**3. Hydrosalpinges**

significant decline in CCL4 in CE, may also increase the employment of NK cells and macro‐

Mostly due to non-standardized treatment protocols and conflicting results about pregnancy outcomes, so far the management of CE to increase in the implantation rate has been contro‐

Some authors recommend treating CE first with of doxycycline for 2 weeks, then with persistent inflammation in a second biopsy, and ciprofloxacin and metronidazole for another 2 weeks [49]. Some others base the treatment on the identified infectious agent and the antibiotic sensitivity profile, giving ciprofloxacin for gram-negative bacteria, amoxicillin/ clavulanate for gram-positive bacteria, and wide spectrum antibiotics (metronidazole cef‐

In one study, a treatment of antibiotics plus steroid was used to treat women with increased

The efficacy of treatment of CE to increase endometrial implantation and pregnancy rate is unclear. In a cohort study, clinical pregnancy per embryo transferred and live birth rates showed no change between the treated and non-treated patients with CE undergoing their first IVF/ICSI cycles. Both groups underwent endometrial biopsy and hysteroscopy as part of

Another study on RIF compared treated women with a positive biopsy for CE (10) to women with a negative biopsy (23). Even after antibiotic therapy, the implantation rates stayed lower in women with CE (11.5 vs. 32.7%) [49]. Cicinelli et al, in a recently published retrospective study of women with RIF, showed an improvement in pregnancy rates and live birth rates with antibiotic treatment in patient with CE compared with the patient with persistent CE, 65 versus 33% and 60.8 versus 13.3%, respectively [18]. To date, this is the only study showing a significant higher live birth rates after antibiotic therapy of CE. Although, it is good to note before generalizing these results as subjects in this research had hysteroscopic evaluation as a first diagnostic module for diagnosis of CE, which can be subjective. Also, instead of blastocyststage embryos, cleavage-stage embryos, were transferred, which may not be applicable to all

Physicians mostly look for the diagnosis of CE, in cases of RIF; however, because the lack of a universally accepted definition for RIF indirectly biases the pool of patients who are worked up for CE. The diagnosis of CE becomes even more complex and difficult by limitations in microbiology and immunohistopatholog, and the subjective nature of hysteroscopy. Manage‐ ment of CE is also non-standardized. Taken all together, the absence of definitive evidence to establish improved pregnancy outcomes after the treatment of CE precludes establishing a

phages into the endometrial environment [48].

triaxone, doxycycline) for even negative cultures [18].

MMP activity in uterine fluid lavage [48].

**2.5. Treatment**

110 Genital Infections and Infertility

a larger RCT [18].

practices.

**2.6. Summary**

standard of care [48].

versial.

Hydrosalpinx is defined as a chronic inflammatory condition in which a fallopian tube is filled with fluid as the result of distal obstruction.

PID caused by chlamydia or gonorrhea is considered as the primary cause of hydrosalpinx; however, other conditions that may cause tubal obstruction include adhesions from previous surgery, endometriosis, non-tubal infections (i.e., appendicitis, inflammatory bowel disease), salpingitis isthmica nodosa and pelvic tuberculosis.

The diagnosis rate of hydrosalpinges ranges from 10 to 13% by ultrasound, and up to 30% by laparoscopy or HSG [50]. Hydrosalpinges are documented in ultrasound as cystic elongated masses in the adnexa that can sometimes wrap around the ovaries [51].

There is some controversy for the definition of a "clinically significant hydrosalpinx," with some studies proposing that the diagnosis should be only made when hydrosalpinges are visible in ultrasound [52]. Findings of distal tubal occlusion on hysterosalpingogram would not qualify. Studies have shown low intra-observer reliability in detecting hydrosalpinges on HSG (kappa -0.28), when the intra-observer reliability for distal tubal obstruction was higher (kappa -0.71) [53]. This demonstrates the fact that hydrosalpinx and distal tubal occlusion are not synonymous conclusions.

A recent survey performed from members of the Society for Reproductive Surgeons and the Society for Reproductive Endocrinology and Infertility has highlighted the variation in clinical practice. The results showed that 60% of the members would make the diagnosis based on transvaginal ultrasound and 70% would make the diagnosis upon visualization of a dilated tube that is distally occluded on laparoscopy. However, commonly 80% of members would diagnose a hydrosalpinx based on a dilated tube that is distally occluded on hysterosalpingo‐ gram [54].

The presence of unilateral or bilateral hydrosalpinges has been shown to adversely affect implantation or pregnancy rates for IVF in different clinical studies. There were two main metaanalyses performed. The first meta-analysis included over 6,700 treatment cycles from 11 studies, which identified that the implantation rate and the clinical pregnancy rate were 50% lower in patients with hydrosalpinges compared to patients without hydrosalpinges. Miscar‐ riage in patients with hydrosalpinges had also a twofold higher rate [55].

