INTRODUCTION

Reproductive surgery includes all the surgical procedures performed to diagnose, conserve, correct, and/or improve reproductive function.¹ It aims to restore normal uterine and tubo-ovarian function whenever possible by resolving the pathology and creating possibilities for spontaneous conception. As such it differs from gynecological or oncological surgery aiming to remove the diseased tissue. Within the era of reproductive medicine, reproductive surgery gained interest with the introduction of microsurgery principles beginning in 1970.^2,3,4 These “gentle tissue handling” principles resulted in a spectacular improvement in pregnancy rates following microsurgical interventions. Later with the introduction of endoscopy (laparoscopy and hysteroscopy) from 1980 onwards and, if the same principles were applied, the results in terms of pregnancy rates were comparable to microsurgery and better in comparison with conventional laparotomy, or even conventional laparoscopy.

With the development of ART, reproductive surgery became less interesting and the uterine infertility factor seemed to be neglected in favor of high-technology ART procedures.

The introduction of in-vitro fertilization (IVF) within reproductive medicine has prompted questions to be asked about the relevance of reproductive surgery to reconstruction or treatment of the tubo-ovarian and peritoneal axis. Reproductive surgery is more than a competing discipline; in fact, it is complementary to IVF techniques. As a complementary discipline, reproductive surgery covers the field of tubal, ovarian, and peritoneal pathology and the correction of uterine congenital or acquired pathology. The role of surgery in reproduction is twofold. First, it offers a selected group of women the possibility of spontaneous conception in consecutive cycles and for consecutive pregnancies; as such, it favors high cumulative pregnancy rates. Second, it can add a complementary value in ameliorating pregnancy rates and live birth rates in women referred to IVF.^5,6

DIAGNOSIS

With the increased accuracy of ultrasound, diagnosis is frequently restricted to the use of these indirect imaging techniques. Though indispensable as a first screening method, their accuracy in the diagnosis of peritubal adhesions, minimal endometriosis, tubal pathology and uterine-endometrial pathology remains debatable. Direct visualization of the female pelvis and uterine cavity has been proven superior.^7,8,9,10 Standard laparoscopy for diagnostic purposes has been banned in the exploration of the female pelvis because of the invasiveness and the lack of laparoscopic equipment and training in many IVF centers.

Transvaginal hydro-laparoscopy (THL) has been proven to be a safe and minimally invasive procedure allowing direct visualization of the female pelvis under local anesthesia or sedation.^11,12 Transvaginal laparoscopy is performed as a simple needle puncture technique of the pouch of Douglas.

Hysteroscopy, proven to be a simple, highly accurate diagnostic methodology is not accepted as a routine exam in most IVF centers, even now that more and more evidence is provided that the combination of hysteroscopy, ultrasound, and transvaginal laparoscopy is the most accurate and complete exploration of the female reproductive organs which can be performed in an office setting, described as the digital hysteroscopic clinic.¹³

TUBAL PATHOLOGY

The expression “tubal pathology” includes abnormalities of the endosalpinx, salpingitis isthmica nodosa (SIN), partial or total obstructions of one or both tubes and/or peritubal and/or peri-ovarian adhesions affecting the normal ovum pick-up function. Tubal occlusion can be a consequence of a previously performed sterilization procedure, but it is most frequently a consequence of an infectious process with different degrees of affecting tubal mucosa and partial or complete obliteration of the tubal lumen. Tubal occlusions can be proximal, distal, or at both ends.

