**4. Congenital uterine anomalies**

Congenital uterine anomalies come from failures along any step of the mullerian duct development process during embryo development, either in the formation, fusion or reabsorption. While an arcuate uterus shows a mild form of anomaly, a bicornuate uterus represents total failure. The actual uterine malformation prevalence is difficult to be determined since many of them are asymptomatic although

#### *Recurrent Implantation Failure: The Role of Anatomical Causes DOI: http://dx.doi.org/10.5772/intechopen.98505*

they reach approximately 5.5% of the general population; 8% among infertile women and 13.5% among women with history of recurrent fetal loss [15]. A prospective observational study evaluated the prevalence of congenital uterine anomalies, including arcuate uterus, and their effect on the reproductive outcome among sub fertile women undergoing assisted reproduction. Clinical pregnancy and live births rates were similar among those with congenital uterine anomalies and the control group. There were no differences in the type of delivery, newborn gender or birthweight between the two groups. However, women with congenital uterine anomalies had more chance of premature delivery. After analysis of the anomalies subtypes, pregnancy and live birth rates were similar between arcuate and normal uterus groups. But the group with larger uterine anomalies showed worse reproductive outcomes [16].

Among the congenital uterine anomalies, the septate uterus is the most common and comprises 35% of the malformations. Its prevalence among infertile women (3%) seems to be comparable with the general population (2.3%) [15].

Women with septate uterus show increased risk of spontaneous abortion (2.9 relative risk [RR]; 95% confidence interval [95% CI] 2.0–4.1), premature delivery (2.1 RR; 95% CI 1.5–3.1) and abnormal fetal presentation (6.24 RR; 4.05–9.96 CI). They also have the lowest clinical pregnancy rates (0.86 RR; 95% CI 0.77–0.96) [17].

Little is known about the physiopathology responsible for the negative reproductive outcomes in women with septate uterus. According to a recent systematic literature review, all the eight studies which histologically investigated the septum showed that it consists of endometrial and myometrial tissue, and that most intrauterine septa are vascularized. One explanation for jeopardized reproductive outcomes of embryos implanted in the intrauterine septum could be the different histologic composition of the endometrial septum tissue. The glandular cells and the stroma have different morphologic characteristics: a smaller number of glandular cells and cilium, and incomplete cilium genesis.

Besides that, the endometrial septum contains the lowest levels of vascular endothelial growth fator (VEGF) receptors. It is believed that they have an important role in the early embryo implantation and placentation. In two studies, the HOXA10 gene expression, which is important for the early embryo implantation, seems to be altered in women with septate uterus. These findings can explain the disruptive development of the embryo implanted in the septum. However, since the studies' results on the issue are conflictive, a more detailed investigation is suggested [18].

#### **4.1 Diagnosis**

The definition of septate uterus has been discussed for a long time. Nowadays, there are three classification systems which are used worldwide. It's important to have a standardized classification system in order to prevent inappropriate or unnecessary surgical procedures and to compare reproductive results. The original classification system of the ASRM was modified and adapted. It currently uses morphometric criteria, such as the uterus internal indentation angle and internal midline cutout measurements to make a distinction between arcuated and septate uterus. It also uses the depth of uterus external surface to make a distinction between those and the bicornuate uterus. The uterus with indentation angle < 90°, length of midline internal cutout > 1.5 cm and uterine external cutout with less than 1 cm is defined as a septate uterus by the ASRM [19]. In 2012, the European Society of Human Reproduction and Embryology and the European Society for Gynecological Endoscopy (ESHRE/ESGE) published a

classification system to replace the subjective criteria of the ASRM classification system by absolute morphometric criteria. Contrary to the American classification, the arcuate uterus is not mentioned and is considered a variant from normality. Septum is defined when the internal indentation is > 50% of the uterine wall thickness and the depth of the external fissure is < 50% of the wall thickness [20]. Women with previous diagnosis of arcuate uterus made by the ASRM (around 58%) would be classified as having a septate uterus when using the ESHRE/ESGE new classification. Thus, there would be an increase on the number of surgical procedures to fix uterine anomalies, with no evidence showing that this practice is beneficial to these women [21]. Recently, a simplified classification was proposed by the Congenital Uterine Malformations Experts (CUME), where the septum is defined as the depth of the internal indentation ≥ 10 mm [22]. It demonstrates the heterogeneity in the classification of mullerian malformations, making it difficult to produce scientific papers on these alterations in a homogeneous way.

