Role of surgery to optimise outcome of assisted conception treatments
Correspondence: Yalanadu Suresh. Email: firstname.lastname@example.org
- Assisted conception technology such as in vitro fertilisation (IVF) is the first-line treatment of many causes of female subfertility and surgery is offered primarily to optimise the outcome of such treatments.
- An awareness and understanding of the evidence about the different surgical interventions used prior to assisted conception is essential in achieving the best possible outcome.
- To assess the fertility needs of women including the need for surgery.
- To understand the role of different surgical interventions prior to assisted conception for the management of hydrosalpinx, uterine fibroids, uterine pathology such as a uterine septum and intrauterine adhesions, and the treatment of endometriosis and ovarian endometriomas.
- Women should be counselled about the benefits and risks of surgery including the risk of delay to their assisted conception.
- A sympathetic approach is needed for women who are already emotionally and physically stressed.
- There are financial implications involved in IVF treatment.
- Psychosocial issues and anxiety require a multidisciplinary approach.
Assisted conception – any treatment controlling the way the egg and sperm are brought together – is the mainstay of modern subfertility management. Surgery is used primarily to optimise the success rates and reproductive outcomes of women undergoing such treatments. The evidence to support removal of hydrosalpinx prior to in vitro fertilisation (IVF) treatment is strong. However, the argument for surgical treatment of other reproductive diseases such as fibroids, endometriosis, uterine anomalies and intrauterine adhesions is less robust and often confusing and misleading.
This article aims to review the current best available evidence as well as provide an expert insight into the various surgical interventions used to optimise the outcome of assisted conception.
Salpingectomy for management of hydrosalpinx
The detrimental effect of hydrosalpinx on the outcome of IVF is now well documented, but the underlying reasons are still not clear. Suggested mechanisms range from exposure of transferred embryos to more direct toxic effects of the hydrosalpinx fluid on embryo development and implantation.2
The first multicentre randomised controlled trial evaluating the efficacy of salpingectomy in 204 women prior to IVF reported a two-fold increase in success rates following laparoscopic salpingectomy compared with no surgery. Subgroup analysis showed a larger treatment effect (up to 3.5-fold increase in delivery rate) for women with more severe disease, that is, those with larger – and therefore easily visible on ultrasound examination – and/or bilateral hydrosalpinx. One-third of women originally randomised to no surgery underwent subsequent interval salpingectomy after one or two failed IVF treatment cycles and a follow-up study showed that cumulative success rates, based on an intention to treat analysis, were similar in the two groups. Since then there have been further randomised controlled trials confirming the benefits of salpingectomy (odds ratio [OR] 2.14, 95% confidence interval [CI] 1.23–3.73).
Although laparoscopic proximal tubal occlusion has been shown to be a suitable alternative,1 we would recommend salpingectomy because the exact mechanism for low pregnancy and birth rates in patients with hydrosalpinx is still unclear. Moreover, salpingectomy confers additional non-fertility benefits such as the treatment of coexisting pain and prevention of sepsis or torsion.
The efficacy of interventions such as laparoscopic salpingostomy, hysteroscopic proximal tubal occlusion and aspiration of hydrosalpinx fluid is unclear and should be evaluated by further large-scale research trials. The authors of this review offer ultrasound-guided aspiration of hydrosalpinx fluid at the time of egg collection in cases where surgery is absolutely contraindicated.
In summary, all women with visible hydrosalpinx should be offered surgery prior to IVF (Table 1). Salpingectomy is the treatment of choice, however, proximal tubal occlusion is a suitable second-line treatment in complex cases. Women who refuse primary surgery should be counselled regarding the benefits of interval surgery after a failed IVF treatment cycle, especially in the presence of good embryo development and quality.
Table 1. Summary of recommendations and available evidence
Salpingectomy as first line;
proximal tubal occlusion for complex surgical cases
|Randomised controlled trials/ expert opinion|
|Uterine septum||Septoplasty||Controlled trial / expert opinion|
|Intramural fibroid||Myomectomy for cavity distorting fibroid or size >50 mm||Controlled trial[11, 20]/ expert opinion|
|Submucous fibroid||Myomectomy||Randomised controlled trial11|
|Subserous fibroid||Conservative management ||Expert opinion|
|Polyps||Polypectomy||Randomised controlled trial|
|Intrauterine adhesions||Adhesiolysis||Expert opinion|
|Superficial endometriosis||Laparoscopic treatment||Randomised controlled trial|
|Deep infiltrating endometriosis||Surgery for symptom relief only||Expert opinion|
|Endometrioma||Surgery for size >40 mm||ESHRE guideline|
|Recurrent endometriosis||Surgery for symptom relief only||Expert opinion|
Myomectomy for management of uterine fibroids
Fibroids are common, benign tumours of the uterus occurring in up to 77% of women approaching the age of 50. Despite a clear biological rationale to support a causal relationship between fibroids and subfertility, large observational studies[6, 7] are inconclusive because of methodological limitations.