Proximal

Proximal tubal blockage accounts for 10–25% of tubal disease cases. It may be due to obstruction resulting from plugs of mucus and amorphous debris, to spasm of the utero-tubal ostium, or to occlusion, which is a true anatomic blockage from fibrosis due to SIN, pelvic inflammatory disease (PID),¹⁴ or tubal ligation. There is good evidence to support hysterosalpingography (HSG) as the standard first-line test to assess tubal patency, but it is limited by false positive diagnoses of proximal tubal blockage. Although not perfect, laparoscopy is considered the gold standard in the evaluation of tubal patency.¹⁵

Selective salpingography or hysteroscopic tubal cannulation may be treatment options for women with proximal tubal obstruction because these treatments improve the chance of pregnancy. Recanalization by guidewire is recommended especially if the blockage is close to the entrance of the Fallopian tube into the uterus¹⁶ (Figure 1). To avoid tubal perforation, laparoscopic control is advisable. A meta-analysis of studies treating patients with bilateral proximal tubal occlusion showed that the obstruction is relieved in about 85% of the tubes with tubal cannulation and that about half of the patients conceive. In case of failure of tubal cannulation, microsurgical tubal repair may be an option in the presence of the necessary surgical expertise.¹⁷

Tubal reversal

Based on the best available evidence, younger patients should be referred for tubal anastomosis in the absence of other fertility-impairing factors. In women younger than 40 years of age, the cumulative intrauterine pregnancy rate is more than 90% after microsurgical reversal of tubal sterilization^18,19 (Figure 2). Even in women 40–45 years old, cumulative intrauterine pregnancy rates of 41.7–70.6% have been reported.^20,21 A retrospective cohort study comparing IVF to tubal anastomosis reported that tubal anastomosis had a significantly higher cumulative pregnancy rate for women younger than 37 years of age, but there was no significant difference in women aged 37 years or older.²² In older patients, IVF can be suggested as the first treatment option, but in case of failed IVF, tubal reversal still stays a valid alternative.

DISTAL TUBAL PATHOLOGY

The beneficial effect of salpingectomy on IVF outcome in cases of thick-walled hydrosalpinges or ultrasonographical visible hydrosalpinges has been reported by several studies.^23,24 A Cochrane review showed that salpingectomy pre-IVF resulted in 1.75- and 2.13-fold higher odds of pregnancy and live birth, respectively.²⁵ However, systematic removal of hydrosalpinges before IVF will deprive several patients with thin-walled hydrosalpinges of the possibility of a spontaneous conception. The decision to repair or remove Fallopian tubes with distal disease has to be made perioperatively based upon the inspection of the tubal mucosa preferably by salpingoscopy. Pregnancy rates depend on the degree of tubal disease and are more favorable with good-prognosis patients. Intrauterine and ectopic pregnancy rates after neo-salpingostomy for mild hydrosalpinges range from 58% to 77% and from 2% to 8%, respectively.^26,27 Salpingostomy before IVF may improve the subsequent likelihood of IVF success while still allowing the patient to attempt spontaneous conception. Results of a European survey reported that in women younger than 35 years, and with minor tubal pathology, tubal surgery was considered the first-line treatment.²⁸ The evidence is fair to recommend laparoscopic fimbrioplasty or neo-salpingostomy for the treatment of mild hydrosalpinges in young women with no other significant infertility factors.

ENDOMETRIOSIS

The choice of treatment between IVF or surgery for endometriosis-related infertility in the absence of severe chronic pelvic pain remains a matter of debate.²⁹ The negative impact of ablative or excisional surgery on ovarian reserve and the subsequent impaired oocyte production after ovarian stimulation for IVF cannot be denied. Endometrioma <3–4 cm does not have a negative impact on IVF results, whereas larger endometrioma can reduce follicular development and increase difficulties at oocyte pickup. Nevertheless, minimally invasive surgery remains a valuable option for the treatment of ovarian endometriosis. There are three main reasons for opting for a surgical approach. First, the spontaneous pregnancy rates are approximately 50-60% when the surgical procedure is performed by skilled surgeons.^30,31 Second, we cannot deny the progressive negative impact of the endometriotic disease by itself on ovarian reserve due to local inflammation and a progressive burnout of the follicles.³² Finally, as many of these patients complain of severe chronic pelvic pain, dyspareunia, and dysmenorrhea, surgery is beneficial in pain relief. In a recent publication of a Fertile Battle,³³ surgery was opposed to IVF in the treatment of ovarian endometrioma favoring surgery in case of pain.

