Pipelle for Pregnancy (PIP): study protocols for three randomised controlled trials

Sarah Lensen, Wellington Martins, Carolina Nastri, Lynn Sadler, Cindy Farquhar, Sarah Lensen, Wellington Martins, Carolina Nastri, Lynn Sadler, Cindy Farquhar

Abstract

Background: The success rate of infertility treatments remains modest. Endometrial injury has been suggested as an intervention to increase the probability of pregnancy in women undergoing assisted reproductive technologies such as in vitro fertilisation (IVF). The majority of studies and systematic reviews have reported that endometrial injury improves the outcomes of IVF, intrauterine insemination and natural conception; however, the size and quality of the studies are poor. The low quality of the available evidence questions the presence of any real beneficial effect, and the applicability of the intervention in different populations remains unclear.

Methods/design: The PIP trials are three multi-centre, randomised controlled trials designed to test three separate hypotheses: whether endometrial injury increases the probability of live birth in women or couples 1) who are undergoing autologous embryo transfer as part of an IVF cycle (PIP-IVF), 2) with unexplained infertility who are attempting to conceive naturally (PIP-UE) and 3) with subfertility related to polycystic ovarian syndrome (PCOS) who are on ovulation induction medication and attempting to conceive (PIP-PCOS). Participants will be randomised to either undergo endometrial injury by endometrial pipelle biopsy or to: • no intervention (PIP-IVF), or • a sham procedure (PIP-PCOS and PIP-UE). In PIP-IVF, endometrial injury will be carried out between day three of the cycle prior to the IVF cycle, and day three of the IVF cycle. In PIP-UE and PIP-PCOS, endometrial injury or a sham procedure will be undertaken between days 1-12 of a menstrual cycle or ovulation induction cycle respectively. Participants in PIP-UE and PIP-PCOS will then be followed for three cycles during which time they will attempt to conceive from sexual intercourse. To ensure allocation concealment, randomisation will be carried out using a web-based system or sequentially numbered, opaque, sealed envelopes. The primary outcome is live birth. Secondary outcomes include ongoing pregnancy, clinical pregnancy and miscarriage. The required sample sizes for the PIP studies have been estimated at 840 (PIP-IVF), 350 (PIP-UE) and 280 (PIP-PCOS). Primary analysis will be as per intention-to-treat principles.

Discussion: The PIP trials are designed to address the gaps in the utility of endometrial scratching as a treatment for subfertility in three different populations. If the beneficial effect of this intervention can be confirmed in these settings, endometrial scratching will provide a cost-effective method for helping women and couples to conceive.

Trial registrations: PIP-IVF ACTRN12614000626662 registered 13/6/2014; PIP-PCOS ACTRN12614000657628 registered 24/6/2014; PIP-UE ACTRN12614000656639 registered 24/6/2014. The trials are ongoing.

Keywords: Endometrial injury; Endometrial receptivity; Endometrial scratching; Implantation; Inflammation.

Figures

Fig. 1
Fig. 1
The endometrial biopsy procedure. Image provided by Krames Staywell, 780 Township Line Road, Yardley, PA 19067, 267-685-2500)
Fig. 2
Fig. 2
Timing of endometrial injury in PIP-IVF in relation to the IVF cycle and the on-study period. OPU = oocyte pick-up, ET = embryo transfer, hCG = human chorionic gonadotrophin (pregnancy) test
Fig. 3
Fig. 3
Timing of endometrial injury in PIP-PCOS in relation to the on-study period. hCG = human chorionic gonadotrophin (pregnancy) test

