Interventions for improving reproductive outcomes in women with recurrent implantation failure undergoing assisted reproductive techniques

  • Protocol
  • Intervention

Authors

  • Carolina O Nastri,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
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  • Danielle M Teixeira,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
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  • Rafael M Moroni,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
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  • Paula A Navarro,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
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  • Rui A Ferriani,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
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  • Wellington P Martins

    Corresponding author
    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
    • Wellington P Martins, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, University of Sao Paulo, Hospital das Clinicas da FMRP-USP, 8 andar, Campus Universitario da USP, Ribeirao Preto, Sao Paulo, 14048-900, Brazil. wpmartins@gmail.com.

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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

The objective of this review is to assess the efficacy and safety of interventions designed to improve reproductive outcomes in women with RIF undergoing ART.

Background

Description of the condition

Many women will not become pregnant, even after several embryo transfers. This condition is known as recurrent implantation failure (RIF). RIF can occur by chance, or because of underlying problems in the gametes and embryos or the lining of the womb (endometrium) or both (Das 2012; Simon 2012). The exact prevalence of RIF is difficult to determine because there are several definitions used to describe the condition (Laufer 2012). The more commonly accepted definition is the absence of a clinical pregnancy after at least three embryo transfers (Tan 2005). Some centres only define RIF after six unsuccessful embryo transfers. However, other centres prefer to use a broader definition of no clinical pregnancy after at least two embryo transfers (Martins 2011; Tan 2005). RIF can be a source of deep frustration to couples and clinicians, who often look for interventions to improve the reproductive outcomes.

Description of the intervention

Several interventions aiming to improve the implantation process in women with RIF have been investigated. These can involve clinical interventions applied to the women undergoing assisted reproductive techniques (ART) or laboratory interventions applied to the gametes or embryos.

Clinical interventions

Clinical interventions applied to women undergoing ART for RIF include physical interventions, cellular mediators and cellular treatments and other drug treatments.

Physical interventions for RIF include the following.

  • Endometrial injury: intentional damage to the to lining of the womb, the endometrium. This is performed before starting controlled ovarian stimulation (COS) (Nastri 2012).

  • Hysteroscopy: the inspection of the uterine cavity by endoscopy with access through the cervix. This procedure may be diagnostic or therapeutic or both and is performed in an attempt to diagnose and treat uterine abnormalities before initiating COS (Bosteels 2013; Bozdag 2008).

Cellular mediators and cellular treatments for RIF include the following.

  • Peripheral blood mononuclear cells (PBMC): the patient's own PBMC are cultured in vitro in the presence of human chorionic gonadotropin (hCG) and administered into the uterine cavity before embryo transfer (Yoshioka 2006).

  • Tumor necrosis factor α antagonists (TNF-α): administration of TNF-α antagonists around the time of embryo implantation (Benschop 2012; Winger 2009).

  • Intravenous immunoglobulins (IVIG): administration of IVIG, usually starting before oocyte retrieval (Clark 2006).

  • Leukemia inhibitory factor (LIF): administered before embryo transfer (Brinsden 2009).

  • Lymphocyte immune therapy (LIT): administered as allogenic immunization with paternal lymphocytes before starting COS (Carp 1994; Kuhn 1993).

  • Granulocyte colony-stimulating factor (G-CSF): administration of G-CSF on the day of hCG administration or luteal phase or both (Benschop 2012; Gleicher 2013).

Other drug treatments used for RIF include the following.

  • Oestrogen: exogenous oestrogen administered during COS or the luteal phase or both (Simon 2012).

  • Fat emulsion: intravenous administration of fat emulsion around the time of implantation (Roussev 2008; Shreeve 2012).

  • Glucocorticoids: administration of glucocorticoids around the time of implantation (Boomsma 2012).

  • Gonadotropin-releasing hormone (GnRH): administration of GnRH agonists during the luteal phase (Kyrou 2011; van der Linden 2011).

  • Heparin: administration of unfractionated heparin or low molecular weight heparin during COS or the luteal phase or both (Akhtar 2013).

