance of miscarriage [2, 49]. Regarding fibroids that do not distort the uterine cavity, there is no evidence indicating that myomectomy may reduce the chances of an abortion [2, 49].

### *6.2.2 Uterine polyps*

There seems to be a higher prevalence of endometrial polyps in women with gestational loss (2.4%), but with no well-defined clinical importance [2, 47]. Hysteroscopy is considered the gold standard exam for the diagnosis and treatment of endometrial polyps but can also be identified through other imaging exams, such as ultrasound with color Doppler [2]. Although there is no evidence of the benefit of polypectomy in women with RPL, hysteroscopic removal should be considered when the polyp is larger than 1 cm when no other known etiology is found [2, 47]. ASRM reports that research for uterine polyps in women with gestational loss is controversial as there is no conclusive evidence that surgical treatment reduces the risk of gestational loss [49].