#### **3.1. Pathophysiology**

There are multiple hypothesis as to how hydrosalpinges can affect and predispose to implan‐ tation failure. These include a direct embryotoxic effect, [56] decrease in subendometrial and endometrial blood flow [57] decrease in endometrial receptivity, [50] possible developmental abnormalities of the endometrium [58] and tubal fluid, which can compromise the contact between the embryo and the endometrial surface as mechanical effect [59].

In a retrospective case-control study, inflammation and inflammatory markers in hydrosal‐ pinges were investigated. This study evaluated 21 cases of hydrosalpinges and 9 cases of chronic salpingitis, and it was shown that the cases with hydrosalpinx were found to have an increase in inflammatory cells in the endometrium, including neutrophils and basophils. This correlation was statistically significant [60]. This case-control study showed that 65% of cases had high-intensity staining of IL-2, a marker for generalized inflammation, compared with only 7.4% in control group.

Inflammatory markers, especially Th-1 inflammatory cytokines, have been implicated in recurrent pregnancy loss, which is in favor of these markers playing a critical role in implan‐ tation failure [61]. In the presence of hydrosalpinx, similar to LIF, the expression of αvβ3 integrins has been reported to be decreased [62] with an increase and return to normal levels following salpingectomy [63]. Integrins mainly play a role in cell-cell and cell-matrix adhesion and interaction in a variety of physiological processes, which include immune defense mechanisms and wound healing and should not be specifically considered inflammatory markers. Interestingly, β3 integrins are cell-cycle-specific and are mainly expressed between cycle days 20-24, proposing the hypothesis that they might play a role during the window of implantation [64].

Poor outcomes have been seen with hydrosalpinx and the reasons are not clearly understood. The unfavorable effect seems to be directly related to the presence of a hydrosalpinx, rather than an embryo or oocyte factor.

Some investigators have researched the affect of the fluid from hydrosalpinx on the embryo and whether it has an embryotoxic effect or not and have determined that there might be an embryotoxic affect. On the contrary, recent studies have raised doubt about this toxin-induced effect. To further investigate this hypothesis, Strandell et al. [65] cultured human embryos in 50% hydrosalpinx fluid and realized that these embryos developed to blastocysts at the same degree as human embryos grew in a standard culture media.

The poor IVF outcomes seen in patients with a hydrosalpinx have been hypothesized to be related to tubal inflammation. A chronic inflammatory process can be present for multiple reasons. It could be observed with recurrent bacterial infections, including chlamydia, as a more common cause, or other bacteria. Acute inflammation can happen during an IVF procedure because of bacterial seeding of the hydrosalpinx during either ET or oocyte retrieval. As there is open communication between the tubes and the endometrium, the inflammatory process could directly spread from the fallopian tubes to the endometrium. The outcome of this process could then impact the development of the pre-implantation embryo and causes a change in the endometrial environment [66].

#### **3.2. Treatment**

The American Society of Reproductive Medicine has proposed that based on the clinical studies there is evidence that for every six women with hydrosalpinges, one more ongoing pregnancy will be successful if salpingectomy is performed prior to initiating IVF treat‐ ment [67].

A known approved alternative to salpingectomy for hydrosalpinges is laparoscopic proximal tubal occlusion.

A randomized control trial was performed to evaluate the efficacy of laparoscopic salpingec‐ tomy and laparoscopic proximal tubal occlusion in 115 patients with bilateral or unilateral hydrosalpinges undergoing IVF treatment. These women were randomized to three groups: two treatment and one control. The outcome in group with laparoscopic proximal tubal occlusion was better than control (no surgery) group and compared to the laparoscopic salpingectomy group [68].

chronic salpingitis, and it was shown that the cases with hydrosalpinx were found to have an increase in inflammatory cells in the endometrium, including neutrophils and basophils. This correlation was statistically significant [60]. This case-control study showed that 65% of cases had high-intensity staining of IL-2, a marker for generalized inflammation, compared with

Inflammatory markers, especially Th-1 inflammatory cytokines, have been implicated in recurrent pregnancy loss, which is in favor of these markers playing a critical role in implan‐ tation failure [61]. In the presence of hydrosalpinx, similar to LIF, the expression of αvβ3 integrins has been reported to be decreased [62] with an increase and return to normal levels following salpingectomy [63]. Integrins mainly play a role in cell-cell and cell-matrix adhesion and interaction in a variety of physiological processes, which include immune defense mechanisms and wound healing and should not be specifically considered inflammatory markers. Interestingly, β3 integrins are cell-cycle-specific and are mainly expressed between cycle days 20-24, proposing the hypothesis that they might play a role during the window of

Poor outcomes have been seen with hydrosalpinx and the reasons are not clearly understood. The unfavorable effect seems to be directly related to the presence of a hydrosalpinx, rather

