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This randomized clinical trial aims to assess the comparative effectiveness of two distinct endometrial preparation protocols for frozen embryo transfer (FET) among women with adenomyosis undergoing IVF/ICSI. Specifically, it seeks to address the following key questions:
Eligible participants will undergo screening before endometrial preparation for FET, following which they will be randomly assigned to one of two groups: GnRHa+AI - AC or AC. In the GnRHa+AI - AC group, participants will be pre-treated with GnRH agonist and letrozole two months before endometrial preparation. After this period, participants will return for endometrial preparation, and any side effects resulting from the down regulation will be evaluated. In contrast, the AC group will receive standard treatment.
Embryo transfer will be scheduled by the time of the initiation of progesterone and embryo stages. Hormonal support will consist of oral estradiol valerate 4 mg/day and vaginal progesterone (Cyclogest®; Actavis) 400 mg twice times a day until the 7th week of gestation. Subsequently, progesterone alone (Cyclogest®; Actavis) at 400 mg twice times a day will be continued for luteal phase support until the 12th week of gestation.
- GnRH agonist + Letrozole - Artificial cycle protocol (GnRHa+AI - AC):
Frozen embryo transfer:
A maximum of 2 cleavage-stage embryos or 1 blastocyst will be thawed on the day of embryo transfer, three or five days after the start of progesterone. Two hours after thawing, surviving embryos will be transferred into the uterus under ultrasound guidance using a soft uterine catheter (Gynétics®, Belgium).
- Future babies' health evaluation and cost-effectiveness analysis will also be performed separately.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| GnRH agonist + Letrzole - Artificial Cycle | Active Comparator | Pre-treatment includes two doses of 3.75 mg GnRH agonist (Diphereline®, Ipsen, France) on days 2-4 of the menstrual cycle and 28 days later, along with daily 2.5 mg Letrozole (Femara®, Novartis, Switzerland) starting from the first agonist injection. Endometrial preparation in an artificial cycle begins 28 days after the second agonist injection. Patients will take 6 mg/day of oral estradiol valerate (Valiera; Abbott) at least 9 days before initiating progesterone. Endometrial thickness is monitored starting on the 10th day. When it reaches ≥7 mm, 400 mg twice times a day of vaginal progesterone (Cyclogest®, Actavis, UK) is initiated. Embryo transfer aligns with progesterone initiation, taking the embryo's stage into account. Luteal phase support comprises oral estradiol valerate 4 mg/day and vaginal progesterone 400 mg twice times a day until the 7th week of gestational age (GA), followed by progesterone alone at 400 mg twice times a day up to the 12th week of GA. |
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| Artificial Cycle | Active Comparator | The endometrium will be prepared using oral estradiol valerate (Valiera; Abbott) 6 mg/day starting from the 2nd to the 4th day of the menstrual cycle. The endometrial thickness will be monitored from day 10th onwards, and vaginal progesterone (Cyclogest®; Actavis) 400 mg twice times a day will be initiated when endometrial thickness reaches ≥7 mm. Estradiol exposure must last for at least 9 days before progesterone administration. Embryo transfer will be scheduled by the time of the initiation of progesterone and embryo stages. Luteal phase support comprises oral estradiol valerate 4 mg/day and vaginal progesterone 400 mg twice times a day until the 7th week of gestational age (GA), followed by progesterone alone at 400 mg twice times a day up to the 12th week of GA. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GnRHa+AI - AC | Procedure | Pre-treatment includes two doses of 3.75 mg GnRH agonist (Diphereline®, Ipsen, France) on days 2-4 of the menstrual cycle and 28 days later, along with daily 2.5 mg Letrozole (Femara®, Novartis, Switzerland) starting from the first agonist injection. Endometrial preparation in an artificial cycle begins 28 days after the second agonist injection. Patients take 6 mg/day of oral estradiol valerate (Valiera; Abbott) at least 9 days before progesterone. Endometrial thickness is monitored starting on the 10th day. When it reaches ≥7 mm, 400 mg twice times a day of vaginal progesterone (Cyclogest®, Actavis, UK) is initiated. Embryo transfer aligns with progesterone initiation, taking the embryo's stage into account. Luteal phase support comprises oral estradiol valerate 4 mg/day and vaginal progesterone 400 mg twice times a day until the 7th week of gestational age (GA), followed by progesterone alone at 400 mg twice times a day up to the 12th week of GA. |