References

    1. Taylor A. ABC of subfertility: Extent of the problem. Br Med J. 2003;327(7412):434–6. doi: 10.1136/bmj.327.7412.434.
    1. Gunby J, Bissonnette F, Librach C, Cowan L. Assisted reproductive technologies (ART) in Canada: 2006 results from the Canadian ART Register. Fertil Steril. 2010;93(7):2189–201. doi: 10.1016/j.fertnstert.2009.03.102.
    1. Macaldowie A, Wang Y, Chambers G, Sullivan E. Assisted reproductive technology in Australia and New Zealand 2011. UNSW 2013. .
    1. Simón C, Moreno C, Remohí J, Pellicer A. Molecular interactions between embryo and uterus in the adhesion phase of human implantation. Hum Reprod. 1998;13(Suppl 3):219–36. doi: 10.1093/humrep/13.suppl_3.219.
    1. Nastri CO, Lensen S, Polanski L, Raine-Fenning N, Farquhar CM, Martins WP. Endometrial injury and reproductive outcomes: there’s more to this story than meets the horse’s blind eye. Hum Reprod. 2015;20:749. doi: 10.1093/humrep/deu365.
    1. Shahid A, Phool B, Yasmeen S. Comparison between dilatation & curettage and Pipelle’s endometrial sampling for safer evaluation in postmenopausal bleeding women. Pak J Biol Sci. 2013;7(4):1121–4.
    1. Hulka JF, Peterson HA, Phillips JM, Surrey MW. Operative hysteroscopy: American Association of Gynecologic Laparoscopists’ 1993 membership survey. J Am Assoc Gynecol Laparosc. 1995;2(2):131–2. doi: 10.1016/S1074-3804(05)80004-0.
    1. Granot I, Dekel N, Bechor E, Segal I, Fieldust S, Barash A. Temporal analysis of connexin43 protein and gene expression throughout the menstrual cycle in human endometrium. Fertil Steril. 2000;73(2):381–6. doi: 10.1016/S0015-0282(99)00531-2.
    1. Barash A, Dekel N, Fieldust S, Segal I, Schechtman E, Granot I. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization. Fertil Steril. 2003;79(6):1317–22. doi: 10.1016/S0015-0282(03)00345-5.
    1. Almog B, Shalom-Paz E, Dufort D, Tulandi T. Promoting implantation by local injury to the endometrium. Fertil Steril. 2010;94(6):2026–9. doi: 10.1016/j.fertnstert.2009.12.075.
    1. El-Toukhy T, Sunkara S, Khalaf Y. Local endometrial injury and IVF outcome: A systematic review and meta-analysis. Reprod BioMed Online. 2012;25(4):345–54. doi: 10.1016/j.rbmo.2012.06.012.
    1. Potdar N, Gelbaya T, Nardo LG. Endometrial injury to overcome recurrent embryo implantation failure: a systematic review and meta-analysis. Reprod BioMed Online. 2012;25(6):561–71. doi: 10.1016/j.rbmo.2012.08.005.
    1. Coughlan C, Ledger W, Wang Q, Liu F, Demirol A, Gurgan T, et al. Recurrent implantation failure: definition and management. Reprod Biomed Online. 2014;28(1):14–38. doi: 10.1016/j.rbmo.2013.08.011.
    1. Karimzade MA, Oskouian H, Ahmadi S, Oskouian L. Local injury to the endometrium on the day of oocyte retrieval has a negative impact on implantation in assisted reproductive cycles: a randomized controlled trial. Arch Gynecol Obstet. 2010;281(3):499–503. doi: 10.1007/s00404-009-1166-1.
    1. Gibreel A, Badawy A, El-Refai W, El-Adawi N. Endometrial scratching to improve pregnancy rate in couples with unexplained subfertility: a randomized controlled trial. J Obstet Gynaecol Res. 2013;39(3):680–4. doi: 10.1111/j.1447-0756.2012.02016.x.
    1. Parsanezhad M, Dadras N, Maharlouei N, Neghahban L, Keramati P, Amini M. Pregnancy rate after endometrial injury in couples with unexplained infertility: a randomized clinical trial. Iran J Reprod Med. 2013;11(11):869–74.
    1. Baum M, Yerushalmi GM, Maman E, Kedem A, MacHtinger R, Hourvitz A, et al. Does local injury to the endometrium before IVF cycle really affect treatment outcome? Results of a randomized placebo controlled trial. Gynecol Endocrinol. 2012;28(12):933–6. doi: 10.3109/09513590.2011.650750.