Concerning minimal ovarian and peritoneal endometriosis a retrospective study³⁴ reported a significantly longer time to spontaneous conception when untreated compared to controls.

Recently, ethanol sclerotherapy of ovarian endometrioma was reported as a minimally invasive approach with a less negative impact on the ovarian reserve and a pregnancy rate of 40%.^35,36 In the absence of other fertility impairing factors, we reported a spontaneous pregnancy rate of 73.2% after treatment of minimal endometriosis using the transvaginal endoscopic approach.³⁷

The debate on the treatment of deep infiltrating endometriosis (DIE) is limited to those patients without pain, although performing IVF in the presence of a deep nodule is questionable as a good practice and not without risk. A significant benefit of surgery for DIE before IVF was reported in a recent meta-analysis³⁸ showing a 2.22 times higher live birth rate in the operated group compared to the non-operated group.

ACQUIRED UTERINE PATHOLOGY

Uterine myoma

Fibroids are traditionally classified according to anatomical location and divided into submucous, intramural, or subserosal locations. Fibroids are the most common benign tumors of the female genital tract and are associated with numerous clinical problems including a possible negative impact on fertility. Recommendations as to which infertile women with fibroids would benefit from myomectomy are varied, given the potential risks and sequelae of surgery. The divergence in published data is a result of heterogeneity of available data, lack of standardization in size, number, and location of myoma, and different endpoints (e.g. pregnancy rates, abortion rates, and obstetric outcomes).³⁹ Transvaginal ultrasound can be used as a first screening method, but is less sensitive and less specific for diagnosing submucous myomas than hysteroscopy and infusion sonohysterography.

The location of a fibroid within the uterus influences its effect on fertility. It is assumed that the submucosal myomas have a deleterious effect on implantation with lower pregnancy rates and a higher incidence of fetal losses. Concerning intramural myomas it is accepted that they have a negative effect on implantation certainly for those with deformation of the uterine cavity, but whether myomectomy has a positive effect on further fertility is still unclear. Subserosal myomas do not affect fertility.⁴⁰

One randomized trial including 87 women with one intramural and/or subserosal fibroid smaller than 4 cm and otherwise unexplained infertility studied the effectiveness of surgery by laparoscopy or laparotomy compared to no surgery. There was no statistically significant difference in outcomes, although there was a trend in improving the pregnancy rate per patient at 12 months (RR 1.2, 95% CI 0.75–1.9).⁴¹ Two randomized studies observed no differences in operative time or blood loss but noted that laparoscopy was associated with less postoperative pain, a shorter length of stay, and more rapid recovery;^15,16 one study also noted no significant differences in pregnancy and spontaneous abortion rates between the two techniques.^42,43

Hysteroscopic myomectomy is indicated for intracavitary myomas and submucous myomas having at least 50% of their volume within the uterine cavity. Myomas may be removed using hysteroscopic scissors, monopolar or bipolar electrosurgical techniques, or mechanical morcellators. In patients with submucosal fibroids with or without intramural fibroids and otherwise unexplained subfertility, hysteroscopic myomectomy doubles the pregnancy rate compared to expectant management (RR 2.2, 95% CI 1.6–2.9) as demonstrated by a meta-analysis of two randomized trials in 298 patients.^41,44 The classification of uterine fibroids in clinicopathological studies may be based on their relationship with the junctional zone myometrium rather than on the impact on the uterine cavity.⁴⁵ Magnetic resonance imaging (MRI) scans and high-resolution ultrasound would be useful to delineate the junctional zone and to determine whether the junctional zone myometrium is involved in the disease process.

Adenomyosis

The development of high-resolution imaging techniques, particularly MRI, marked a real turning point in the acknowledgment of adenomyosis as an important disorder of the female reproductive tract. The subendometrial-myometrial zone, also called the junctional zone, can be clearly identified and differentiated from the outer myometrium which has the function of the muscle power of delivery.