| Measure | Description | Time Frame |
|---|---|---|
| Live birth rate after one frozen embryo transfer cycle | 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 heart beat, umbilical cord pulsation or definite movement of voluntary muscles, irrespective of whether the umbilical cord has been cut or the placenta is attached. A birth weight of 500 grams or more can be used if gestational age is unknown | At 22 weeks of gestation |
| Measure | Description | Time Frame |
|---|---|---|
| Cancellation rate | Cancellation due to: thin endometrium (thickness <7mm after ≥21 days using oral estradiol valerate), endometrial cavity fluid, functional cyst (homogeneous anechoic cyst with d ≥14 mm present after 10 days using estradiol valerate), or has side effects(Cluster headache, mood swing, abnormal uterine bleeding, nausea, vomit, VTE, stroke) | At 3 weeks from the start of artificial cycle |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Tien K Le, MD | Contact | +84962803875 | bstien.lk@myduchospital.vn | |
| Vu NA Ho, MD | Contact | +84935843336 | bsvu.hna@myduchospital.vn |
| Name | Affiliation | Role |
|---|---|---|
| Lan N Vuong, MD, PhD | University of Medicine and Pharmacy at Ho Chi Minh City | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| My Duc Hospital | Recruiting | Ho Chi Minh City | Ho Chi Minh City | 70000 | Vietnam |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32212520 | Background | Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020 Mar 26;382(13):1244-1256. doi: 10.1056/NEJMra1810764. No abstract available. | |
| 33573117 | Background | Szubert M, Kozirog E, Olszak O, Krygier-Kurz K, Kazmierczak J, Wilczynski J. Adenomyosis and Infertility-Review of Medical and Surgical Approaches. Int J Environ Res Public Health. 2021 Jan 30;18(3):1235. doi: 10.3390/ijerph18031235. |
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| ID | Term |
|---|---|
| D062788 | Adenomyosis |
| ID | Term |
|---|---|
| D014591 | Uterine Diseases |
| D005831 | Genital Diseases, Female |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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| Artificial cycle | Procedure | The endometrium will be prepared using oral estradiol valerate (Valiera; Abbott) 6 mg/day starting from the 2nd to the 4th day of the menstrual cycle. The endometrial thickness will be monitored from day 10th onwards, and vaginal progesterone (Cyclogest®; Actavis) 400 mg twice times a day will be initiated when endometrial thickness reaches ≥7 mm. Estradiol exposure must last for at least 9 days before progesterone administration. Embryo transfer will be scheduled by the time of the initiation of progesterone and embryo stages. Luteal phase support comprises estradiol 4 mg/day and vaginal progesterone 400 mg twice times a day until the 7th week of gestational age (GA), followed by progesterone alone at 400 mg twice times a day up to the 12th week of GA. |
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| Hypoestrogenic side effects | Side effects include hot flushes, bone loss, vaginal dryness, decreased libido, unpredictable mood changes, and headache. | At 8 weeks from the start of the first dose of 3.75 mg GnRH agonist |
| Classification of adenomyosis | The classification of adenomyosis under ultrasound scan according to MUSA criteria | during ultrasound procedure |
| Differentiation of adenomyosis | The differentiation of adenomyosis under ultrasound scan according to MUSA criteria | during ultrasound procedure |
| Positive pregnancy test | Serum ß-hCG ≥25mIU/mL | At 2 weeks after embryo placement |
| Implantation rate | Implantation rate is explained as the number of gestational sacs per number of embryos transferred. | At 3 weeks after embryo placement |
| Clinical pregnancy | 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 the last menstrual period. In addition to intra-uterine pregnancy, it includes a clinically documented ectopic pregnancy. | At 5 weeks after embryo placement |
| Ectopic pregnancy | A pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualisation, or histopathology | At 7 weeks of gestation |