  • Non-steroidal anti-inflammatory drugs (NSAID): administration of one of several drugs that inhibit cyclooxygenase (Cox) enzymes around the time of implantation. The most commonly used NSAID for this purpose is acetylsalicylic acid (Benschop 2012).

Laboratory interventions

Laboratory interventions are used either before or during embryo transfer.

Interventions used before embryo transfer include the following.

  • Assisted hatching: the artificial rupture or thinning of the zona pellucida of the embryo. Methods of administration include laser, chemical, mechanical, or enzymatic (Martins 2011).

  • Autologous endometrial cell co-culture: endometrial cells obtained by biopsy performed before COS are added to the embryo culture media (Eyheremendy 2010).

  • Blastocyst transfer: the embryos are transferred in blastocyst stage, five to six days after fertilization (Glujovsky 2012).

  • Intracytoplasmic morphologically selected sperm injection (IMSI): ultra-high magnification (6000x) microscopy is used to select the sperm that will be used in a ICSI procedure by motile sperm organelle morphology examination (MSOME) (Teixeira 2012).

  • Preimplantation genetic screening (PGS): include opening the zona pellucida to remove (i) the first or second polar bodies or both from unfertilised and fertilised oocytes; (ii) one or two blastomeres from cleavage-stage embryos; or (iii) trophectoderm cells from blastocyst-stage embryos. The removed material is examined for chromosomal abnormalities and genetic diseases (Mastenbroek 2011; Twisk 2006).

Interventions used during embryo transfer include the following.

  • Fibrin sealant: the addition of fibrin sealant to the embryo transfer media (Bontekoe 2010).

  • Hyaluronic acid (also called hyaluronan): the addition of hyaluronic acid to the embryo transfer media (Bontekoe 2010).

We plan to include any other intervention designed to improve implantation in women with RIF identified during the review process. Interventions that require a specific condition (e.g. surgical removal of the uterine tubes from women with hydrosalpinx) will not be included in this review because the results cannot be generalized to all women with RIF.

How the intervention might work

Clinical interventions

Physical interventions

  • Endometrial injury: the proposed rationales are (i) synchronizing embryo and endometrium development; (ii) inducing local inflammation; and (iii) promoting endometrial decidualisation (Nastri 2012).

  • Hysteroscopy: the endoscopic correction of endometrial abnormalities (e.g. polyps and leiomyomas) may improve the chance of successful implantation (Bosteels 2013). However, the endometrial injury associated with this procedure is also thought to be the responsible for improving the chance of successful implantation (Potdar 2012).

Cellular mediators and cellular treatments

  • PBMC: the proposed rationale is that the incubation of PBMC with hCG can induce functional changes in these cells. The administration of these cells into a woman's intrauterine cavity could facilitate embryo implantation (Yoshioka 2006).

  • TNF-α antagonists: the proposed rationale is that TNF-α antagonists might counteract increased Th1 cytokine production which is associated with early reproduction failure (Clark 2010).

  • IVIG: the proposed rationale is that IVIG can act against the excess of pro-inflammatory Th1-type cytokines relative to Th2 and Th3 cytokines (Clark 2006).

  • LIF: the proposed rationale is that LIF can induce decidualisation and implantation (Chen 2000).

  • LIT: the proposed rationale is that LIT can promote immune tolerance and re-polarisation of the Th1 and Th2 response (Benschop 2012).

  • G-CSF: the proposed rationale is that G-CSF can support trophoblast growth and placental metabolism (Benschop 2012).

Other drugs

  • Oestrogen: the proposed rationale is that higher oestrogen levels might increase endometrial blood flow improving its receptivity (Simon 2012).

  • Fat emulsion: fat emulsion suppresses the number and activity of peripheral natural-killer (NK) cells (Roussev 2008). This could favourably modulate the immune system response.

