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
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.
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
Time frame: At 22 weeks of gestation
Positive pregnancy test
Serum human chorionic gonadotropin level greater than 25 mIU/mL (milli-International Unit per milliliter)
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: At 7 weeks after embryo(s) placement
Cumulative live birth rate at 12 months after randomization
Cumulative live birth at 12 months after randomization
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
784
Time frame: At 12 months after randomization
Ectopic pregnancy rate
A pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualization or histopathology
Time frame: At 12 weeks of gestation
Early miscarriage rate (Miscarriage <12 weeks)
A spontaneous loss of pregnancy up to 12 weeks of gestation.
Time frame: At 12 weeks of gestation
Late miscarriage rate (Miscarriage <22 weeks)
A spontaneous loss of pregnancy between 12 to 22 weeks.
Time frame: 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
Time frame: After 22 weeks of gestation
Adverse events
Include intravasation of Lipiodol® and lipogranuloma formation, as well as all other adverse events
Time frame: At delivery
Maternal thyroid function
Serum TSH and FT4
Time frame: 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)
Time frame: At 24-28 weeks of gestation
Hypertensive disorders of pregnancy rate
Percentage of pregnancy-induced hypertension (PIH), pre-eclampsia (PET), eclampsia, and HELLP syndrome
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: At delivery
Percentage of magnesium sulfate administration for neuroprotection
Administration of magnesium sulfate for preventing seizures in case of preeclampsia/eclampsia
Time frame: At delivery
Antenatal corticosteroids for lung maturation
Administration of corticosteroids prior to preterm birth
Time frame: At delivery
Administration of tocolytics agents
Administration of tocolytics agents to prevent preterm birth
Time frame: 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)
Time frame: At delivery
Large for gestational age
Birth weight \>90th centile for gestation, based on standardized ethnicity-based charts
Time frame: At delivery
Small for gestational age
Birth weight \<10th centile for gestation age based on standardized ethnicity-based charts
Time frame: At delivery
Gestational age at birth
Calculated by gestational age of all live births
Time frame: At delivery
Mode of delivery
including vaginal delivery, C-section (elective, suspected fetal distress, non-progressive labor)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Within 28 days of birth
Neonatal mortality
Death of a live born baby within 28 days of birth
Time frame: Within 28 days of birth
neonatal intensive care unit (NICU) admission
The admittance of the newborn to NICU
Time frame: Within 28 days of birth
1-minute Apgar score
The Apgar score at 1 minute after birth
Time frame: At 1 minute after birth
5-minute Apgar score
The Apgar score at 5 minute after birth
Time frame: At 5 minute after birth
Low 5-minute Apgar score
Defined as 5-minute Apgar score \<7.
Time frame: At 5 minute after birth
Neonatal thyroid function
Serum thyroid-stimulating hormone (TSH) and free thyroxine (fT4)
Time frame: At delivery
Mode of conception
Including natural conception, intrauterine insemination (IUI), and in vitro fertilization (IVF)
Time frame: From date of randomization until the date of pregnancy test or date of ultrasound, whichever came first, assessed up to 12 months