Surgical Interventions to Improve In Vitro Fertilization Outcomes: A Systematic Review of the Literature

Abstract

Background: Various gynecologic pathologies affect in-vitro fertilization (IVF) treatment detrimentally. Timely management of these pathologies could improve IVF outcomes. However, there is a lack of evidence-based guidelines on the appropriate surgical interventions prior to starting IVF treatment. Materials and Methods: The current authors systematically reviewed the literature published on surgical interventions described for different gynecologic pathologies related to IVF outcomes and summarized the literature available according to its level of evidence (Scottish Intercollegiate Guidelines Network [SIGN] classification). Results: This review found that resection of an endometrial polyp diagnosed before the start of an IVF cycle is recommended (level: 1−), whereas management of polyps diagnosed after the start of controlled ovarian stimulation should be individualized (level: 1−). Removal of subserosal uterine fibroids may not be warranted before IVF (level: 1−). There is insufficient evidence regarding the role of myomectomy for managing noncavity distorting intramural fibroids to improve IVF outcomes (level: 1−). Removal of submucosal fibroids is likely to improve IVF outcomes (level: 1−). Data from observational studies suggested that uterine septum resection before IVF treatment may be of benefit, but further evidence from randomized controlled trials is required (level: 2++). Laparoscopic salpingectomy or tubal occlusion improves IVF pregnancy rates in women with hydrosalpinges (level: 1+). There is no evidence to support surgical treatment (aspiration or cystectomy) of ovarian endometrioma over expectant management (level: 1+). Laparoscopic ovarian drilling could be a useful adjunct prior to IVF for women who have previously had IVF treatment cycles that were abandoned because of the risk of ovarian hyperstimulation syndrome (OHSS) or who have had severe OHSS in a previous treatment cycle (level: 1). There is insufficient evidence available to determine if surgical excision of peritoneal endometriosis enhances pregnancy rates in an IVF cycle (level: 2–). Conclusions: There is good evidence for surgical management of endometrial polyps, submucosal fibroids, and tubal hydrosalpinges to improve IVF outcomes. However, well-designed randomized trials are needed urgently to inform clinical practice better regarding surgical interventions for other gynecologic pathologies found prior to IVF treatment. (J GYNECOL SURG 30:189)

Introduction

The presence of gynecologic (uterine, ovarian, tubal or peritoneal) pathology could affect an in-vitro fertilization (IVF) outcome. The indications, techniques and effects of hysteroscopic endometrial polyps (EPs) resection; open, laparoscopic, and robotic myomectomy; hysteroscopic septum resection; treatment of hydrosalpinx; removal of ovarian endometrioma and management of pelvic endometriosis, on the implantation, clinical pregnancy, miscarriage and live birth rates are still debatable. Significant clinical and methodological heterogeneity—such as differences in patient inclusion criteria, method of diagnosis, type of fertility treatment offered, and methodological inconsistencies related to study design—among articles in the published literature exist, rendering it difficult to implement evidence-based practice in routine clinical care.

The aim of this review was to examine the literature available on the surgical interventions to correct uterine, tubal, ovarian, and peritoneal pathology, which could improve the implantation, clinical pregnancy, and live birth rates after IVF treatment.

Materials and Methods

The Cochrane Library and MEDLINE® electronic databases were searched for relevant studies from date of inception to date of the review (May 2012). The databases were searched using the relevant Medical Subject Headings (MeSH) terms including: In vitro fertilization, intracytoplasmic sperm injection, myoma, fibroid, fibromyoma, polyp, congenital uterine abnormalities, mullerian anomalies, hydrosalpinges, salpingectomy, salpingostomy, endometriosis, endometrioma, polycystic ovarian syndrome (PCOS), and ovarian hyperstimulation syndrome (OHSS). The search was restricted to articles published in the English language. The total number of abstracts obtained was 4298. Three of the current authors (HAR, KN, and SS) scrutinized the extracted titles and abstracts after the initial electronic search was completed. After further examination of these abstracts, the full texts of 83 relevant articles were retrieved.

