The ReceptIVFity cohort study protocol to validate the urogenital microbiome as predictor for IVF or IVF/ICSI outcome

Rivka Koedooder, Martin Singer, Sam Schoenmakers, Paul Hendrik Maria Savelkoul, Servaas Antonie Morré, Jonathan Dennis de Jonge, Linda Poort, Willem-Jan Simon Stephanus Cuypers, Andries Edward Budding, Joop Stephanus Elisabeth Laven, ReceptIVFity study group, K Fleischer, B J Cohlen, C B Lambalk, J M J S Smeenk, N G M Beckers, F J M Broekmans, J E den Hartog, Rivka Koedooder, Martin Singer, Sam Schoenmakers, Paul Hendrik Maria Savelkoul, Servaas Antonie Morré, Jonathan Dennis de Jonge, Linda Poort, Willem-Jan Simon Stephanus Cuypers, Andries Edward Budding, Joop Stephanus Elisabeth Laven, ReceptIVFity study group, K Fleischer, B J Cohlen, C B Lambalk, J M J S Smeenk, N G M Beckers, F J M Broekmans, J E den Hartog

Abstract

Background: During the last decade, research has shown that besides the known predictive factors, such as duration of subfertility, a women's age, the body mass index, also the microbiome might affect fertility. Micro-organisms together with their genetic information and the milieu in which they interact are called the microbiome. Studies have shown that the presence of certain microbiota during assisted reproductive technology (ART) has a positive impact on the outcome. However, the potential role of using the microbiome as a predictor for outcome of ART has not yet been investigated.

Methods: In a prospective study, 300 women of reproductive age and with an indication for in-vitro Fertilization (IVF) with or without Intra Cytoplasmic Sperm Injection (ICSI) treatment will be included. Prior to the IVF or IVF-ICSI treatment, these women provided a midstream urine sample and a vaginal swab. The composition of the urinary and vaginal microbiome will be analysed with both Next Generation Sequencing and the IS-pro technique. The endpoints of the study are pregnancy achieved after fresh embryo transfer (ET) and within the subsequent year after inclusion. External validation of the findings will take place in an additional cohort of 50 women with an IVF or IVF-ICSI indication.

Discussion: In the proposed study, the predictive accuracy of the composition of the urinary and vaginal microbiome for IVF or IVF-ICSI outcome will be only validated for fresh ET. Follow-up has to show whether the predictive accuracy will be similar during the consecutive frozen ET's as part of the IVF or IVF-ICSI treatment or for subsequent stimulated or natural cycles. In addition, external validation will take place in another cohort and hospital. Predictive knowledge of the microbiome profile may enable couples to make a more substantiated decision on whether to continue treatment or not. Hence, the unnecessary physical and emotional burden of a failed IVF or IVF-ICSI treatment can be avoided.

Trial registration: ISRCTN ISRCTN83157250 . Registered 17 August 2018. Retrospectively registered.

Keywords: Implantation; Microbiota; Prediction; Urinary; Vaginal.

Conflict of interest statement

Authors’ information

Not applicable.

Ethics approval and consent to participate

The protocol was approved by the Institutional Medical Ethical Review Board of all participating centres (MEC-2014-455). Written informed consent was obtained from all participants.

Consent for publication

Not applicable.

Competing interests

RK reports that she is an employee at ARTPred B.V. during her PhD at Erasmus MC.

PHMS reports that he is a co-owner of IS-Diagnostics Ltd. and he has a patent MICROBIAL POPULATION ANALYSIS (9506109) licensed to ARTPred B.V., a patent MICROBIAL POPULATION ANALYSIS (20170159108) licensed to ARTPred.

SAM has a 100% University appointment is co-owner of IS-diagnostics Ltd., (a spin-off company inside the VU University Medical center Amsterdam, NL), which is the company that developed the IS-pro technique.

JDdJ reports personal fees from ARTPred B.V., grants from NGI Pre-Seed, other from RedMedTech Discovery Fund, from STW Valorisation grant 1, other from Take-off early phase trajectory, grants from Innovatie Prestatie Contract, other from Microbiome Ltd., grants from MIT Haalbaarheid, grants from EUROSTARS, other from Dutch R&D tax credit (WBSO), other from Erasmus MC, during the conduct of the study; personal fees and other from ARTPred B.V., outside the submitted work; In addition, Dr. de Jonge has a patent New method and kit for prediction success of in vitro fertilization licensed to ARTPred, a patent MICROBIAL POPULATION ANALYSIS (9506109) licensed to ARTPred, a patent MICROBIAL POPULATION ANALYSIS (20170159108) licensed to ARTPred, a patent METHOD AND KIT FOR PREDICTING THE OUTCOME OF AN ASSISTEDÐEPRODUCTIVE TECHNOLOGY PROCEDURE pending to ARTPred and a patent METHOD AND KIT FOR ALTERING THE OUTCOME OF AN ASSISTED REPRODUCTIVE TECHNOLOGY PROCEDURE pending to ARTPred.

LP reports other from IS-Diagnostics Ltd., during the conduct of the study; other from IS-Diagnostics Ltd., outside the submitted work.

WJSSC received personal consultancy and educational fees from Goodlife Fertility B.V. His employer has in collaboration with ARTPred acquired a MIND subsidy to cover part of the costs of this collaboration project.

AEB reports that he is a co-owner of IS-Diagnostics Ltd. In addition, Dr. Budding has a patent 392EPP0 pending, has a patent MICROBIAL POPULATION ANALYSIS (9506109) licensed to ARTPred, a patent MICROBIAL POPULATION ANALYSIS (20170159108) licensed to ARTPred, a patent METHOD AND KIT FOR PREDICTING THE OUTCOME OF AN ASSISTEDÐEPRODUCTIVE TECHNOLOGY PROCEDURE pending to ARTPred and a patent METHOD AND KIT FOR ALTERING THE OUTCOME OF AN ASSISTED REPRODUCTIVE TECHNOLOGY PROCEDURE pending to ARTPred.

JSEL reports grants from Dutch Heart Foundation, Ferring, Metagenics Inc.. He received personal consultancy fees from ARTPred B.V., Danone, Euroscreen, Roche, during the conduct of the study. In addition, JSEL is a co applicant on a Erasmus MC patent (New method and kit for prediction success of in vitro fertilization), that predicts IVF outcome based on the urinary microbiome. This particular patent is licensed to ARTPred B.V.

The other authors declare that they have no competing interests.

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