Lipiodol Prior to FET (LIFE) (LIFE)

Lipiodol® For Enhancing Live Birth Rates In Infertile Couples Undergoing In Vitro Fertilization/ Intracytoplasmic Sperm Injection A Randomized Controlled Trial

Lipiodol® flushing is an effective fertility treatment for women with unexplained infertility. It is speculated that the treatment effect could work through a direct effect of Lipiodol® on the endometrium. Given this direct effect on the endometrium, it is further hypothesized that Lipiodol® uterine treatment prior to In Vitro Fertilization (IVF)/ Intracytoplasmic Sperm Injection (ICSI) may also improve pregnancy rates. However, the effectiveness of Lipiodol® as an adjunct to IVF/ICSI treatment has not previously been examined in a well-powered and properly conducted randomised clinical trial.

Study Overview

• Status: Not yet recruiting
• Conditions: Frozen Embryo Transfer; IVF; Hysterosalpingography
• Intervention / Treatment: Procedure: Lipiodol® uterine treatment prior to IVF/ICSI

Detailed Description

Study procedures:

Recruitment:

Potentially eligible patients will be given information about the study and a copy of the informed consent documents on day 2 - 3 of their menstrual cycle, when the ovarian stimulation starts. On the day of freeze-all (3 days or 5 days after oocyte retrieval), screening for eligibility will be performed by treating physicians. Eligible couples will have about an hour to decide if they will participate in the study or not. If they choose to participate in the study, investigators will ask them to sign the consent form.

Once a participant signs an informed consent she is enrolled in the study. An individual record of all non-recruited patients and reasons for exclusion (at any stage) will be obtained and stored

Randomization:

Assignment to treatment allocation will be done via a web portal hosted by Hope Research Center, Viet Nam. The randomisation schedule will be computer-generated at Hope Research Center by using HRC (Hope Research Center) Epi software, in a 1:1 ratio, with a permuted random block size of 4 or 6.

Other standard assisted reproductive treatments are similar and parallel between the two groups, except for the use of Lipiodol® flushing in the intervention group. Due to the type of interventions, this study will only be blinded to clinicians who performed the embryo transfer and embryologists in the IVF clinics.

In the subsequent cycle, all patients in both groups will undergo frozen embryo transfer by using exogenous steroids regimen, starting from day 2 to day 4 of the menstrual cycle. Oral estradiol valerate (Progynova, Bayer Schering Pharma, Germany) 8 mg/day is given for 10-12 days. Ultrasound monitoring will be performed from day tenth onward. When endometrial thickness reaches greater than or equal to 8 mm, along with a triple-line pattern, micronized progesterone 800 mg will be administrated. Frozen embryo transfer (FET) will be performed 3-5 days after progesterone administration, depending on embryo staging. After FET, estradiol and progesterone supplementation are continued for all patients until the day of the pregnancy test. Patients with a positive pregnancy test will continue to receive luteal phase support regimen until 7 weeks of gestation.

All participants will be followed up per local protocol until outcomes are achieved

• Study Type: Interventional
• Enrollment (Estimated): 784
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Tuong M Ho, MD; Phone Number: (+84) 903633377; Email: tuongho.ivfmd@gmail.com
• Study Contact Backup: Name: Tien K Le, MD; Phone Number: (+84) 962803875; Email: bstien.lk@myduchospita.vn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Women undergoing IVF/ICSI
• Having indications for freeze-all (day-3 or day-5)
• Agree to have ≤ 2 frozen embryos transferred
• TSH < 2.5 mIU/mL
• Permanent resident in Viet Nam
• Agree to participate in the study by signing the inform consent

Exclusion Criteria:

• Iodine allergy
• History of salpingectomy or tubal ligation
• History of using Lipiodol® within 6 months prior, starting from the screening time
• At high risk of having Fallopian tube disorders (history of Chlamydia infection, history of pelvic inflammatory diseases, current endometriosis)
• Having evidence of Fallopian tube disorders on Hysterosalpingo - Foam Sonography (HyFoSy), hysterosalpingography (HSG), ultrasonography or laparoscopy
• Having untreated intrauterine lesions such as endometrial polyps, submucosal fibroids, etc which affect the outcome of IVF treatment
• Have a history of thyroid disease or being treated for thyroid disease
• Undergoing curettage within 30 days before performing HSG technique
• Patients having embryos from oocyte donation or in vitro maturation (IVM) cycles
• Unable or unwilling to attend Lipiodol® procedure
• Participating in another interventional study at the same time

