Frozen Embryo Transfer, Hysterosalpingography, IVF
Conditions
Keywords
Lipiodol, Hysterosalpingography
Brief summary
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.
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
Interventions
PROCEDURELipiodol® 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.
Sponsors
Guerbet
Mỹ Đức Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Live birth rate after the first transfer | At 22 weeks of gestation | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Large for gestational age | At delivery | Birth weight \>90th centile for gestation, based on standardized ethnicity-based charts |
| Small for gestational age | At delivery | Birth weight \<10th centile for gestation age based on standardized ethnicity-based charts |
| Positive pregnancy test | At 2 weeks after embryo(s) placement | Serum human chorionic gonadotropin level greater than 25 mIU/mL (milli-International Unit per milliliter) |
| Administration of tocolytics agents | At delivery | Administration of tocolytics agents to prevent preterm birth |
| Birth weight | At delivery | 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) |
| Clinical pregnancy rate | At 5 weeks after embryo(s) placement | 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 |
| Ongoing pregnancy rate | At 10 weeks after embryo(s) placement | Ongoing pregnancy is a pregnancy with a detectable heart rate at 12 weeks gestation or beyond |
| Multiple pregnancy | At 7 weeks after embryo(s) placement | The presence of more than one gestational sac at early pregnancy ultrasound (6-9 weeks gestation) |
| Cumulative live birth rate at 12 months after randomization | At 12 months after randomization | Cumulative live birth at 12 months after randomization |
| Ectopic pregnancy rate | At 12 weeks of gestation | A pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualization or histopathology |
| Early miscarriage rate (Miscarriage <12 weeks) | At 12 weeks of gestation | A spontaneous loss of pregnancy up to 12 weeks of gestation. |
| Late miscarriage rate (Miscarriage <22 weeks) | At 22 weeks of gestation | A spontaneous loss of pregnancy between 12 to 22 weeks. |
| Still birth rate | After 22 weeks of gestation | 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 |
| Adverse events | At delivery | Include intravasation of Lipiodol® and lipogranuloma formation, as well as all other adverse events |
| Maternal thyroid function | 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 | Serum TSH and FT4 |
| Gestational diabetes mellitus rate | At 24-28 weeks of gestation | 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) |
| Gestational age at birth | At delivery | Calculated by gestational age of all live births |
| Preterm birth rate | At 22, 28, 32 and 37 weeks of gestation | Defined as any delivery at \<24, \<28, \<32, \<37 completed weeks' gestation |
| Premature rupture of membranes rate | At 37 weeks of gestation | A rupture of the membranes (amniotic sac) prior to 37 weeks' gestation. |
| Chorioamnionitis rate | At delivery | Chorioamnionitis is defined as intraamniotic infection with resultant inflammation of any combination of the amniotic fluid, placenta, fetus, fetal membranes, or decidua |
| Percentage of magnesium sulfate administration for neuroprotection | At delivery | Administration of magnesium sulfate for preventing seizures in case of preeclampsia/eclampsia |
| Antenatal corticosteroids for lung maturation | At delivery | Administration of corticosteroids prior to preterm birth |
| Mode of delivery | At delivery | including vaginal delivery, C-section (elective, suspected fetal distress, non-progressive labor) |
| Postpartum hemorrhage | At delivery | 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 |
| Maternal death | At delivery | 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 |
| Congenital anomalies | Within 28 days of birth | Structural or functional disorders that occur during intra-uterine life and can be identified prenatally, at birth or later in life |
| Neonatal mortality | Within 28 days of birth | Death of a live born baby within 28 days of birth |
| neonatal intensive care unit (NICU) admission | Within 28 days of birth | The admittance of the newborn to NICU |
| 1-minute Apgar score | At 1 minute after birth | The Apgar score at 1 minute after birth |
| 5-minute Apgar score | At 5 minute after birth | The Apgar score at 5 minute after birth |
| Low 5-minute Apgar score | At 5 minute after birth | Defined as 5-minute Apgar score \<7. |
| Neonatal thyroid function | At delivery | Serum thyroid-stimulating hormone (TSH) and free thyroxine (fT4) |
| Mode of conception | From date of randomization until the date of pregnancy test or date of ultrasound, whichever came first, assessed up to 12 months | Including natural conception, intrauterine insemination (IUI), and in vitro fertilization (IVF) |
| Hypertensive disorders of pregnancy rate | From date of randomization until the date of first documented progression, assessed up to 12 months after randomization | Percentage of pregnancy-induced hypertension (PIH), pre-eclampsia (PET), eclampsia, and HELLP syndrome |
Contacts
Primary ContactTuong M Ho, MD
Backup ContactTien K Le, MD
Outcome results
None listed