Trial Title:
The Impact of Myomectomy on IVF Outcomes
NCT ID:
NCT05932082
Condition:
Myoma;Uterus
IVF
Surgery
Conditions: Official terms:
Leiomyoma
Myofibroma
Study type:
Interventional
Study phase:
N/A
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
myomectomy or not
Description:
The study group receive myomectomy, while the control group don't receive myomectomy.
Arm group label:
control group
Arm group label:
myomectomy group
Summary:
In 2% to 3% infertility women, myoma is the only factor relevant to their infertility.
However, the effects of intramural myoma on fertility are controversial. For infertile
women with intramural myoma (types IV, V, VI of FIGO system) of 4 to 6 cm diameter, it is
not clear whether myomectomy could improve pregnancy outcomes, especially in women
undergoing ART. Besides, rigorous clinical research is needed to explore the changes and
relevant biomarkers of endometrial receptivity through multi-omics study in patients
undergoing myomectomy and ART treatment.
Method Intervention and follow-up: (1) For the control group, evaluation protocols such
as salpingography and/or laparoscopic tubal fluxation should be implemented to identify
disorders such as hydrosalpinx. (2) Imaging evaluation: all pelvic MRI were performed.
Other options such as transvaginal ultrasound are not excluded, but won't replace MRI.
Enhanced MRI or DWI may be considered, but are not always required. (3) Surgical
intervention: laparoscopic myomectomy is preferred, and abdominal myomectomy is also
acceptable. (4) IVF treatment: the IVF regimen should include detailed records of the
downregulation plan, number of cycles, frozen or fresh blastocysts.
Study endpoints
(1) Primary study endpoint: Live birth rate after IVF. (2) Secondary study endpoints:
Clinical pregnancy rate after IVF; Cumulative pregnancy rate after IVF; Biochemical
pregnancy rate after IVF; Sustained pregnancy rate after IVF (≥20 weeks); Miscarriage
rate after IVF; Cycles of IVF; Pregnancy-related complications; Perinatal maternal and
neonatal complications. (3) Exploratory endpoints: The correlation between imaging index
and assisted reproductive outcomes, including endometrial thickness, uterine volume, type
of endometrial echo, uterine contraction; endometrial vascular index (VI), flow index
(FI), tubular flow index (VFI); uterine artery pulsation index (PI), uterine artery
resistance index (RI), systolic/diastolic blood pressure of uterine artery (S/D).
The correlation between endometrial receptivity and assisted reproductive outcomes is
analyzed based on transcriptomics, metabolomics, methylation and proteomics in samples
from peripheral blood, endometrial biopsy, endometrial exfoliated cells, cervical
exfoliated cells and myoma.
Detailed description:
Grouping and blinding method This is a national multicenter, randomized controlled study.
Competitive enrollment is performed among all centers. The study group received IVF after
myomectomy and the control group was directed to IVF after the routine evaluation,
probably including diagnostic laparoscopy. In this study, 792 patients were randomly
divided into 2 groups with 396 patients in each group according to centralized random
system. A random sequence is generated with a random block size of a block size of 4.
Collection of clinical data and samples Data and samples are collected according to Case
Report Form (CRF) form, including randomized information, epidemiologic and clinical
information. Evaluation of infertility history and details, imaging results, ovarian
reservation and surgical findings are of special interest and detailed recorded.
Samples of peripheral blood, cervical exfoliated cells, endometrial exfoliated cells,
endometrial biopsy and myoma in study group are collected for multi-omics analysis. The
process of sample harvest shouldn't interfere or deteriorate the surgical and IVF
treatment.
IVF treatment: the IVF regimen should include detailed records of the downregulation
plan, number of cycles, frozen or fresh blastocysts, ①Study group: IVF treatment is
performed 6 months after myomectomy, and patients should be followed up for 1 year after
the start of IVF. If the endometrium is exposed during myomectoy, IVF treatment is
performed 12 months after myomectomy. It should be noted that the time for postoperative
contraception should be recorded, and also the time interval between myomectomy and IVF.
②Control group: IVF treatment was performed immediately after relevant evaluation, and
follow-up for 1 year after the start of IVF.
Genomic feature examination and bioinformatics analysis
1. Endometrial receptive array (ERA) is a molecular diagnostic test based on microarray
technology, which divides endometrial biopsy into receptive, pre receptive, or
proliferative types based on the expression of 238 selected genes. ER Map/ER Stage
is based on the expression of 184 genes involved in maternal immune response related
to endometrial proliferation and embryo implantation.
2. Methylation sequencing: Extract DNA related to peripheral blood, tissue, and cells,
and accurately quantify DNA concentration using Qubit 2.0. The total amount of DNA
detected should not be less than 1ug. Library construction: After passing the sample
detection, 1 µ g of sample genomic DNA was mixed with unmethylated lambda DNA using
the Biouptor system, and then fragmented to an average size of approximately 250bp.