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: Lipiodol® uterine treatment prior to IVF/ICSI; For those who are randomized to Lipiodol®, treatment will be performed by a HSG technique with X-ray screening on day 3 or day 5 after oocyte retrieval. The contrast medium will be Lipiodol Ultra Fluide® (Guerbet, France), an iodized poppy seed oil obtained by substitution of ethyl esters for the glyceryl esters of Lipiodol®. After that the procedure to assess study participants' pain perception. Endometrial preparation for frozen embryo transfer will perform on the subsequence cycle	Procedure: Lipiodol® uterine treatment prior to IVF/ICSI; Lipiodol®, treatment will be performed by a HSG technique with X-ray screening on day 3 or day 5 after oocyte retrieval. The contrast medium will be Lipiodol Ultra Fluide® (Guerbet, France), an iodized poppy seed oil obtained by substitution of ethyl esters for the glyceryl esters of Lipiodol®. One millilitre of Lipiodol Ultra Fluide® contains 0.48g iodine. Women will lie in the left lateral or supine position. Radiologists will use a 'no touch' technique after applying antiseptic solution to the cervix. Uterine cannulation using the Cook HSG catheter will be applied to conduct Lipiodol® treatment. Prewarmed (37oC) Lipiodol® will be slowly instilled, with intermittent fluoroscopic X-ray guidance. Up to 10 ml of Lipiodol® will be slowly injected into the uterus and directly monitored by fluoroscopy. If intravasation was observed on X-ray (contrast apparent in the venous system), instillation will be stopped immediately.; Other Names: Lipiodol® flushing prior to IVF/ICSI
No Intervention: No Lipiodol® uterine treatment prior to IVF/ICSI; For those who are randomized to no intervention arm (control group), there will be no HSG performed. Endometrial preparation for frozen embryo transfer will perform on the subsequence cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Live birth rate after the first transfer	Live birth is defined as the complete expulsion or extraction from a woman of a product of fertilization, after 22 completed weeks of gestational age, which, after such separation, breathes or shows any other evidence of life, such as heartbeat, umbilical cord pulsation or definite movement of voluntary muscles, irrespective of whether the umbilical cord has been cut or the placenta is attached. If gestational age is unknown, a birth weight of 500 grams or more will be used instead	At 22 weeks of gestation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neonatal mortality	Death of a live born baby within 28 days of birth	Within 28 days of birth
Positive pregnancy test	Serum human chorionic gonadotropin level greater than 25 mIU/mL (milli-International Unit per milliliter)	At 2 weeks after embryo(s) placement
Clinical pregnancy rate	Clinical pregnancy is diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy at 6 weeks or more after the onset of last menstrual period. In addition to intra-uterine pregnancy, it includes a clinically documented ectopic pregnancy	At 5 weeks after embryo(s) placement
Ongoing pregnancy rate	Ongoing pregnancy is a pregnancy with a detectable heart rate at 12 weeks gestation or beyond	At 10 weeks after embryo(s) placement
Multiple pregnancy	The presence of more than one gestational sac at early pregnancy ultrasound (6-9 weeks gestation)	At 7 weeks after embryo(s) placement
Cumulative live birth rate at 12 months after randomization	Cumulative live birth at 12 months after randomization	At 12 months after randomization
Ectopic pregnancy rate	A pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualization or histopathology	At 12 weeks of gestation
Early miscarriage rate (Miscarriage <12 weeks)	A spontaneous loss of pregnancy up to 12 weeks of gestation.	At 12 weeks of gestation
Late miscarriage rate (Miscarriage <22 weeks)	A spontaneous loss of pregnancy between 12 to 22 weeks.	At 22 weeks of gestation
