**6.1 Diagnosis**

The diagnosis can be done after case history, clinical evaluation and image assessment with 2D/3D transvaginal ultrasound or magnetic resonance [52]. The transvaginal ultrasound for its facility of access and low cost in relation to other types of screenings has become a very useful tool to the diagnosis. Several ultrasographic criteria have been used to the adenomyosis diagnosis, including uterine size increase, anterior and posterior uterine walls thickness asymmetry, presence of heterogeneous myometrial areas, presence of myometrial anechoic areas, presence of sub endometrial echogenic striations, sub endometrial echogenic nodules, irregular endometrial-myometrial interface, poor definition and thickness of the junctional zone [57].

A meta-analysis about ultrasound accuracy in the diagnosis of adenomyosis demonstrated 82.5% sensitivity (95% CI), 77.5–87.9) and 84.6% specificity (95% CI, 79.8–89.8) with 4.7 positive likelihood ratio (3.1–7.0) and 0.26 negative likelihood ratio (0.18–0.39) which is comparable to the magnetic resonance [59].

The magnetic resonance is a precise and non-invasive technique used to the diagnostic of adenomyosis [60]. Its sensitivity and specificity in this diagnostic range from 88–93% and 67–91%, respectively [57]. The diagnosis of adenomyosis by magnetic resonance is essentially related to junctional zone characteristics, but can also include direct and indirect signs of endometrial glands inside the myometrium and smooth muscle cells hypertrophy [61, 62].

#### **6.2 Treatment**

Clinical pregnancy, implantation, and ongoing pregnancy rates were significantly higher in women undergoing frozen embryo transfer after long-term GnRHanalog therapy compared to those not pretreated with GnRH-analog [63].

Tremellen et al. reported that hypothalamic–pituitary- ovarian axis suppression therapy with GnRH agonist can produce a significant decrease in the number of endometrial macrophages, presumably interfering with the estradiol-mediated recruitment of macrophages to the endometrium and a subsequent normalization of embryo implantation rates [64]. Wang et al. showed that patients with normal ovarian reserve who underwent IVF/ICSI, adenomyosis seemed to negatively affect IVF/ICSI outcomes after a long GnRH agonist protocol (subcutaneous administration of short acting GnRH agonist on the dosage of 0.1 mg/day, for 10 days followed by 0.05 mg/day until the day of hCG injection which was started in the mid-luteal phase of the previous cycle), but patients with adenomyosis following an ultra-long GnRH-agonist protocol could experience stronger pituitary inhibition and lower ovarian responses but still could have a better IVF/ICSI outcomes. Ultra-long GnRH agonist protocol was considered the use of a depot injection of the long-acting GnRH agonist, triptorelin acetate (triptorelin) 3.75 mg, intramuscularly, every 28 days for at least 3 months before starting ovarian stimulation [65]. This therapy may produce a window of time with improved implantation rates [66].

The use of a levonorgestrel-releasing intrauterine device, danazol, or aromatase inhibitors may temporarily induce regression of adenomyosis and oral contraceptive pills, high-dose progestins, and selective progesterone receptor modulators can temporarily improve its symptoms, but these are not used in fertility treatments [66].

Patients with adenomyosis present a higher number of uterine contractions. Oxytocin (OT), a nonapeptide synthesized by neurons of the supraoptic nucleus and released from the posterior pituitary gland, has diverse effects on the female reproductive system. It is known to be a factor causing uterine contractions. It has also been shown in animal models that endometrial cells contain oxytocin receptors (OTRs) and that OT has the capacity to trigger the production of prostaglandin (PG) F2a from these cells. Atosiban, an OTR antagonist, treatment before ET in endometriosis is effective in the priming of the uterus, suitable for embryo implantation [67]. Since uterine contractions in IVF cycles are significantly increased following ovarian stimulation and women with frequent uterine contractions have a lower pregnancy rate, the use of atosiban around embryo transfer may resulted in higher pregnancy rates in women with RIF and adenomyosis. According to Hung Yu et al., the use of atosiban around embryo transfer did not improve the live birth rate in a general population of IVF patients [68].

## **7. Hydrosalpinx**

Hydrosalpinx refers to a condition in which the fallopian tube is filled with fluids following infundibulum obstruction. It is a common condition among infertile women with 10–13% diagnosis rate after ultrasound scan. These numbers can be increased when other diagnostic methods such as hysterosalpingography or laparoscopy are used [69].

Perhaps the real cause for the implantation failure is not known, but studies suggest a decrease in live births rates in patients with hydrosalpinx [70].