The presence of fibroids significantly reduces the success of IVF treatments.[8, 9] Submucosal fibroids strongly interfere with conception (OR for delivery of 0.3 [a 70% reduction], 95% CI 0.1–0.8).[8, 9] Even intramural fibroids not distorting the endometrial cavity result in a reduction in live birth rate (LBR) (OR for LBR of 0.79 [a 21% reduction], 95% CI 0.70–0.88).[8, 9] The presence of subserous fibroids was not associated with a reduction in treatment success. Most of the trials included in these meta-analyses used retrospectively matched controls; however, the results are not dissimilar if the analysis is restricted to prospective matching only.[8, 9] The results must also be interpreted with caution, as there was significant heterogeneity in the diagnostic methods used to ascertain normality of the uterine cavity, which may lead to an overestimate of the impact of non-cavity distorting intramural fibroids. A review restricting methodology to 10 controlled studies concluded that there was insufficient evidence to draw any conclusions regarding the effect of intramural fibroids on treatment outcomes.
Observational studies suggest a fertility benefit for the surgical removal of fibroids (myomectomy). There are a variety of surgical methods to remove fibroids including laparotomy, laparoscopy and hysteroscopy. The relative advantages and disadvantages of these modalities in terms of efficacy and side effects are unknown.
The first randomised controlled trial evaluating the benefits of myomectomy in women with submucosal and intramural fibroids was reported in 2006. A total of 181 women with at least 12 months of subfertility and no more than one uterine fibroid larger than 40 mm were randomised to surgery (laparotomy and operative hysteroscopy) or expectant management and followed up for 12 months. The study reported a significant improvement in spontaneous conception rates following removal of submucous fibroids and intramural fibroids distorting the uterine cavity. However, the study was underpowered, not blinded and it is unclear whether hysteroscopy was performed systematically in all women. Moreover, a recent re-analysis of the published data showed only marginal benefit of myomectomy for the entire study population and none for the subgroup of women with submucous fibroids, in direct contrast to the results of the original study.
The controlled trials reporting fertility benefits of laparoscopic and hysteroscopic myomectomy have used inappropriate controls. There are no controlled studies reporting the obstetric outcome of women who underwent myomectomy and the potential risk of uterine rupture during pregnancy and labour, although unquantifiable, is likely to be very low (<1%).
Removal of submucous and intramural fibroids that distort the endometrial cavity is usually recommended prior to IVF despite the lack of good evidence to support such practice. The staging first described by Wamsteker et al. is widely used to classify submucous fibroids at hysteroscopy and is also increasingly used during ultrasound examination. There is general consensus that type 0 and type 1 fibroids, where at least 50% of the fibroid is within the uterine cavity, are best removed hysteroscopically, whereas the removal of type 2 fibroids, where more than 50% is within the myometrium, is more complex. Type 2 fibroids larger than 40 mm may need two to three surgical procedures to ensure completeness of resection, thus increasing the risk of endometrial damage and complications. A suitable alternative is to remove such fibroids laparoscopically (or by laparotomy) should this be deemed necessary. Although laparoscopic removal of fibroids has not been shown to confer additional fertility benefits over laparotomy, there is significant reduction in hospital stay and febrile morbidity. The management of multiple submucous fibroids or multiple uterine fibroids with submucous lesions is unclear.
Controlled trials reporting the outcome of IVF treatment following myomectomy[17-19] have used inappropriate controls. The only prospective controlled trial using un-operated women with fibroids as a control group reported a significant benefit of myomectomy (cumulative delivery rate 25% versus 12%). The study population consisted of 168 women with at least one intramural or subserosal fibroid larger than 50 mm who self-allocated to surgery or no surgery after receiving full information about the benefits and risks of surgery.
In summary, myomectomy is recommended for the management of submucous and cavity distorting intramural fibroids before IVF, although there is no strong evidence that this improves outcomes (Table 1).
Hysteroscopy and hysteroscopic surgery for the management of uterine cavity abnormalities
A wide range of endometrial and uterine cavity abnormalities has been reported in women with subfertility. These include polyps, fibroids, intrauterine adhesions and uterine anomalies. The underlying mechanisms interfere with fertility by affecting sperm migration and embryo implantation.
