First Line Surgery or First Line Fertility Treatment Using Assisted Reproductive Technologies in Patients With Advanced Endometriosis: A National Multicenter Randomized-controlled Trial
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 350
- 试验地点
- 4
- 主要终点
- Cumulative live-birth rate (CLBR)
研究概览
简要总结
Endometriosis is a chronic disease affecting approximately 10% of women of reproductive age. It is strongly associated with pelvic pain and infertility. Women with advanced stages of the disease (stage III-IV) have markedly reduced fertility compared with the general population. A Swedish study has shown that about 22% of women undergoing treatments with assisted reproductive technologies (ART), such as in vitro fertilization (IVF), are affected by endometriosis.
The optimal management of women with advanced endometriosis and infertility remains uncertain. Some clinicians advocate proceeding directly to IVF, while others suggest surgical removal of endometriosis lesions prior to IVF in order to improve the chances of pregnancy. Currently, evidence is limited to a small number of observational studies. Two observational studies and one meta-analysis have suggested that surgery before IVF in women with deep endometriosis may increase both pregnancy and live birth rates compared with IVF alone. However, no randomized controlled trial (RCT) has yet been conducted to answer this important clinical question.
This study will be the first national multicenter randomized controlled trial to compare surgery followed by IVF with IVF alone in women with advanced endometriosis and infertility. All Swedish centers for highly specialized endometriosis surgery and fertility treatment will participate.
Eligible participants are women under 39 years of age with stage III-IV endometriosis who seek fertility treatment. Participants will be randomized in a 1:1 ratio to one of two groups:
- Surgery prior to IVF (laparoscopic excision of endometriosis lesions, followed by IVF).
- Direct IVF without prior surgery. The primary outcome is the cumulative live birth rate within three years of randomization and initiation of the allocated treatment. Secondary outcomes include pregnancy rates, time to pregnancy, treatment-related complications, patient-reported quality of life, and cost-effectiveness.
Our hypothesis is that surgery before IVF will lead to a higher cumulative live birth rate compared with IVF without prior surgery in women with advanced endometriosis.
The results of this trial are expected to have significant impact on clinical practice and international guidelines. Regardless of outcome, the study will provide robust evidence to guide treatment strategies, improve the care of women with advanced endometriosis and infertility, and potentially reduce healthcare costs by identifying the most effective pathway to achieving pregnancy.
详细描述
WHY THIS TRIAL IS NEEDED
BACKGROUND
Endometriosis Endometriosis is a prevalent condition affecting 10% of female population of reproductive age, leading to pain and sub-fertility. An earlier systematic literature reviews and meta-analysis suggests that women with advanced endometriosis (revised American Society for Reproductive Medicine classification of endometriosis (rASRM) stage III-IV) have a lower likelihood of achieving clinical pregnancy/live birth compared to women without endometriosis, while this difference has not been observed for mild disease (stage I-II).
Gynaecological Ultrasound and staging The prevalence of endometrioma and deep endometriosis found through systematic transvaginal ultrasound on women referred for ART treatment in Sweden has been estimated at 21.8%. Additionally, 75.8% of those with endometriosis were unaware of their condition prior to diagnosis. In recent years, two staging systems, namely the American Association of Gynecologic Laparoscopists (AAGL) Endometriosis classification and #ENZIAN have gained prominence owing to their accuracy when juxtaposed with surgical findings.
Surgical Treatment Women with endometriosis seem to experience pain relief after bowel surgery due to endometriosis. Consensus from the European Society of Human Reproduction and Embryology (ESHRE) indicates that surgery can be performed prior to treatment with assisted reproductive technologies (ART). Additionally, the number of spontaneous pregnancies is high after surgery on patients with deep endometriosis. Furthermore, in patients with endometriosis stage I-II or in infertile patients with endometriomas, surgery can in some cases be considered to improve fertility. However, the risk of severe complications in patients undergoing rectal surgery is up to 10% including anastomosis leakage and fistulas.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 38 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Age 18 - 38 years old
- •Endometriosis AAGL stage III-IV
- •Referred or eligible for ART-treatment such as IVF or ICSI, independent of infertility diagnosis (28) (including sperm donation cycles for social reasons) and/or infertility due to dyspareunia/dysmenorrhea caused by endometriosis
- •Body mass index 18-35 kg/m2
- •Patients who have signed an approved Informed Consent
排除标准
- •Previous surgery for endometriosis except diagnostic laparoscopy.