#### **4.2 Treatment**

The uterine septum is the only malformation that can be corrected. There are many discussions about the impact of the septum resection on the reproductive results and if it improves natural conception rates and implantation rates after embryo transfer. Nowadays, the ASRM guidelines for septate uterus management recommend the hysteroscopic resection [18]. In contrast, the ESHRE, the National Institute for Health and Care Excellence (NICE) and the Royal College of Obstetricians and Gynecologists (RCOG) guidelines for recurrent fetal loss associated to septate uterus do not support this procedure until further studies can demonstrate its effectiveness [23–25]. Lavergne et al. found a retrospective multicentric study which shows that implantation rates after IVF cycle were significantly lower in patients with malformed uterus (septate, bicornuate or unicornuate) in comparison with patients with a normal uterus (6% vs. 12%, p < 0.01). There was significant improvement when the uterine anomaly was corrected (septate uterus) [26]. One study compared gestation and abortion rates after embryo transfer on an IVF cycle in patients with septate uterus before and after septum resection. They were compared to a control group, showing that pregnancy rates before hysteroscopic resection (both in women with septate or subseptate and arcuate uterus) were significantly lower in comparison to the patients in the normal control group [OR 2.9 (P < 0.002) and 2.2 (P < 0.001)], respectively. After surgery, pregnancy rate was comparable to the women with a normal uterus (OR 1.2 and 1.1). The uterine septum size did not influence pregnancy rate. The study conclusion recommends the hysteroscopic resection in order to improve the reproductive outcome, not limited to women with recurrent early fetal loss or premature labor, but it is also recommended to infertile women in order to improve pregnancy and live birth rates, especially if IVF is a choice [27]. Ozgur et al. showed that a history of abortion and IVF failure was frequent among women with untreated incomplete septate uterus in comparison to the infertile general population. After surgical correction of the septum, pregnancy rates in IVF cycle were similar to the group with normal uterine cavity [28]. In a recent article by the SWOT infertility group in Spain, the researchers stated that a septate uterus has been associated to a high prevalence of repeated implantation failure in assisted reproduction and abortion after IVF. In these cases, septum resection seems to be useful to improve IVF pregnancy rates [29]. These studies suggest that the correction of anatomical alterations which distort the uterine cavity, especially the septate uterus, can improve reproductive results.

#### *Recurrent Implantation Failure: The Role of Anatomical Causes DOI: http://dx.doi.org/10.5772/intechopen.98505*

In other studies, we saw that the septate uterus correction may not bring benefits. In an international multicentric cohort study with women with septate uterus and showing desire for pregnancy (which opted for septum resection or expectant approach), Rikken et al. showed that the septum resection did not increase the chance of live births nor reduced the risk of abortion or premature birth [30]. The only controlled randomized trial assessing the reproductive outcome after uterine septum resection was recently published. Women in reproductive age with a septate uterus and the wish to get pregnant and a history of subfertility, fetal loss or premature birth were selected. The results of this randomized clinical trial showed that the hysteroscopic resection of the septum did not improve live birth rates or other reproductive outcomes in women with septate uterus. In this study, one patient undergoing septum resection had a perioperative uterine perforation. The authors concluded that if there is no proven efficacy, they do not recommend septum resection as a routine procedure in clinical practice. Women with septate uterus need to be informed about this study data. After counseling and according to the principles of shared decision-making, an informed consent must be provided [31].

