The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial

D Kamphuis; K Rosielle; N van Welie; I Roest; A J C M van Dongen; E A Brinkhuis; P Bourdrez; A Mozes; H R Verhoeve; D P van der Ham; F P J M Vrouenraets; J J Risseeuw; T van de Laar; F Janse; J E den Hartog; M de Hundt; A B Hooker; A G Huppelschoten; Q D Pieterse; M Y Bongers; J Stoker; C A M Koks; C B Lambalk; A Hemingway; W Li; B W J Mol; K Dreyer; V Mijatovic

doi:10.1186/s12905-023-02385-1

The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial

D Kamphuis, K Rosielle, N van Welie, I Roest, A J C M van Dongen, E A Brinkhuis, P Bourdrez, A Mozes, H R Verhoeve, D P van der Ham, F P J M Vrouenraets, J J Risseeuw, T van de Laar, F Janse, J E den Hartog, M de Hundt, A B Hooker, A G Huppelschoten, Q D Pieterse, M Y BongersJ Stoker, C A M Koks, C B Lambalk, A Hemingway, W Li, B W J Mol, K Dreyer, V Mijatovic

Research output: Contribution to journal › Article

1 Citation (Scopus)

Abstract

BACKGROUND: In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study.

METHODS: This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90%, a sample size of 554 women is calculated.

DISCUSSION: The H2Oil-timing study will provide insight into whether tubal flushing with oil-based contrast during hysterosalpingography should be incorporated in the initial fertility work-up in women with unexplained infertility as a therapeutic procedure. If this multicenter RCT shows that tubal flushing with oil-based contrast incorporated in the initial fertility work-up reduces time to conception and is a cost-effective strategy, the results may lead to adjustments of (inter)national guidelines and change clinical practice.

TRIAL REGISTRATION NUMBER: The study was retrospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL).

Original language	English
Article number	233
Journal	BMC Women's Health
Volume	23
Issue number	1
DOIs	https://doi.org/10.1186/s12905-023-02385-1 https://doi.org/10.1186/s12905-023-02574-y
Publication status	Published - 6 May 2023

Bibliographical note

Funding Information:
DK, NvW, IR, AJCMvD, EAB, PB, AM, HRV, DPvdH, FPJMV, JJR, TvdL, JEdH, MdH, AGH, QDP, MYB, and CAMK have nothing to declare. KR and FJ reports receiving a travel grant from Merck. ABH reports receiving a travel –and speaker’s fee from Merck and speakers fee from Nordic Pharma. JS has a research agreement with Takeda not related to this topic. CBL reports receiving research grants from Merck, Ferring and Guerbet. AH reports receiving travel and speaker’s fees from Guerbet and reports past consultancy for Guerbet. WL reports receiving research grants from the NHMRC Centre for Research Excellence in Women’s Health in Reproductive Life and Norman Beischer Medical Research Foundation not related to this study. BWM is supported by a NHMRC investigator grant (GNT1176437) and reports consultancy for ObsEva and Merck and travel support from Merck. KD reports receiving travel and speaker’s fees from Guerbet and research grants from Guerbet. VM reports receiving travel -and speaker’s fees from Guerbet as well as research grants from Guerbet, Merck and Ferring.

Funding Information:
This study is an investigator-initiated study funded by ZonMw, the Dutch organization for Health Research and Development (project number 852001932) and an additional funding of Guerbet, France. The study is designed without contribution of the funders. The funders will have no role in collection, analyses, and interpretation of the data, nor in writing the manuscript.

Publisher Copyright:
© 2023, The Author(s).

Correction: The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial
BMC Women's Health volume 23, Article number: 424 (2023)
Correction: BMC Women’s Health 23, 233 (2023) https://doi.org/10.1186/s12905-023-02385-1

Data Availability Statement

This manuscript is a study protocol. Datasets generated during the study will be available and published along with the results of the study.

Keywords

Female
Humans
Pregnancy
Contrast Media/therapeutic use
Fallopian Tubes/diagnostic imaging
Hysterosalpingography/adverse effects
Infertility, Female/etiology
Multicenter Studies as Topic
Pregnancy Rate
Randomized Controlled Trials as Topic
Randomized controlled trial
Tubal flushing
Infertility
Fallopian tubes
Hysterosalpingography (HSG)
Live birth
Oil-based contrast medium
Fertility work-up
Cost-effectiveness

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Kamphuis, D., Rosielle, K., van Welie, N., Roest, I., van Dongen, A. J. C. M., Brinkhuis, E. A., Bourdrez, P., Mozes, A., Verhoeve, H. R., van der Ham, D. P., Vrouenraets, F. P. J. M., Risseeuw, J. J., van de Laar, T., Janse, F., den Hartog, J. E., de Hundt, M., Hooker, A. B., Huppelschoten, A. G., Pieterse, Q. D., ... Mijatovic, V. (2023). The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial. BMC Women's Health, 23(1), Article 233. https://doi.org/10.1186/s12905-023-02385-1, https://doi.org/10.1186/s12905-023-02574-y