Systematic reviews, randomized controlled trials (RCTs), and large observational trials published between 1971 and 2012 were included. Recent consensus documents were also studied. The full texts of the extracted articles were assessed and their references were scrutinized. The different studies were classified based on the SIGN [Scottish Intercollegiate Guidelines Network] classification system¹ and the best available evidence was selected to generate evidence-based recommendations (see Boxes 1 and 2). Pregnancy was defined as a positive urine test result for human chorionic gonadotropin 2 weeks after embryo transfer. A clinical pregnancy was defined as the observation of a gestational sac with fetal heart pulsations noted on ultrasound scanning 3 weeks after the positive pregnancy test result. Live birth was defined as any birth event in which at least 1 neonate was born alive.

Box 1.

SIGN Grading

1++	High-quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias
1+	Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias
1−	Meta-analyses, systematic reviews, or RCTs with a high risk of bias
2++	High-quality systematic reviews of case-control or cohort studies
	High-quality case-control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal
2+	Well-conducted case-control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal
2−	Case-control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal
3	Nonanalytical studies; for example, case reports, case series
4	Expert opinion

SIGN, Scottish Intercollegiate Guidelines Network; RCT, randomized controlled trial

Results

The full manuscripts obtained were classified into groups dealing with uterine, tubal, and ovarian pathology.

Uterine pathology

The evidence related to EPs, uterine fibroids, and Müllerian duct anomalies (mainly septate uteri) were considered because these three conditions represent the most common pathologic entities encountered in clinical practice.

Endometrial polyps

EPs represent a common uterine pathology, being present in up to 24% of subfertile women.² The effect of EPs on embryo implantation has been documented. They interfere with conception in both the natural cycle^3–5 as well as in assisted reproductive technology (ART) cycles.⁶ However, it is not clear if resection of EPs could improve embryo implantation or live birth rate in patients receiving IVF treatments.

Evidence suggests that, if a preliminary diagnosis of an EP is made before the start of IVF treatment, then the polyp should be resected.⁶

The strongest evidence in favor of surgical resection of EPs came from an RCT. Polyps were diagnosed using two-dimensional (2D) ultrasound scanning and varied in size between 3 and 24 mm, with a mean size of 16 mm. The cumulative pregnancy and live birth rates after four cycles of intrauterine insemination were significantly higher in women who underwent hysteroscopic polypectomy prior to treatment, compared with patients in a control group.⁷

A systematic review by Afifi and colleagues⁸ found only three EP studies, one randomized⁷ and two retrospective studies.^9,10 The diagnosis of endometrial polyps was made using 2D ultrasound in the latter two studies, with the polyp sizes being <20 mm and <15 mm, respectively. The review⁸ confirmed that EPs diagnosed prior to commencement of controlled ovarian hyperstimulation (COH) should be resected. The review also suggested that management of EPs noted during the course of COH for IVF should be individualized, based on the sizes and sites of the polyps, number of embryos created, previous reproductive history of the patient, and the success rate of clinic's frozen-embryo program. Management options include continuation of ovarian stimulation followed by a fresh embryo transfer or freezing of all embryos and subsequent replacement of frozen-thawed embryos after removal of the polyps. A well-designed, RCT trial is needed to determine the optimum treatment option.

Uterine fibroids

Fibroids are the most common benign uterine tumors, with an incidence of up to 77% in women of reproductive age.¹¹ Most fibroids are asymptomatic. However, fibroids could impede embryo implantation by promoting abnormal uterine contractility, by altering endometrial blood flow and by inducing localized endometrial inflammation or secretion of vasoactive substances.¹² There are three types of fibroids to consider:

• Subserosal fibroids—A recent systematic review and meta-analysis showed that the presence of subserosal fibroids does not affect IVF outcome.¹³ When the outcome of IVF in women with subserosal fibroids was compared with that in women without fibroids, no difference was observed in clinical pregnancy, implantation, live birth, spontaneous abortion and preterm birth rates. Therefore, removal of these fibroids may not be recommended unless a patient has pressure or menstrual symptoms.