  • Glucocorticoids: the proposed rationales are (i) acting as immunosuppressives to reduce the NK cell count to the normal range; (ii) normalising the cytokine expression profile in the endometrium; (iii) suppressing endometrial inflammation (Boomsma 2012)

  • GnRH agonist in luteal phase: the proposed rationales include (i) inducing LH secretion by the pituitary; (ii) stimulating the endometrial GnRH receptors; and (iii) increasing embryonic hCG secretion (Kyrou 2011; van der Linden 2011).

  • Heparin: the proposed rationales are (i) treating an undiagnosed thrombophilia; and (ii) promoting decidualisation (Akhtar 2013).

  • NSAIDs: NSAIDS (i) improve uterine and ovarian blood flow; (ii) prevent thrombosis in the placental vasculature; (iii) stimulate interleukin-3 (IL-3); (iv) raise leukotriene production; (v) increase endometrial thickness; (vi) decrease endometrial inflammatory response; and (vii) reduce myometrial contractions (Nyachieo 2009; Siristatidis 2011)

Laboratory interventions

Interventions used before embryo transfer

  • Assisted hatching: the proposed rationales of assisted hatching include (i) facilitating embryo hatching; (ii) anticipating embryo implantation, which can improve the synchronization between the embryo and the endometrium during ART; and (iii) facilitating the exchange of metabolites, growth factors and messages between the embryo and endometrium (Carney 2012; Martins 2011).

  • Autologous endometrial cell co-culture: these cells produce transforming growth factor (TGF)-α, TGF-β1, platelet-derived growth factor α, insulin-like growth factor I and II, and granulocyte–macrophage colony-stimulating factor which may have a beneficial effect on embryos (Eyheremendy 2010);

  • Blastocyst transfer: blastocyst transfer helps early-stage embryos avoid exposure to the uterine environment, particularly one that has been subjected to controlled ovarian stimulation and thus high levels of oestrogen. This intervention also improves embryo selection, as only some cleavage-stage embryos with a reduced proportion of chromosomal abnormalities will reach the blastocyst-stage (Glujovsky 2012).

  • IMSI: sperm selection is improved by the examination of subcellular organelle malformations that are not detectable using ordinary magnifications (Teixeira 2012).

  • PGS: PGS reduces the chance of transferring embryos with chromosomal abnormalities or genetic diseases or both (Mastenbroek 2011; Twisk 2006).

Interventions used during embryo transfer

  • Fibrin sealant: fibrinolysis provoked by the presence of fibrin sealant in utero may cause the chemical absorption of the membrane of the zona pellucida, facilitating the hatching of the embryo. Embryos surrounded by sealant are compelled to stay in place for at least a few days, until the clot dissolves. The enhanced adhesive quality of the embryo surface facilitates the initial implantation process. The increased size of the complex embryo and sealant may increase the chances of the embryo remaining within the uterine cavity (Bontekoe 2010; Feichtinger 1992).

  • Hyaluronic acid: the proposed rationales include (i) increasing cell-to-cell adhesion and cell-to-matrix adhesion; (ii) producing a viscous solution that might enhance the embryo transfer process; and (iii) acting in CD44 receptors, which are expressed both on the pre-implantation embryo and endometrium (Bontekoe 2010; Loutradi 2008).

Why it is important to do this review

Although some systematic reviews have evaluated specific interventions for RIF, there are no systematic reviews that focus on all potential interventions for improving reproductive outcomes in women with RIF undergoing ART. The efficacy and safety of these interventions are not clear. Because of the large number of potential interventions for this condition, it would be very difficult to be aware of the current evidence for all of them. We believe this systematic review is important for subfertile couples, clinicians and researchers.

Objectives

The objective of this review is to assess the efficacy and safety of interventions designed to improve reproductive outcomes in women with RIF undergoing ART.

Methods

Criteria for considering studies for this review

Types of studies

Published and unpublished randomised controlled trials (RCTs) will be eligible for inclusion. We will exclude non-randomised studies (e.g. studies with evidence of inadequate sequence generation such as alternate days, patient numbers) as they are associated with a high risk of bias. Cross-over trials will be included if outcome data from the first phase of the study are available. There will be no limitation on language, publication date or status.