Some investigators have researched the affect of the fluid from hydrosalpinx on the embryo and whether it has an embryotoxic effect or not and have determined that there might be an embryotoxic affect. On the contrary, recent studies have raised doubt about this toxin-induced effect. To further investigate this hypothesis, Strandell et al. [65] cultured human embryos in 50% hydrosalpinx fluid and realized that these embryos developed to blastocysts at the same

The poor IVF outcomes seen in patients with a hydrosalpinx have been hypothesized to be related to tubal inflammation. A chronic inflammatory process can be present for multiple reasons. It could be observed with recurrent bacterial infections, including chlamydia, as a more common cause, or other bacteria. Acute inflammation can happen during an IVF procedure because of bacterial seeding of the hydrosalpinx during either ET or oocyte retrieval. As there is open communication between the tubes and the endometrium, the inflammatory process could directly spread from the fallopian tubes to the endometrium. The outcome of this process could then impact the development of the pre-implantation embryo and causes a

The American Society of Reproductive Medicine has proposed that based on the clinical studies there is evidence that for every six women with hydrosalpinges, one more ongoing pregnancy will be successful if salpingectomy is performed prior to initiating IVF treat‐

A known approved alternative to salpingectomy for hydrosalpinges is laparoscopic proximal

only 7.4% in control group.

112 Genital Infections and Infertility

implantation [64].

**3.2. Treatment**

ment [67].

tubal occlusion.

than an embryo or oocyte factor.

degree as human embryos grew in a standard culture media.

change in the endometrial environment [66].

In a recent meta-analysis of eight RCTs evaluating the efficacy of salpingectomy versus proximal tubal occlusion in hydrosalpinges, same results as above was achieved in which the implantation and clinical pregnancy rates were not significantly different between the treatments, odds ratio (OR), 0.86 (95% CI: 0.53–1.4) and OR, 1.56 (95% CI: 0.81–3.0), respective‐ ly [69].

The use of hysteroscopic Essure microinsert placements to occlude hydrosalpinges has been studied, mainly in women who have contraindications to laparoscopic procedure. The Essure system is a spring device composed of nickel–titanium and Dacron fibers. The Food and drug Administration (FDA) has approved the Essure system as a sterilization method. The device is space occupying, and can induce an inflammatory response that can cause fibrosis in the tubal lumen. To this date, the studies and literature on the use of Essure for occluding hydrosalpinges is limited to small case series with unclear outcomes and mixed results.

The first live birth from IVF using Essure, following proximal occlusion of a hydrosalpinx, was reported by Rosenfield et al in 2005. This was performed in a 31-year-old nulligravid woman with a history of significant pelvic adhesions and a body mass index of 50 [70]. This unfavorable surgical candidate delivered a dichorionic-diamniotic twins at 34 weeks of gestation after the transfer of three cleavage-stage embryos.

In a case series of 15 patients who underwent Essure placement, 6 were reported to have successful pregnancies. On the other hand, there are also reports of complications using the Essure device, such as unsuccessful placement of the device, subsequent expansion of the hydrosalpinx and PID, which could potentially require an emergency laparotomy and bilateral adnexectomy. There also seems to be a hypothetical concern for having the Essure coils in the uterine cavity [48]. Larger scale studies and prospective multicenter clinical trials should be performed before recommendations regarding hysteroscopic tubal occlusion can become part of standard of care in patients with hydrosalpinx.

Retrospective studies have shown that the larger the hydrosalpinx, the worse the outcome after IVF, which raises the question of embryo toxic effect of the fluid.

Whatever the exact mechanism, an interruption of the communicating hydrosalpinx appears appropriate to improve the implantation in the endometrial environment [71].

In a study performed by Hurst et al, patients with an increased quantitative serum *Chlamydia trachomatis* IgG antibody titer were considered for treatment with doxycycline 100 mg twice daily for a total of 10 days before the first IVF cycle was initiated. This group also included 75% of the patients who had hydrosalpinx. The outcome of the study, which was implantation and pregnancy rates, was slightly lower in the group with hydrosalpinx than in the control group; however, this difference was not statistically significant. In summary, patients treated with doxycycline for extended periods whom had hydrosalpinx did not have lower IVF success rates. On the contrary, the highest implantation rate was present in the group with hydrosal‐ pinx [66].

An unfavorable effect of a hydrosalpinx could be caused by a chronic or acute tubal bacterial infection that could potentially affect the endometrium. This detrimental effect could be suppressed and become ineffective by using extended antibiotic therapy. In addition, health‐ care cost can be prevented and minimized if initiating treatment with a 2-week course of an inexpensive antibiotic provides the same outcome comparable to surgical treatment of a hydrosalpinx prior to IVF treatment.
