Natural Cycle vs Programmed Cycle Frozen Embryo Transfer

Infertility Clinical Trial

Official title:

Preeclampsia Following Natural vs. Artificial Cycle Frozen Embryo Transfer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05716139
• Other study ID #: IIHPL-UDR/RCT/013_2022
• Status: Recruiting
• Phase: N/A
• Start date: July 15, 2023
• Est. completion date: January 2025

Study information

• Verified date: July 2023
• Source: Indira IVF Hospital Pvt Ltd
• Contact: Nikolaos P. Polyzos, MD
• Phone: +34 932274896
• Email: nikpol[@]dexeus.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 3026
• Est. completion date: January 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 21 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Eclampsia
• Frozen Embryo Transfer
• Infertility
• Pre-Eclampsia
• Preeclampsia and Eclampsia

Intervention

Procedure:
• Natural Cycle
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.
• Artificial Cycle
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.

Locations

Country	Name	City	State
India	Indira IVF Hospital Private Limited	Udaipur	Rajasthan

Sponsors (1)

Lead Sponsor	Collaborator
Indira IVF Hospital Pvt Ltd

Country where clinical trial is conducted

India, 

References & Publications (13)

American College of Obstetricians and Gynecologists' Committee on Obstetric Practice; Committee on Genetics; U.S. Food and Drug Administration. Committee Opinion No 671: Perinatal Risks Associated With Assisted Reproductive Technology. Obstet Gynecol. 201 — View Citation

Baksh S, Casper A, Christianson MS, Devine K, Doody KJ, Ehrhardt S, Hansen KR, Lathi RB, Timbo F, Usadi R, Vitek W, Shade DM, Segars J, Baker VL; NatPro Study Group. Natural vs. programmed cycles for frozen embryo transfer: study protocol for an investiga — View Citation

Busnelli A, Schirripa I, Fedele F, Bulfoni A, Levi-Setti PE. Obstetric and perinatal outcomes following programmed compared to natural frozen-thawed embryo transfer cycles: a systematic review and meta-analysis. Hum Reprod. 2022 Jun 30;37(7):1619-1641. do — View Citation

Chen JZ, Sheehan PM, Brennecke SP, Keogh RJ. Vessel remodelling, pregnancy hormones and extravillous trophoblast function. Mol Cell Endocrinol. 2012 Feb 26;349(2):138-44. doi: 10.1016/j.mce.2011.10.014. Epub 2011 Oct 25. — View Citation

Devroey P, Polyzos NP, Blockeel C. An OHSS-Free Clinic by segmentation of IVF treatment. Hum Reprod. 2011 Oct;26(10):2593-7. doi: 10.1093/humrep/der251. Epub 2011 Aug 9. — View Citation

Ginstrom Ernstad E, Wennerholm UB, Khatibi A, Petzold M, Bergh C. Neonatal and maternal outcome after frozen embryo transfer: Increased risks in programmed cycles. Am J Obstet Gynecol. 2019 Aug;221(2):126.e1-126.e18. doi: 10.1016/j.ajog.2019.03.010. Epub 2019 Mar 22. — View Citation

Kawwass JF, Badell ML. Maternal and Fetal Risk Associated With Assisted Reproductive Technology. Obstet Gynecol. 2018 Sep;132(3):763-772. doi: 10.1097/AOG.0000000000002786. — View Citation

Lee JC, Badell ML, Kawwass JF. The impact of endometrial preparation for frozen embryo transfer on maternal and neonatal outcomes: a review. Reprod Biol Endocrinol. 2022 Feb 28;20(1):40. doi: 10.1186/s12958-021-00869-z. — View Citation

Luke B. Pregnancy and birth outcomes in couples with infertility with and without assisted reproductive technology: with an emphasis on US population-based studies. Am J Obstet Gynecol. 2017 Sep;217(3):270-281. doi: 10.1016/j.ajog.2017.03.012. Epub 2017 M — View Citation

Malik A, Jee B, Gupta SK. Preeclampsia: Disease biology and burden, its management strategies with reference to India. Pregnancy Hypertens. 2019 Jan;15:23-31. doi: 10.1016/j.preghy.2018.10.011. Epub 2018 Nov 2. — View Citation

Rienzi L, Gracia C, Maggiulli R, LaBarbera AR, Kaser DJ, Ubaldi FM, Vanderpoel S, Racowsky C. Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for t — View Citation

Shi Y, Sun Y, Hao C, Zhang H, Wei D, Zhang Y, Zhu Y, Deng X, Qi X, Li H, Ma X, Ren H, Wang Y, Zhang D, Wang B, Liu F, Wu Q, Wang Z, Bai H, Li Y, Zhou Y, Sun M, Liu H, Li J, Zhang L, Chen X, Zhang S, Sun X, Legro RS, Chen ZJ. Transfer of Fresh versus Froze — View Citation

von Versen-Hoynck F, Schaub AM, Chi YY, Chiu KH, Liu J, Lingis M, Stan Williams R, Rhoton-Vlasak A, Nichols WW, Fleischmann RR, Zhang W, Winn VD, Segal MS, Conrad KP, Baker VL. Increased Preeclampsia Risk and Reduced Aortic Compliance With In Vitro Fertil — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Biochemical Pregnancy Rate	Pregnancies diagnosed only by ß-human chorionic gonadotropin detection without a gestational sac visualized by vaginal ultrasound at the 6th gestational week.	6 weeks after Embryo Transfer
Secondary	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
Secondary	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
Secondary	Ongoing Pregnancy Rate	Presence of gestational sacs with a heartbeat at the 12th gestational week per embryo transfer cycle.	12 weeks after embryo Transfer
Secondary	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
Secondary	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
Secondary	Preterm birth	Preterm is defined as babies born alive before 37 weeks of pregnancy are completed	< 37 weeks
Secondary	Extreme preterm birth	Extreme Preterm is defined as babies born alive before 28 weeks of pregnancy	20-28 weeks
Secondary	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
Secondary	Fetal birthweight	Is defined as the weight of baby just after birth	within 30 minutes of birth
Secondary	Premature detachment of normally inserted placenta	It is defined as a premature separation of the placenta before delivery.	12 weeks of GA till labor
Secondary	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
Secondary	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
Secondary	HELLP Syndrome	It is defined as hemodialysis, elevated liver enzymes, and low platelet count	After 20 weeks of GA till 6 weeks postpartum
Secondary	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
Secondary	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
Secondary	Frequency of adverse events	An adverse event (AE) is any untoward medical occurrence in a patient.	through study completion, an average of 1 year