The theories regarding hydrosalpinx and implantation failure are about a possible embryo toxicity, changes in the endometrium quality or even embryos washout mechanical effect [71].

The endometrial involvement secondary to hydrosalpinx is related to the presence of fluid inside the uterine cavity, altered endometrial flow, altered in inhibiting factors and increase in the inflammatory response. Besides the endometrial changes and a possible embryo toxicity, the implantation failure can be related to a negative effect on sperm motility and survival.

#### **7.1 Diagnosis**

A history of ectopic pregnancy, pelvic inflammatory disease, endometriosis or previous pelvic surgery increase the suspect of infertility by tubal factors [72]. For patients without risk factors, a negative antibody test for chlamydia indicates that there is less than 15% chance of tubal pathologies [73]. For an accurate diagnosis and an effective treatment of the tubal blockage it is necessary to do exams as the hysterosalpingography (HSG) which uses water or lipids soluble contrast medium. It is a golden standard method to evaluate tubal permeability and can bring some therapeutic benefits. The HSG can document tubal blockage in proximal and distal sites, show salpingitis isthmic nodosa, reveal fimbrial phimosis or peri tubal adhesions [74]. The HSG positive and negative predictive factors are 38% and 94%, respectively [75].

The laparoscopy with chromotubation with methylene blue test (dye test) injected thorough the cervix can demonstrate tubal permeability, proximal or distal tubal occlusion. This surgical route can also identify and correct peritoneal and tubal factors such as fimbriae or peri tubal adhesions which cannot be seen with less invasive methods as the HSG [74].

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

#### **7.2 Treatment**

The techniques used for the treatment of hydrosalpinx are many: laparoscopy or laparotomy for salpingectomy, salpingostomy or even uterine proximal occlusion.

A meta-analysis published in 2020 evaluated the effect of hydrosalpinx on the pregnancy rates, compared different types of treatment and the impact on the ovarian reserve after treatment for hydrosalpinx [70]. They reviewed 17 studies and observed that the hydrosalpinx was associated with a significant decrease in the implantation rate with embryo transfer with 0.41 OR [0.32–0.53]. Besides that, the clinical pregnancy rate per subject and per transference significantly decreased in women with hydrosalpinx (OR = 0.54; [0.32–0.89] and 0.44 [0.27–0.73], respectively) [70].

The hydrosalpinx removal with salpingectomy leads to an improvement of in vitro fertilization outcomes in comparison with no treatment, which turns it into a golden standard management before IVF. This evidence is replicated in other studies, such as Palagiano et al., where the pregnancy rates in patients with hydrosalpinx is lower than the control group [69]. There were negative effects either in fresh or frozen embryo transfers. An increase of two or threefold in abortions in women with hydrosalpinx was observed.

The hydrosalpinx mechanism action is still uncertain. Studies show a negative impact in IVF treatment outcomes, including a decrease in implantation rates, clinical pregnancy and in course pregnancies. Besides that, they show a risk of miscarriages (1.68 OR) and ectopic pregnancy (3.48 OR), according to Capmas et al. [70]. The salpingectomy is the treatment that increases success rate and prevents secondary aggressive factors. According to some authors, it is considered a golden standard. But it can be related to a decrease in the Anti-Mullerian Hormone average of 0.99 ng/ml, as shown the meta-analysis by Capmas et al. [70].

#### **8. Conclusion**

The recurrent implantation failure is a complex clinical condition with a wide variety of etiologies. Its criteria are not still well defined. Despite the lack of consensus, studies strongly show that anatomical factors affecting the uterine cavity contribute to implantation failure. Most of these factors are treatable, though.

Each patient approach must be individualized and offered to women with adequate RIF investigations to eliminate the possibility of all structural causes. The lack of success of an IVF can be devastating for some couples.

Uterine pathologies such as fibroids, adenomyosis, endometrial polyp, congenital abnormalities and synechiae must be considered in the diagnosis of RIF and must be excluded using image exams. Hydrosalpinx is known as a factor for implantation failure and a laparoscopy with salpingectomy or uterine proximal occlusion must be offered as a therapy option.

Even after more than 40 years of IVF procedures worldwide, the causes of RIF remain challenging and controversial. It is necessary to establish a consensus about diagnosis and therapeutic approaches to reduce expensive treatments which are not efficient and are time-consuming for infertile patients.

#### **Conflict of interest**

"The authors declare no conflict of interest."

*Infertility and Assisted Reproduction*