    1. Yeung T, Chai J, Li R, Lee V, Ho P, Ng E. The effect of endometrial injury on ongoing pregnancy rate in unselected subfertile women undergoing in vitro fertilization: a randomized controlled trial. Hum Reprod. 2014;29(11):2474–81. doi: 10.1093/humrep/deu213.
    1. Narvekar S, Gupta N, Shetty N, Kottur A, Srinivas M, Rao K. Does local endometrial injury in the nontransfer cycle improve the IVF-ET outcome in the subsequent cycle in patients with previous unsuccessful IVF? A randomized controlled pilot study. J Hum Reprod Sci. 2010;3(1):15–9. doi: 10.4103/0974-1208.63116.
    1. Shohayeb A, El-Khayat W. Does a single endometrial biopsy regimen (S-EBR) improve ICSI outcome in patients with repeated implantation failure? A randomised controlled trial. Eur J Obstet Gynecol Reprod Biol. 2012;164(2):176–9. doi: 10.1016/j.ejogrb.2012.06.029.
    1. Siristatidis C, Vrachnis N, Vogiatzi P, Chrelias C, Retamar AQ, Bettocchi S, et al. Potential pathophysiological mechanisms of the beneficial role of endometrial injury in in vitro fertilization outcome. Reprod Sci. 2014;21(8):955–65. doi: 10.1177/1933719114525270.
    1. Gnainsky Y, Granot I, Aldo PB, Barash A, Or Y, Mor G, et al. Biopsy-induced inflammatory conditions improve endometrial receptivity: the mechanism of action. Reproduction. 2014;149(1):75–85. doi: 10.1530/REP-14-0395.
    1. Gnainsky Y, Granot I, Aldo PB, Barash A, Or Y, Schechtman E, et al. Local injury of the endometrium induces an inflammatory response that promotes successful implantation. Fertil Steril. 2010;94(6):2030–6. doi: 10.1016/j.fertnstert.2010.02.022.
    1. Kalma Y, Granot I, Gnainsky Y, Or Y, Czernobilsky B, Dekel N, et al. Endometrial biopsy-induced gene modulation: first evidence for the expression of bladder-transmembranal uroplakin Ib in human endometrium. Fertil Steril. 2009;91(4):1042–9. doi: 10.1016/j.fertnstert.2008.01.043.
    1. Granot I, Gnainsky Y, Dekel N. Endometrial inflammation and effect on implantation improvement and pregnancy outcome. Reproduction. 2012;144(6):661–8. doi: 10.1530/REP-12-0217.
    1. Jokimaa V, Oksjoki S, Kujari H, Vuorio E, Anttila L. Altered expression of genes involved in the production and degradation of endometrial extracellular matrix in patients with unexplained infertility and recurrent miscarriages. Mol Hum Reprod. 2002;8(12):1111–6. doi: 10.1093/molehr/8.12.1111.
    1. Lessey BA, Holoch KJ, Franasiak J, Yuan L, Fritz MA, Young SL. Prospective assessment of mid-secretory endometrial LIF and beta3 integrin expression as a predictor of pregnancy outcome and endometriosis in unexplained infertility. Human Reproduction. 2012;27. .
    1. Hambartsoumian E. Endometrial leukemia inhibitory factor (LIF) as a possible cause of unexplained infertility and multiple failures of implantation. Am J Reprod Immunol. 1998;39(2):137–43. doi: 10.1111/j.1600-0897.1998.tb00345.x.
    1. Bellver J, Martínez-Conejero JA, Labarta E, Alamá P, Melo MAB, Remohí J, et al. Endometrial gene expression in the window of implantation is altered in obese women especially in association with polycystic ovary syndrome. Fertil Steril. 2011;95(7):2335–41. doi: 10.1016/j.fertnstert.2011.03.021.
    1. Jana SK, Banerjee P, Mukherjee R, Chakravarty B, Chaudhury K. HOXA-11 mediated dysregulation of matrix remodeling during implantation window in women with endometriosis. J Assist Reprod Genet. 2013;30(11):1505–12. doi: 10.1007/s10815-013-0088-9.
    1. Evers JLH. A nod is as good as a wink to a blind horse. Hum Reprod. 2014;29(11):2355. doi: 10.1093/humrep/deu224.