Still birth rate	The death of a fetus prior to the complete expulsion or extraction from its mother after 20 completed weeks of gestational age. The death is determined by the fact that, after such separation, the fetus does not breathe or show any other evidence of life, such as heartbeat, umbilical cord pulsation, or definite movement of voluntary muscles. It includes deaths occurring during labor	After 22 weeks of gestation
Adverse events	Include intravasation of Lipiodol® and lipogranuloma formation, as well as all other adverse events	At delivery
Maternal thyroid function	Serum TSH and FT4	At the day of pregnancy test, 3 months (at 7 weeks of pregnancy if the patient is pregnant) and 6 months (at 22 weeks of pregnancy if the patient is pregnant) after randomization
Gestational diabetes mellitus rate	Using a 75g oral glucose tolerance test, with plasma glucose measurement when patient is fasting and at 1 and 2 h, at 24-28 weeks of gestation in women not previously diagnosed with diabetes.; Fasting: 92 mg/dL (5.1 mmol/L); 1 h: 180 mg/dL (10.0 mmol/L); 2 h: 153 mg/dL (8.5 mmol/L)	At 24-28 weeks of gestation
Hypertensive disorders of pregnancy rate	Percentage of pregnancy-induced hypertension (PIH), pre-eclampsia (PET), eclampsia, and HELLP syndrome	From date of randomization until the date of first documented progression, assessed up to 12 months after randomization
Preterm birth rate	Defined as any delivery at <24, <28, <32, <37 completed weeks' gestation	At 22, 28, 32 and 37 weeks of gestation
Premature rupture of membranes rate	A rupture of the membranes (amniotic sac) prior to 37 weeks' gestation.	At 37 weeks of gestation
Chorioamnionitis rate	Chorioamnionitis is defined as intraamniotic infection with resultant inflammation of any combination of the amniotic fluid, placenta, fetus, fetal membranes, or decidua	At delivery
Percentage of magnesium sulfate administration for neuroprotection	Administration of magnesium sulfate for preventing seizures in case of preeclampsia/eclampsia	At delivery
Antenatal corticosteroids for lung maturation	Administration of corticosteroids prior to preterm birth	At delivery
Administration of tocolytics agents	Administration of tocolytics agents to prevent preterm birth	At delivery
Birth weight	including low birth weight (defined as weight < 2,500 gram at birth), very low birth weight (defined as < 1,500 gram at birth), high birth weight (defined as >4,000 gram at birth) and very high birth weight (defined as >4,500 gram at birth)	At delivery
Large for gestational age	Birth weight >90th centile for gestation, based on standardized ethnicity-based charts	At delivery
Small for gestational age	Birth weight <10th centile for gestation age based on standardized ethnicity-based charts	At delivery
Gestational age at birth	Calculated by gestational age of all live births	At delivery
Mode of delivery	including vaginal delivery, C-section (elective, suspected fetal distress, non-progressive labor)	At delivery
Postpartum hemorrhage	Cumulative blood loss greater than or equal to 1,000 mL or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth process (includes intrapartum loss) regardless of route of delivery	At delivery
Maternal death	Female deaths from any cause related to or aggravated by pregnancy or its management (excluding accidental or incidental causes) during pregnancy and childbirth or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy	At delivery
Congenital anomalies	Structural or functional disorders that occur during intra-uterine life and can be identified prenatally, at birth or later in life	Within 28 days of birth
neonatal intensive care unit (NICU) admission	The admittance of the newborn to NICU	Within 28 days of birth
1-minute Apgar score	The Apgar score at 1 minute after birth	At 1 minute after birth
5-minute Apgar score	The Apgar score at 5 minute after birth	At 5 minute after birth
Low 5-minute Apgar score	Defined as 5-minute Apgar score <7.	At 5 minute after birth
Neonatal thyroid function	Serum thyroid-stimulating hormone (TSH) and free thyroxine (fT4)	At delivery
Mode of conception	Including natural conception, intrauterine insemination (IUI), and in vitro fertilization (IVF)	From date of randomization until the date of pregnancy test or date of ultrasound, whichever came first, assessed up to 12 months

