Live Birth After Additional Tubal Flushing With Oil-based Contrast Versus no Additional Flushing: (HYFOIL)

Live Birth After Additional Tubal Flushing With Oil-based Contrast Versus no Additional Flushing: a Randomised, Multicentre, Parallel Group Pragmatic Trial in Infertile Women With at Least One Patent Tube at Hysterosalpingo-foam Sonography

Ten to 15 percent of couples in their reproductive lifetime face fertility problems which is defined by WHO as the absence of pregnancy after minimal 12 months of unprotected sexual intercourse. The three most frequent causes of subfertility are: sperm defects, ovulation disorders and tubal pathology. In order to exclude tubal pathology, tubal patency tests are performed under ultrasound guidance with foam (hysterosalpingo-foam sonography (Hyfosy)) or with contrast/water (hysterosalpingo-contrast sonography (Hycosy)).

This trial will investigate whether tubal flushing with an oil-soluble contrast medium (OSCM) can increase the likelihood of a spontaneous conception after tubal patency testing with Hyfosy under ultrasound guidance compared to no additional flushing in a population of infertile women between 18 and 40 years of age with absence of pregnancy after 12 months of unprotected sexual intercourse or who have three cycles of donor insemination without pregnancy or three ovulatory ovulation induction cycles without pregnancy. The use of Lipiodol Ultra Fluide® is off-label in Hyfosy.

This multicenter, randomised, open-label, comparative and pragmatic trial compares 2 arms which will be randomised 1:1:

• Intervention group: Tubal flush with 5-10mL oil-soluble contrast medium (Lipiodol Ultra Fluide®, Guerbet, France) immediately after Hyfosy
• Control group: No additional intervention after Hyfosy The study comprises a screening period of maximum 8 weeks (w-8 to d1), randomisation (w-8 to d1), a start study visit at which the Hyfosy is performed (d1) and a fertility treatment period of 6 months (d1-w26). If the woman is not pregnant at 6 months after Hyfosy, the follow-up will last till 12 months (w52). If the participant is pregnant at 6 months after Hyfosy, the follow-up will last till maximal 4 months after live birth or miscarriage.

The primary endpoint is the occurrence of live birth, with the first day of the last menstrual cycle in which the patient conceives within 6 months after Hyfosy. Secondary endpoints consist of reproductive outcomes, gestational age at delivery, birth weight, neonatal mortality, major congenital anomaly, neonatal outcomes and thyroid function, pregnancy complications, number of complications during or immediately after the intervention, pain score of the Hyfosy and additional flush, thyroid function of the mother, general and disease-specific quality of life.

Study Overview

• Status: Recruiting
• Conditions: Infertility, Female
• Intervention / Treatment: Drug: Lipiodol Ultra Fluide®

• Study Type: Interventional
• Enrollment (Anticipated): 736
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Diane De Neubourg; Phone Number: +32 3 821 45 98; Email: diane.deneubourg@uza.be

Study Locations

• Belgium
  • Antwerp, Belgium
    • Recruiting
    • Antwerp University Hospital
    • Contact: Diane De Neubourg
  • Antwerp, Belgium
    • Recruiting
    • Gza Sint Augustinus
    • Contact: Brecht Geysenbergh
  • Bonheiden, Belgium
    • Recruiting
    • Imelda
    • Contact: Sophie Pelckmans
  • Brasschaat, Belgium
    • Recruiting
    • AZ Klina
    • Contact: Alessa Sugihara
  • Brugge, Belgium
    • Terminated
    • AZ Sint Jan Brugge
  • Brussel, Belgium
    • Recruiting
    • UZ Brussel
    • Contact: Christophe Blockeel
  • Brussel, Belgium
    • Terminated
    • CHIREC
  • Brussel, Belgium
    • Recruiting
    • UCL Saint Luc
    • Contact: Christine Wyns
  • Genk, Belgium
    • Recruiting
    • Ziekenhuis Oost Limburg
    • Contact: Nathalie Dhont
  • Gent, Belgium
    • Recruiting
    • UZ Gent
    • Contact: Dominic Stoop
  • Gent, Belgium
    • Recruiting
    • AZ Sint Lucas
    • Contact: Nele Van Renterghem
  • Lennik, Belgium
    • Recruiting
    • Hôpital Erasme
    • Contact: Anne Delbaere
  • Leuven, Belgium
    • Recruiting
    • UZ Leuven
    • Contact: Sharon Lie Fong
  • Liège, Belgium
    • Recruiting
    • CHR Citadelle
    • Contact: Larie Henry
  • Liège, Belgium
    • Recruiting
    • CHC Mont Legia
    • Contact: Vincent Goffioul
  • Turnhout, Belgium
    • Recruiting
    • Az Turnhout
    • Contact: Astrid Verest

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Infertile women undergoing Hyfosy as part of the fertility workup. Women will be eligible if they

• are ≥ 18 years and < 40 years

• have infertility defined as

  • lack of conception despite 12 months of unprotected intercourse OR;
  • if they are taking part in a donor sperm insemination programme: three cycles of donor insemination without pregnancy OR;
  • in case of treated ovulation disorder: three ovulatory ovulation induction cycles without pregnancy
• have tubal patency of at least one Fallopian tube on Hyfosy

Exclusion Criteria:

Women with

• known iodine allergy
• allergy to poppy seed oil
• ovulation disorders defined as less than eight menstrual cycles per year who did not have three ovulatory cycles after ovulation induction
• contra-indication to have tubal patency testing according to the site's indication
• active thyroid disorders
• untreated subclinical hypothyroidism (TSH>2.5mIU/L) in case of auto-immune thyroid disease
• uterine surgery in the past two months before Hyfosy

• a male partner (if applicable)

  • with a post-wash Total Motile Sperm Count (TMC) < 1x106 and/or TMC < 3x106 in the native sperm analysis [TMC is defined as volume X concentration X (A* (progressive) + B* (non progressive) motility in %) divided by 100] OR
  • with a history suspect of severe male factor infertility if no sperm sample is available at time of randomisation
• an indication for IVF defined as patients who are advised to go to IVF immediately because of bilateral tubal block, severe male factor infertility, unsolved anovulatory problems, endometriosis with residual functional problems"

• no Belgian national number (RRN/INS)

  • A+B when A,B,C is used (WHO 2010) A+B+C when A,B,C, D is used (WHO 2021)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tubal flush with Lipiodol Ultra Fluide® after Hyfosy	Drug: Lipiodol Ultra Fluide®; Tubal flush with 5-10mL oil-soluble contrast medium (OSCM) (Lipiodol Ultra Fluide®, Guerbet, France) immediately after Hyfosy. The use will be off-label.
No Intervention: No tubal flush after Hyfosy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Live birth	the occurrence of live birth, counting from the first day of the last menstrual cycle in which the patient conceives within 6 months after Hyfosy.	Delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Type of pregnancy	single or multiple pregnancy	15 months after Hyfosy
Number of miscarriages	presence of miscarriages	15 months after Hyfosy
Amount of pregnancy complications	gestational diabetes, hypertensive disease, placenta praevia, intrauterin growth restriction, premature birth	15 months after Hyfosy
Number of ectopic pregnancies	the presence of ectopic pregnancy	15 months after Hyfosy
Number of clinical pregnancies	the presence of clinical pregnancy	15 months after Hyfosy
Complication during or after Hyfosy with intervention	embolism, anaphylactic shock, pelvic inflammatory disease, intravasation, infection and hemorrhage	immediately after intervention
Pain score of the Hyfosy with or without intervention	VAS (0 = no pain; 10 = worst possible pain)	immediately after Hyfosy
Pain score of the intervention with IMP if applicable	VAS (0 = no pain; 10 = worst possible pain)	immediately after intervention
Thyroid function of baby	heel prick test (TSH, FT4)	3 days after delivery
Birthweight	Birthweight of baby	at delivery
Gestational age at delivery	Live birth after how many weeks pregnancy	at delivery
Neonatal care	Neonatal care (Yes/No)	at delivery
Number of babies	Number of babies after live birth	at delivery
Maternal thyroid function	TSH, FT4 determination	4 weeks, 26 weeks, 15 weeks after delivery
General quality of life	EuroQol-5D-5Levels (EQ-5D-5L): Level 1: indicating no problem Level 2: indicating slightproblems Level 3: indicating moderateproblems Level 4: indicating severe problems Level 5:indicating extreme problems; VAS (score 0 = worst health status; score 100 = best health status) How higher the score, how better the quality of life	26 weeks
Disease-specific quality of life	Fertility Quality Of Life tool (FertiQol): Very poor (0), poor (1), neither poor nor good (2), very good (4); Very dissatisfied (0), dissatisfied (1), neither satisfied nor dissatisfied (2), satisfied (3), very satisfied (4); Always (0), very often (1), quite often (2), Seldom (3), never (4); An extreme amount (0), very much (1), a moderate amount (2), a little (3), not at all (4); Completely (0), a great deal (1), moderately (2), not much (3), not at all (4) Scores on the response scales are reversed, summed and scaled to range from 0 to 100. Higher scores on the subscales and total scores indicate better quality of life	26 weeks
Neonatal Mortality	Neonatal death after delivery	at delivery
Major Congenital Anomaly	Neonatal major anomaly	at delivery
Gender of baby	Gender of baby (M/F)	at delivery

Collaborators and Investigators

• Sponsor: Dafne Balemans

Publications and helpful links

General Publications

• De Neubourg D, Janssens L, Verhaegen I, Smits E, Mol BW, Roelant E. Live birth after additional tubal flushing with oil-based contrast versus no additional flushing: a randomised, multicentre, parallel-group pragmatic trial in infertile women with at least one patent tube at hysterosalpingo-foam sonography (HYFOIL study). BMJ Open. 2021 Nov 29;11(11):e054845. doi: 10.1136/bmjopen-2021-054845.

Study record dates

Study Major Dates

• Study Start (Actual): May 25, 2021
• Primary Completion (Anticipated): January 1, 2024
• Study Completion (Anticipated): November 1, 2024

Study Registration Dates

• First Submitted: April 23, 2020
• First Submitted That Met QC Criteria: May 4, 2020
• First Posted (Actual): May 8, 2020

Study Record Updates

• Last Update Posted (Actual): April 24, 2023
• Last Update Submitted That Met QC Criteria: April 21, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Manifestations; Infertility; Flushing; Infertility, Female; Antineoplastic Agents; Ethiodized Oil
• Other Study ID Numbers: HYOIL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No