Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the effectiveness and safety of long‐term GnRH agonist therapy versus no pretreatment or other pretreatment modalities, (such as long‐term continuous COC or surgical therapy), before standard IVF or ICSI in women with endometriosis.
Background
Description of the condition
Endometriosis is a challenging disease observed in 20% to 50% of infertile women (Hart 2003; Moulemen 2009). A cause‐and‐effect relationship between endometriosis and infertility has not been established, but it has been postulated that a combination of distorted pelvic anatomy, altered peritoneal function, alteration of immunological milieu within the peritoneal cavity, diminished ovarian reserve and altered endometrial receptivity could be the cause of infertility (ASRM 2006; Giudice 2010). Women with endometriosis often require in vitro fertilization (IVF) to improve the chance of pregnancy, and more than a third of women undergoing IVF have endometriosis (Ozkan 2008). The benefits of in vitro fertilization‐embryo transfer (IVF‐ET) in endometriosis‐associated infertility are well established (Barnhart 2002; Olivennes 2003; Opoein 2012). A meta‐analysis of 22 non‐randomised studies on the effect of endometriosis on IVF outcomes concluded that endometriosis interferes with all aspects of the reproductive process and is associated with lower success rates than other indications for IVF (Barnhart 2002). The overall chance of achieving pregnancy with IVF in these 22 studies was 25%. Nevertheless, a recent large retrospective cohort study of 2245 women reported comparable pregnancy rates and live birth rates of IVF/intracytoplasmic sperm injection (ICSI) treatment in women with endometriosis‐related infertility as in women with tubal factors, except for those with ovarian endometrioma (Opoein 2012).
The severity of endometriosis has been shown to have a direct impact on the outcomes of IVF/ICSI treatment (Azem 1999; Olivennes 2003; Coccia 2011). A recent meta‐analysis of 27 non‐randomised studies (Harb 2013) reported a slight reduction in fertilisation rates among women with stage I/II endometriosis undergoing IVF/ICSI treatment (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.87 to 0.99, P value 0.03), but in women with severe pelvic endometriosis and stage III/IV disease, implantation rates were significantly reduced (RR 0.79, 95% CI 0.67 to 0.93, P value 0.006), as were clinical pregnancy rates (RR 0.76, 95% CI 0.69 to 0.91, P value 0.0008). In stage I/II disease, a hostile pelvic environment due to alteration of immunological milieu within the peritoneal cavity may be responsible for impaired gamete and early embryo development (Ryan 1997; Surrey 1998). On the other hand, in stage III/IV endometriosis, lower oocyte yield and poor oocyte quality (Norenstedt 2001; Pal 1998) resulting in embryos of lesser quality have been reported (Arici 1996; Barnhart 2002) to be responsible for lower pregnancy and implantation rates post IVF/ICSI.
Description of the intervention
The surgical management of asymptomatic ovarian endometrioma in women desiring pregnancy or before IVF is debatable. A systematic review and meta‐analysis of 21 cohort studies (Raffi 2012) and recent non‐randomised studies (Tang 2013; Urman 2013) reported a negative impact of excision of endometriomas on ovarian reserve. Another systematic review of 20 non‐randomised studies (Tsoumpou 2009) concluded that excision of endometriomas has no significant effect on IVF pregnancy rates and ovarian response to stimulation compared with no treatment, nor does it improve fertility outcomes (Garcia‐Velasco 2004; Geber 2002; Suzuki 2005). On the other hand, non‐randomised studies (Harkki 2010; Marconi 2002) have reported that resection of mild endometriosis and/or restoration of the normality of the pelvic anatomy, especially if done laparoscopically, may enhance the efficacy of assisted reproductive techniques (ART), but that aggressive ovarian surgery should be avoided. Because of the negative effect of surgical management of endometriosis on the ovarian reserve, pituitary suppression therapy with gonadotrophin‐releasing hormone (GnRH) agonists before IVF has become a popular alternative chosen by many clinicians.
Long‐term therapy with GnRH agonists, synthetic peptide analogues of GnRH, has been shown to be effective in treating symptomatic endometriosis, thereby decreasing the size of endometriomas (Surrey 2010). However whether this improves fecundity is questionable. Several non‐randomised studies (Ma 2008; Marcus 1994; Nakamura 1992; Van der Hauven 2013) suggest that in women with endometriosis‐related infertility, long‐term treatment with GnRH agonists for at least three months (and up to six months) before IVF cycles are initiated may improve implantation and clinical pregnancy rates and reduce preclinical miscarriages, compared with a conventional IVF protocol. GnRH agonists (leuprorelin, goserelin, buserelin, gonadorelin, triptorelin, nafarelin), depending on their formulation, can be given intramuscularly, subcutaneously or intranasally. Upon completion of GnRH treatment, approximately two to four weeks from the last administration, an ovarian stimulation protocol with gonadotrophins is initiated according to standard IVF/ICSI procedures.
