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.

May 08, 2023

Contributors: 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

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

© 2023. The Author(s).

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ABOUT THE CONTRIBUTORS

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
D Kamphuis

Department of Reproductive Medicine, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, 1081 HV, The Netherlands. d.kamphuis@amsterdamumc.nl.

Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands. d.kamphuis@amsterdamumc.nl.

K Rosielle

Department of Reproductive Medicine, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, 1081 HV, The Netherlands.

Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.

N van Welie

Department of Reproductive Medicine, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, 1081 HV, The Netherlands.

Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.

Department of Obstetrics and Gynaecology, OLVG, Amsterdam, 1091 AC, The Netherlands.

I Roest

Department of Reproductive Medicine, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, 1081 HV, The Netherlands.

Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.

Department of Obstetrics and Gynaecology, Máxima Medisch Centrum, Veldhoven, Eindhoven, 4600 DB, The Netherlands.

Grow research school for Oncology and Reproduction, Maastricht University, Universiteitssingel 40, Maastricht, 6229 ER, The Netherlands.

A J C M van Dongen

Department of Obstetrics and Gynaecology, Ziekenhuis Gelderse Vallei, Ede, 6716 RP, The Netherlands.

E A Brinkhuis

Department of Obstetrics and Gynaecology, Meander Medisch Centrum, Amersfoort, 3813 TZ, The Netherlands.

P Bourdrez

Department of Obstetrics and Gynaecology, VieCuri Medisch Centrum, Venlo, 5912 BL, The Netherlands.

A Mozes

Department of Obstetrics and Gynaecology, Ziekenhuis Amstelland, Amstelveen, 1186 AM, The Netherlands.

H R Verhoeve

Department of Obstetrics and Gynaecology, OLVG, Amsterdam, 1091 AC, The Netherlands.

D P van der Ham

Department of Obstetrics and Gynaecology, Martini Ziekenhuis, Groningen, 9728 NT, The Netherlands.

F P J M Vrouenraets

Department of Obstetrics and Gynaecology, Zuyderland Medisch Centrum, Heerlen, 6419 PC, The Netherlands.

J J Risseeuw

Department of Obstetrics and Gynaecology, St. Jansdal Ziekenhuis, Harderwijk, 3844 DG, The Netherlands.

T van de Laar

Department of Obstetrics and Gynaecology, Elkerliek Ziekenhuis, Helmond, 5707 HA, The Netherlands.

F Janse

Department of Obstetrics and Gynaecology, Rijnstate Ziekenhuis, Arnhem, 6815 AD, The Netherlands.

J E den Hartog

Department of Obstetrics and Gynaecology, Maastricht Universitair Medisch Centrum +, Maastricht, 6229 HX, The Netherlands.

M de Hundt

Department of Obstetrics and Gynaecology, Noordwest Ziekenhuisgroep, Alkmaar, 1815 JD, The Netherlands.

A B Hooker

Department of Obstetrics and Gynaecology, Zaans Medisch Centrum, Zaandam, 1502 DV, The Netherlands.

A G Huppelschoten

Department of Obstetrics and Gynaecology, Catharina Ziekenhuis, Eindhoven, 5623 EJ, The Netherlands.

Q D Pieterse

Department of Obstetrics and Gynaecology, Haga Ziekenhuis, Den Haag, 2545 AA, The Netherlands.

M Y Bongers

Department of Obstetrics and Gynaecology, Máxima Medisch Centrum, Veldhoven, Eindhoven, 4600 DB, The Netherlands.

Grow research school for Oncology and Reproduction, Maastricht University, Universiteitssingel 40, Maastricht, 6229 ER, The Netherlands.

J Stoker

Radiology and Nuclear Medicine, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, Netherlands.

C A M Koks

Department of Obstetrics and Gynaecology, Máxima Medisch Centrum, Veldhoven, Eindhoven, 4600 DB, The Netherlands.

C B Lambalk

Department of Reproductive Medicine, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, 1081 HV, The Netherlands.

Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.

A Hemingway

Department of Radiology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, W12 0HS, England.

W Li

Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, 3168, Australia.

B W J Mol

Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, 3168, Australia.

Aberdeen Centre for Women’s Health Research, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.

K Dreyer

Department of Reproductive Medicine, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, 1081 HV, The Netherlands.

Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.

V Mijatovic

Department of Reproductive Medicine, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, 1081 HV, The Netherlands.

Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.