Despite the advances in ultrasound imaging technology, its accuracy in screening intrauterine pathology remains unsatisfactory. For example, one study reported a previously unsuspected intrauterine abnormality in 11% of women due to undergo IVF treatment;21 reassuringly, the majority were polyps smaller than 10 mm. Other abnormalities such as fibroids, adhesions and septa were also reported.
Two randomised controlled trials[22, 23] investigated the role of hysteroscopy in women with at least two failed IVF treatments; overall 941 women were randomised to further IVF treatment with or without prior outpatient hysteroscopy. Office hysteroscopy immediately prior to a new cycle of IVF significantly increased clinical pregnancy rate compared with the rate seen in women without prior hysteroscopy (OR 1.6, 95% CI 1.3–1.9). In the intervention group, there was no significant difference in treatment effect between women with normal findings and women with abnormalities (314/465 versus 151/465, OR 1.0, 95% CI 0.7–1.2). The underlying mechanism for the beneficial effect, especially in the absence of any treatable pathology is unknown; however, mechanistic studies suggest it may be related to pro-implantation changes induced by inadvertent local endometrial injury during hysteroscopy. There were methodological deficiencies in the two reported randomised controlled trials and a multicentre trial is now under way to validate the results.
While promising, the results need to be validated by further research and so hysteroscopy is not recommended as first-line investigation in subfertile women despite its safety and patient acceptability.
Perez-Medina et al. randomised women with a clear sonographic diagnosis of endometrial polyps and at least 24 months of subfertility to hysteroscopy and polypectomy or hysteroscopy and polyp biopsy prior to planned intrauterine insemination (IUI) treatment. The mean polyp diameter in the treated group was 16 mm (3–24 mm). The pregnancy rates after four cycles of stimulated IUI starting at least 3 months after surgery were significantly higher in the polypectomy group (63% versus 28%). Interestingly, 65% of all pregnancies in the polypectomy group occurred before the first IUI cycle and no difference was found between different polyp group sizes.
Despite a lack of clinical evidence, most clinicians would recommend hysteroscopic removal of endometrial polyps prior to IVF (Table 1). The management of polyps newly diagnosed during IVF treatment and that of recurrent polyps or polypoidal endometrium is unclear.
Hysteroscopy is the gold standard for the diagnosis and treatment of intrauterine adhesions. The conception rate following adhesiolysis in subfertile women is reported to be between 35% and 84%. Treatment has been shown to be more successful in younger women and in those with minimal disease. However, no meaningful conclusions can be drawn from these trials as they were uncontrolled, subject to sampling and reporting bias, and failed to account for confounders. A variety of non-validated classification systems were used to assess disease severity and surgical outcomes such as degree of normalisation of uterine cavity, post-surgical endometrial development and recurrence rates were not properly reported.
No controlled trials have assessed the impact of adhesions and the role of surgical treatment prior to assisted conception. Hysteroscopic division of adhesions with scissors or electrosurgery is usually recommended and some women may require multiple procedures to achieve a satisfactory anatomical result. Postoperative mechanical distension of the uterine cavity with an intrauterine device and hormonal treatment with estrogen to facilitate endometrial regrowth are commonly used to decrease the high rate of adhesion reformation. None of these adjuvant therapies have been evaluated in properly designed clinical trials and newer anti-adhesive therapies are still in their infancy.
In summary, hysteroscopic adhesiolysis is recommended to all women with intrauterine adhesions prior to assisted conception (Table 1). We use an intrauterine copper coil for 6 weeks and/or estrogen therapy as adjuvant treatment. The surgical result rather than disease severity should be used to assess suitability for further assisted conception treatment and women offered surrogacy where appropriate.
Uterine septum and other uterine anomalies
Women with uterine anomaly have poor reproductive outcomes.[31-37] Research in this area has mainly been restricted to observational studies, but now a small number of controlled trials have been published.[37-39]
A review of non-controlled trials reported a 74% reduction in miscarriage risk following hysteroscopic division of uterine septum (septoplasty) in women with recurrent miscarriage. The precise mechanism by which a septum may cause subfertility is not fully understood, however, observational studies[31, 32, 35, 37] have shown that the presence of a septum represents an important hysteroscopically preventable risk factor for spontaneous miscarriage and lower implantation rates in women undergoing IVF treatment. The available evidence also suggests poor outcomes for women with arcuate uterus[36, 37]; however, there is no agreement over whether this anomaly should be treated even in women with recurrent miscarriage.