Collaborators and Investigators

• Sponsor: Mỹ Đức Hospital
• Collaborators: Guerbet

Publications and helpful links

General Publications

• Thoma ME, McLain AC, Louis JF, King RB, Trumble AC, Sundaram R, Buck Louis GM. Prevalence of infertility in the United States as estimated by the current duration approach and a traditional constructed approach. Fertil Steril. 2013 Apr;99(5):1324-1331.e1. doi: 10.1016/j.fertnstert.2012.11.037. Epub 2013 Jan 3.
• Mohiyiddeen L, Hardiman A, Fitzgerald C, Hughes E, Mol BW, Johnson N, Watson A. Tubal flushing for subfertility. Cochrane Database Syst Rev. 2015 May 1;2015(5):CD003718. doi: 10.1002/14651858.CD003718.pub4.
• Johnson JV, Montoya IA, Olive DL. Ethiodol oil contrast medium inhibits macrophage phagocytosis and adherence by altering membrane electronegativity and microviscosity. Fertil Steril. 1992 Sep;58(3):511-7. doi: 10.1016/s0015-0282(16)55254-6.
• Abrao MS, Muzii L, Marana R. Anatomical causes of female infertility and their management. Int J Gynaecol Obstet. 2013 Dec;123 Suppl 2:S18-24. doi: 10.1016/j.ijgo.2013.09.008. Epub 2013 Sep 11.
• WEIR WC, WEIR DR. Therapeutic value of salpingograms in infertility. Fertil Steril. 1951 Nov-Dec;2(6):514-22. doi: 10.1016/s0015-0282(16)30725-7. No abstract available.
• KING EL, HERRING JS. Sterility studies in private practice. Am J Obstet Gynecol. 1949 Aug;58(2):258-66. doi: 10.1016/0002-9378(49)90378-6. No abstract available.
• Watson A, Vandekerckhove P, Lilford R, Vail A, Brosens I, Hughes E. A meta-analysis of the therapeutic role of oil soluble contrast media at hysterosalpingography: a surprising result? Fertil Steril. 1994 Mar;61(3):470-7. doi: 10.1016/s0015-0282(16)56578-9.
• Dreyer K, van Rijswijk J, Mijatovic V, Goddijn M, Verhoeve HR, van Rooij IAJ, Hoek A, Bourdrez P, Nap AW, Rijnsaardt-Lukassen HGM, Timmerman CCM, Kaplan M, Hooker AB, Gijsen AP, van Golde R, van Heteren CF, Sluijmer AV, de Bruin JP, Smeenk JMJ, de Boer JAM, Scheenjes E, Duijn AEJ, Mozes A, Pelinck MJ, Traas MAF, van Hooff MHA, van Unnik GA, de Koning CH, van Geloven N, Twisk JWR, Hompes PGA, Mol BWJ. Oil-Based or Water-Based Contrast for Hysterosalpingography in Infertile Women. N Engl J Med. 2017 May 25;376(21):2043-2052. doi: 10.1056/NEJMoa1612337. Epub 2017 May 18.
• Sawatari Y, Horii T, Hoshiai H. Oily contrast medium as a therapeutic agent for infertility because of mild endometriosis. Fertil Steril. 1993 Apr;59(4):907-11. doi: 10.1016/s0015-0282(16)55880-4.
• Mikulska D, Kurzawa R, Rozewicka L. Morphology of in vitro sperm phagocytosis by rat peritoneal macrophages under influence of oily contrast medium (Lipiodol). Acta Eur Fertil. 1994 May-Jun;25(3):203-6.
• Johnson NP, Farquhar CM, Hadden WE, Suckling J, Yu Y, Sadler L. The FLUSH trial--flushing with lipiodol for unexplained (and endometriosis-related) subfertility by hysterosalpingography: a randomized trial. Hum Reprod. 2004 Sep;19(9):2043-51. doi: 10.1093/humrep/deh418. Epub 2004 Jul 22.
• Johnson NP, Bhattu S, Wagner A, Blake DA, Chamley LW. Lipiodol alters murine uterine dendritic cell populations: a potential mechanism for the fertility-enhancing effect of lipiodol. Fertil Steril. 2005 Jun;83(6):1814-21. doi: 10.1016/j.fertnstert.2004.11.065.
• Reilly SJ, Glanville EJ, Dhorepatil B, Prentice LR, Mol BW, Johnson NP. The IVF-LUBE trial - a randomized trial to assess Lipiodol(R) uterine bathing effect in women with endometriosis or repeat implantation failure undergoing IVF. Reprod Biomed Online. 2019 Mar;38(3):380-386. doi: 10.1016/j.rbmo.2018.11.015. Epub 2018 Dec 7.
• Fatourechi V. Subclinical hypothyroidism: an update for primary care physicians. Mayo Clin Proc. 2009;84(1):65-71. doi: 10.4065/84.1.65.

Study record dates

Study Major Dates

• Study Start (Estimated): August 10, 2024
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: August 1, 2024
• First Submitted That Met QC Criteria: August 18, 2024
• First Posted (Actual): August 21, 2024

Study Record Updates

• Last Update Posted (Actual): August 21, 2024
• Last Update Submitted That Met QC Criteria: August 18, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Hysterosalpingography; Lipiodol
• Additional Relevant MeSH Terms: Antineoplastic Agents; Ethiodized Oil
• Other Study ID Numbers: 1767/QD-BYT

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