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Gynecology Research Unit, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Av. Mounier 52, 1200 Brussels, BelgiumDepartment of Gynecology, Cliniques Universitaires Saint-Luc, Av. Hippocrate 10, 1200 Brussels, Belgium
Could IVF replace reproductive surgery? The answer is no. Reproductive surgery has still a place, at least in some indications that we will explore in this contribution. While IVF can offer infertile couples the chance to have a healthy baby, it should be acknowledged that reproductive surgery can heal or harm organs where reproduction takes place.
In this paper, we have reviewed different diseases and conditions responsible for infertility, which may benefit from technological innovations of recent decades, novel applications, and the skill of reproductive surgeons. Reproductive surgery is certainly not dead. It lives on with the promise of restoring the functional anatomy to enhance the chances of pregnancy. It is our responsibility to train young residents adequately in this field to provide the right treatment at the right time.
When indications for reproductive surgery versus IVF are discussed, the fundamental question remains the same one: could simply IVF replace reproductive surgery? The answer is no. Reproductive surgery has still a place, at least in some indications. We will explore them one by one.
1) Uterine septum resection
The need or otherwise for uterine septum resection has been one of the most controversial issues of the last decade. Indeed, Rikken et al (Rikken et al, 2020) reported that septum resection does not increase live birth rates nor reduce pregnancy loss or preterm birth compared to expectant management but a number of experts, in a letter to the editor, felt compelled to point out numerous sources of bias in Rikken's study. First among them were the many centers involved (n=21) and long recruiting time frame applied (n=19 years), resulting in an average of just 0.37 cases/center/year. Further, the potential impact of overdiagnosis of septate uterus needs to be taken into account. The diagnostic methods used in the study do not reflect current gold standard diagnostic modalities, and the extension of the septum was not even defined.
Two recent meta-analysis and systematic reviews both support the notion that hysteroscopic metroplasty for uterine septum can lower the risk of miscarriage and increase the live birth rate. In experienced hands, the risk of complications is minimal and the risk-benefit balance weighs in favor of metroplasty, which is why experts should continue to offer the procedure to infertile women with uterine septum.
2) Endometriomas: IVF vs surgery
As stressed by Lessey et al (Lessey et al, 2018), women with endometrioma-related infertility face a dilemma when choosing the right approach to achieve their dream: surgery or IVF. One cannot overstate the concerns about the potential toxicity of endometrioma content (iron, reactive oxygen species, among others), which may cause local inflammation culminating in the so-called burn-out effect, responsible for a diminished ovarian reserve.
Despite misgivings about the impact of endometrioma surgery on the ovarian reserve, surgery does have a fundamental role to play, as the benefits in terms of pain relief and spontaneous pregnancy rates endorse this approach. Large series of women undergoing operative laparoscopy for management of endometriomas achieved spontaneous pregnancy rates of >50% after surgery. Of course, to keep any damage to the ovary to a minimum, knowledge of the appropriate technique and a certain level of expertise are required.
In 2018, a Fertile Battle (Lessey et al, 2018) on the pro and cons of surgery versus IVF opposed surgery as the first-line approach in case of infertility (Figure 1). However, even IVF advocates consider surgery to be indicated when the patient is in pain that interferes with her daily life, or when rapid growth or features of malignancy are detected on ultrasound. Surgery also improves follicles accessibility.
There are therefore strict indications for surgery and the most recent ESHRE guidelines state that operative laparoscopy may increase the chances of natural pregnancy, albeit in the absence of data from comparative studies (Becker et al, 2022). Overall, there is a broad consensus that for endometriomas over 4 cm in size, the clinical balance tips more towards surgery, especially since it was demonstrated that endometriomas measuring more than 4 cm interfere with the ovarian response to ovarian stimulation (Somigliana et al, 2020). Patient age and preferences (co-sharing the decision), history of previous surgery (recurrence), the ovarian reserve and physician expertise are factors which should guide the decision.