How the intervention might work
Continuous hypophyseal exposure to GnRH agonists leads to down‐regulation of GnRH receptors, which desensitises the pituitary gland. The hypogonadotrophic‐hypogonadal state results in prolonged amenorrhoea and a low estradiol level (E2), thus depriving existing endometriotic lesions. This may improve the symptoms of endometriosis, and it is plausible that it may also reverse the negative effects of endometriosis on IVF cycles. These include poor folliculogenesis resulting in oocytes of reduced quality; a hostile peritoneal environment from macrophages, cytokines or vasoactive substances in the peritoneal fluid; mechanical interference with oocyte pickup and transportation and anatomical dysfunction of the fallopian tubes and ovaries (Cahill 1996; Harb 2013; Harlow 1996). It has been suggested by several non‐randomised studies that poor oocyte quality results in decreased fertilisation rates (Bergendal 1998; Garrido 2000; Pal 1998). This in turn leads to embryos of lesser quality, along with a reduced implantation rate, especially in severe endometriosis (Arici 1996; Simon 1994). In some studies (Edward 1995), a higher rate of implantation and multiple pregnancy after ovarian stimulation was reported in women in a hypergonadotrophic‐hypogonadal state; this might be due to improved endometrial responsiveness following amenorrhoea. However, other studies (Haouzi 2010; Hickman 2002) have reported contradictory findings.
Why it is important to do this review
Although IVF/ICSI with long‐term pituitary down‐regulation has been recommended as the first choice treatment for women with endometriosis, many clinicians still have doubts about its effectiveness. Concerns include the possibility that it may lower ovarian response to ovarian stimulation, especially among poor responders. The beneficial effects of prolonged GnRH treatment before IVF are seen most often for severe endometriosis, and the benefits and harms of the intervention in mild to moderate disease have not been fully evaluated. Other concerns focus on its unpleasant side effects, such as vasomotor irritability, which may seriously affect women's quality of life. Complications associated with treatment such as infection, pelvic abscess and ovarian hyperstimulation syndrome (OHSS) have not been fully assessed. Alternatively, continuous use of combined oral contraceptive pills (COCs) (which have the fewest side effects) for 6‐8 weeks before IVF or ICSI in women with endometriosis has shown favourable fertility outcomes (de Zeigler 2010), although no comparison with long‐term GnRH treatment has been made.
Objectives
To determine the effectiveness and safety of long‐term GnRH agonist therapy versus no pretreatment or other pretreatment modalities, (such as long‐term continuous COC or surgical therapy), before standard IVF or ICSI in women with endometriosis.
Methods
Criteria for considering studies for this review
Types of studies
We will include all randomised controlled trials that report use of any type of GnRH for at least three months before an IVF/ICSI protocol is started in women diagnosed with endometriosis. Cross‐over trials will be included only if phase one data can be extracted. Quasi‐randomised trials will be excluded.
Types of participants
Infertile women diagnosed with endometriosis (regardless of the grade of the disease) and treated with IVF or ICSI. The diagnosis of endometriosis must have been based on laparoscopy or laparotomy. For severity of endometriosis, grades according to the American Society of Reproductive Medicine (ASRM) score at laparotomy or laparoscopy will be used.
Types of interventions
Intervention
Any type of GnRH agonist preparation used to down‐regulate the hypothalamic‐pituitary complex for three months or longer before a standard IVF or ICSI protocol in women diagnosed with endometriosis.
Comparison
Standard IVF/ICSI protocol only
Continuous COC therapy for a minimum of six weeks before a standard IVF/ICSI protocol
Surgical excision of endometrioma within six months before the start of a standard IVF/ICSI protocol.
Studies with a co‐intervention (e.g. surgical treatment of endometriosis in both groups prior to the study intervention) will be eligible for inclusion.
Types of outcome measures
The following outcomes will be recorded if the information is available.
Primary outcomes
Live birth rate: Delivery of a live fetus after 22 completed weeks of gestational age
Complication rate: adverse effects per woman (e.g. infection, OHSS, serious vasomotor instability, overall adverse effects).
Secondary outcomes
Clinical pregnancy rate per couple/woman: defined as pregnancy confirmed by visualisation of a fetal sac on ultrasound (Zegers‐Hochschild 2017)
Multiple pregnancy rate: number of twin, triplet or higher‐order pregnancies (specified if possible) per pregnancy and confirmed by ultrasound or delivery
Miscarriage rate: miscarriage defined as the spontaneous loss of an intra‐uterine pregnancy prior to 22 completed weeks of gestational age (Zegers‐Hochschild 2017)
Ectopic pregnancy rate: ectopic pregnancy defined as a pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualization or histopathology, per couple/woman (Zegers‐Hochschild 2017)
Fetal abnormalities: number of women giving birth to a child with a fetal abnormality
Mean number of oocytes retrieved per woman
Mean number of embryos obtained per woman.
Search methods for identification of studies
We will search for all published and unpublished randomised controlled trials (RCTs) of women diagnosed with endometriosis and treated with GnRH agonists to down‐regulate the hypothalamic‐pituitary complex before IVF or ICSI, without language restriction and in consultation with the Cochrane Gynaecology and Fertility (CGF) Group Information Specialist.
Electronic searches
We will search the following electronic databases from their inception to present:
The CGF Specialised Register of Controlled Trials (PROCITE platform) (Appendix 1)
CENTRAL via the Cochrane CENTRAL Register of Studies ONLINE (CRSO) (Web platform) (Appendix 2)
MEDLINE (OVID platform) (1946 to present) (Appendix 3)
EMBASE (OVID platform) (1980 to present) (Appendix 4)
PsycINFO (OVID platform) (1806 to present) (Appendix 5)
Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO platform) (1961 to present) (Appendix 6)
The MEDLINE search will be combined with the Cochrane highly sensitive search strategy for identifying randomised trials, which appears in the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.0.2, Chapter 6, 6.4.11). EMBASE, PsycINFO and CINAHL searches will be combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN; http://www.sign.ac.uk/methodology/filters.html#random).