Kamphuis, D, Rosielle, K, van Welie, N, Roest, I, van Dongen, AJCM, Brinkhuis, EA, Bourdrez, P, Mozes, A, Verhoeve, HR, van der Ham, DP, Vrouenraets, FPJM, Risseeuw, JJ, van de Laar, T, Janse, F, den Hartog, JE, de Hundt, M, Hooker, AB, Huppelschoten, AG, Pieterse, QD, Bongers, MY, Stoker, J, Koks, CAM, Lambalk, CB, Hemingway, A, Li, W, Mol, BWJ, Dreyer, K & Mijatovic, V 2023, 'The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial', BMC Women's Health, vol. 23, no. 1, 233. https://doi.org/10.1186/s12905-023-02385-1, https://doi.org/10.1186/s12905-023-02574-y

Kamphuis D, Rosielle K, van Welie N, Roest I, van Dongen AJCM, Brinkhuis EA et al. The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial. BMC Women's Health. 2023 May 6;23(1):233. doi: 10.1186/s12905-023-02385-1, 10.1186/s12905-023-02574-y

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title = "The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial",

abstract = "BACKGROUND: In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study.METHODS: This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90%, a sample size of 554 women is calculated.DISCUSSION: The H2Oil-timing study will provide insight into whether tubal flushing with oil-based contrast during hysterosalpingography should be incorporated in the initial fertility work-up in women with unexplained infertility as a therapeutic procedure. If this multicenter RCT shows that tubal flushing with oil-based contrast incorporated in the initial fertility work-up reduces time to conception and is a cost-effective strategy, the results may lead to adjustments of (inter)national guidelines and change clinical practice.TRIAL REGISTRATION NUMBER: The study was retrospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL).",

keywords = "Female, Humans, Pregnancy, Contrast Media/therapeutic use, Fallopian Tubes/diagnostic imaging, Hysterosalpingography/adverse effects, Infertility, Female/etiology, Multicenter Studies as Topic, Pregnancy Rate, Randomized Controlled Trials as Topic, Randomized controlled trial, Tubal flushing, Infertility, Fallopian tubes, Hysterosalpingography (HSG), Live birth, Oil-based contrast medium, Fertility work-up, Cost-effectiveness",

author = "D Kamphuis and K Rosielle and {van Welie}, N and I Roest and {van Dongen}, {A J C M} and Brinkhuis, {E A} and P Bourdrez and A Mozes and Verhoeve, {H R} and {van der Ham}, {D P} and Vrouenraets, {F P J M} and Risseeuw, {J J} and {van de Laar}, T and F Janse and {den Hartog}, {J E} and {de Hundt}, M and Hooker, {A B} and Huppelschoten, {A G} and Pieterse, {Q D} and Bongers, {M Y} and J Stoker and Koks, {C A M} and Lambalk, {C B} and A Hemingway and W Li and Mol, {B W J} and K Dreyer and V Mijatovic",

note = "Funding Information: DK, NvW, IR, AJCMvD, EAB, PB, AM, HRV, DPvdH, FPJMV, JJR, TvdL, JEdH, MdH, AGH, QDP, MYB, and CAMK have nothing to declare. KR and FJ reports receiving a travel grant from Merck. ABH reports receiving a travel –and speaker{\textquoteright}s fee from Merck and speakers fee from Nordic Pharma. JS has a research agreement with Takeda not related to this topic. CBL reports receiving research grants from Merck, Ferring and Guerbet. AH reports receiving travel and speaker{\textquoteright}s fees from Guerbet and reports past consultancy for Guerbet. WL reports receiving research grants from the NHMRC Centre for Research Excellence in Women{\textquoteright}s Health in Reproductive Life and Norman Beischer Medical Research Foundation not related to this study. BWM is supported by a NHMRC investigator grant (GNT1176437) and reports consultancy for ObsEva and Merck and travel support from Merck. KD reports receiving travel and speaker{\textquoteright}s fees from Guerbet and research grants from Guerbet. VM reports receiving travel -and speaker{\textquoteright}s fees from Guerbet as well as research grants from Guerbet, Merck and Ferring. Funding Information: This study is an investigator-initiated study funded by ZonMw, the Dutch organization for Health Research and Development (project number 852001932) and an additional funding of Guerbet, France. The study is designed without contribution of the funders. The funders will have no role in collection, analyses, and interpretation of the data, nor in writing the manuscript. Publisher Copyright: {\textcopyright} 2023, The Author(s). Correction: The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial BMC Women's Health volume 23, Article number: 424 (2023) Correction: BMC Women{\textquoteright}s Health 23, 233 (2023) https://doi.org/10.1186/s12905-023-02385-1 ",