While the usefulness of septoplasty is yet to be established, a randomised controlled trial has been published that compared septoplasty performed using a bipolar Versapoint® electrode (Ethicon Gynecare, Johnson & Johnson Medical Ltd., Livingston, UK) (5 mm telescope) with that performed using a monopolar electrode (8 mm telescope) in 161 women with septate uterus and a history of recurrent miscarriage or primary subfertility. There was no difference in pregnancy rates between the two groups. A re-analysis of the original data showed that treatment was less beneficial to women with subfertility than to those with recurrent miscarriage. Non-randomised controlled trials have shown that hysteroscopic septoplasty improves natural conception rates in women with otherwise unexplained subfertility, as well as the success of women undergoing IVF treatment.
In summary, the feasibility and safety of hysteroscopic septoplasty justifies the treatment of uterine septum prior to IVF (Table 1).
Surgery for endometriosis
Endometriosis is the presence of endometrial glands or stroma in sites other than the uterine cavity. Endometriosis affects 20–40% of women with history of subfertility, as compared to the background prevalence of 5–10% in the general female population. The possible reasons for subfertility in endometriosis include dyspareunia and alterations in pelvic anatomy and peritoneal and tubal environments. Other proposed mechanisms include interference with fertilisation, oocyte and embryo development, and implantation. However, mechanistic studies in IVF populations are inconclusive and analysis of large registry data and results of other controlled trials show that IVF success is similar if not better in women with endometriosis than in women with other aetiologies such as tubal factor subfertility,[43, 44] despite reduced responsiveness to ovarian stimulation.
The American Society for Reproductive Medicine (ASRM) system that is widely used to ‘stage’ endometriosis is complex to implement and has limited prognostic value. Hence, some clinicians prefer a descriptive system where endometriosis is classified into three main entities based on anatomical location: superficial endometriosis, ovarian endometrioma and deep infiltrating endometriosis including rectovaginal endometriosis. Endometrioma and deep infiltrating endometriosis can be diagnosed accurately using clinical and transvaginal ultrasound examination.[47-50] Consequently, laparoscopy, which hitherto has been considered as gold standard, is indispensible only for the identification of superficial lesions. Medical treatment, while useful for managing pain symptoms and limiting progression of disease, is not compatible with fertility. Surgical treatment of endometriosis aims to remove all areas of endometriosis (optimal debulking) and restore anatomy by the division of adhesions.
The Endometriosis Canadian (ENDOCAN) multicentre randomised controlled trial showed a two-fold (OR 2.06, 95% CI 1.28–3.33) increase in conception rate following laparoscopy and treatment of superficial endometriosis compared with diagnostic laparoscopy alone. In contrast, a smaller Italian multicentre randomised controlled trial failed to confirm treatment benefits. Pooling the results of the two trials indicates a marginal treatment benefit (OR 1.65, 95% CI 1.06–2.58). Since preoperative diagnosis of superficial lesions is not feasible, the findings cannot be the basis for routine diagnostic laparoscopy in the workup of subfertility, especially in populations where the prevalence of endometriosis is low. However, ablation or excision of superficial endometriosis should be offered to all subfertile women undergoing diagnostic laparoscopy for other indications such as chronic pelvic pain or tubal patency testing.
No studies have investigated the role of laparoscopic treatment in the management of superficial endometriosis prior to assisted conception. However, following successful treatment, women can be advised about natural conception or IUI as deemed appropriate. It is the authors' opinion that women with chronic anovulation are unlikely to have significant endometriosis as an attributable cause for subfertility.
The management of subfertility associated with endometriomas (endometriotic ovarian cysts) is controversial. Spontaneous conception rates following treatment range from 30% to 67% with a weighted mean of 50%. This is based on a review of observational uncontrolled trials and therefore likely to be an overestimate. Although the risk of physical reduction in ovarian reserve is greater with excision than with simple drainage and ablative therapy of endometrioma, pooled analysis of randomised controlled trials[55, 56] favours excision to improve the chance of natural conception (OR 5.11, 95% CI 2.03–12.85), to reduce recurrence of disease (OR 0.41, 95% CI 0.13–0.93) and to reduce recurrence rate of dysmenorrhea (OR 0.15, 95%CI 0.06–0.38), dyspareunia (OR 0.08, 95% CI 0.01–0.51) and non-menstrual pelvic pain (OR 0.10, 95% CI 0.02–0.56). There are currently insufficient data to clarify whether endometrioma-related ovarian damage precedes or follows surgery.
