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| Name | Class |
|---|---|
| Guerbet | INDUSTRY |
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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 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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Lipiodol® uterine treatment prior to IVF/ICSI | Experimental | 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 |
|
| No Lipiodol® uterine treatment prior to IVF/ICSI | No Intervention | 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 |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lipiodol® uterine treatment prior to IVF/ICSI | Procedure | 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. |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Tuong M Ho, MD | Contact | (+84) 903633377 | tuongho.ivfmd@gmail.com | |
| Tien K Le, MD | Contact | (+84) 962803875 | bstien.lk@myduchospita.vn |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23290741 | Background | 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. | |
| 24119894 | Background |
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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.
| 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 mortality | Death of a live born baby within 28 days of birth | 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 |
| 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. |
| 14887769 | Background | 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. |
| 18133559 | Background | 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. |
| 8137969 | Background | 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. |
| 25929235 | Background | 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. |
| 28520519 | Background | 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. |
| 1325928 | Background | 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. |
| 8384577 | Background | 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. |
| 7900503 | Background | 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. |
| 15271870 | Background | 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. |
| 15950655 | Background | 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. |
| 30679138 | Background | 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. |
| 19121255 | Background | Fatourechi V. Subclinical hypothyroidism: an update for primary care physicians. Mayo Clin Proc. 2009;84(1):65-71. doi: 10.4065/84.1.65. |