Other electronic sources of trials will include the following.
-
Trial registers for ongoing and registered trials.
http://www.clinicaltrials.gov (a service of the US National Institutes of Health).
http://www.who.int/trialsearch/Default.aspx (World Health Organization International Trials Registry Platform search portal).
DARE (Database of Abstracts of Reviews of Effects) of The Cochrane Library at http://onlinelibrary.wiley.com/o/cochrane/cochrane_cldare_articles_fs.html (for reference lists from relevant non‐Cochrane reviews).
Web of Knowledge (http://wokinfo.com/) (another source of trials and conference abstracts).
OpenGrey (http://www.opengrey.eu/) (for unpublished literature from Europe).
LILACS (Latin American and Caribbean Health Science Information Database) at http://regional.bvsalud.org/php/index.php?lang=en) (for trials from the Portuguese and Spanish speaking world).
PubMed and Google (for recent trials not yet indexed in MEDLINE).
Searching other resources
We will handsearch reference lists of articles retrieved by the search and will contact experts in the field to obtain additional data. We will also handsearch relevant journals and conference abstracts that are not covered in the CGF register, in liaison with the Information Specialist.
Data collection and analysis
Selection of studies
Two review authors will carry out an initial screen of titles and abstracts retrieved by the search and identify potentially eligible studies. We will retrieve the full texts of these studies. Two review authors will independently examine these full‐text articles for compliance with the inclusion criteria and will select studies eligible for inclusion in the review. We will correspond with study investigators as required to clarify study eligibility. Disagreements as to study eligibility will be resolved by discussion or by discussion with a third review author. We will document the selection process using a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) flow chart.
Data extraction and management
Data extraction will be performed independently by two review authors. Any discrepancies will be resolved by consensus with another review author. If a study appears to meet the eligibility criteria but has aspects of methodology that are unclear, or if the data are provided in a form that is unsuitable for meta‐analysis, the study authors will be contacted, and additional information on trial methodology or actual original trial data, or both, will be sought. When studies have multiple publications, the review authors will collate multiple reports of the same study, so that each study rather than each report is the unit of interest in the review, and such studies will have a single study ID with multiple references.
Assessment of risk of bias in included studies
Two review authors will independently assess the included studies for risk of bias using the Cochrane 'Risk of bias' assessment tool (Higgins 2011) to assess allocation (random sequence generation and allocation concealment); blinding of participants and personnel; blinding of outcome assessors; incomplete outcome data; selective reporting and other bias. Disagreements will be resolved by discussion or by consultation with a third review author. We will fully describe all judgements and will present the conclusions in the 'Risk of bias' table, which will be incorporated into the interpretation of review findings by means of sensitivity analyses.
We will take care to search for within‐trial selective reporting, such as trials failing to report obvious outcomes or reporting them in insufficient detail to allow inclusion. We will seek published protocols and will compare outcomes between the protocol and the final published study.
Measures of treatment effect
For dichotomous data (e.g. live birth rate) we will use the numbers of events in the control and intervention groups of each study to calculate risk ratios. For continuous data we will calculate mean difference (MDs) between treatment groups. We will present 95% confidence intervals for all outcomes. If appropriate, we will use number needed to treat for an additional beneficial outcome (NNTB), number needed to treat for an additional harmful outcome (NNTH), or both, to describe significant findings.
Unit of analysis issues
The primary analysis will focus on data per woman randomly assigned; a sensitivity analysis using per pregnancy data will also be included for relevant outcomes (multiple pregnancy, miscarriage, ectopic pregnancy, fetal abnormalities). We will briefly summarise in an additional table data that do not allow valid analysis (e.g. 'per cycle' or 'per embryo' data), and these will not be meta‐analysed.
If studies report only 'per cycle' data, we will contact study authors to request 'per woman randomly assigned' data.
We will count multiple live births (e.g. twins, triplets) as one live birth event.
Dealing with missing data
We will analyse the data on an intention‐to‐treat basis as far as possible and will make attempts to obtain missing data from the original trialists. When data on live birth or clinical pregnancy cannot be obtained, we will assume that the outcome did not occur. For other outcomes, we will analyse only available data.
Assessment of heterogeneity
We will consider whether clinical and methodological characteristics of the included studies are sufficiently similar for meta‐analysis to provide a clinically meaningful summary. We will assess statistical heterogeneity by measuring the I2 statistic. We will take an I2 measurement greater than 50% to indicate substantial heterogeneity (Higgins 2003; Higgins 2008). If we detect substantial heterogeneity, we will explore possible explanations in sensitivity analyses (see below) and will consider a subgroup analysis. We will take any statistical heterogeneity into account when interpreting the results, especially if variation in the direction of effect is noted.
Assessment of reporting biases
The review authors will aim to minimise the potential impact of publication bias and other reporting biases by ensuring a comprehensive search for eligible studies. If 10 or more studies are included in an analysis, we will use a funnel plot to explore the possibility of small‐study effects (a tendency for estimates of the intervention effect to be more beneficial in smaller studies (Higgins 2011).
Data synthesis
If studies are sufficiently similar, we will combine the data using a fixed‐effect model in the following comparisons.
Long‐term GnRH agonist pretreatment followed by standard IVF/ICSI versus standard IVF/ICSI only
Long term GnRH agonist pretreatment versus at least 6 weeks of COC pretreatment, both followed by standard IVF/ICSI
Long term GnRH agonist treatment versus surgical excision of endometriomata, both followed by standard IVF/ICSI
Analyses will be stratified by months of GnRH pre‐treatment: three months, six months, over 6 months.