Recent research has demonstrated that the junctional zone (JZ) is exam dependent and not a well-defined entity, as it differs in MRI from ultrasound and histology.⁴⁶

Adenomyosis is a histological definition and a hysteroscopic or hystero-ultrasound guided biopsy is mandatory to confirm the diagnosis.

The Campo Trophyscope® hysteroscope provides the possibility to use the outer sheet as a guide to insert an endometrial sampler or an endometrial–myometrial biopsy probe called the spirotome.¹³ The spirotome consists of a corkscrew and cutting sheet which permits the collection of a biopsy of up to 2 cm in length under ultrasound guidance. This technique claims to collect tissue with minimal risk of cell spreading and bleeding. In practice, after removing the spirotome the Trophy optic can be reinserted to inspect the area where the biopsy was collected.^47,48 Today, also the new 15 French IBS Shaver optic provides the possibility to insert the spirotome under direct vision giving the superior possibility of eye directed and ultrasound controlled sampling.

Like endometriosis, adenomyosis may present itself in various disguises, ranging from simple JZ thickening to nodular or diffuse lesions involving the entire uterine wall. Adenomyosis is likely to impair fertility through disturbed peristalsis of the junctional zone negatively affecting sperm transport. It is not very clear whether implantation as such is disturbed, but a possible higher rate of spontaneous abortion is reported.⁴⁹ In the case of diffuse adenomyosis, surgery is not a first treatment option. In women who wish to preserve their fertility, medical therapy with gonadotropin-releasing hormone agnonist (GnRHa) and GnRH antagonists seems to have a beneficial effect with reduction of the adenomyotic lesions and regression of abnormal uterine bleeding.⁵⁰ An adenomyoma can be removed both by hysteroscopy or laparoscopy, with results comparable to myomectomy in spite of the fact that borders are less defined. Focal adenomyosis or cystic structures located in the subendometrial area are treated by an operative hysteroscopy procedure.⁵¹ In case of diffuse adenomyosis, the triple flap technique by laparotomy is advocated.^52,53

Uterine niche

A uterine niche is defined as an indentation at the site of a cesarean section with a depth of at least 2 mm. Diagnosis is most accurately defined by gel or saline contrast sonography. Length, depth, and width should be measured, and also the residual and adjacent myometrial thickness in the sagittal plane.⁵⁴ The added value of hysteroscopic examination is dual. First, access to the uterine cavity can become very difficult due to displacement and stricture of the internal cervical ostium. Second, hysteroscopy allows visualization of whether the niche is filled with bloody vascular implants and the presence of blood and/or glair in the cavity in the peri-ovulatory phase. This information seems  to be important for a well-prepared embryo transfer or IUI.

The presence of blood in the cavity can even interfere with the likelihood of spontaneous pregnancy. The persistent presence of blood creates a toxic environment for embryo implantation, through excessive iron content and higher amplitude of subendometrial contractions.⁵⁵ It negatively affects pregnancy rates even after IVF.^56,57 Treatment can be done through a laparoscopic, hysteroscopic, or vaginal approach. Hysteroscopic resection consists of shaving the distal rich of the niche allowing the drainage of menstrual blood; in order to reduce the risk of bladder injury, the residual myometrium thickness should be between 2.5 and 4 mm.^58,59,60 It seems to be more effective for small niches and less for relatively large niches. In the latter case, the laparoscopic or vaginal approach are recommended resulting in better postoperative results, and in contrast with the hysteroscopic approach they repairs the uterine wall thickness.⁶¹ Reported results of laparoscopic niche repair are an improvement of symptoms in nearly 77% of patients, restoration of fertility in 73%, and decreased time to conception.⁶²

UTERINE CONGENITAL ANOMALIES

Following the ESHRE/ESGE classification,⁶³ the uterine deformations of class U1 (dysmorphic ) and class U2 sub-septus seem the most relevant anomalies in reproductive medicine. There is no doubt that the incidence of uterine malformations U1 and U2 is higher in the infertile population and that it influences the pregnancy outcome in IVF.

The current controversies result from the fact that different diagnostic methods have different levels of accuracy and there is subjectivity in the criteria used to classify anomalies, especially hysteroscopy has a significant interobserver variation.