• Submucosal fibroids—Hysteroscopic myomectomy is considered the “gold standard” treatment managing submucosal fibroids. Shokeir et al.,¹⁴ in a randomized trial, reported a significant improvement in the pregnancy rate in a group of women who had type 0 (entirely within endometrial cavity, no myometrial extension) and type I (50% myometrial extension, 90° angle of myoma surface to uterine wall) myomas resected hysteroscopically, compared to control subjects (63.4% versus 28.2%, p<0.05). Myomas were diagnosed ultrasonographically and were <5 cm in mean diameter.

• Intramural fibroids—The extent to which non–cavity distorting intramural fibroids affect fertility in patients receiving IVF treatment was addressed in two meta-analyses: (1) Somigliana et al., in 2007¹⁵ and (2) Sunkara et al., in 2010.¹⁶ Both reviews concluded that there was a significant decrease in IVF clinical pregnancy and live birth rates in women with non–cavity-distorting intramural fibroids, compared to patients in the control groups in these two trials. However, demonstration of reduction in IVF live births in women with non–cavity-distorting intramural fibroids does not necessarily mean that removal of such fibroids will restore the live birth rates to the levels expected in women without these fibroids. The only evidence to suggest a beneficial effect of myomectomy came from a small quasirandomized study¹⁷ in which women who underwent surgical removal of intramural fibroids before IVF treatment had cumulative pregnancy and delivery rates of 33% and 25%, respectively; whereas women who underwent IVF treatment without myomectomy had 15% and 12% clinical pregnancy and delivery rates. Ultrasonography, saline hysterosonography, or hysteroscopy was performed in the subjects to establish the number, size, location and depth of fibroid invasions. Patients enrolled in this study had 1–5 fibroid growths (with at least one that was >5 cm in diameter) and no submucosal fibroids. Thus, a well-designed randomized trial is warranted to address the role of myomectomy prior to IVF in the presence of non–cavity-distorting intramural fibroids.

With regard to the routes of surgery for fibroids, abdominal myomectomy is the classical approach for most surgeons faced with multiple or large fibroids. For surgeons skilled in laparoscopic and robotically assisted laparoscopic surgery, both approaches may be undertaken. Laparoscopic and robotic myomectomy are associated with reduced postoperative hemoglobin drops, operative blood losses, quicker recovery, reduced postoperative pain, and fewer overall complications.^18,19

When comparing robot-assisted and conventional laparoscopic myomectomy, a recent Cochrane review showed that limited evidence supported the claim that robotic surgery was not associated with improved patient care or safety.²⁰ In fact, the relative effects of laparoscopic and robotic versus abdominal myomectomy on IVF outcomes are unknown.

Müllerian duct anomalies

Congenital Müllerian duct abnormalities are present in 2%–8% of infertile women,^21–24 and in 5%–30% of women with histories of miscarriages^21,22,25,26 These anomalies have been shown to exert a negative impact on reproductive outcome. Among Müllerian duct anomalies, the septate uterus is the most common.

A recent systematic review,²⁷ showed that canalization defects (septate and subseptate) were associated with reduced clinical pregnancy rates and increased rates of first-trimester miscarriage, preterm birth, and fetal malpresentation. No randomized studies were found that related to treatment of Müllerian duct anomalies in patients receiving IVF treatment.

However, data from two observational studies evaluating the value of septum resection in women undergoing IVF have provided useful information.

First, Tomazevic et al.,²⁸ in a retrospective matched-control study, evaluated the effect of hysteroscopic septum resection in women with uterine septa, compared to normal controls. The live birth rates before hysteroscopic resections were significantly lower, compared with normal controls, both in women with subseptate or septate uteri (2.7% versus 21.7%; odds ratio [OR]: 10.15; 95% confidence interval [CI]: 3.27–31.40; p<0.001) and in women with small partial uterine septa with arcuate abnormality (2.8% versus 21.3%; OR: 9.26; 95% CI: 3.77–22.67; p<0.001). After surgery, the live birth rate was comparable, both in the group of women with subseptate or septate uterus (24.3% versus 32.0%; OR: 1.46; 95% CI: 0.97–2.09; p-value nonsignificant) and in women with small partial septa with arcuate abnormality (28.0% versus 32.2%; OR: 1.22; 95% CI: 0.84–1.77; p-value nonsignificant).