    1. Yeung TW, Chai J, Li RH, Lee VC, Ho PC, Ng EH. Reply: Endometrial injury and reproductive outcomes: there’s more to this story than meets the horse’s blind eye. Hum Reprod. 2015;30(3):749–50. doi: 10.1093/humrep/deu366.
    1. Simón C, Bellver J. Scratching beneath ‘the Scratching Case’: systematic reviews and meta-analyses, the back door for evidence-based medicine. Hum Reprod. 2014;29(8):1618–21. doi: 10.1093/humrep/deu126.
    1. Simón C, Bosch E, Bellver J. Reply: Endometrial scratching for women with repeated implantation failure. Hum Reprod. 2014;29(12):2856–7. doi: 10.1093/humrep/deu258.
    1. Zegers-Hochschild F, Adamson GD, De Mouzon J, Ishihara O, Mansour R, Nygren K, et al. The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology, 2009. Hum Reprod. 2009;24(11):2683–7. doi: 10.1093/humrep/dep343.
    1. Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HG, Behre HM, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2009;16(3):231–45. doi: 10.1093/humupd/dmp048.
    1. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Hum Reprod. 2004;19(1):41–7. doi: 10.1093/humrep/deh098.
    1. Evers JLH. Female subfertility. Lancet. 2002;360(9327):151–9. doi: 10.1016/S0140-6736(02)09417-5.
    1. Rai R, Regan L. Recurrent miscarriage. Lancet. 2006;368(9535):601–11. doi: 10.1016/S0140-6736(06)69204-0.
    1. Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, et al. CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol. 2010;63(8):e1–37. doi: 10.1016/j.jclinepi.2010.03.004.
    1. Guven S, Kart C, Unsal MA, Yildirim O, Odaci E, Yulug E. Endometrial injury may increase the clinical pregnancy rate in normoresponders undergoing long agonist protocol ICSI cycles with single embryo transfer. Eur J Obstet Gynaecol Reprod Biol. 2014;173(1):58–62. doi: 10.1016/j.ejogrb.2013.11.005.
    1. Loeb L. The experimental proof changes in the uterine decidua of guinea pig after mating. Zentralbl Allg Pathol. 1907;18:563–5.
    1. Nastri CO, Gibreel A, Raine-Fenning N, Maheshwari A, Ferriani RA, Bhattacharya S, et al. Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database Syst Rev. 2012;7:CD009517.
    1. Hunault CC, Habbema JDF, Eijkemans MJC, Collins JA, Evers JLH, te Velde ER. Two new prediction rules for spontaneous pregnancy leading to live birth among subfertile couples, based on the synthesis of three previous models. Hum Reprod. 2004;19(9):2019–26. doi: 10.1093/humrep/deh365.
    1. Clarke JF, Van Rumste MME, Farquhar CM, Johnson NP, Mol BWJ, Herbison P. Measuring outcomes in fertility trials: can we rely on clinical pregnancy rates? Fertil Steril. 2010;94(5):1647–51. doi: 10.1016/j.fertnstert.2009.11.018.
    1. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356(6):551–66. doi: 10.1056/NEJMoa063971.
    1. Bang H, Flaherty SP, Kolahi J, Park J. Blinding assessment in clinical trials: a review of statistical methods and a proposal of blinding assessment protocol. Clin Res Regul Aff. 2010;27(2):42–51. doi: 10.3109/10601331003777444.
    1. James KE, Block DA, Lee KK, Kraemer HC, Fuller RK. An index for assessing blindness in a multi-centre clinical trial: disulfiram for alcohol cessation - a VA cooperative study. Stat Med. 1996;15(13):1421–34. doi: 10.1002/(SICI)1097-0258(19960715)15:13<1421::AID-SIM266>;2-H.
    1. Moorthy VS, Karam G, Vannice KS, Kieny M. Rationale for WHO’s new position calling for prompt reporting and public disclosure of interventional clinical trial results. PLoS Med. 2015;12(4):e1001819. doi: 10.1371/journal.pmed.1001819.

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