Natural Cycle vs Programmed Cycle Frozen Embryo Transfer

Study Overview
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Brief Summary
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The goal of this[ type of study: randomized controlled trial]is to compare Preeclampsia following Natural vs. Artificial Cycle in patients undergoing frozen embryo transfer. The main question[s] it aims to answer is • Does NC-FET decreases the incidence of preeclampsia in patients undergoing frozen embryo transfer as compared to AC-FET ? The main objective is to compare the proportion of preeclampsia in women with a viable pregnancy with natural cycle protocol to artificial cycle protocol when practicing frozen embryo transfer. Participants recruited will be divided into two ARM(1513 per arm). ARM 1 will undergo the Natural Cycle procedure of Embryo transfer, and ARM 2 will undergo the Artificial Cycle procedure of Embryo transfer. The primary outcome will be the proportion of preeclampsia. The duration of the study is around 2 year.

Detailed Description
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The Research question(PICO) addressed is Does NC-FET decreases the incidence of preeclampsia in patients undergoing frozen embryo transfer as compared to AC-FET . The hypothesis taken is NC-FET will decrease the incidence of preeclampsia compared to AC-FET. The sample size is taken as 3026 (1513 per arm). The Primary Objective is to compare the proportion of preeclampsia in women with a viable pregnancy with natural cycle protocol to artificial cycle protocol when practicing frozen embryo transfer. The study outcome of the proportion of preeclampsia after 20 weeks of gestation or 6 weeks post-delivery. There are two arms-Arm 1 Active Comparator: Natural Cycle and Arm 2 control: Artificial Cycle FET. The Randomization is done through Random Allocation as per computer generated sequence. The Blinding/masking is done Open labeled. The Study Duration is from Feb 2023 to Jan 2025. Participation Duration is 10 months.

Official Title
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Preeclampsia Following Natural vs. Artificial Cycle Frozen Embryo Transfer

Conditions
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Infertility, Frozen Embryo Transfer, Preeclampsia and Eclampsia

Intervention / Treatment
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* Procedure: Natural Cycle
* Procedure: Artificial Cycle


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Endometrial preparation with Hormone replacement therapy/ Natural cycle. Age 21-45 years following an autologous IVF cycle (with or without preimplantation genetic testing for aneuploidy) BMI > 18 and < 30 kg/m2 Endometrial thickness ≥ 7 mm after estrogen therapy or on the day of ovulation Blastocyst embryo transfer Exclusion Criteria: Uterine diseases (e.g. submucosal fibroids, polyps, previously diagnosed Müllerian abnormalities) Hydrosalpinx untreated. Recurrent pregnancy loss (≥ 3 previous miscarriages) Recurrent implantation failure (≥ 3 previously failed embryo transfers of good-quality blastocysts) Allergy to study medication Pregnancy or lactation at recruitment Contraindications for hormonal treatment

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open labelled parallel group randomized Controlled Trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Natural Cycle<br>In this,hCG trigger and Luteal Phase Support is monitored for the natural frozen embryo cycle procedure of IVF. | Procedure: Natural Cycle<br>* The participant will be administered a S/C injection of 250mcg r-hCG to assist ovulation and timing of the embryo transfer, when the dominant follicle reaches ≥ 18mm and serum LH < 20 IU/L, the administration of r-hCG will be in the evening, and the embryo transfer will be scheduled seven days later (window of ± two days). The participant will begin transvaginal progesterone gel (8 %) twice daily starting 36 hrs after the trigger until ten weeks of gestation.<br>|
| Other: Artificial Cycle<br>In this, endometrial preparation and Luteal Phase Support is monitored for the artificial frozen embryo cycle procedure of IVF. | Procedure: Artificial Cycle<br>* Estrogen priming with oral estradiol valerate 6mg/day (2mg every 8 hours) starting from cycle D1-D5 after a first TVU. TVU will be performed 10-15 days after beginning estradiol until ET ≥ 7mm, maximum until 21 days. Patients will begin progesterone injection 100mg/day until blastocyst transfer. Frozen embryo transfer will be performed on day 6 +/- 2 days of progesterone administration. After embryo transfer, a supplementation with transvaginal progesterone gel (8 %) twice daily starting from the day of embryo transfer until ten weeks of gestation. Patients will continue Estradiol 2 mg thrice daily until 6 weeks of gestation; then dose tapering will be done to 2 mg twice daily until 9 wks of gestation. From 9th wk the estrogen dose will be tapered further to 2 mg once daily for 10 days before stopping.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| proportion of preeclampsia | The primary efficacy endpoint is the proportion of preeclampsia in women assigned to a natural cycle protocol compared to the proportion of preeclampsia in women assigned to an artificial cycle protocol. | after the 20th week of gestation up to six weeks postpartum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical Pregnancy Rate | Pregnancies diagnosed only by β-human chorionic gonadotropin detection without a gestational sac visualized by vaginal ultrasound at the 6th gestational week. | 6 weeks after Embryo Transfer | 
| Implantation Rate | The number of gestational sacs observed by transvaginal ultrasound at the 6th gestational week per the number of embryos transferred. | 4 weeks +2 weeks after ET | 
| Clinical Pregnancy Rate | Detection of a foetal heartbeat on transvaginal ultrasound at the 6th gestational week per embryo transfer cycle. | 4 weeks +2 weeks after ET | 
| Ongoing Pregnancy Rate | Presence of gestational sacs with a heartbeat at the 12th gestational week per embryo transfer cycle. | 12 weeks after embryo Transfer | 
| Live Birth Rate | The number of deliveries that resulted in at least one live birth per 100 Embryo transferred cycle. | 28 weeks(+12 weeks) after embryo transfer | 
| Miscarriage Rate | Number of spontaneous pregnancy losses in which a gestational sac/s was previously observed (before 20th gestational weeks) per 100 clinical pregnancy. | Within 20 weeks of gestation | 
| Preterm birth | Preterm is defined as babies born alive before 37 weeks of pregnancy are completed | < 37 weeks | 
| Extreme preterm birth | Extreme Preterm is defined as babies born alive before 28 weeks of pregnancy | 20-28 weeks | 
| Fetal growth restriction | Fetal growth restriction (FGR) is most often defined as an estimated fetal weight less than the 10th percentile for gestational age by prenatal ultrasound evaluation | 20-40 weeks of gestation | 
| Fetal birthweight | Is defined as the weight of baby just after birth | within 30 minutes of birth | 
| Premature detachment of normally inserted placenta | It is defined as a premature separation of the placenta before delivery. | 12 weeks of GA till labor | 
| Maternal hypertension | It is defined as blood pressure more than 140/90 mm Hg detected first time after 20 weeks of gestation till 6 weeks of postpartum without proteinuria | After 20 weeks of GA till 6 weeks postpartum | 
| Eclampsia | Eclampsia is defined as the new onset of generalized tonic-clonic seizures in a woman with preeclampsia. | After 20 weeks of GA till 6 weeks postpartum | 
| HELLP Syndrome | It is defined as hemodialysis, elevated liver enzymes, and low platelet count | After 20 weeks of GA till 6 weeks postpartum | 
| Maternal mortality | Maternal death is defined as 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 | from start of pregnancy to 42 weeks of pregnancy | 
| Fetal death | Fetal death refers to the spontaneous intrauterine death of a fetus after 20 weeks of GA before delivery | 20 weeks of GA before delivery | 
| Frequency of adverse events | An adverse event (AE) is any untoward medical occurrence in a patient. | through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Reproduction, In vitro fertilization, Natural Frozen Embryo Transfer, Artificial Frozen Embryo Transfer, Preeclampsia