Although international guidelines recommend treatment of endometrioma ≥40 mm prior to IVF, the available evidence does not support this practice.[40, 54, 59] The European Society of Human Reproduction and Embryology (ESHRE) guideline is based on data comparing the number of developing follicles in the endometrioma-affected ovary using the contralateral intact gonad as a control.[60, 61] The presence of endometriomas <40 mm at the time of IVF did not markedly affect responsiveness to ovarian stimulation,[60, 61] thus suggesting a mild, if any, impact on ovarian reserve. The only published randomised controlled trial on management of endometrioma prior to IVF failed to show significant differences in fertilisation, implantation and pregnancy rates in 99 women allocated to either surgery or no surgery. Surgery, however, resulted in significantly longer stimulation, higher follicle-stimulating hormone requirements and lower oocyte numbers. There is limited evidence on the treatment of endometriomas prior to IUI and most clinicians would recommend surgery followed by natural conception or IVF in women with endometriomas.
The location of endometriomas and relative immobility of the ovary can impede safe access to the follicles during oocyte retrieval, thus potentially compromising oocyte yield and success of IVF treatment. There is also a tiny risk of pelvic and ovarian abscess due to inadvertent puncture of endometriomas during oocyte collection. We routinely prescribe a single dose of antibiotic at the time of oocyte retrieval in women with endometriomas.
Deep infiltrating endometriosis
Endometriosis infiltrating posterior cervicovaginal and anterior rectal tissue causes deep dyspareunia and defecation pain. Incomplete resection of the lesion does not relieve pain and therefore surgery is technically demanding and often needing colorectal surgical support. Most studies on the treatment of deep infiltrating endometriosis focus on the relief of pain and only one non-randomised controlled trial has been published that compared the reproductive outcome in 44 women who underwent surgery with 61 matched controls who did not undergo surgery. There was no difference in conception rates at 12 and 24 months, but recurrence rates and symptom control was significantly better for the treated group. However, in common practice, relief of dyspareunia and co-treatment of superficial and ovarian endometriosis is likely to confer fertility benefits.
No studies have investigated the role of surgical treatment of deep infiltrating endometriosis prior to assisted conception.
The fertility management of recurrent endometriosis is unclear. Based on the limited evidence, the benefits of surgery are smaller than first-line surgery. Women with superficial and deep endometriosis should be offered IVF treatment, whereas surgery for large endometriomas in order to optimise patients for oocyte retrieval should be limited to drainage and adhesiolysis only.
Surgery after failed IVF
A retrospective controlled trial reported significantly higher spontaneous conception and IVF success rates in 29 women who underwent complete excision of ASRM stage 1–4 disease following at least one failed IVF treatment. The description of the 35 women who chose not to undergo surgery (controls) is poor and therefore the treatment effect is likely to be an overestimate.
Adjuvant medical therapy
There is no reported fertility and non-fertility benefit of preoperative and postoperative gonadotrophin-releasing hormone (GnRH) analogue treatment, whereas a major reduction in recurrence rates of endometriosis has been demonstrated following the postoperative use of oral contraceptives. A Cochrane review of three randomised controlled trials found that administration of GnRH agonists for a period of 3–6 months prior to IVF in women increased the odds of clinical pregnancy by four-fold.
In summary, women with endometriosis-associated infertility should be offered surgery to manage pain symptoms and to improve their chance of natural conception; the reproductive benefits of treating deep infiltrating endometriosis is unclear and may be associated with significant morbidity (Table 1). The management of endometriomas prior to IVF is unclear; surgery is usually offered to women with large lesions (≥60 mm at our unit) in order to optimise oocyte retrieval and exclude the risk of malignancy (Table 1). Excision rather than ablation is the preferred treatment unless the ovary has been operated on previously. All women with confirmed diagnosis of endometriosis should be offered 3–6 months of pituitary suppression with a GnRH analogue prior to IVF. The optimal management of recurrent endometriosis is unclear, but patients desirous of conception should be offered IVF treatment.
The influence of fibroids, endometriosis and uterine anomalies on fertility is poorly understood and this limits a proper understanding of the role of various surgical interventions in the context of subfertility management. Most of the available evidence is retrospective and while prospective data using appropriately matched controls are emerging, the heterogeneity of reproductive diseases and their treatments presents a significant challenge to conduct large well-designed randomised trials.
An individualised treatment plan should be implemented taking into account the patient's age, duration of subfertility, previous treatments, local surgical expertise and other causative factors. A pragmatic approach has been proposed in this article based on a review of the best available evidence and the authors' clinical experience.
Disclosure of interests