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doi = "10.1186/s12905-023-02385-1",

language = "English",

volume = "23",

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TY - JOUR

T1 - The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study)

T2 - study protocol of a randomized controlled trial

AU - Kamphuis, D

AU - Rosielle, K

AU - van Welie, N

AU - Roest, I

AU - van Dongen, A J C M

AU - Brinkhuis, E A

AU - Bourdrez, P

AU - Mozes, A

AU - Verhoeve, H R

AU - van der Ham, D P

AU - Vrouenraets, F P J M

AU - Risseeuw, J J

AU - van de Laar, T

AU - Janse, F

AU - den Hartog, J E

AU - de Hundt, M

AU - Hooker, A B

AU - Huppelschoten, A G

AU - Pieterse, Q D

AU - Bongers, M Y

AU - Stoker, J

AU - Koks, C A M

AU - Lambalk, C B

AU - Hemingway, A

AU - Li, W

AU - Mol, B W J

AU - Dreyer, K

AU - Mijatovic, V

N1 - Funding Information: DK, NvW, IR, AJCMvD, EAB, PB, AM, HRV, DPvdH, FPJMV, JJR, TvdL, JEdH, MdH, AGH, QDP, MYB, and CAMK have nothing to declare. KR and FJ reports receiving a travel grant from Merck. ABH reports receiving a travel –and speaker’s fee from Merck and speakers fee from Nordic Pharma. JS has a research agreement with Takeda not related to this topic. CBL reports receiving research grants from Merck, Ferring and Guerbet. AH reports receiving travel and speaker’s fees from Guerbet and reports past consultancy for Guerbet. WL reports receiving research grants from the NHMRC Centre for Research Excellence in Women’s Health in Reproductive Life and Norman Beischer Medical Research Foundation not related to this study. BWM is supported by a NHMRC investigator grant (GNT1176437) and reports consultancy for ObsEva and Merck and travel support from Merck. KD reports receiving travel and speaker’s fees from Guerbet and research grants from Guerbet. VM reports receiving travel -and speaker’s fees from Guerbet as well as research grants from Guerbet, Merck and Ferring. Funding Information: This study is an investigator-initiated study funded by ZonMw, the Dutch organization for Health Research and Development (project number 852001932) and an additional funding of Guerbet, France. The study is designed without contribution of the funders. The funders will have no role in collection, analyses, and interpretation of the data, nor in writing the manuscript. Publisher Copyright: © 2023, The Author(s). Correction: The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial BMC Women's Health volume 23, Article number: 424 (2023) Correction: BMC Women’s Health 23, 233 (2023) https://doi.org/10.1186/s12905-023-02385-1

PY - 2023/5/6

Y1 - 2023/5/6

N2 - BACKGROUND: In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study.METHODS: This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90%, a sample size of 554 women is calculated.DISCUSSION: The H2Oil-timing study will provide insight into whether tubal flushing with oil-based contrast during hysterosalpingography should be incorporated in the initial fertility work-up in women with unexplained infertility as a therapeutic procedure. If this multicenter RCT shows that tubal flushing with oil-based contrast incorporated in the initial fertility work-up reduces time to conception and is a cost-effective strategy, the results may lead to adjustments of (inter)national guidelines and change clinical practice.TRIAL REGISTRATION NUMBER: The study was retrospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL).

AB - BACKGROUND: In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study.METHODS: This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90%, a sample size of 554 women is calculated.DISCUSSION: The H2Oil-timing study will provide insight into whether tubal flushing with oil-based contrast during hysterosalpingography should be incorporated in the initial fertility work-up in women with unexplained infertility as a therapeutic procedure. If this multicenter RCT shows that tubal flushing with oil-based contrast incorporated in the initial fertility work-up reduces time to conception and is a cost-effective strategy, the results may lead to adjustments of (inter)national guidelines and change clinical practice.TRIAL REGISTRATION NUMBER: The study was retrospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL).

KW - Female

KW - Humans

KW - Pregnancy

KW - Contrast Media/therapeutic use

KW - Fallopian Tubes/diagnostic imaging

KW - Hysterosalpingography/adverse effects

KW - Infertility, Female/etiology

KW - Multicenter Studies as Topic

KW - Pregnancy Rate

KW - Randomized Controlled Trials as Topic

KW - Randomized controlled trial

KW - Tubal flushing

KW - Infertility

KW - Fallopian tubes

KW - Hysterosalpingography (HSG)

KW - Live birth

KW - Oil-based contrast medium

KW - Fertility work-up

KW - Cost-effectiveness

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DO - 10.1186/s12905-023-02385-1

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The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial

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Bibliographical note

Data Availability Statement

Keywords

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