In relation to other malformations, except septate uterus, surgical correction seems not to bring benefits. Surrey et al. demonstrated that the arcuate uterus does not have an impact on the results of IVF cycle after euploid embryos transfer. Women undergoing IVF with indentation between 4 and 10 mm experience excellent results which are similar to those of women with internal indentation < 4 mm (live birth rate; 68.7% vs. 68.7%). Besides that, there were no differences in the reproductive outcome among those with arcuate or normal uterus, according to Salim et al. Criteria [32]. Chen et al. compared the reproductive outcome between unicornuate and morphologically normal uterus. There were no significant differences in the pregnancy, clinical pregnancy or live births rates. The abortion rates were similar. In single pregnancies, there were no differences in the preterm birth, birthweight or birth size rates. However, prematurity rates, lower birthweight and lower birth size rates as well as higher very low birth rates were found in twin pregnancies with unicornuate uterus. A single embryo transfer is recommended for unicornuate uterus [33].

The difficulty of having an agreement on the scientific studies is due to the impediments to unite mullerian malformations classification, differences on the definition of recurrent embryo implantation failure and a low prevalence of these events. Thus, we suggest the individualization of the cases in which mullerian malformations and recurrent implantation failure appear. Among all the malformations, the septate uterus is the one whose correction is possible in order to improve the reproductive outcome. Nevertheless, further studies are necessary to confirm this statement.

#### **5. Intrauterine synechiae**

Intrauterine synechiae, intrauterine adhesions or Asherman syndrome are names that define lesions on the endometrial tissue caused after aggressive curettage or any other intrauterine procedure that destroys the endometrium.

It is known that gestational complications such as missed or incomplete abortion and afterbirth bleeding are responsible for approximately 90% of the cases [34]. Nonetheless, infections in a non-pregnant uterus and surgeries such as myomectomies or septoplasty, for example, can lead to synechiae formation [35], causing or not secondary amenorrhea.

In terms of physiopathology, the assessment by electronic microscopy shows that the glandular cells have severe alterations in women with Asherman syndrome. It is mainly due to ribosome metabolism which culminates in ATP depletion and subsequent tissue hypoxia. There is an abnormal expression of different growth factors which leads to the activation of cytokines related to the adhesion and a proinflammatory cascade [36]. There are also theories that associate the occurrence, severity and recurrence of intrauterine adhesions to an alteration of the endometrial microbiome, but they lack strong scientific evidence.

The presence of adhesions in the uterine walls can interfere in the embryo implantation impeding the embryo cellular fixation on the endometrial luminal layer. Demirol and Gurgaon found a prevalence of 8.5% of intrauterine synechiae in women with embryo implantation failure, which confirms the importance of a clinical investigation [37].

#### **5.1 Diagnosis**

For 20 years, the hysterosalpingography was the first line exam for the diagnosis of intrauterine synechiae. Today it is still used by many gynecologists for the evaluation of the uterine cavity, since it is a low-cost analysis showing 75% sensitivity [38]. It is similar to the hysterosonography whose sensitivity is of 82% [39]. The transvaginal ultrasound scan is also used to confirm a thin endometrium, but it has low accuracy for the diagnosis of synechiae [40], so that it is not considered the best method of investigation. The 3D hysterosonography has 91.1% sensitivity and 98.8% specificity, which makes it a good examination for the diagnosis of intrauterine adhesions [41]. However, despite the data forementioned, the hysteroscopy is certainly a golden standard for the diagnosis of synechiae, once it allows direct visualization of the uterine cavity [42] and enables treatment. There is concrete evidence that the synechiae lysis during hysteroscopy improves the reproductive outcomes [43].

#### **5.2 Treatment**

Before hysteroscopy, cervix dilation and curettage associated with estrogenic therapy and use of IUD ensured 84% success rate in the treatment of Asherman syndrome. However, today we have the hysteroscopy as a golden standard in the diagnosis and treatment of this endometrial complication. It became necessary to define the site and severity of intrauterine adhesions. Classifying the disease process can be important once the severity imposes the prognosis after treatment [44]. The hysteroscopy enables the amplification and general observation of adhesions allowing the viewing of all structures, which decreases the risk of uterine perforation. However, there should be maximum care when using mechanic and electronic section since errors can bring undesirable repercussions [45].