A prospective cohort study by Neal et al.⁶⁴ performing 3D ultrasound in 648 patients defining uterine cavity morphology the day before embryo transfer, demonstrates that T-shaped uterine cavity morphology is associated with adverse pregnancy outcomes after transfer of a single thawed euploid blastocyst

New diagnostic methods like 3D ultrasound and the combination of HSC and ultrasound challenge the definitions and interpretation of uterine cavity deformation. As such the Congenital Uterine Malformation by Experts (CUME) criteria⁶⁵ have contributed to better defining the dysmorphic uterus. Although the hysteroscopic criteria do not equal the ultrasound ones, by using only the hysteroscopic criteria, Ferro demonstrated in patients with failed IVF, in the IVI clinic of Valencia, that after reconstruction of the cavity with the micro-scissors, 77.9% (147/190) delivered and the abortion rate was only 8.9%.^66,77 This study has a significant value because it is a single center, single observer, surgeon study with both IVF and hysteroscopic surgery approved champion class.

All other studies with a single surgeon approach per center have similar results.^67,68,69,70

Nawroth observed an increased interval of pregnancy seeking in patients with septa with otherwise unexplained primary and secondary infertility.⁷¹ Homer et al.⁷² compared the reproductive outcome before and after hysteroscopic metroplasty, resulting in a decreased abortion rate from 88% before to 14% after metroplasty and an increased live birth rate from 3% before to 80% after. Although the role of metroplasty in infertility remains debated, this study reported an overall crude pregnancy rate of 48% after metroplasty.

The anomalies of the uterus can affect endometrial receptivity, resulting in implantation failure with pregnancy loss or infertility. They can be the reason for prolonged pregnancy seeking in women with so-called ‘idiopathic infertility’.⁷³

Two recent meta-analyses reported a better reproductive outcome after hysteroscopic metroplasty.^74,75 In patients with infertility or recurrent abortions, data support the correction of the uterine anomaly. In the hands of experienced hysteroscopist complications are rare.

For the above reasons, Rikken et al.⁷⁶ study cannot be accepted, and their conclusions must be seen as scientifically debatable. This study was criticized because of the lack of standardization of diagnostic methods, the long recruiting time of 19 years, the many centers involved, and the lack of surgical quality control and postoperative control hysteroscopy. Dysmorphic and septate uterus are the most frequent malformations seen in the infertile patient. Hysteroscopic metroplasty prior to ART or in the case of recurrent abortions is associated with an improvement in the achievement of pregnancy and in pregnancy outcome. In an individual case where a U1 or U2 malformation has been diagnosed accidentally, we do not yet have the possibility to predict the future reproductive capacity of the individual. There is an urgent need for a clear definition of the normal uterus and diagnostic and surgical recommendations to reduce interobserver variability.

CONCLUSION

Techniques in MAR (medically assisted reproduction) improved resulting in the perception of a diminished need for reproductive surgery. However, the possibilities of reproductive surgery  have also changed over the years with the development of new technologies and instrumentation and new indications for surgical repair. Technical evolution in the field of imaging provides us with more information on different organs and more particularly on the uterus including cesarean scar defects, dysmorphic uteri, and adenomyosis. Reproductive laparoscopic skills will be necessary for new fields of fertility preservation and the further development of uterine transplantation. To optimize the outcome of reproductive surgery there will be a continuous need for skilled reproductive surgeons, skills which in many places are no longer available. Therefore, continuous training and accreditation programs are mandatory to reach the highest standards in reproductive surgery. Centers of excellence in reproductive medicine should combine the highest standards in MAR technologies and possibilities of reproductive surgery. ESHRE/ESGE and others have defined a validated program of certification and diploma in reproductive and minimal invasive surgery called GESEA (www.GESEA.eu). It is the first step in standardization of the surgical skills. Each IVF center should have access to a level 2 or 3 ECRES-accredited surgeon.

PRACTICE RECOMMENDATIONS