We will display an increase in the risk of a particular outcome, which may be beneficial (e.g. live birth) or detrimental (e.g. adverse effects), graphically in the meta‐analyses to the right of the centre‐line, and a decrease in the odds of an outcome to the left of the centre‐line.
Subgroup analysis and investigation of heterogeneity
When data become available, we will conduct subgroup analyses to determine separate evidence within the following subgroups.
Severity of endometriosis; stage I/II and stage III/IV disease.
Previous history of surgery for endometriosis.
Type of embryo transfer: fresh or cryopreserved
Sensitivity analysis
We will conduct sensitivity analyses for the primary outcome measures to determine whether the conclusions are robust to arbitrary decisions made regarding eligibility and analysis. These analyses will include consideration of whether the review conclusions would have differed if:
eligibility had been restricted to studies at low risk of bias
a random‐effects model had been adopted; or
the effect measure had been expressed as odds ratio rather than risk ratio.
the unit of analysis had been per pregnancy rather than per woman, for relevant outcomes (multiple pregnancy, miscarriage, ectopic pregnancy, fetal abnormalities).
If we detect substantial heterogeneity, we will explore clinical or methodological differences between studies that might account for the heterogeneity.
Overall quality of the body of evidence: 'Summary of findings' table
We will generate a 'Summary of findings' table using GRADEpro software (GRADEpro GDT 2015). This table will be prepared by two review authors working independently, with disagreements resolved by consensus. It will evaluate the overall quality of the body of evidence for the main review comparison (GnRH pretreatment versus no pretreatment) and will report the main review outcomes (live birth rate, complication rate and clinical pregnancy rate), using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) criteria (study limitations (i.e. risk of bias), consistency of effect, imprecision, indirectness and publication bias). We will justify, document and incorporate into the report of results for each outcome our judgements about evidence quality (high, moderate low or very low). Additional Summary of findings tables will be generated for other comparisons (GnRH pretreatment versus COC pretreatment, GnRH pretreatment versus surgical pretreatment).
Acknowledgements
The authors thank Dr Sofia Dias for her contributions to the Cochrane systematic review 'Long‐term pituitary down‐regulation before in vitro fertilization (IVF) for women with endometriosis' that will be replaced by this current work.
Appendices
Appendix 1. Gynaecology and Fertility Group Specialised Register search strategy
Searched to present
PROCITE platform
Keywords CONTAINS "Gonadorelin" or "GnRHa‐gonadotropin" or "GnRHa" or "GnRh" or "GnRH analog" or "GnRH analogue" or "GnRH analogues" or "GnRH agonist" or "Gonadotrophin releasing hormones" or "Gonadotrophin releasing agonist" or "gonadotropin releasing hormone agonist" or "Goserelin" or "Gosereline " or "buserelin" or "busereline" or "Nafarelin" or "Zoladex" or "Lupron" or "triptoielin" or "triptorelin" or "triptoreline" or "triptorelyn" or "triptrolein" or Title CONTAINS "Gonadorelin" or "GnRHa‐gonadotropin" or "GnRHa" or "GnRh" or "GnRH analog" or "GnRH analogue" or "GnRH analogues" or "GnRH agonist" or "Gonadotrophin releasing hormones" or "Gonadotrophin releasing agonist" or "gonadotropin releasing hormone agonist" or "Goserelin" or "Gosereline " or "buserelin" or "busereline" or "Nafarelin" or "Zoladex" or "Lupron" or "triptoielin" or "triptorelin" or "triptoreline" or "triptorelyn" or "triptrolein"
AND
Keywords CONTAINS "endometriosis" or "adenomyosis" or Title CONTAINS "endometriosis" or "adenomyosis"
AND
Keywords CONTAINS "IVF" or "in vitro fertilization" or "in‐vitro fertilisation" or "ICSI" or "intracytoplasmic sperm injection" or "Embryo" or "in‐vitro fertilization" or "Embryo Transfer" or "ET" or "Blastocyst" or "implantation" or "poor implantation" or "poor prognostic patients" or "recurrent implantation failure" or "repeated implantation failure" or Title CONTAINS"IVF" or "in vitro fertilization" or "in‐vitro fertilisation" or "ICSI" or "intracytoplasmic sperm injection" or "Embryo" or "in‐vitro fertilization" or "Embryo Transfer" or "ET" or "Blastocyst" or "implantation" or "poor implantation" or "poor prognostic patients" or "recurrent implantation failure" or "repeated implantation failure"
