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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Infertility, Female

Intervention / Treatment
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* Drug: Lipiodol Ultra Fluide®


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 |