The surgical treatment shows success rate after adhesiolysis ranging between 75 to 100% [46]. This rate can be evaluated by the return of menstrual periods, rates and pregnancy outcome. After a hysteroscopic surgery, around 92 to 96% of women returned to their bleeding pattern prior to the syndrome showing 63% pregnancy rate and 75% live births rate [44]. The most frequent complication in pregnancies after hysteroscopic treatment for uterine adhesions is the abnormal placentation [44].

The intraoperative fluoroscopy and transabdominal ultrasound scan or the laparoscopy are also efficient alternatives [45]. The fluoroscopic guidance enables the surgeon to see endometrium islands behind the scar tissue in an obliterated uterine cavity. The radio opaque dye is injected into a dense scar area in the place where the cavity is obliterated. Some endometrial adhesions can be identified using fluoroscopy. The area can be opened through acute dissection under hysteroscopy.

#### *Recurrent Implantation Failure: The Role of Anatomical Causes DOI: http://dx.doi.org/10.5772/intechopen.98505*

However, this technique is considered limited by the high cost, by technical difficulties or by the requirement for ionizing radiation [46].

The laparoscopic guidance for severe cases of intrauterine adhesiolysis has been advocated for the immediate recognition and treatment of uterine perforation, thus minimizing the extrauterine trauma. The intraoperative ultrasound scan, fluoroscopy or laparoscopy together with the hysteroscopy have been used as guidance to reduce the risk of perforation. Nevertheless, nowadays it is known that these interventions do not prevent uterine perforation or improve the outcome [46].

The stem cell therapy approach is much more efficient due to the potential for multiplication of a single cell and its transformation into undifferentiated forms (self-renovation) and into mature cells. Besides that, it can produce other types of cells, such as totipotent, pluripotent and multipotent cells [35].

In 2016, Tan et al. [47] investigated mesenchymal stem cells derived from bone marrow and stromal cells coming from the menstrual bleeding through transmiometral administration in the subendothelial area, direct installation of stromal cells in the uterine cavity and infusion of cells in spiral arteries through a catheter. Five out of six women with Asherman syndrome recovered their menstrual periods. Others reached adequate endometrial thickness and regular menstruation cycles and were able to get pregnant right after that. In this study, the authors compared some types of stem cells and could observe endometrial regeneration in most of the cases.

Thus, stem cells therapy has become a new method of treatment for the regenerative medicine, and more specifically, for the regeneration of endometrial diseases with Asherman syndrome and thin endometrium. However, stem cells transplant for Asherman syndrome is far from being common [46].

The biggest challenge for the treatment of Asherman syndrome is to prevent the recurrence of adhesions after the early treatment, which reaches 66% [46]. The treatment is defined by time. There are studies that evaluated the post-operative period comparing the use of intrauterine device (IUD) with intrauterine balloon catheter, Foley catheter, hormonal treatment and barriers such as amniotic membranes. The results are conflicting.

For instance, the copper IUD can provoke inflammation and is contraindicated [44]. Similarly, the hormone IUD have a small surface that limits its capacity to keep the endometrial cavity walls separated during healing [39]. The risk of infection after the insertion of an IUD after surgical resection of intrauterine adhesions is about 8% [44].

The placement of a Foley catheter with an IUD was assessed as a possible adjuvant treatment to prevent the formation of synechiae after hysteroscopy. The authors concluded that the Foley catheter placed one week and a half after adhesiolysis showed 81% success rate while the group which placed an IUD twelve weeks after the adhesiolysis showed 62% success rate [48]. The use of intrauterine hyaluronic gel after hysteroscopic treatment reduces adhesions recurrence [48], but further studies are needed for its incorporation into the treatment [44, 45].

Platelet-rich plasma (PRP) is a form of treatment for intrauterine adhesions after operative hysteroscopy and may be a substitute for the intrauterine balloon. However, randomized controlled trials with large sample sizes are warranted to further confirm the conclusions to compare the efficacy of intrauterine infusions of PRP with intrauterine balloons applied immediately after transcervical resection of the adhesions by hysteroscopy [49].