Appendix 2. CENTRAL Register of Studies Online (CRSO) search strategy
Searched to present
Web platform
#1 MESH DESCRIPTOR Endometriosis EXPLODE ALL TREES
#2 Endometrio*:TI,AB,KY
#3 #1 OR #2
#4 MESH DESCRIPTOR Gonadotropin‐Releasing Hormone EXPLODE ALL TREES
#5 (Gonadotropin* or Gonadotrophin*):TI,AB,KY
#6 (buserelin or goserelin):TI,AB,KY
#7 (leuprolide or nafarelin):TI,AB,KY
#8 triptorelin:TI,AB,KY
#9 (GnRH or lhrh or gn‐rh or lfrh or lh‐rh or lhfshrh):TI,AB,KY
#10 (gonadorelin or luliberin or luteinizing hormone‐releasing hormone or
cystorelin):TI,AB,KY
#11 (dirigestran or factrel or gonadoliberin):TI,AB,KY
#12 leuprorelin:TI,AB,KY
#13 (down regulat*):TI,AB,KY
#14 downregulat*:TI,AB,KY
#15 (pituitary suppress*):TI,AB,KY
#16 (Ovar* adj2 suppress*):TI,AB,KY
#17 (suprecur or suprefact):TI,AB,KY
#18 (zoladex or lupron):TI,AB,KY
#19 GnRHa:TI,AB,KY
#20 #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19
#21 #3 AND #20
#22 MESH DESCRIPTOR Fertilization in Vitro EXPLODE ALL TREES
#23 (vitro fertili?ation):TI,AB,KY
#24 (ovar* stimulat*):TI,AB,KY
#25 (ovar* adj3 hyperstimulat*):TI,AB,KY
#26 (intracytoplasmic sperm injection*):TI,AB,KY
#27 (ivf or icsi):TI,AB,KY
#28 implantation:TI,AB,KY
#29 (infertil* or subfertil*):TI,AB,KY
#30 (assisted reproducti* treatment*):TI,AB,KY
#31 (assisted reproducti* techn*):TI,AB,KY
#32 (artificial* reproducti* techn*):TI,AB,KY
#33 pregnanc*:TI,AB,KY
#34 embryo*:TI,AB,KY
#35 blastocyst*:TI,AB,KY
#36 fertil*:TI,AB,KY
#37 #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36
#38 #21 AND #37
Appendix 3. MEDLINE search strategy
Searched from 1946 to present
OVID platform
1 exp ENDOMETRIOSIS/ 2 Endometrio*.tw. 3 or/1‐2 4 (buserelin or goserelin).tw. 5 (leuprolide or nafarelin).tw. 6 triptorelin.tw. 7 (GnRH or lhrh or gn‐rh or lfrh or lh‐rh or lhfshrh).tw. 8 (gonadorelin or luliberin or luteinizing hormone‐releasing hormone or cystorelin).tw. 9 (dirigestran or factrel or gonadoliberin).tw. 10 leuprorelin.tw. 11 down regulat*.tw. 12 downregulat*.tw. 13 pituitary suppress*.tw. 14 (Ovar* adj2 suppress*).tw. 15 (suprecur or suprefact).tw. 16 (zoladex or lupron).tw. 17 exp Gonadotropin‐Releasing Hormone/ 18 (Gonadotropin* or Gonadotrophin*).tw. 19 GnRHa.tw. 20 or/4‐19 21 exp embryo transfer/ or exp fertilization in vitro/ or exp sperm injections, intracytoplasmic/ 22 vitro fertili?ation.tw. 23 ovar* stimulat*.tw. 24 (ovar* adj3 hyperstimulat*).tw. 25 intracytoplasmic sperm injection$.tw. 26 (ivf or icsi).tw. 27 implantation.tw. 28 (infertil* or subfertil*).tw. 29 assisted reproducti* treatment*.tw. 30 assisted reproducti* techn*.tw. 31 artificial* reproducti* techn*.tw. 32 pregnanc*.tw. 33 embryo*.tw. 34 blastocyst*.tw. 35 fertil*.tw. 36 or/21‐35 37 randomized controlled trial.pt. 38 controlled clinical trial.pt. 39 randomized.ab. 40 randomised.ab. 41 placebo.tw. 42 clinical trials as topic.sh. 43 randomly.ab. 44 trial.ti. 45 (crossover or cross‐over or cross over).tw. 46 or/37‐45 47 exp animals/ not humans.sh. 48 46 not 47 49 3 and 20 and 36 and 48
Appendix 4. Embase search strategy
Searched from 1980 to present
OVID platform
1 exp endometriosis/ 2 endometrio*.tw. 3 or/1‐2 4 (buserelin or goserelin).tw. 5 (leuprolide or nafarelin).tw. 6 triptorelin.tw. 7 (GnRH or lhrh or gn‐rh or lfrh or lh‐rh or lhfshrh).tw. 8 (gonadorelin or luliberin or luteinizing hormone‐releasing hormone or cystorelin).tw. 9 (dirigestran or factrel or gonadoliberin).tw. 10 leuprorelin.tw. 11 down regulat*.tw. 12 downregulat*.tw. 13 pituitary suppress*.tw. 14 (Ovar* adj2 suppress*).tw. 15 (suprecur or suprefact).tw. 16 (zoladex or lupron).tw. 17 exp gonadorelin/ 18 (Gonadotropin* or Gonadotrophin*).tw. 19 GnRHa.tw. 20 or/4‐19 21 exp in vitro fertilization/ 22 exp intracytoplasmic sperm injection/ 23 exp embryo transfer/ 24 vitro fertili?ation.tw. 25 ovar* stimulat*.tw. 26 (ovar* adj3 hyperstimulat*).tw. 27 intracytoplasmic sperm injection*.tw. 28 (ivf or icsi).tw. 29 implantation.tw. 30 (infertil* or subfertil*).tw. 31 assisted reproducti* treatment*.tw. 32 assisted reproducti* techn*.tw. 33 artificial* reproducti* techn*.tw. 34 pregnanc*.tw. 35 embryo*.tw. 36 blastocyst*.tw. 37 fertil*.tw. 38 or/21‐37 39 Clinical Trial/ 40 Randomized Controlled Trial/ 41 exp randomization/ 42 Single Blind Procedure/ 43 Double Blind Procedure/ 44 Crossover Procedure/ 45 Placebo/ 46 Randomi?ed controlled trial$.tw. 47 Rct.tw. 48 random allocation.tw. 49 randomly.tw. 50 randomly allocated.tw. 51 allocated randomly.tw. 52 (allocated adj2 random).tw. 53 Single blind$.tw. 54 Double blind$.tw. 55 ((treble or triple) adj blind$).tw. 56 placebo$.tw. 57 prospective study/ 58 or/39‐57 59 case study/ 60 case report.tw. 61 abstract report/ or letter/ 62 or/59‐61 63 58 not 62 64 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) ) 65 63 not 64 66 3 and 20 and 38 and 65
