Danie Botha FEMBRYO Fertility and Gynaecology Clinic,PE SASREG Conference 2015 Sandton The patient with Endometriosis planning to conceive: Best Practice Guidelines

Endometriosis related infertility poses a challenge to physicians Patients need a clear understanding of the complexities of the disease for informed decision. Limitations on evidence from randomized trials, practice guidelines based on Best available Evidence. Early diagnosis, individualized treatment plans and early referral to centers with special interest Introduction

Current issues: Is medical treatment/pre treatment effective? Should Agonist stimulation be used rather than Antagonist protocols? Is there a role for surgery/repeated surgeries in patients with known /suspected endometriosis? Should endometriomas be treated surgically if IVF is planned? Does DIE play a role in endometriosis related infertility? When can non IVF treatment be offered? Overview

ESHRE Guidelines 2005 Canadian Guidelines 2010 ESHRE Guidelines 2013/2014 Best Practice Guidelines. Leyland, N., Casper,R. Laberge,P Endometriosis: Diagnosis and Mnagement. SOGC Clinical Guidelines JOGC, Vol 32,No 7 Suppl 2 (July 2010) Dunselman,GAJ. Vermeulen, N. Becker et al. (2014) ESHRE guideline:Management of women with endometriosis. Human reproduction, Vol. 29,No3 pp History

ESHRE guidelines: Quality assessment and systematic search of published literature up to January Guidelines made by consensus and had a patient representative.83 Recommendations Diagnosis Management of endometriosis related pain Incidentally found asymptomatic disease Prevention and possible association with malignancy Menopausal women known with endometriosis 19 recommendations related to infertility Interesting facts

Endometriosis App ESHRE

1.Is there any role for medical treatment of patients trying to conceive?

1. Are hormonal therapies effective for infertility associated with endometriosis? All forms of medical treatment which are often prescribed for endometriosis (combined estrogen progestogen contraceptives, progestans, GnRH analogues, danazol), block ovarian function and are contraceptive in action.

1.2. Are hormonal therapies effective as an adjunct to surgical therapy for treatment of infertility? A recent updated Cochrane review (Furness et al., 2011) concluded that there is no evidence of benefit associated with post-surgical medical therapy and insufficient evidence to determine whether there is a benefit from pre-surgical medical therapy.

A Cochrane review by Sallam (Sallam et al., 2006) on the effect of medical treatment before Assisted Reproductive Technology(ART) reported an 4 –fold increase in the odds of clinical pregnancy rates after 3-6 months of GnRH agonist down-regulation before controlled hyper stimulation. 1.3 Are medical therapies effective as an adjunct to treatment with ART for endometriosis associated infertility?

2. Is surgery effective for infertility associated with endometriosis?

Jacobson and colleagues performed a meta-analysis and Cochrane review on laparoscopic surgery for sub-fertility associated with endometriosis where above mentioned studies were included (Jacobson et al., 2010).When the results are combined, there is no significant statistical difference and the overall absolute difference is 8.6% in favour of therapy. For every 12 patients having stage I or II endometriosis diagnosed at laparoscopy, there will be one additional successful pregnancy if ablation or resection of visible endometriosis is performed compared to no treatment. 2.1 Surgery for minimal (Stage I) and mild (Stage II) Endometriosis The issue of whether surgical removal of endometriotic lesions improves a woman’s chance of spontaneous conception is complex (De Ziegler et al., 2010). Two randomized control trials reported on the effectiveness of laparoscopic surgery for stage I or II endometriosis associated with infertility (Marcoux et al., 1997).(Parazzini, 1999.)

The benefit of surgery for subfertility associated with moderate to severe disease is generally accepted, without sound evidence of a beneficial effect. No randomized control trials or meta-analysis are available to answer the question whether surgical excision of moderate to severe endometriosis compared to expectant management enhances pregnancy rates. 2.2 Surgery for moderate (Stage III) to severe (Stage IV) endometriosis and infertility

The effect of endometriomata on fertility, its surgical treatment and its effect on IVF outcome are topics of debate. Several studies support the removal of endometriomata, demonstrating improved fertility rates. However, there is growing and consistent evidence that ovarian reserve is affected by surgical excision (Gupta et al.) ( Garcia-Velasco and Somigliana, 2009); (Tsoumpou et al., 2009). A potential deleterious mechanism of surgery is accidental removal of a significant amount of healthy ovarian tissue during cystectomy (Muzii et al, 2002.). 2.3 Surgery for endometriomata and infertility