Second, Ban-Frangez et al.²⁹ evaluated the influence of subseptate, septate, and arcuate uteri on the miscarriage rates in singleton pregnancies after IVF/intracytoplasmic sperm injection (ICSI). The miscarriage rate in IVF/ICSI singleton pregnancies before hysteroscopic metroplasty was significantly higher, both in women with subseptate uteri (OR: 12.08; 95% CI: 3.2–45.8; p<0.001) as well as in those with larger septa (OR: 25.00; 95% CI: 3.9–160; p<0.001), compared with normal controls. After surgery, the miscarriage rates in women with subseptate uteri (OR: 1.63; 95% CI: 0.78–3.43; p-value nonsignificant) and in those with larger septa (OR: 1.72; 95% CI: 0.79–3.76; p-value nonsignificant) were comparable to the rate in women with normal uteri.

Although hysteroscopic metroplasty is a minimally invasive, safe procedure that could improve reproductive outcomes after IVF treatment, evidence from randomized trials is needed to confirm hysteroscopy's efficacy prior to IVF treatment.

Tubal pathology

Tubal-factor infertility, such as hydrosalpinx, accounts for more than a third of all cases of female infertility. It is widely accepted that hydrosalpinx impedes IVF treatment outcomes.^30–41 Two systematic reviews have shown a 50% reduction in clinical pregnancy and live birth rates and a twofold increase in miscarriage rate in women with hydrosalpinges.^42,43

Treatment of hydrosalpinx before IVF treatment could improve its outcome. Several therapeutic modalities have been proposed including: salpingectomy; salpingostomy; aspiration of hydrosalpinx fluid; tubal ligation and tubal occlusion by means of Filshie clips; Essure® micro-inserts; or electrocautery. However, salpingectomy remains the most frequently undertaken procedure.

A recent Cochrane review⁴⁴ assessed the efficacy of the different surgical interventions for tubal hydrosalpinges before IVF treatment. The review showed that the odds of clinical pregnancy were increased after laparoscopic salpingectomy or occlusion of the Fallopian tube versus no intervention. Comparison of tubal occlusion with salpingectomy did not show a significant advantage of either surgical procedure in terms of clinical pregnancy or ongoing pregnancy rate. One RCT, including 66 women, reported efficacy of ultrasound-guided aspiration of the hydrosalpingeal fluid at the time of oocyte retrieval, although the 95% CIs were wide because of the small size of the study (relative risk: 1.8; 95% CI: 0.8–4.3; p=0.02).⁴⁵ Among the different surgical treatments studied, no significant differences were noted regarding the incidence of adverse effects.

Ovarian pathology

The evidence related to the presence of ovarian endometrioma and polycystic ovarian syndrome was considered.

Ovarian endometrioma

Endometrioma is a circumscribed ovarian collection of ectopic endometrial tissue, the wall of which is formed by the inverted ovarian cortex.⁴⁶ It is estimated that 10%–25% of all patients undergoing IVF are diagnosed with endometriosis and 17%–44% of those have ovarian endometriomas.^47,48 The standard management of endometrioma prior to IVF is still controversial owing to the presence of insufficient evidence to favor one treatment strategy over another.

A recent Cochrane review⁴⁹ assessed the optimum treatment approach for women with endometriomas undergoing assisted conception treatment. Surgical treatment (aspiration or cystectomy) prior to IVF showed no evidence of benefit compared to expectant management. Furthermore, comparing endometrioma aspiration versus ovarian cystectomy showed no difference in the number of mature oocytes retrieved or the clinical pregnancy rate. Thus, RCTs are needed to guide clinical decisions. However, until such trials are available, treatment should be individualized and the decision to operate before IVF must be made on a case-by-case basis. The factors that could influence such a clinical decision include the size of the endometriotic cyst, history of previous ovarian surgery, previous ovarian response to stimulation/IVF outcome, a surgeon's laparoscopic skills, and a patient's choice.

Polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) undergoing IVF treatment are considered to be at increased risk of developing ovarian hyperstimulation syndrome (OHSS) and are consequently at greater risk of having the IVF cycle canceled. The reported prevalence of PCOS in women who overrespond to gonadotropin stimulation and develop severe OHSS is 38%–100%.^50–55 Laparoscopic ovarian drilling (LOD) is thought to have beneficial effects on IVF outcomes and reduce the rates of treatment cancellations and OHSS. In an RCT,⁵⁶ a significantly lower number of women with PCOS undergoing LOD before IVF had to have the treatment cycle abandoned because of the impending development of OHSS. In addition, the risk of developing moderate or severe OHSS in completed cycles was lower in this group of women. The pregnancy and miscarriage rates remained the same.

Therefore, LOD seems to be a potentially useful treatment for women who have previously had an IVF treatment cycle that was abandoned because of the risk of OHSS or who have had OHSS in a previous treatment cycle. In a more recent retrospective study, Tozer et al.⁵⁷ evaluated COH and various outcome parameters in 31 women with clomiphene-resistant PCOS. Of these women, 15 underwent LOD prior to IVF (a total of 22 cycles) and 16 did not (a total of 24 cycles). The clinical and ongoing pregnancy rates per embryo transfer improved and the miscarriage rates were reduced in the group of women who had undergone LOD, although fewer embryos were available for transfer. Moreover, in the same group of patients, the incidence of severe OHSS was significantly lower. Therefore, LOD before ART may be considered as a therapeutic option in patients who have PCOS and who have previously had severe OHSS.

Peritoneal endometriosis

Endometriosis is present in a third of women with infertility⁵⁸ and in ∼10% of reproductive-age women. There are no randomized trials suggesting that surgical treatment of peritoneal endometriosis via ablation and resection could improve IVF outcomes in women with mild/moderate/severe endometriosis. A Cochrane review summarizing the results of two randomized trials concluded that laparoscopic surgery (ablation of endometriotic lesions plus adhesiolysis) for mild endometriosis increased the chance of natural conception in subfertile women compared to diagnostic laparoscopy.⁵⁹ However, there are no randomized trials to date evaluating the role of surgical treatment in infertile women with moderate-to-severe endometriosis. In 2011, a retrospective cohort study demonstrated the benefit of surgical excision of mild endometriosis on the pregnancy rates prior to an IVF cycle.⁶⁰ In this study, 399 women underwent surgical excision of endometriosis, compared to 262 women who underwent diagnostic laparoscopy alone. The clinical pregnancy and the live birth rates were significantly higher in the group of women who underwent treatment (40.1% versus 29.4%; p=0.004 and 27.7% versus 20.6%; p=0.04, respectively). There is insufficient evidence to determine if surgical excision of moderate-severe endometriosis enhances pregnancy rates in an IVF cycle.

There should be well-designed and adequately powered randomized trials conducted to address the role of surgery in women with coexisting endometriosis prior to IVF.

Conclusions

Patients who undergo IVF represent a specific subgroup of the infertile population, and extrapolating data from the general infertile population may not be appropriate.

In this systematic review, the current authors specifically examined the best available evidence relating to the effect of surgical techniques designed to treat gynecologic pathologies on IVF outcome. Existing studies varied in design and methodological quality, with an obvious scarcity of well-designed randomized studies. In addition, most studies included a relatively small number of patients, rendering the results imprecise.

Good evidence exists regarding surgical management of endometrial polyps, submucosal fibroids, and tubal hydrosalpinges in order to improve IVF outcome.

Well-designed randomized trials are urgently needed to inform clinical practice better regarding the role of surgical interventions for other gynecologic pathologies prior to IVF treatment.

Footnotes

Disclosure Statement

No competing financial conflicts exist.

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