Appendix 5. PsycINFO search strategy
Searched from 1806 to present
OVID platform
1 Endometrio*.tw. 2 exp Gonadotropic Hormones/ 3 (Gonadotropin* or Gonadotrophin*).tw. 4 (buserelin or goserelin).tw. 5 (leuprolide or nafarelin).tw. 6 triptorelin.tw. 7 (GnRH or lhrh or gn‐rh or lfrh or lh‐rh or lhfshrh).tw. 8 (gonadorelin or luliberin or luteinizing hormone‐releasing hormone or cystorelin).tw. 9 (dirigestran or factrel or gonadoliberin).tw. 10 leuprorelin.tw. 11 down regulat*.tw. 12 downregulat*.tw. 13 pituitary suppress*.tw. 14 (Ovar* adj2 suppress*).tw. 15 (suprecur or suprefact).tw. 16 (zoladex or lupron).tw. 17 GnRHa.tw. 18 or/2‐17 19 1 and 18 20 random.tw. 21 control.tw. 22 double‐blind.tw. 23 clinical trials/ 24 placebo/ 25 exp Treatment/ 26 or/20‐25 27 19 and 26
Appendix 6. CINAHL search strategy
Searched from 1961 to present
EBSCO platform
| # | Query |
| S51 | S38 AND S50 |
| S50 | S39 OR S40 OR S41 OR S42 OR S43 OR S44 OR S45 OR S46 OR S47 OR S48 OR S49 |
| S49 | TX allocat* random* |
| S48 | (MH "Quantitative Studies") |
| S47 | (MH "Placebos") |
| S46 | TX placebo* |
| S45 | TX random* allocat* |
| S44 | (MH "Random Assignment") |
| S43 | TX randomi* control* trial* |
| S42 | TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (doubl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) ) |
| S41 | TX clinic* n1 trial* |
| S40 | PT Clinical trial |
| S39 | (MH "Clinical Trials+") |
| S38 | S21 AND S37 |
| S37 | S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S34 OR S35 OR S36 |
| S36 | TX fertil* |
| S35 | TX blastocyst* |
| S34 | TX embryo* |
| S33 | TX pregnanc* |
| S32 | TX artificial* reproducti* techn* |
| S31 | TX assisted reproducti* techn* |
| S30 | TX assisted reproducti* treatment* |
| S29 | TX (infertil* or subfertil*) |
| S28 | TX implantation |
| S27 | TX intracytoplasmic sperm injection* |
| S26 | TX vitro fertili?ation |
| S25 | TX ovar* stimulat* |
| S24 | TX ovar* N3 hyperstimulat* |
| S23 | TX IVF or TX ICSI |
| S22 | (MM "Fertilization in Vitro") |
| S21 | S3 AND S20 |
| S20 | S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 |
| S19 | TX GnRHa* |
| S18 | TX (Gonadotropin* or Gonadotrophin*) |
| S17 | TX (zoladex or lupron) |
| S16 | TX (suprecur or suprefact) |
| S15 | TX (Ovar* N2 suppress*) |
| S14 | TX pituitary suppress* |
| S13 | TX downregulat* |
| S12 | TX down regulat* |
| S11 | TX leuprorelin |
| S10 | TX (dirigestran or factrel or gonadoliberin) |
| S9 | TX(gonadorelin or luliberin or luteinizing hormone‐releasing hormone or cystorelin) |
| S8 | TX(GnRH or lhrh or gn‐rh or lfrh or lh‐rh or lhfshrh) |
| S7 | TX triptorelin |
| S6 | TX (leuprolide or nafarelin) |
| S5 | TX (buserelin or goserelin) |
| S4 | (MM "Gonadorelin+") |
| S3 | S1 OR S2 |
| S2 | TX Endometrio* |
| S1 | (MM "Endometriosis") OR (MM "Adenomyosis") |
Contributions of authors
SHJ took the lead on the review update; wrote the entire background of the first draft of the protocol and developed the selection criteria and methods and search strategy. JGV contributed to the background of the revised draft of the protocol by applying methodological and statistical expertise. HNS wrote the original review and commented on all drafts of the protocol including search strategy methods. AA commented on the draft protocol, and will contribute methodological and statistical expertise later on in the review process and during the analysis phase of the review. AMAS participated in the first review, commented on the draft protocol and will help prepare the results and discussion sections of the review.
Sources of support
Internal sources
KPJ Ipoh Specialist Hospital, Other.
External sources
None, Other.
Declarations of interest
SHJ, AA, and AMAS have no interests to declare. HNS is a co‐editor of 2 textbooks on infertility and has received royalties from the publishers. JGV has received consultancy and lecture fees from MSD, Merck Serono, Ferring and Gedeon Richter.