Types of participants

Participants will include women with RIF undergoing ART. Since there are several definitions for RIF, we will consider any definition that restricted eligibility to women with at least two previous embryo transfers without achieving clinical pregnancy.

Types of interventions

Any intervention designed to improve reproductive outcomes in women with RIF undergoing ART compared to no treatment, placebo or other active intervention(s) for the same purpose will be eligible for inclusion.

Types of outcome measures

Primary outcomes

Efficacy

1.1 Live birth per randomised woman.

Adverse events

1.2 Multiple pregnancy per randomised woman and per clinical pregnancy.

Secondary outcomes

Effectiveness

1.3 Clinical pregnancy per randomised woman.

Adverse events

1.4 Ovarian hyperstimulation syndrome (OHSS) per randomised woman.

1.5 Miscarriage per randomised woman and per clinical pregnancy.

1.6 Congenital abnormality per randomised woman and per clinical pregnancy.

The implantation rate will not be included in the quantitative meta-analysis because the denominator is not randomised (women, not embryos transferred, are randomised). However, the implantation rate will be reported in the 'Characteristics of included studies' tables.

Search methods for identification of studies

The search strategy will be developed in consultation with the Menstrual Disorders and Subfertility Group (MDSG) Trials Search Co-ordinator.

Electronic searches

We will search the following electronic databases for applicable RCTs: The Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of Controlled Trials (Appendix 1), the Cochrane Central Register of Controlled Trials (Appendix 2), MEDLINE (Appendix 3), EMBASE (Appendix 4), PsycINFO (Appendix 5), CINAHL (Appendix 6), and LILACS (Appendix 7). We will search for studies in trial registers including: ClinicalTrials.gov (http://clinicaltrials.gov; Appendix 8), Current Controlled Trials (http://www.controlled-trials.com, Appendix 9), and the WHO International Clinical Trials Registry Platform (http://www.who.int/trialsearch/Default.aspx, Appendix 10). Grey literature will be searched using OpenGrey (http://www.opengrey.eu, Appendix 11).

Searching other resources

We will handsearch the reference lists of included and excluded trials and review articles to identify additional studies that may have been missed by the database searches.

Data collection and analysis

Selection of studies

Two authors (DMT and RMM) will independently screen the titles and abstracts of the studies retrieved by the literature search. The full texts of all potentially eligible studies will be retrieved. The same two authors will independently examine these full text articles for compliance with the inclusion criteria and 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 consulting a third review author (CON). The selection process will be documented with a “PRISMA” flow chart.

Data extraction and management

Two review authors (DMT and RMM) will independently extract data from eligible studies using a data extraction form designed and pilot-tested by the authors. Any disagreements will be resolved by discussion or by consulting a third review author (CON). We will extract data on study characteristics and outcomes. Where studies have multiple publications, the main trial report will be used as the reference and additional details will be derived from secondary papers. We will correspond with study investigators for further data on methods and results, as required.

Assessment of risk of bias in included studies

Two review authors (DMT and RMM) will independently assess the risk of selection bias (random sequence generation and allocation concealment); performance bias (blinding of participants and personnel); detection bias (blinding of outcome assessors); attrition bias (incomplete outcome data); reporting bias (selective outcome reporting) and other potential sources of bias (e.g. difference in the number of embryos transferred, age of participants, co-interventions, and early stopping). Disagreements will be resolved by discussion or by consulting a third review author (CON). To assess selective outcome reporting we will search for published protocols of the included studies and compare them to the published articles reporting study results. We will describe all judgements fully and present the results in the 'Risk of bias' table.

Measures of treatment effect

For dichotomous outcomes the effects of the intervention will be summarized using the relative risk (RR) or odds ratio (OR) and corresponding 95% confidence intervals (95% CI). We prefer to use the RR because it is easier to interpret; however, we plan to use the Peto OR if there is a zero cell count or the prevalence of an event is less than 1% (in at least one intervention group). We will reverse the direction of effect of individual studies, if required, to ensure consistency across trials. We will compare the magnitude and direction of effect reported by studies with how they are presented in the review, taking legitimate differences into account. We will consider the clinical relevance of any statistically significant findings and in these situations we will also calculate the number needed to treat for an additional beneficial outcome (NNTB) or the number needed to treat for an additional harmful outcome (NNTH) as appropriate.