3) Deep endometriosis
Treatment of deep endometriosis-related infertility is still challenging. In an extensive review, Donnez (Donnez, 2021) concluded that rectal shaving should be considered the primary surgical approach in most women and reported spontaneous pregnancy in more than 50% of cases after surgery for deep endometriosis.
On the other hand, some teams favor performing IVF before surgery, but starting IVF in a woman with a deep endometriosis nodule left in place is somewhat questionable. It is even more questionable in women suffering from severe dysmenorrhea, dyspareunia and chronic pelvic pain, which are frequent symptoms. Several studies have shown that IVF procedures do not have a positive impact on pain symptoms, while others point out the difficulty of ovum pick-up due to the presence of a large nodule.
A recent systematic review and meta-analysis (Casals et al, 2021) revealed significant benefits of surgery for deep endometriosis nodules before IVF. Indeed, the live birth rate was 2.22 times higher in patients with previous surgery than in those undergoing IVF without previous surgery. Although the debate is not settled, there are some absolute indications for surgery (preferably the shaving approach) in case of: (i) painful nodules of ≥3 cm in size; (ii) ureteral involvement (occurring in over 10% of cases if the nodule is >3cm in size); (iii) association with bladder endometriosis; (iv) bowel involvement with severe substenosis (80%); and (v) association with a ≥3/4 cm endometrioma (Donnez, 2021). While it is suspected that infertility and deep endometriosis are strongly related, surgery versus first-line assisted reproductive technology (ART) for infertile women with deep endometriosis is still a matter of debate.
4) Uterine fibroids
Uterine fibroids-related infertility may be explained by uterine cavity distortion, impaired endometrial/myometrial blood supply, defective endometrial receptivity and HOXA-10 expression and, finally greater uterine contractility (Dolmans et al, 2021).
In case of FIGO type 0-1-2, hysteroscopic myomectomy is the standard minimally invasive procedure.
For type 2, or if the myoma exceeds 3 cm in size, use of preoperative gonadotropin-releasing hormone (GnRH) agonist/antagonist may facilitate surgery by reducing fibroid size.
In case of intramural fibroids that do not distort the endometrial lining (type 3-4), several meta-analyses conclude that their removal is indicated in infertile woman seeking to conceive through ART. Indeed, it is suggested that type 3 fibroids measuring more than 2.5 cm should be removed before ART, as they exert a negative effect on implantation, clinical pregnancy and live birth rates in women undergoing IVF. Concerning the surgical approach, the decision to perform a laparoscopy should take into account the experience of the surgeon and their ability to achieve an appropriate suturing of the uterine wall.
5) Cesarean scar
The presence of blood and endometrial debris in the cesarean scar defect (CSD) may impair fertility through several mechanisms, including the flow of bloody fluid or bleeding from the defect and the cytotoxicity of iron. Excess iron in the uterine cavity is toxic to embryos and may impair their implantation by disrupting endometrial receptivity or uterine microbiota (Donnez, 2020). It was very recently reported that the presence of a CSD could negatively impact pregnancy outcomes after IVF with frozen-thawed embryo transfer (Zhang et al, 2022).
It is therefore both logical and appropriate to propose surgery before contemplating IVF in these women, and also in infertile and symptomatic patients wishing to conceive. Laparoscopic repair should be considered in case of residual myometrial thickness of <3 mm, in which case repair is essential, while hysteroscopic resection should be carried out if the thickness is >3 mm. The take-home baby rate after surgery was found to range from 21.8% to 75% (Donnez et al, 2020).
6) Tubal reanastomosis
Approximately 1-3% of women who have undergone tubal ligation request a reversal looking to conceive, but debate is ongoing between surgery and IVF. We favor surgery because, according to a review of 15 studies (Sato et al, 2021), there is at least a 60% chance of giving birth within the following five years if tubal reversal is done before 40 years of age. After 40 years, the rate falls to half that number.