New
References
Additional references
- Arici A, Oral E, Bukulmez O, Duleba A, Olive DL, Jones EE. The effect of endometriosis on implantation: results from the Yale University in vitro fertilization and embryo transfer program. Fertility and Sterility 1996;65(3):603‐7. [DOI] [PubMed] [Google Scholar]
- The Practice Committee of the American Society of Reproductive Medicine. Endometriosis and infertility. Fertility and Sterility 2006;86(4):S156‐60. 17055813 [Google Scholar]
- Azem F, Lessing JB, Geva A, Shahar A, Lerner‐Geva L. Patients with stages III and IV endometriosis have a poorer outcome of in vitro fertilization‐embryo transfer than patients with tubal infertility. Fertility and Sterility 1999;72(6):1107‐9. [DOI] [PubMed] [Google Scholar]
- Banhart K, Dunsmoore‐Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertility and Sterility 2002;77(6):1148‐55. [DOI] [PubMed] [Google Scholar]
- Bergendal A, Naffah S, Nagy C, Bergqvist A, Sjoblom P, Hillensjo T. Outcome of IVF in patients with endometriosis in comparison with tubal‐factor infertility. Journal of Assisted Reproduction and Genetics 1998;15(9):530‐4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cahill DJ, Wardle PG, Harlow CR, Hull MG. Ovarian dysfunction in endometriosis‐associated and unexplained infertility. Journal of Assisted Reproduction and Genetics 1997;14(10):554‐7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coccia ME, Rizzello F, Mariani G, Bulletti C, Palagiano A, Scarselli G. Impact of endometriosis on in vitro fertilization and embryo transfer cycles in young women: a stage‐dependent interference. Acta Obstetricia et Gynecologica Scandinavica 2011;90(11):1232‐8. [DOI] [PubMed] [Google Scholar]
- Zeigler D, Gayet V, Aubriot FX, Fauque P, Steuli I, Wolf JP, et al. Use of oral contraceptives in women with endometriosis before assisted reproduction treatment improves outcome. Fertility and Sterility 2010;94(7):2796‐9. [DOI] [PubMed] [Google Scholar]
- Edward RG. Clinical approaches to improving uterine receptivity during human implantation. Human Reproduction 1995;10(S):60‐6. [DOI] [PubMed] [Google Scholar]
- Garcia‐Velasco JA, Mahutte MG, Corona J, Zuniga V, Giles J, Arici A, et al. Removal of endometriomas before in vitro fertilization does not improve fertility outcomes: a matched case‐control study. Fertility and Sterility 2004;81:1194‐7. [DOI] [PubMed] [Google Scholar]
- Garrido N, Nevarro J, Remohi J, Simon C, Pellicer A. Follicular hormonal environment and embryo quality in women with endometriosis. Human Reproduction Update 2000;6(1):67‐74. [DOI] [PubMed] [Google Scholar]
- Geber S, Ferreira DP, Spyer Prates LF, Sales L, Sampaio M. Effects of previous ovarian surgery for endometriosis on the outcome of assisted reproduction treatment. Reproductive BioMedicine Online 2002;5:162‐5. [DOI] [PubMed] [Google Scholar]
- Guidice LC. Clinical practice. Endometriosis. New England Journal of Medicine 2010;362:2389‐98. [DOI] [PMC free article] [PubMed] [Google Scholar]
- GRADE Working Group, McMaster University. GRADEpro GDT. Version accessed XXX. Hamilton (ON): GRADE Working Group, McMaster University, 2015. Available at gradepro.org.
- Haouzi D, Assou S, Dechanel C, Anthony T, Dechaud S, Vos J. Controlled ovarian hyperstimulation for in vitro fertilization alters endometrial receptivity in human: protocol effects. Biology of Reproduction 2010;82:679‐83. [DOI] [PubMed] [Google Scholar]
- Harb HM, Gallos ID, Chu J, Harb M, Coomarasamy A. The effect of endometriosis on in vitro fertilization outcome: a systematic review and meta‐analysis. BJOG 2013;120:1308‐20. [DOI] [PubMed] [Google Scholar]
- Härkki P, Tiitinen A, Ylikorkala O. Endometriosis and assisted reproduction techniques. Annals of the New York Academy of Sciences 2010;1205(Feb):207‐13. [DOI] [PubMed] [Google Scholar]
- Harlow CR, Cahill DJ, Maile LA, Talbot MW, Mears J, Wardle PG. Reduced perovulatory granulosa cell steroidogenesis in women with endometriosis. Journal of Clinical Endocrinology and Metabolism 1996;81:426‐9. [DOI] [PubMed] [Google Scholar]
- Hart R. Unexplained infertility. Endometriosis and fibroids. BMJ 2003;27:721‐4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hickman TN. Impact of endometriosis on implantation. Data from the Wilford Hall Medical Centre IVF‐ET Program. Journal of Reproductive Medicine 2002;47(10):801‐8. [PubMed] [Google Scholar]
- Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration: Available from handbook.cochrane.org, 2011. [Google Scholar]
- Ma C, Qiao J, Liu P, Chen G. Ovarian suppression treatment prior to in‐vitro fertilization and embryo transfer in Chinese women with stage III or IV endometriosis. International Journal of Gynaecology and Obstetrics 2008;100:167‐70. [DOI] [PubMed] [Google Scholar]