| Ongoing pregnancy | Having at least one gestational sac on ultrasound at 12 weeks' gestation with heart beat activity | At 10 weeks after embryo placement |
| Miscarriage | The spontaneous loss of an intra-uterine pregnancy before 22 completed weeks of gestational age | before 22 completed weeks of gestational age |
| Venous thromboembolism relating to medication | Venous thromboembolism is diagnosed after clinical examination, ultrasound scan and blood test | From the start of treatment up to 10 weeks of gestation |
| Preterm delivery | Multiple definitions, defined as delivery at <24, <28, <32, <37 completed weeks | At 22, 28, 32 weeks and 37 weeks of gestation |
| Gestational diabetes mellitus | GDM is diagnosed using a 75g oral glucose tolerance test | At 24 to 28 weeks of gestation |
| Hypertension in pregnancy | Pregnancy-induced hypertension, pre-eclampsia, eclampsia and HELLP syndrome | after 20 weeks of gestation or beyond |
| Major congenital abnormalities | Structural or functional disorders that occur during intra-uterine life and can be identified prenatally, at birth or later in life. Congenital anomalies can be caused by single gene defects, chromosomal disorders, multifactorial inheritance, environmental teratogens and micronutrient deficiencies. The time of identification should be reported. Any congenital anomaly will be included as followed definition of congenital abnormalities in Surveillance of Congenital Anomalies by Division of Birth Defects and Developmental Disabilities, NCBDDD, Centers for Disease Control and Prevention (2020). | At birth |
| Birth weight | Weight of singletons and twins | At the time of delivery |
| Low birth weight | Weight < 2500 gm at birth | At the time of delivery |
| Very low birth weight | Weight < 1500 gm at birth | At the time of delivery |
| High birth weight | Weight 4000 gm or 4500 gm at birth | At the time of delivery |
| Very high birth weight | Weight over than 4.500 g for women with diabetes, and a threshold of 5000 g for women without diabetes | At the time of delivery |
| Admission to NICU | The admittance of the newborn to NICU | At birth |
| Multiple pregnancy | ≥2 gestational sac at early pregnancy ultrasound | At 6 to 8 weeks' gestation |
| Multiple delivery | Birth of more than one baby beyond 22 weeks | At 22 weeks' gestation |
| Still birth | 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. | At 20 weeks' gestation |
| Neonatal mortality | Death of a live-born baby within 28 days of birth. This can be divided into early neonatal mortality, if death occurs in the first seven days after birth, and late neonatal if death occurs between eight and 28 days after delivery | within 28 days of birth |
| Direct costs to live birth | Total direct cost to have a live birth after embryo transfer. Direct cost include medical consultations, ovulation stimulation drugs, laboratory and embryology services, ultrasound scanning, medical procedures such as oocyte retrieval and embryo transfer, hospital charges, nursing and counselling services and administrative and overhead charges (Mark P. Connolly et al., 2010). Cost data will be collected for a supplementary analysis and will be reported in a separated paper. | At the time of delivery |
| 33080632 | Background | Antero MF, Ayhan A, Segars J, Shih IM. Pathology and Pathogenesis of Adenomyosis. Semin Reprod Med. 2020 May;38(2-03):108-118. doi: 10.1055/s-0040-1718922. Epub 2020 Oct 20. |
| 34305815 | Background | Mumusoglu S, Polat M, Ozbek IY, Bozdag G, Papanikolaou EG, Esteves SC, Humaidan P, Yarali H. Preparation of the Endometrium for Frozen Embryo Transfer: A Systematic Review. Front Endocrinol (Lausanne). 2021 Jul 9;12:688237. doi: 10.3389/fendo.2021.688237. eCollection 2021. |
| 37291605 | Background | Zhang Y, Fu X, Gao S, Gao S, Gao S, Ma J, Chen ZJ. Preparation of the endometrium for frozen embryo transfer: an update on clinical practices. Reprod Biol Endocrinol. 2023 Jun 8;21(1):52. doi: 10.1186/s12958-023-01106-5. |
| 34587658 | Background | Harmsen MJ, Van den Bosch T, de Leeuw RA, Dueholm M, Exacoustos C, Valentin L, Hehenkamp WJK, Groenman F, De Bruyn C, Rasmussen C, Lazzeri L, Jokubkiene L, Jurkovic D, Naftalin J, Tellum T, Bourne T, Timmerman D, Huirne JAF. Consensus on revised definitions of Morphological Uterus Sonographic Assessment (MUSA) features of adenomyosis: results of modified Delphi procedure. Ultrasound Obstet Gynecol. 2022 Jul;60(1):118-131. doi: 10.1002/uog.24786. |
| D000091642 | Urogenital Diseases |
| D000091662 | Genital Diseases |