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: 1. Does the protocol involving the combination of GnRH agonist and letrozole for down regulation with exogenous steroids (GnRHa+AI - AC) result in a higher live birth rate compared to the use of exogenous steroids alone (AC) in women with adenomyosis undergoing frozen embryo transfer? 2. What are the common side effects of the GnRHa+AI - AC regimen? 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.
* Adenomyosis is a benign gynecological disease in which the endometrial stroma invades the uterine myometrium. Adenomyosis affects approximately 10% of women of reproductive age. There are several hypothetical mechanisms in adenomyosis-associated infertility, including dysregulations of the myometrial architecture and function, chronic inflammation, presence of local oxygen, and altered endometrial function, which can cause implantation failure. The abnormal presence of endometrial tissue composed of glands and stroma impacts uterine smooth muscle's regular contractile function and peristalsis, resulting in menometrorrhagia, infertility, and adverse obstetric consequences. There is currently no consensus on the optimal protocol for endometrial preparation in this population, and a lack of data on this issue. Current protocols include routine protocols with or without the pre-treatment of GnRH agonist. However, it is still controversial whether GnRH agonist down-regulation can help patients with adenomyosis have better reproductive outcomes. To our knowledge, there have not been any randomized controlled trials to investigate the effectiveness of the protocols used for endometrial preparation in women with adenomyosis undergoing frozen embryo transfer. * This will be a superiority-designed randomized clinical trial. * This trial will be conducted at My Duc Hospital, Ho Chi Minh City, Vietnam. Potentially eligible women will be provided information about the trial as long as their stimulation cycles are initiated. * Screening for eligibility will be performed by treating physicians on days 2nd - 4th of the menstrual cycle in the subsequent frozen embryo transfer cycles. Patients will be provided a copy of the informed consent documents. Written informed consent will be obtained from all women by the investigator before enrollment. * Women will be randomized (1:1) to either AC (artificial cycle) or GnRHa+AI - AC (Down-Regulation with GnRH agonist and Letrozole combined with artificial cycle) protocols using block randomization with a variable block size of 4, 6, using HOPE Epi with a computer-generated random list. * Artificial cycle (AC): the endometrium will be prepared using oral estradiol valerate (Valiera; Abbott) 6 mg/day starting from the second or fourth day of the menstrual cycle (5). The endometrial thickness will be monitored from the tenth day of estradiol-priming onwards, and vaginal progesterone (Cyclogest®; Actavis) 400 mg twice times a day will be initiated when endometrial thickness reaches 7 mm or more and received oestradiol valerate for at least nine days. 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): * Pre-treatment with GnRH agonist: GnRHa (Triptorelin - Diphereline®, Ipsen, France) will be injected at a dose of 3.75 mg on days 2nd - 4th of menstruation. In addition to GnRHa administration duration, the patients will be indicated letrozole 2.5 mg daily (Femara®, Novartis, Switzerland) to prevent the estradiol flare-up effect from the day of GnRH agonist injection. Repeat the same regimen for the second time 28 days after the first injection of GnRH agonist. * After 55 days of Down Regulation with GnRH agonist, before starting the artificial cycle protocol for endometrial preparation, estradiol serum level will be tested before endometrial preparation. * Endometrial preparation with AC protocol will be started 28 days after the second injection of GnRH agonist, as described previously 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
222
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.
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.
My Duc Hospital
Ho Chi Minh City, Ho Chi Minh City, Vietnam
RECRUITINGLive 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
Time frame: At 22 weeks of gestation
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)
Time frame: At 3 weeks from the start of artificial cycle
Hypoestrogenic side effects
Side effects include hot flushes, bone loss, vaginal dryness, decreased libido, unpredictable mood changes, and headache.
Time frame: 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
Time frame: during ultrasound procedure
Differentiation of adenomyosis
The differentiation of adenomyosis under ultrasound scan according to MUSA criteria
Time frame: during ultrasound procedure
Positive pregnancy test
Serum ß-hCG ≥25mIU/mL
Time frame: At 2 weeks after embryo placement
Implantation rate
Implantation rate is explained as the number of gestational sacs per number of embryos transferred.
Time frame: 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.
Time frame: At 5 weeks after embryo placement
Ectopic pregnancy
A pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualisation, or histopathology
Time frame: At 7 weeks of gestation
Ongoing pregnancy
Having at least one gestational sac on ultrasound at 12 weeks' gestation with heart beat activity
Time frame: At 10 weeks after embryo placement
Miscarriage
The spontaneous loss of an intra-uterine pregnancy before 22 completed weeks of gestational age
Time frame: before 22 completed weeks of gestational age
Venous thromboembolism relating to medication
Venous thromboembolism is diagnosed after clinical examination, ultrasound scan and blood test
Time frame: 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
Time frame: At 22, 28, 32 weeks and 37 weeks of gestation
Gestational diabetes mellitus
GDM is diagnosed using a 75g oral glucose tolerance test
Time frame: At 24 to 28 weeks of gestation
Hypertension in pregnancy
Pregnancy-induced hypertension, pre-eclampsia, eclampsia and HELLP syndrome
Time frame: 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).
Time frame: At birth
Birth weight
Weight of singletons and twins
Time frame: At the time of delivery
Low birth weight
Weight \< 2500 gm at birth
Time frame: At the time of delivery
Very low birth weight
Weight \< 1500 gm at birth
Time frame: At the time of delivery
High birth weight
Weight 4000 gm or 4500 gm at birth
Time frame: 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
Time frame: At the time of delivery
Admission to NICU
The admittance of the newborn to NICU
Time frame: At birth
Multiple pregnancy
≥2 gestational sac at early pregnancy ultrasound
Time frame: At 6 to 8 weeks' gestation
Multiple delivery
Birth of more than one baby beyond 22 weeks
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: At the time of delivery
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