After fragmentation, the purified random fragmented DNA was then repaired,
passivated and phosphorylated with a mixture of T4 DNA polymerase, Klenow fragment
and T4 polynucleotide kinase. The blunt DNA fragment was then 3 'adenosylated with
Klenow fragment (3' -5'exo -), and then linked to the linker connecting 5 '- methyl
Cytosine instead of Cytosine using T4 DNA ligase. After completing each step, use
magnetic beads to purify DNA. Then, use ZYMO EZ DNA methylation gold kit to convert
unmethylated Cytosine to Uracil according to instructions. Finally, use JumpStart
Taq DNA polymerase for PCR amplification, and then use magnetic beads to purify the
PCR product to obtain the final library. Library quality inspection: After the
construction of the library is completed, preliminary quantification is carried out
using Qubit2.0, and the library is diluted to 1ng/ul. Then, the insert size of the
library is tested using Agilent 2100. After the insert size meets expectations, the
effective concentration of the library is accurately quantified using qPCR method
(effective concentration of the library>2nM) to ensure library quality. Online
sequencing: After passing the library detection, different libraries are pooled
according to the effective concentration and target offline data volume
requirements, and then sequenced on the Illumina Nova platform using the PE150
sequencing strategy. After that, quality control of original offline data, sequence
comparison, calculation of methylation level, identification and statistics of
differential methylation region (DMR) were carried out.
Urinary protein detection and bioinformatics analysis
1. Protein separation technology: two-dimensional gel electrophoresis (2DE),
two-dimensional fluorescence differential electrophoresis (2D-DIGE), isoelectric
focusing electrophoresis (IEF), liquid chromatography; Multidimensional
chromatography (MDC) (including size exclusion chromatography, ion exchange
chromatography, reverse phase high performance chromatography, hydrophobic
interaction chromatography, etc.), and multidimensional liquid chromatography
(MDLC).
2. Protein identification technology: primary mass spectrometry: according to different
ion sources, it can be divided into matrix assisted laser desorption ionization time
of flight mass spectrometry (MALDI-TOF-MS) and electric spray mass spectrometry (ESI
MS); Secondary mass spectrometry: peptide mass fingerprint (PMF); New technology:
Stable nuclide signature bio mass spectrometry (SIAMS).
3. Identification of protein peptide segments: amino and carboxyl end analysis, such as
Edman; Mass spectrometry, including peptide fragment mass spectrometry and tandem
mass spectrometry.
4. Protein interactions: Immunoprecipitation technology, Yeast two hybrid system,
Protein chip technology.
Metabolomics and Bioinformatics Analysis
1. The endometrium tissue was immediately frozen in liquid nitrogen after being
isolated, and then the tissue was stored at -80 ℃, ground and crushed, and extracted
with cold organic Liquid-liquid extraction. Attention must be paid to avoiding
metabolic changes before and during sampling. Perform metabolomics analysis on
collected cells, tissues, blood, and urine.
2. Metabolite extraction: The most commonly used method in metabolite extraction is to
precipitate protein with organic solvents, and extract the supernatant through
high-speed centrifugation or ultrafast filtration to remove protein precipitation.
Concentrate using freeze-drying or nitrogen blowing, and dissolve the residue in a
complex solvent.
3. Sample detection: Take a certain amount of redissolved supernatant and use Thermo
Vanquish UHPLC ultra-high performance liquid chromatography system and Thermo Q
Active HF-X mass spectrometry platform for machine detection.
4. Data processing: After the mass spectrometry detection is completed, the offline
data (. raw) file is imported into the search software for simple screening of
retention time, mass charge ratio, and other parameters. Then, according to the
retention time deviation, quality deviation and signal strength deviation, signal to
noise ratio, minimum signal strength and other information of different samples,
peak alignment and peak extraction are carried out. At the same time, the peak area
is quantified, and then the target ions are integrated to predict the Molecular
formula and compare with the database to obtain the identification and quantitative
results of the data. Therefore, non targeted metabolomics databases and search
software play a decisive role in the experimental results. However, LC-MS has very
few public databases, and most of them are platform built databases. The commonly
used databases include HMDB, METLIN, and some self built libraries.
5. Information analysis: Principal component analysis, differential metabolite
analysis, etc.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Female aged between 20-40 years old.
2. Primary or secondary infertility consisting of following factors rather than uterine
factors: male factors, ovulation disorders, fallopian tube factors, endometriosis,
other non-uterine factors including infertility with unexplained reason.
3. Myoma: FIGO type 4-6 discovered by MRI with the maximum diameter surgically targeted
between 4-6cm; Single myoma, or multiple myomas with non-surgically targeted
intramural or subserous myoma(s) < 2cm in maximum diameter.
4. Justifying the IVF criteria and willing to undergo IVF.
Exclusion Criteria:
1. Not meeting all the inclusion criteria.
2. Complicated with infertility factors of uterine factors or diseases, including
adenomyosis, endometrial adhesion, endometritis, submucous myoma. However,
resectable endometrial polyps need not be excluded.
3. Complicated with malignancies or borderline tumors of the reproductive tract
4. Complicated with other malignancies not been treated or still being treated.
5. Complicated with active pelvic inflammatory disease.
6. Previously receiving cytotoxic therapy or abdominal-abdominal chemoradiotherapy.
7. Previous uterine body surgery, including but not limited to: myomectomy, resection
for adenomyosis lesions, uterine artery embolization, uterine tumor coagulation
(high energy focused ultrasound or electrocoagulation, hysteroscopically myomectomy.
However, diagnostic hysteroscopy, diagnostic curettage and polypectomy need not be
excluded.
8. No willing to undergo IVF.
9. Unable to be followed-up.
Gender:
Female
Minimum age:
20 Years
Maximum age:
40 Years
Healthy volunteers:
No
Start date:
September 1, 2023
Completion date:
September 1, 2026
Lead sponsor:
Agency:
Peking Union Medical College Hospital
Agency class:
Other
Source:
Peking Union Medical College Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05932082