Clinical treatment with drugs such as aspirin, sildenafil and nitroglycerin have been done to increase endometrial blood flow in an attempt of stimulate cell regeneration. Successful pregnancies were reported after using them. However, more robust and well designed studies are required to confirm it [44].

Hormonal therapy with post-operative estrogen was not standardized in terms of dose, duration, route of administration or a combination with progesterone, Data about its efficacy are limited [44]. The American Association of Gynecologic Laparoscopists (AAGL) guidelines recommend hormonal therapy with estrogen after adhesiolysis, but there is no definition for dose or standard regimen [46]. The combination of this and adjuvant treatments is necessary for a maximum effect on patients with mild to severe adhesions.

As for the therapy with antibiotics, there is a lack of studies addressing the risks and benefits of those before, during and after surgical lysis of intrauterine adhesions. The American College of Obstetrics and Gynecology (ACOG) does not recommend the routine use of antibiotics with this objective [44, 46].

Hysteroscopic adhesiolysis cure infertility in mild, moderate and severe IUA in around 90, 70 and 30%, respectively [50]. Gestational surrogacy remains an alternative for those patients with intrauterine adhesions that stay infertile [51].

#### **6. Adenomyosis**

Adenomyosis is a benign uterine pathology known by the invasion of glandular endometrial tissue and myometrial stromal tissue which leads to disorders in the myometrial natural architecture [52].

There are some theories explaining the emergence of adenomyosis. The theory of tissue injury and repair (TIAR) as the main mechanism of myometrial invasion has been the most accepted hypothesis. Chronic peristaltic myometrial contractions can lead to micro lesions close to the endometrial-myometrial junction causing inflammation which in turn leads to an increase in local production of estrogen inducing a vicious cycle. Thus, the TIAR theory highlights the importance of tissue damages to the endometrial-myometrial interface supporting the common knowledge that the adenomyosis is associated with multiple births, previous cesarean section and previous uterine surgery [53]. However, it is known that there is a considerable number of macrophages in the ectopic endometrium of patients with endometriosis, fibroids and adenomyosis. Therefore, the potential for embryo implantation can be affected by adenomyosis [54]. This increase in the number of macrophages induced by adenomyosis can cause a hostile immunologic environment for embryos transferred during the implantation process. The interleukin-1 alpha tumor necrosis factor as well as reactive oxygen and nitrogen species are potentially toxic for embryos. It was demonstrated that an increased level of nitric oxygen is related to an adverse development of embryos and low pregnancy rates in the endometrial environment in patients with adenomyosis. Besides that, endometrial biopsies taken from adenomyosis showed that this tissue is composed of a high quantity of antioxidant enzymes as superoxide dismutase, catalase and glutathione peroxidase which are clear signs of oxidative stress caused by excessive ROS production [55].

Other risk factors are age over 40 years, multiple births, previous cesarean sections or other uterine surgeries. The disease is often diagnosed in young and infertile women or those with pain or abnormal uterine bleeding, or both [56].

Adenomyosis is associated with a great variety of symptoms. The common symptoms include pelvic pain (as dysmenorrhea, dyspareunia or chronic pelvic pain), abnormal uterine bleeding and impaired reproductive potential or even infertility itself. However, it is important to observe that 30% of women with adenomyosis have no symptoms [57]. In infertile women with adenomyosis, the topic endometrium shows a great variety of molecular alterations causing altered receptivity. That includes the alteration in the sexual steroid hormone via, increase of inflammatory markers and oxidative stress, decrease on the implantation markers expression, lack of adhesion molecular expression and altered gene function for the embryo development. Not only fertility outcomes are affected, but also pregnancy outcomes [58]. These include premature birth, premature rupture of membranes, postpartum hemorrhage, abnormal fetal presentation, increase on the risk of abortion in the second trimester and abnormal placental position [57].