Unit of analysis issues

The primary analysis will be per woman randomised. However, the number of clinical pregnancies will be considered as the denominator for miscarriage, multiple pregnancy, and congenital abnormalities because these adverse events are related to pregnancy. Data that do not allow valid analysis (e.g. "per cycle" data) will be briefly summarised in an additional table and will not be meta-analysed. Multiple live births (e.g. twins or triplets) will be counted as one live birth event.

Dealing with missing data

Data will be analysed on an intention-to-treat basis as far as possible and attempts will be made to obtain missing data from the original trials. Where these data are unobtainable, imputation of individual values will be undertaken. We will assume that clinical pregnancy and OHSS did not occur in participants without a reported outcome. For other outcomes, only the available data will be analysed. Any imputation undertaken will be subjected to sensitivity analysis, as the study will be judged to be at high risk of attrition bias.

Assessment of heterogeneity

To provide a clinically meaningful summary, we will consider whether the clinical and methodological characteristics of the included studies are sufficiently similar for meta-analysis. We will assess statistical heterogeneity using the I² statistic. If a network meta-analysis is performed we will also calculate incoherence.

Assessment of reporting biases

In view of the difficulty of detecting and correcting for publication bias and other reporting biases, the authors will aim to minimise the potential impact of bias by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. If there are ten or more studies in an analysis, we will use a funnel plot to explore the possibility of small study effects (i.e. a tendency for estimates of the intervention effect to be more beneficial in smaller studies).

Data synthesis

If the studies are sufficiently similar, we will combine data for meta-analysis using a random-effects model for all included comparisons. We prefer to use a random-effects model because the estimated 95% CI is more conservative in the presence of heterogeneity; and similar to that estimated by a fixed-effect model when heterogeneity is minimal or absent. The data from primary studies will be combined comparing the intervention to no intervention or placebo; or, when appropriate, by comparing interventions to other active interventions.

Planned comparisons include the following:

  1. Endometrial injury versus control;

  2. Hysteroscopy versus control;

  3. Peripheral blood mononuclear cells (PBMC) versus control;

  4. Tumor necrosis factor α antagonists (TNF-α) versus control;

  5. Intravenous immunoglobulins (IVIG) versus control;

  6. Leukemia inhibitory factor (LIF) versus control;

  7. Lymphocyte immune therapy (LIT) versus control;

  8. Granulocyte colony-stimulating factor (G-CSF) versus control;

  9. Estrogen versus control;

  10. Fat emulsion versus control;

  11. Glucocorticoids versus control;

  12. Gonadotropin-releasing hormone (GnRH) agonist versus control;

  13. Heparin versus control;

  14. Non-steroidal anti-inflammatory drugs (NSAID) versus control;

  15. Assisted hatching versus control;

  16. Autologous endometrial cell co-culture versus control;

  17. Blastocyst transfer versus control;

  18. Intracytoplasmic morphologically selected sperm injection (IMSI) versus control;

  19. Preimplantation genetic screening (PGS) versus control;

  20. Fibrin sealant versus control;

  21. Hyaluronic acid (also called hyaluronan) versus control; and

  22. Intervention A versus intervention B.

Subgroup analysis and investigation of heterogeneity

Where substantial heterogeneity is observed (I² > 50%) we will address it by: (1) checking that the data are correct; (2) exploring possible explanations in sensitivity analyses; (3) performing the planned subgroup analysis. We will take any statistical heterogeneity into account when interpreting the results, especially if there is any variation in the direction of effect. The subgroup analysis will be based on the number of previous embryo transfer failures: two or three previous failures versus four or more previous failures.