- Marconi G, Vilela M, Quintana R, Sueldo C. Laparoscopic ovarian cystectomy of endometriomas does not affect the ovarian response to gonadotropin stimulation. Fertility and Sterility 2002;78(4):876‐8. [DOI] [PubMed] [Google Scholar]
- Marcus SF, Edwards RG. High rates of pregnancy after long term down regulation of women with endometriosis. American Journal of Obstetrics and Gynaecology 1994;171:812‐7. [DOI] [PubMed] [Google Scholar]
- Moulemen C, Vandenabeele B, Fieuw S, Splessen C, Timmermen D, D'Hooghe T. High prevalence of endometriosis in infertile women with normal ovulation and normosperm partners. Fertility and Sterility 2009;92:64‐74. [DOI] [PubMed] [Google Scholar]
- Nakamura K, Oosawa M, Kondou I, Ingaki S, Shibata H, Narita O. Menotrophin stimulation after prolonged gonadotrophin releasing hormone agonist pretreatment for in‐vitro fertilization in patients with endometriosis. Journal of Assisted Reproduction and Genetics 1992;9:113‐7. [DOI] [PubMed] [Google Scholar]
- Norenstedt SN, Linderoth‐Nagy C, Bergendal A, Sjoblom P, Bergqvist A. Reduced developmental potential in oocytes from women with endometriosis. Journal of Assisted Reproduction and Genetics 2001;18(12):644‐9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Olivennes F. Result of IVF in women with endometriosis. Journal of Gynaecology Obstetrics and Biology of Reproduction 2003;32:547‐7. [PubMed] [Google Scholar]
- Opoein HO, Peter F, Anne KO, Thomas A, Sveere B, Gudvor E. In vitro fertilization is a successful treatment in endometriosis‐associated infertility. Fertility and Sterility 2012;97(4):913‐8. [DOI] [PubMed] [Google Scholar]
- Ozkan S, Murk W, Arici A. Endometriosis and Infertility: epidemiology and evidence‐based treatments. Annals of New York Academy of Sciences 2008;1127:92‐100. [DOI] [PubMed] [Google Scholar]
- Pal L, Shifren JL, Isaacson KB, Chang Y, Toth TL. Impact of varying stages of endometriosis on the outcome of in vitro fertilisation and embryo transfer. Journal of Assisted Reproduction and Genetics 1998;43:351‐2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Raffi F, Metwally M, Amer S. The impact of excision of ovarian endometrioma on ovarian reserve: a systematic review and meta‐analysis. Journal of Clinical Endocrinology and Metabolism 2012;97(9):3146‐54. [DOI] [PubMed] [Google Scholar]
- Ryan IP, Taylor RN. Endometriosis and infertility: new concept. Obstetrical and Gynaecological Survey 1997;52:365‐71. [DOI] [PubMed] [Google Scholar]
- Simon C, Gutierrez A, Vidal A, Santos MJ, Tarin JJ, Remohi J, et al. Outcome of patients with endometriosis in assisted reproduction: results from in‐vitro fertilization and oocyte donation. Human Reproduction 1994;9(4):725‐9. [DOI] [PubMed] [Google Scholar]
- Surrey ES, Halme J. Effect of peritoneal fluid from endometriosis patient on endometrial stromal cell proliferation in vitro. Obstetrics and Gynaecology 1990;76:792‐7. [DOI] [PubMed] [Google Scholar]
- Surrey ES. Gonadotrophin‐releasing hormone agonists and add‐back therapy: what do the data show?. Current Opinion on Obstetrics and Gynaecology 2010;22:283‐8. [DOI] [PubMed] [Google Scholar]
- Suzuki T, Izumi S, Matsubayashi H, Awaji H, Yoshikata K, Makino T. Impact of ovarian endometrioma on oocytes and pregnancy outcome in in‐vitro fertilization. Fertility and Sterility 2005;83(4):908‐13. [DOI] [PubMed] [Google Scholar]
- Tang Y, Chen SL, Chen X, He YX, Ye DS, Guo W, et al. Ovarian damage after laparoscopic endometrioma excision might be related to the size of cyst. Fertility and Sterility 2013;100(2):464‐9. [DOI] [PubMed] [Google Scholar]
- Tsoumpou I, Kyrgiou M, Gelbaya TA, Nardo LG. The effect of surgical treatment for endometrioma on in vitro fertilization outcomes: a systematic review and meta‐analysis. Fertility and Sterility 2009;92:75‐87. [DOI] [PubMed] [Google Scholar]
- Urman B, Alper E, Yakin K, Oktem O, Aksoy S, Alatas C, et al. Removal of unilateral endometriomas is associated with immediate and sustained reduction in ovarian reserve. Reproductive BioMedicine Online 2013;27(2):212‐6. [DOI] [PubMed] [Google Scholar]
- Hauven LEE, Mijatovic V, Leemhius E, Schats R, Heymans MW, Lambalk CB, et al. Efficacy & safety of IVF/ICSI in patients with severe endometriosis after long term pituitary down regulation. Reproductive BioMedicine Online 2013;28(1):39‐46. [http://www.rbmojournal.com/article/S1472‐6483(13)00523‐3/] [DOI] [PubMed] [Google Scholar]
- Zegers‐Hochschild F, Adamson GD, Dyer S, Racowsky C, Mouzon J, Sokol R, et al. The International Glossary on Infertility and Fertility Care, 2017. Fertility and Sterility 2017;108(3):393‐406. [DOI: 10.1016/j.fertnstert.2017.06.005] [DOI] [PubMed] [Google Scholar]