The role of operative laparoscopy before IVF is controversial and the available evidence on this issue is generally inconsistent (Vercellini et al.2009). 2.4 Surgery for endometriosis before In Vitro Fertilization (IVF) No clear data supports the possible beneficial role of surgery prior to IVF based on RCT’s. A Cochrane review found no benefit from surgery for endometriomas prior to IVF versus expectant management with clinical pregnancy as outcome (Benshop et al., 2010). From the limited evidence ovarian endometrioma cystectomy before starting ovulation induction in ART does not seem to improve outcome in asymptomatic patients with endometriosis related infertility. This is supported by the findings of the Cochrane Review (Benshop et al.,2010) published on interventions prior to assisted reproductive technology in patients with endometriosis related infertility.

Surgery before IVF

Certain clinical variables needs to be considered when deciding whether to perform surgery or not in women selected for IVF. Garcia-Velasco(2009) et al published a practical outline of factors suggesting conservative or surgical approach. Although not prospectively tested in RCT’S, this may help the clinician in decision making processes where patients needs to be counselled.

Littman et al.(2005) reported on patients who underwent surgery after failed IVF and suggested that in the setting of multiple IVF failures, surgery may increase the pregnancy rate before alternative measures are advised. Despite the limitations of the study and criticism raised on the design, the notion of IVF being the only option for patients with endometriosis has been challenged by this study. Due to the underlying chronic inflammatory disease present in these patients, restoring anatomy and reducing the inflammatory peritoneal reaction, may be the reason for the improvement in outcome. 2.5 Surgery for endometriosis after failed in vitro fertilization (IVF)

The pathogenesis of endometriosis related infertility  Altered peritoneal function Increased concentrations of PG’s, proteases,cytokines IL-1, IL-6,TNF,VEGF produced by macrophages – Increased systemic serum levels of inflammatory cytokines – ? Inflammation due to endometriosis or vice versa Altered Hormonal and Cell Mediated Function IgG and IgA increased in eutopic endometrium, decreased implantation rates Endocrine and Ovulatory disorders Luteinized unruptured follicle syndrome, luteal phase dysfunction, premature and multiple LH surges, prolonged follicular phase and lower estradiol levels, Impaired implantation Recently demonstrated low levels of enzyme involved in synthesis of the endometrial ligand for L-selectin (a protein that coats the trophoblast on the surface of the blastocyst) Oocyte and embryo quality Due to altered progesterone and cytokine concentrations in follicular fluid

3.1.IUI and Ovulation induction in patients with endometriosis associated infertility. Tummon et al(1997)showed in a RCT that active treatment of patients known with minimal to mild endometriosis improved live birth rates compared to expectant management. When controlled ovarian stimulation with gonadotrophins was followed with intra uterine insemination(IUI), the live birth rate was 5.6 times higher in treatment group(95% confidence interval (CI) Adamson and Pasta (Adamson et al., 2010) recently developed the Endometriosis Fertility Index (EFI) in order to develop a system for treatment of patients with endometriosis and infertility. This new staging system has been validated prospectively and has been modified to optimize the staging system. The purpose was to develop a clinical tool that predicts pregnancy rates in patients with surgically documented endometriosis who attempt non-IVF conception. 3. Is ART effective for infertility associated with endometriosis?

EFI Score

It can reassure many patients with a good prognosis and also avoid wasting time in treatment for those with poor prognosis. As very few patients overall can afford ART, the EFI can bring major benefits to the vast majority of endometriosis patients who wish to conceive (Adamson et al., 2010).

3.2 IVF for endometriosis associated infertility

What’s new in the literature since ESHRE Guidelines publication?

 Impact of endometriosis and its staging on assisted reproduction outcome: – M.A.P. Barbosa, Ultrasound Obstet Gynecol 2014;44: – Systematic review and meta-analysis: No difference in outcome VS Barnhart % reduction in pregnancy rates.

Conclusion and practice recommendations

Consider female age, stage of disease, duration of infertility and previous surgical therapy as well as previous treatments when recommending treatment Evaluate the possibility of a contributing male factorIn younger women (<35), expectant management post surgery may be considered In patients older than 35 years or where other contributing factors are present, use the EFI score to guide treatment.

In patients with advanced disease, expectant management post surgery may be considered for 6 months. Early initiation of IVF should be considered if disease recurrence rather than repeat surgery Use ERA to evaluate endometrial receptivity if failed implantation due to altered luteal response/prog effect. Possibly advisable to use Agonist stimulation to decrease systemic/peritoneal inflammatory and intra follicular endocrine milieu

Thank you