After patient age, the next most important prognostic factors are the remaining tubal length and the integrity of the ampulla, which is the site of fertilization and early embryo development.
In our personal series, the live birth rate following laparoscopic tubal reanastomosis after ligation by clips or rings is more than 90% in women aged less than 40 years. What about women over 40 years of age? A study found delivery rates to be 27.3% in women over 42 years. This good prognosis for women of advanced reproductive age compared to outcomes in women undergoing IVF at the same age also endorses surgery, even in this age group.
7) Uterine transplantation
Uterine factor infertility affects up to 1/500 reproductive-age women and Mayer-Rokitansky-Küster-Hauser syndrome is the predominant congenital cause. Uterine transplantation gives these women the chance to become pregnant, avoiding the need for surrogacy or adoption.
Conditions for surgery are: (i) a vaginal length of >5 cm and wide enough to receive a parous cervix; and (ii) a sufficient number of frozen embryos (minimum 6 blastocysts). In transplant recipients, spontaneous menstruation was achieved in 100% of cases. To date (2023), 92 uterine transplantations and 49 live births (essentially in Sweden and the USA) have been recorded, perfectly illustrating the successful collaboration between IVF and surgery.
One key issue is the risk-benefit ratio of living versus deceased donors. In the first series published by Brännström (Brännström et al, 2019), the operating time for living donors was more than 10 hours. Efforts are being made to reduce this time, possibly with robotic assistance
8) Uterine adenomyosis
Two systematic reviews and meta-analysis found women with adenomyosis to exhibit a lower pregnancy and higher miscarriage rates than unaffected women. Inflammatory factors, endometrial receptivity alterations and macrophages linked to the presence of adenomyotic lesions could be responsible for decreased fertility in these subjects (Stratopoulou et al, 2023).
Focal adenomyosis can be resected (adenomyomectomy) by laparoscopy. Surgery is similar to myomectomy, but the plane of dissection between the adenomyoma and healthy myometrium is relatively difficult to identify.
In case of diffuse adenomyosis, the triple-flap method, described is best done by laparotomy, as this surgical procedure is extremely difficult to perform by laparoscopy. Indeed, diffuse adenomyotic tissue should be removed by finger palpation and delicate suturing by hand. This surgery requires a light touch and the risk of rupture during pregnancy is real. For severe adenomyosis in an enlarged uterus, we would advocate medical therapy like oral GnRH antagonist for 3 months to first reduce the size of the uterus and severity of the lesions. Then, 2 weeks after the end of therapy, frozen-thawed embryos collected before starting the medical therapy (Donnez et al, 2022) can be transferred.
9) Intrauterine adhesions
Hysteroscopy remains the gold standard to confirm how far of intrauterine adhesions extend and is an effective tool for treatment, seeking to restore the functional anatomy and endometrial activity to boost the chances of pregnancy. The likelihood of pregnancy depends on the extension of the lesions and the presence of remaining endometrial lining covering at least 50% of the surface (Santamaria et al, 2020). Postoperative pregnancy rates range from 35% to 60% depending on the severity of the lesions. When there is no endometrial lining and no chance of it being regenerated, the likelihood of pregnancy is, of course, very low (Santamaria et al,2020). Studies are urgently needed to find ways of regenerating the injured endometrium (barriers, stem cell therapy, etc).
Quo vadis, reproductive surgery? Surely a pertinent question for the 21st century, even if most reproductive endocrinology and infertility specialists are either inadequately trained or not interested in this field (Gargiulo and Bhagavath,2019). While IVF can offer infertile couples the chance to have a healthy baby, it should be acknowledged that reproductive surgery can heal or harm organs where reproduction takes place.
Different diseases and conditions responsible for infertility may benefit from technological innovations of recent decades, novel applications, and the skill of reproductive surgeons. Reproductive surgery is certainly not dead. It lives on with the promise of restoring the functional anatomy to enhance the chances of pregnancy. It is our responsibility to train young residents adequately in this field to provide the right treatment at the right time.
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