- •Previous IVF/ICSI-cycles (including prior fertility preservation cycles)
- •Hemato- and/or hydrosalpinx
- •Clear indication for surgery such as ureteral stenosis or intestinal sub-occlusive symptoms
- •Suspicion of malignancy
- •Submucosal fibroids (The International Federation of Gynecology and Obstetrics (FIGO) 0-1, any size) or intramural fibroids (FIGO 2-5, > 4 cm largest diameter of the largest myoma) (29)
- •Uterine malformations (class U1-U6 according to ESHRE/ESGE-classification) (30)
- •Patients with contraindications to surgery
- •Patients undergoing ART with donated oocytes
研究组 & 干预措施
First-line ART
Women allocated in the ART arm will undergo up to three cycles of controlled ovarian stimulation (COS) followed by oocyte retrievals and embryo transfers. In Sweden, ART-treatment costs for women under the age of forty and without having children in current relationship are covered by the tax-funded healthcare system, with up to 3 IVF/ICSI treatments, given that they are considered medically meaningful, and that each stimulation is started before the woman turns 40 years of age (39). In case the treatment results in cryopreserved embryos, it is planned that they should be transferred prior to the start of any new COS. Women will be managed according to a routine clinical protocol at each reproductive unit. Stimulation protocols will be chosen individually by clinicians, taking into consideration age and ovarian reserve of each woman, as it is a standard routine in the collaborating Reproductive Units.
First-line surgery followed by ART
Surgery will be performed at one of four nationally specialized centers in advanced endometriosis surgery (Södersjukhuset Stockholm, Sahlgrenska University Hospital Göteborg, Skånes University Hospital, Malmö/Lund, Uppsala University Hospital). Surgery will be conducted according to the ESHRE recommendations of surgery in endometriomas and deep endometriosis (32, 33). Surgery should be multidisciplinary when needed (colorectal surgeons and urologists). The goal of the procedure is to remove as many endometriotic lesions as possible while also minimizing negative impact on organ function, since endometriosis is a benign disease. Rectal endometriosis will be removed with rectal shaving, discoid or segmental resection depending on the size and placement of the lesion in the rectal wall. Laparoscopic cyst enucleation is considered the "golden standard". In cases where ovarian reserve is already diminished, more gentle ablation methods could be employed
干预措施: Endometriosis surgery (Procedure)
结局指标
主要结局
Cumulative live-birth rate (CLBR)
时间窗: Three years from first treatment (surgery or ART treatment)
CLBR is defined as any live births from first treatment until end of follow up (three years from first ART treatment or surgery or drop out from the study, whichever comes first).
次要结局
- Blastocysts cryopreserved per cycle(at the end of embryo culture (Day 6 after oocyte pick-up))
- Quality of life and pain(Within 1 month before first intervention; at oocyte retrieval; 2 months after ART or surgery; and at 3-year follow-up.)
- Health care costs(From randomization to end of trial)
- Cumulative Pregnancy Rate (CPR)(From first treatment (surgery or ART) until three years of follow up)
- Time to pregnancy and live birth(Time is measured up to three years after first treatment)
- Spontaneous Pregnancy Rate(between first treatment and end of follow-up (three years))
- Fertilisation rate(The day after oocyte pick-up in each IVF/ICSI-cycle)
- Miscarriage rate and/or extrauterine pregnancies(occurring between first treatment and end of follow-up (three years))
- Number of oocytes per IVF/ICSI cycle(At the day of oocyte retrieval for each IVF/ICSI cycle)
- Fresh embryo transfer per IVF/ICSI cycle(At the time of transfer or at the end of embryo culture (up to Day 6), per IVF/ICSI cycle)
- Pregnancy outcomes per embryo transfer (ET)(From ET until delivery (up to 10 months))
- Cumulative reproductive outcomes per IVF/ICSI cycle(From the start of each IVF/ICSI cycle until completion of all embryo transfers from that cycle (up to 12 months))
- Rate of recurrent implantation failure (RIF), (20) evaluated at the end of the study period(Assessed at the end of the study period ( 3 years after randomisation))
- Infections after oocyte retrieval(From each oocyte retrieval and within 2 following months)
- Peri- and two months postoperative complications classified by Clavien-Dindo and Classic systems(Postoperative complications up to two months after surgery)
- Obstetrical outcomes and complications(From pregnancy week 22 through 8 weeks postpartum)
研究者
Malin Brunes
Principal Investigator
Karolinska Institutet