Sensitivity analysis

We will conduct sensitivity analyses for the primary outcomes to determine whether the conclusions are robust or due to arbitrary decisions made regarding study eligibility and analysis. These analyses will determine whether the review conclusions would have differed if:

1. Eligibility were restricted to studies without high risk of bias;
2. A fixed-effect model was used to calculate the effect estimate; and
3. The summary effect measure was an OR rather than the RR.

Overall quality of the body of evidence: Summary of Findings Table

A 'Summary of findings' table will be generated using GRADEpro software. This table will evaluate the overall quality of the body of evidence for the main review outcomes using GRADE criteria (i.e. studies will be downgraded for study limitations including risk of bias, inconsistency, imprecision, indirectness and publication bias). Judgements about evidence quality (high, moderate, low or very low) will be justified, documented, and incorporated into the reporting of results for each outcome (Schünemann 2009).

Acknowledgements

We acknowledge the important help provided by Helen Nagels, Managing Editor of the Cochrane MDSG, and by Marian Showell, Trials Search Coordinator of the Cochrane MDSG.

Appendices

Appendix 1. MDSG search strategy

Menstrual disorders and subfertility Group database (MDSG) search strategy:

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 "ART"or "subfertility"or"subfertility-Female" or "artificial insemination" or "intrauterine insemination"or "IUI" 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 "ART"or "subfertility"or"subfertility-Female"or "IUI" or "artificial insemination" or "intrauterine insemination"

AND

Keywords CONTAINS "failed implantation" or "implantation failure" or "implantation"or "implantation rate" or "recurrent implantation failure" or "endometrial biopsy" or "endometrial injury" or Title  CONTAINS "failed implantation" or "implantation failure" or "implantation"or "recurrent implantation failure" or "endometrial biopsy" or "endometrial injury"

Appendix 2. CENTRAL search strategy

Cochrane Central Register of Controlled Trials search strategy:

1 exp embryo transfer/ or exp fertilization in vitro/ or exp sperm injections, intracytoplasmic/
2 embryo transfer$.tw.
3 vitro fertili?ation.tw.
4 ivf-et.tw.
5 ivf.tw.
6 icsi.tw.
7 intracytoplasmic sperm injection$.tw.
8 (blastocyst adj2 transfer$).tw.
9 exp reproductive techniques, assisted/ or exp insemination, artificial/ or exp ovulation induction/
10 assisted reproduct$.tw.
11 artificial insemination.tw.
12 iui.tw.
13 intrauterine insemination$.tw.
14 ovulation induc$.tw.
15 (ovari$ adj2 stimulat$).tw.
16 superovulat$.tw.
17 ovarian hyperstimulation.tw.
18 COH.tw.
19 infertil$.tw.
20 subfertil$.tw.
21 (ovari$ adj2 induction).tw.
22 or/1-21
23 RIF.tw.
24 (fail$ adj5 cycle$).tw.
25 (fail$ adj5 ivf).tw.
26 (recurrent adj5 fail$).tw.
27 (implant or implantation or implanting).tw.
28 (fail$ adj5 conceive).tw.
29 (fail$ adj5 conception).tw.
30 (unsuccessful adj5 ivf).tw.
31 (unsuccessful adj5 in vitro fertili?ation).tw.
32 (fail$ adj5 in vitro fertili?ation).tw.
33 (endometrial adj5 injur$).tw.
34 (endometrium adj5 injur$).tw.
35 (endometrial adj5 biops$).tw.
36 (endometrium adj5 biops$).tw.
37 or/23-36
38 22 and 37

Appendix 3. MEDLINE search strategy

Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <Inception to Present> search strategy:

1 exp embryo transfer/ or exp fertilization in vitro/ or exp sperm injections, intracytoplasmic/
2 embryo transfer$.tw.
3 vitro fertili?ation.tw.
4 ivf-et.tw.
5 ivf.tw.
6 icsi.tw.
7 intracytoplasmic sperm injection$.tw.
8 (blastocyst adj2 transfer$).tw.
9 exp reproductive techniques, assisted/ or exp insemination, artificial/ or exp ovulation induction/
10 assisted reproduct$.tw.
11 artificial insemination.tw.
12 iui.tw.
13 intrauterine insemination$.tw.
14 ovulation induc$.tw.
15 (ovari$ adj2 stimulat$).tw.
16 superovulat$.tw.
17 ovarian hyperstimulation.tw.
18 COH.tw.
19 infertil$.tw.
20 subfertil$.tw.
21 (ovari$ adj2 induction).tw.
22 or/1-21
23 RIF.tw.
24 (fail$ adj5 cycle$).tw.
25 (fail$ adj5 ivf).tw.
26 (recurrent adj5 fail$).tw.
27 (implant or implantation or implanting).tw.
28 (fail$ adj5 conceive).tw.
29 (fail$ adj5 conception).tw.
30 (unsuccessful adj5 ivf).tw.
31 (unsuccessful adj5 in vitro fertili?ation).tw.
32 (fail$ adj5 in vitro fertili?ation).tw.
33 (endometrial adj5 injur$).tw.
34 (endometrium adj5 injur$).tw.
35 (endometrial adj5 biops$).tw.
36 (endometrium adj5 biops$).tw.
37 or/23-36
38 22 and 37
39 randomized controlled trial.pt.
40 controlled clinical trial.pt.
41 randomized.ab.
42 placebo.tw.
43 clinical trials as topic.sh.
44 randomly.ab.
45 trial.ti.
46 (crossover or cross-over or cross over).tw.
47 or/39-46
48 (animals not (humans and animals)).sh.
49 47 not 48
50 38 and 49

Appendix 4. Embase search strategy

Embase search strategy:

1 exp embryo transfer/ or exp fertilization in vitro/ or exp intracytoplasmic sperm injection/
2 embryo$ transfer$.tw.
3 in vitro fertili?ation.tw.
4 icsi.tw.
5 intracytoplasmic sperm injection$.tw.
6 (blastocyst adj2 transfer$).tw.
7 ivf.tw.
8 exp infertility therapy/ or exp artificial insemination/ or exp intrauterine insemination/ or exp ovulation induction/
9 assisted reproduct$.tw.
10 artificial insemination.tw.
11 iui.tw.
12 intrauterine insemination$.tw.
13 ovulation induc$.tw.
14 (ovari$ adj2 stimulat$).tw.
15 superovulat$.tw.
16 ovarian hyperstimulation.tw.
17 COH.tw.
18 infertil$.tw.
19 subfertil$.tw.
20 (ovari$ adj2 induction).tw.
21 or/1-20
22 RIF.tw.
23 (fail$ adj5 cycle$).tw.
24 (recurrent adj5 fail$).tw.
25 (implant or implantation or implanting).tw.
26 (fail$ adj5 conceive).tw.
27 (fail$ adj5 conception).tw.
28 (unsuccessful adj5 ivf).tw.
29 (unsuccessful adj5 in vitro fertili?ation).tw.
30 (fail$ adj5 in vitro fertili?ation).tw.
31 (endometrial adj5 injur$).tw.
32 (endometrium adj5 injur$).tw.
33 (endometrial adj5 biops$).tw.
34 (endometrium adj5 biops$).tw.
35 (fail$ adj5 ivf).tw.
36 or/22-35
37 21 and 36
38 Clinical Trial/
39 Randomized Controlled Trial/
40 exp randomization/
41 Single Blind Procedure/
42 Double Blind Procedure/
43 Crossover Procedure/
44 Placebo/
45 Randomi?ed controlled trial$.tw.
46 Rct.tw.
47 random allocation.tw.
48 randomly allocated.tw.
49 allocated randomly.tw.
50 (allocated adj2 random).tw.
51 Single blind$.tw.
52 Double blind$.tw.
53 ((treble or triple) adj blind$).tw.
54 placebo$.tw.
55 prospective study/
56 or/38-55
57 case study/
58 case report.tw.
59 abstract report/ or letter/
60 or/57-59
61 56 not 60
62 37 and 61

Appendix 5. PsycINFO search strategy

PsycINFO <inception to current> search strategy:

1 exp reproductive technology/
2 in vitro fertili?ation.tw.
3 ivf-et.tw.
4 (ivf or et).tw.
5 icsi.tw.
6 intracytoplasmic sperm injection$.tw.
7 (blastocyst adj2 transfer$).tw.
8 assisted reproduct$.tw.
9 artificial insemination.tw.
10 iui.tw.
11 intrauterine insemination$.tw.
12 ovulation induc$.tw.
13 (ovari$ adj2 stimulat$).tw.
14 ovarian hyperstimulation.tw.
15 COH.tw.
16 superovulat$.tw.
17 infertil$.tw.
18 subfertil$.tw.
19 (ovari$ adj2 induction).tw.
20 or/1-19
21 RIF.tw.
22 (fail$ adj5 cycle$).tw.
23 (fail$ adj5 ivf).tw.
24 (recurrent adj5 fail$).tw.
25 (implant or implantation or implanting).tw.
26 (fail$ adj5 conceive).tw.
27 (fail$ adj5 conception).tw.
28 (unsuccessful adj5 ivf).tw.
29 (unsuccessful adj5 in vitro fertili?ation).tw.
30 (fail$ adj5 in vitro fertili?ation).tw.
31 (endometrial adj5 injur$).tw.
32 (endometrium adj5 injur$).tw.
33 (endometrial adj5 biops$).tw.
34 (endometrium adj5 biops$).tw.
35 or/21-34
36 20 and 35
37 random.tw.
38 control.tw.
39 double-blind.tw.
40 clinical trials/
41 placebo/
42 exp Treatment/
43 or/37-42
44 36 and 43

Appendix 6. CINAHL search strategy

CINAHL search strategy:

((repeated) OR (recurrent) OR (previous)) AND (implantation) AND ((IVF) OR (ICSI) OR (embryo)) AND ((trial) OR (random$))

Appendix 7. LILACS search strategy

LILACS search strategy:

((repeated) OR (recurrent) OR (previous)) AND (implantation) AND ((IVF) OR (ICSI) OR (embryo)) AND ((trial) OR (random$))

Appendix 8. ClinicalTrials.gov search strategy

ClinicalTrials.gov search strategy:

((repeated) OR (recurrent) OR (previous)) AND (implantation) AND ((IVF) OR (ICSI) OR (embryo))

Appendix 9. Current Controlled Trials search strategy

Current Controlled Trials search strategy:

((repeated) OR (recurrent) OR (previous)) AND (implantation) AND ((IVF) OR (ICSI) OR (embryo))

Appendix 10. WHO Trials Registry Platform search strategy

WHO Trials Registry Platform search strategy:

implantation AND failure

Appendix 11. Open Grey search strategy

Open Grey search strategy:

((repeated) OR (recurrent) OR (previous)) AND (implantation) AND ((IVF) OR (ICSI) OR (embryo))

Contributions of authors

Drafting the protocol: CON (methodologist, topic area specialist), DMT (methodologist, topic area specialist), PAN (topic area specialist), RAF (topic area specialist), RMM (methodologist), WPM (methodologist, statistics, topic area specialist).

Development of search strategy: CON and WPM, consulting Marian Showell, Trials Search Coordinator from the Cochrane MDSG

Search for trials: DMT and RMM (anticipated)

Obtaining copies of trials: CON (anticipated)

Contact authors from trials: CON and WPM (anticipated)

Selection of which trials to include: CON, DMT, RMM (anticipated)

Extraction of data from trials: CON, DMT, RMM (anticipated)

Assessment of risk of bias in included studies: CON, DMT, RMM (anticipated)

Entry of data into RevMan: CON, DMT, RMM, WPM (anticipated)

Drafting the review: CON, DMT, PAN, RAF, RMM, WPM (anticipated)

Declarations of interest

None known

Sources of support

Internal sources

  • CAPES, Brazil.

  • FMRP-USP, Brazil.

  • CNPq, Brazil.

External sources

  • No sources of support supplied

Ancillary